Full Report - Biomarkers of Longevity

Biomarkers of Longevity
Analytical Report
Current State, Challenges and Opportunities

Landscape Overview 2019
DEEP
Increasing Role of Data Science and Artificial KNOWLEDGE
Intelligence in Biomarker Discovery and GROUP
Monitoring
www.aginganalytics.com
Biomarkers of Longevity
Current state, Challenges and Opportunities Landscape Overview 2019
Table of Contents
Executive Summary 3 Blood-based Biomarkers 100
Deep Knowledge Group: Scope of Activities 13 - Biomarkers of Endocrine Function 105
Introduction 19 - Biomarkers of Immune Function 108
Report Methodology 41 - Molecular Level Biomarkers 111
The Role of AI in Biomarker Discovery and Monitoring 55 Cognitive Biomarkers 115
Selected Biomarkers by Comprehensiveness Level 67 Panels of Biomarkers of Aging 119
- Minimum Required Biomarkers 76 - Most Viable Panels 138
- Most Comprehensive Biomarkers 77 - Most Comprehensive Panels 139
- Digital Biomarkers 79 Conclusions 140
Biomarkers of Physical Function and Physiology 89 Disclaimer 145

Executive Summary
Executive Summary
The use of biomarkers is an indispensable component of industry analytics and assessment. It is

“Biomarkers of Longevity: Current the foundation upon which measurement of Healthy Longevity and the effectiveness of P4
state, Challenges and Opportunities Medicine, Regenerative Medicine and Longevity therapeutics are built. In this sense, the present
Landscape Overview 2019” is an report is designed as an in-depth review of the state of the art in biomarkers of biological age R&D
to advise accurately the market, industry and public sectors. It was produced to offer a panoramic
open-access special analytical case
review of the global landscape of aging and Longevity biomarkers, containing selected lists,
study by Aging Analytics Agency rankings and enhanced profiles with more than 70 Single Biomarkers directly correlated with the
that uses comprehensive analytical trajectories of age-related diseases and geriatric syndromes and exceeding 100 diverse Biomarker
frameworks to rank and benchmark Panels for analytical science-driven comparisons that allow an optimal integration of multiple
existing panels of biomarkers of biomarkers for practical uses, such as drugs discovery and development for Longevity, Longevity
aging, health and Longevity therapies development, enhanced and sophisticated aging health monitoring in precision clinics,
or development of digital environments aimed at assessing the aging trajectory to mention some
according to their ratios of accuracy particular utilities.
vs. actionability, identifying the
panels of biomarkers that can have The purpose of the approach offered here is to facilitate the achievement of highly actionable
monitoring systems for healthcare in general, and for healthcare during aging in particular; the
the greatest impact on increasing beneficiary sectors are multiple, including clinical practice itself, but also translational research
both individual and national Healthy initiatives, frontier development frames that exploit the current conditioning of the mature field of
Longevity in the next few years; Longevity, investment intentions in a market with the highest complexification rate in human
providing advice to the industry for history, and administrative initiatives for policy programs pointed to health promotion and precise
the conception, development and prevention of age-related diseases, whose design and consolidation according to the subsequent
criteria will guarantee a renaissance never seen before in economic and social dynamics.
maturation of their action plans, and
to policy makers in order to combat In addition to their purely descriptive and analytical approaches, the report is designed to make
the problem of Ageing Population key strategic recommendations, advice and guidance regarding biomarker implementations,
technologies and techniques, within the reach of companies, other entities, and nations, in order
and realize that opportunity of to assist them in optimizing their action plans and strategies, providing specialized guidelines for
National Healthy Longevity. business and investment core decisions.
Aging Analytics Agency 4

Executive Summary
Based on the results of this analysis, the special case study presents its formulation of an ideal Minimum Viable Panel (MVP) of Longevity biomarkers:
a panel of biomarkers which though not as precise as possible are precise enough and easily implementable. The report also presents a “most
comprehensive” list of biomarkers of aging, devotes analysis to recent novel biomarkers of aging just entering R&D processes today, and highlights the
core conclusion that uses of Digital Biomarkers and AI in biomarker discovery, development and assessments will come to be a necessary and
indispensable component of Longevity Industry as the volume of data on both biomarkers and the complex networks of how they interact together
continues to grow.
The report also delivers extensive profiles of single biomarkers and whole panels: their advantages and strengths, disadvantages and weaknesses, and
future perspectives, challenges and opportunities with a focus on technologies currently used for assessment; concrete analysis of routine, advanced
and novel biomarkers of aging, emerging tools and platforms, and insights about the impact of these biomarkers on health systems and clinical
practice. The central purpose of those characterizations is to submit practical conclusions and recommendations regarding the Most Comprehensive
and Most Viable (or Minimum Required) single biomarkers and panels of aging for their immediate implementation, either in biomedical research,
therapeutic development and clinical trials, P4 Medicine and overall clinical practice, emphasizing the intersection between this wide new market,
digital environments designed for real-time integration of aging and Longevity health metrics, and the new possibilities offered by AI platforms. The
ultimate intention of Aging Analytics Agency is to solidly establish the relative and absolute usefulness of these presentations for precise and
actionable measurement of biological age and enhanced assessments of health status, age-related diseases, geriatric syndromes, and Longevity.
As the scope of P4 Medicine broadens actively and healthily, the number of biomarkers, measurement technologies and platforms will increase rapidly
to the thousands in the coming years; this will provide the opportunity to improve medical stratification to its maximum degree reaching Personalized,
Participatory, Precision and Preventive Medicine for both, non-healthy populations and the healthy and young; also, to achieve the conditions for
exhaustive and precise studies with samples of only one individual and allowing to prescind from conventional model organisms for biomedical
research, due to the enormous flow of biological digital data that will be extracted continuously, individual to individual. These vast amounts of
biomarkers data in the form of zeros and ones will make impractical the implementation of P4 Medicine by current, manual means; the construction
and evaluation of massive networks of interconnected biomarkers will be carried out by highly specialized digital systems in pattern recognition,
trained with aggregate information from hundreds of thousands of individuals minute by minute. Prototypes of these systems already exist, and are
beginning to be implemented today.

Executive Summary
Aggregation of biomarkers of Longevity, rather than biomarkers of disease only, and from healthy populations - among the young and the even younger,
rather than bedside data from the hospital populations, will be part of everyday life due to the novel Digital Health platforms capable of extracting truly
massive amounts of clinical relevance data from a single patient through electronic layers.
These transformations already underway in biomarkers assessment modality will allow to move from the conventional therapeutic approach toward
large-scale precision preventive medicine, the necessary vehicle to build both individual and national Healthy Longevity; and this will also be the
foundation for the achievement of a unified theory of the root causes of aging and Longevity. The one plus the other, these two emerging together, will
provide -are providing- a framework to intervene the process of aging, in a rather accelerated way than gradual. Tech companies rather than healthcare
companies will play the leading role in this process; the threshold is already blurring. The use of AI will give sense to the thumping amount of digital
biomarkers data, and it will allow the development of undoubtedly multiple optimal biomarker panels for the monitoring of aging and its correction, as
well as countless other health biomarkers (digital and non-digital) for AI-driven analysis of each person's deep health status, allowing to orchestrate
extremely personalized therapeutic interventions in response to minimal and currently imperceptible fluctuations in all those biomarkers. As the
number of data points increases, AI-driven analysis will be strictly necessary in the Longevity industry and the health industry as a whole.
At this point, it is impossible to determine whether biotechnologies for Longevity have been successful if we cannot tell how advanced the aging
process is in any given individual; but at the same time the latter will not be feasible until successfully achieving highly actionable Panels that allow to
evaluate the aging process in broad healthy and less healthy differentiated ranges of the population spectrum. Is in this sense that Biomarkers are an
essential factor in Aging Analytics Agency's strategic agenda, which includes recommendations for the establishment of AI centres in the United
Kingdom, the indispensable medium to nail down the implementation of P4 Medicine and also to guarantee competitiveness in this new global health
market, in the same way that highly specialized advice for the success of longevity-related government initiatives worldwide. It is important to develop
and promote the widespread use of a comprehensive enough Panel of Biomarkers but, primarily, immediately actionable. We have documented many
of the aging Biomarkers here and identified from among them those which, by the metrics described - and never reported in pre existing literature-,
belong to this category we have named Minimum Required: the Most Viable Products for immediate implementation.
It is our hope that regardless of whether it is adopted wholesale, this entire work may serve as a starting point for discussion on how best to utilize the
deep knowledge we already have to maximum effect on health of aging populations and aging economies, as soon as possible.

Methodology
The significance of biomarkers in the Longevity Industry is central since they are the primary metric in Geroscience, Regenerative Medicine, multiple
AgeTech implementations and especially in P4 Medicine. Biomarkers also provide the prime source of data for the AI for Longevity industry, Drug
Discovery and Development, Clinical Trials and for Translational Research. For these reasons, standardized metrics are needed to evaluate the
biomarkers and the Panels that occupy us.
Within the scope of the report, the following methodology will be implemented,
outlining the quantitative evaluation approach:
Accuracy Assessment Availability Assessment Actionability Assessment

● It is a measure of the precision of the ● It measures only the material capacity of ● Actionability is an expression or
Single Biomarker or the Panel to predict extensive implementation for the combination of both the accuracy and
overall biological age reference character; i.e., for the single availability of a Biomarker or a Panel
Biomarker or the Panel
● Its magnitude depends on the number of ● Actionability Assessment allows to
biomarkers evaluated by the Panel, the ● That material implementation capacity is evaluate not only the current material
nature of those biomarkers, the scientific understood as an expression of market capacity of implementation of a
background of its direct association with availability of assays, tests, technologies biomarker or a Panel but also its viability
age-related conditions and processes, or platforms, its invasiveness, monetary for biological age prediction in such an
and qualitative characterizations that value, and the proposed classification immediate and effective frame of
assigns or removes scores framework for qualitative implementation, thus empowering Single
characterizations used also in Accuracy Biomarker and Panel comparisons with a
Assessments purely pragmatic sense
Such precision assessment will maximize the capacities of decision-makers to increase the efficiency of public health
programs and policies, as well as decision-making processes in the core of healthcare industries.
Report Value Proposition
1. What are the current most comprehensive biomarkers and panels to This report seeks to answer these three specific questions, with an
follow the aging trajectory and its related conditions and the most upcoming +300 pages version that will be produced over the next 3-6
viable or minimum required ones, and how they can be implemented months, and a new edition of its content during each financial quarter,
in the most ideal and useful manner? incrementally increasing its breadth and depth as we go along, and with
each edition providing a deeper, more comprehensive and more precise
2. What leading personalised and preventive market-ready health understanding of the landscape. It will deliver:
assessments can aging biomarkers and panels dispense to the
existing pipeline of healthcare entities to maximize their competitive ● Concrete deep analysis of which biomarkers and biomarker panels are
advantage? available today; its strengths and weaknesses, their accuracy,
3. What novel updates and advances in biomarker-related research and availability and current actionability, and the opportunities and
development will impact the health industry in the next years? Which challenges related to its uses for real-time and precision monitoring of
of those should be watched closely for integration into clinics and health status, and ultimately the reversal of biological age;
biomedical or healthcare companies’ existing pipelines as soon as ● Tangible estimations of which biological age biomarkers and
their conditioning is achieved? implementations are consolidated, or their current conditioning stage
We feel that our efforts over the course of the past five years have for precision assessment of health status and endpoints of clinical
established a solid foundation of knowledge and expertise upon which we trials and therapies;
intend to summarize the entire landscape of aging and Longevity
● Highlights regarding the role of digital biomarkers and AI platforms
biomarker utilities in the health industry: the production of this new report
and how they will become necessary and indispensable components
entitled Biomarkers of Longevity Landscape Overview 2019: Current
of ageing and Longevity biomarker discovery, research, development
State, Challenges and Opportunities.
and users daily use;
The parties who will have early access to this report will gain deep expertise on how they can optimize their clinics’
strategic, technological and scientific prospects in order to deliver the most sophisticated and comprehensive precision
health products and services for their clients.

Approved for Clinical Use - 41
Biomarkers of Longevity Research Use Only - 45
Healthcare-Ready - 33
1st edition. Selection

and Current Status, Biomarker Panels Digital Panel Platforms Single Biomarkers
2019
Approved for Clinical Use
Healthcare-Ready
(waiting for clinical approval)
Research Use Only

Biomarkers of Longevity Distribution by Operational Category
Research Kit Informational Purpose Epidemiological or

or Other Laboratory Medical Test AI Platform
Test or Platform Theoretical Panel Only
Practice Supplies
Biomarkers Real-Time
Assessment
Technology
Biomarkers of Longevity Distribution by Conditioning Stage
Stage Three: Approved for

Stage One: Research Use Only Stage Two: Healthcare-Ready
Clinical Use
Biomarkers of Longevity Distribution by Amplitude Level
Panels Single Biomarker Digital Panel Platform
Baseline Amplitude Level Maximum Amplitude Level

Deep Knowledge Group:
Scope of Activities
Deep Knowledge Group Analytical Subsidiaries
Deep Knowledge Analytics Pharma Division GovTech Division
Deep Knowledge Analytics is a deep tech The Pharma Division of Deep Knowledge The GovTech Division of Deep Knowledge
analytical agency using multidimensional Analytics specializes in the production of the Analytics focuses on producing sophisticated
algorithms to produce advanced industrial most comprehensive analytical reports on the open-access and proprietary analytics the reveal
reports on DeepTech and frontier technologies. topics of Artificial Intelligence, Drug Discovery, factors driving the ongoing transformation of the
An online analytics platform with interactive Data Science and Digital Health within the global GovTech industry, main sectors to be
visuals updated in real-time was released early broader Pharma Healthcare Industry and changed, barriers to this process, and ways to
this year. intersection of AI and Pharma. overcome them.
Aging Analytics Agency Innovation Eye
Aging Analytics Agency began producing reports before the industry emerged Innovation Eye is a company providing market analytics and benchmark case
and it is exclusively focused on Longevity, Geroscience, AgeTech and studies. It has advanced tools for analysis and visualisation of Tech and innovation
Preventive Medicine. The company has been developing its methodology ecosystems. Its ultimate goal is to optimize the strategic agendas of corporations
since 2015 and is the main source of market intelligence in the field. and governments seeking to optimise their Tech driven industries.

Aging Analytics Agency: Producing Longevity Industry Reports Since 2013
Aging Analytics Agency is the only specialized analytics agency in the world that focuses exclusively on the emerging Longevity Industry, Aging,
Geroscience, P4 Medicine and AgeTech. Being recognized internationally as the premier analytics agency for advanced data analysis, industry reports
and next-generation infographics on the topics of Aging and Longevity, also provides strategic consulting in the fields of Longevity and Economics of
Aging.
Since its establishment in 2013,
Now in its 5th year, Aging Analytics Agency has been on the frontlines of Longevity Analytics since the Aging Analytics Agency has been
inception of the industry. systematically producing reports
documenting the rise of Longevity
Industry and Geroscience.
Dmitry Kaminskiy, co-founder of Aging Analytics Agency, boldly predicted in 2014 that
the Longevity Industry would see an inflection point in its development in 2017, In 2014, Aging Analytics Agency
becoming a recognized industry in the eyes of conservative investors, business successfully predicted the boom in
analysts and top business media. This was at a time when investors and Longevity Industry development
and financing rounds of 2017, at a
gero-scientists alike were highly skeptical of the industry’s emergence within the next
time when the vast majority of
decade. investors, business analysts, and
This prediction turned out to be true. 2017 witnessed an unprecedented rise in the even geroscientists believed that
its emergence will only take place
number of Longevity-focused companies and investment deals, the emergence of
in the next decade. Its advantage
half a dozen of geroscience-focused VC firms, coupled with widespread coverage of over other analytics entities lays in
Longevity as a topic by mainstream media including The Economist, Financial Times its specific focus on the emerging
and Bloomberg. Longevity Industry as well as P4
Medicine.
Aging
The use of advanced infographics to distill The use of tangible, quantifiable, and proven A strong focus on the convergence of multiple
Analytics
complex industry landscapes into unified metrics to conduct near-future industry industries and technologies enabling the
Agency
frameworks, enabling comprehension of forecasts, including Technology Readiness identification of indiscernible mega-trends and
Unique Levels (TRLs), to examine a given providing a bird-eye view of industry
pertinent data at a single glance.
Approach technology’s market-readiness. developments as a whole.

Uniquely Positioned to Provide
World-Class Longevity Analytics Reports and Services
Aging Analytics Agency not only forecast the true dawn of the Longevity Industry years before its mainstream recognition, but was willing to put its
reputation at stake with a bold yet precise prediction when no one else saw it coming. Aging Analytics Agency’s confidence stems from its reliance on
tangible and quantitative predictive metrics, including the use of cross-disciplinary and synergetic analytical tools and frameworks to map the
enormous diversity and complexity of the Longevity Industry.
The fruits of Aging Analytics Agency’s labor significantly contributed to the exponential growth of Longevity as a topic in the mainstream, including its
acceptance by business experts, media and even governments. The UK, for example, has listed Aging Population as one of its four grand challenges
and launched a government-backed Healthy Aging Industrial Strategy Challenge Fund. Other governments have also launched similar strategic national
development plans devoted to Longevity. Leading media brands, including TIME, Forbes, Bloomberg and others regularly publish Longevity-oriented
cover stories. High-profile conferences on the subject of Longevity are more numerous than ever before.
The company has been involved in charting the

LONGEVITY GOVERNANCE AND POLICY INITIATIVES rise of the Longevity sphere since its inception
and remained at the forefront throughout the past
half decade. Thus, Aging Analytics Agency is
uniquely positioned to produce both broadly-
accessible reports and specialized case studies
for specialized clientele including companies,
investment firms, family offices and government
agencies.
Many of these efforts are currently focused on the

Metabesity and Longevity: topics of Longevity policy, politics and
Proposal to the UK All Response to the World Proposal to the United
USA Special Case Study. governance, the formulation and development of
Party Parliamentary Group Health Organization's Nations on
Joint Project with Targeting National Longevity Development Plans, and
on Longevity: "Decade of Healthy Optimization of
Metabesity 2019 targeted recommendations regarding decreasing
“National Strategy for Five Aging: 2020 – 2030 International Longevity the gap between life expectancy and health-
Conference in Washington.
More Years of Healthy Life Draft Zero Action Plan" Policy and Governance adjusted life expectancy (HALE), developing
Policy Proposal to the US various nation's Longevity industry to scale.
Expectancy in the UK.
Congress.
Open Access Analytical Reports by Aging Analytics Agency
Published / Q1 2019 Published / Q2 2019
Longevity Industry in Longevity Industry in Top-50 Women Top-100

California Singapore Longevity Leaders Longevity Leaders
Landscape Overview 2019 Landscape Overview 2019
Longevity Industry in Israel Longevity Industry in UK FemTech Healthcare National Longevity

Landscape Overview 2019 Landscape Overview 2019 Landscape Overview Q1 Development Plans: Global
2019 Overview 2019
(First Edition)

Upcoming Analytical Reports by Aging Analytics Agency
Longevity Industry and the Microbiome Top-100 Supercentenarians Metabesity & Longevity
Landscape Overview 2019 USA Special Case Study
Longevity Industry in Switzerland Longevity Industry in Hong Kong Longevity Industry in Japan
Landscape Overview 2019 Landscape Overview 2019 Landscape Overview 2019

Introduction
Introduction
Aging Analytics Agency is currently developing a comprehensive, open-access report, Biomarkers of Longevity: Current state, Challenges and
Opportunities Landscape Overview 2019, a special analytical case study that uses comprehensive analytical frameworks to rank and benchmark
existing panels of biomarkers of aging, health and Longevity according to their ratios of accuracy vs. actionability, identifying the panels of biomarkers
that can have the greatest impact on increasing both individual and national Healthy Longevity in the next few years.
The use of biomarkers is an indispensable component of industry analytics and assessment. It is the foundation upon which measurement of Healthy
Longevity and the effectiveness of Longevity therapeutics is built. The report is designed as an in-depth review of the state of the art in biomarkers
development to advise accurately the market, industry and public sectors when addressing the challenges related to our following conclusions and
forecasts about the immediate future of the Biomarker and Longevity industries as a whole:
As the scope of P4 Medicine Aggregation of biomarkers That described shift will The use of AI will give sense to this
broadens, the number of of longevity and aging, allow to move from the thumping amount of data, and it will
biomarkers and rather than biomarkers of conventional therapeutic allow the development of surely multiple
measurement technologies disease, and from healthy approach toward precision optimal panels of aging biomarkers as
and platforms will increase populations - among the preventive medicine, and will well as other health biomarkers (digital
rapidly to the thousands in young and the even younger, also be the foundation for a and non-digital) for analysis of each
the coming years. This rather than bedside data unified theory of the root person's outcomes, and for orchestrating
makes the implementation from the hospital causes of aging and extremely personalized therapeutic
of P4 medicine impractical populations, will be part of longevity; both providing a interventions in response to fluctuations
by current, manual means. everyday life due to the framework to intervene the in those biomarkers. As the number of
novel Digital Biomarkers process. Tech companies data points increases, it becomes not
capable of extracting truly rather than healthcare only optimal, but strictly necessary to
massive amounts of clinical companies will play the use AI and big data analysis in not only
relevance data from a single leading role in this process. the longevity industry, but in the health
patient through electronics. industry as a whole.

Introduction
The report is designed to make key strategic recommendations regarding technologies and biomarkers implementations within the reach of
companies, entities and nations in order to assist them in optimizing their developmental action plans and strategies, providing specialized guidance
for business and investment core decisions. It will deliver:
● A "most comprehensive" list of single biomarkers of aging and Panels, their advantages and strengths, disadvantages and weaknesses, and
future perspectives, challenges and opportunities with a focus on technologies currently used for assessment;
● Concrete analysis of recent novel biomarkers of aging just entering R&D processes today, emerging tools, and novel assay platforms
awaiting approval or standardization for clinical implementation, one step away of being market-ready within the next several years;
● Highlights respecting why AI platforms will come to be a necessary and indispensable component of Longevity biomarker discovery,
research and development;
● Overview of different categories of panels, whether for Research Use Only or Approved for Clinical Use;
● Conclusions and practical recommendations regarding the Most Comprehensive Panels and the Most Viable (Minimum Required) Panels for
immediate implementation, either in biomedical research, therapy development, P4 medicine and clinical practice, emphasizing the relative
and absolute usefulness of these Panels for precision measurement of biological age and enhanced assessments of health status,
age-related diseases, geriatric syndromes, and Longevity.
The parties with early access to this report will gain deep expertise on how they can optimize their development and implementation strategies, and
how to analyze the technological and scientific backgrounds and prospects of the Longevity industry in order to deliver sophisticated action plans
aimed for remaining at the forefront in the broad and changing field of healthcare.

Biomarkers for Paradigm Shift
from Treatment to Prevention
Jamie Metzl for Longevity. Technology: "First, we’re increasingly understanding the biomarkers of aging. And that is giving us a language of
measurement. We can assess with more precision whether certain interventions are working or not working. With the new tools of AI and machine
learning we’re really seeing is a super convergence of different technologies that are all pushing forward, including the science of human
Longevity."

Biomarkers for Paradigm Shift from
P4 Medicine to Precision Health
Since 2013, Deep Learning systems have surpassed human performance in multiple applications, such as face and image recognition. Predictors
of chronological age, and biological age - or functional age-, are rapidly gaining popularity and with this a deep outburst of research and
development is awakened, both in the scientific and industrial spheres. A new market is brewing. AI has shown that it is possible to overcome the
best human ophthalmologists or radiologists, the best conventional predictors of complex pathologies such as Parkinson's and Alzheimer's have
been surpassed. And in this framework, AI-driven biomedical research and development efforts are now already facing aging.

Introduction to Biomarkers
Increased knowledge around the human

A Biomarker or a biological marker is a characteristic that is objectively measured and genome and other omics, and correlations with
evaluated as an indicator of some biological state, condition or process. Biomarkers are used in disease risks and progression are expected to
many scientific fields and commercial activities, and subjected to several and dissimilar shift the current biomarker focus. Drug
classifications that follow different criteria. Regarding health related activities: companies have been increasing their
investment into exploratory biomarkers that
focus on areas such as infectious diseases,
central nervous system (CNS) disease
conditions and cardiovascular diseases to
broaden their overall biomarker research and
development strategies. For example, CNS
disease conditions such as schizophrenia,
Parkinson’s and Alzheimer’s are finding initial
success in biomarker identification for targeted
therapies.
In drug discovery and development,
biomarkers can be used to predict or identify
safety problems related to a drug candidate,
In biomedical research and clinical practice, for patient selection for clinical study
biomarkers include measurements that enrollment, stratification of patients during
suggest the etiology of, susceptibility to, study, identification of toxic responses
activity of, or progress of a disease. The use before they becomes clinically evident, in
of biomarkers in basic and clinical research addition to reveal an expected or unexpected
as well as in clinical practice has become so pharmacological activity such as reversal,
commonplace that their presence as primary deceleration or acceleration of biological
endpoints in clinical trials is now accepted age, the particular case that appeals us.
almost without question.

Introduction to Biomarkers. Conventional Classification Frameworks
For practical purposes, single biomarkers and biomarker panels used in the setting of biomedical research, drug discovery and development, and
clinical practice are often classified following any of the criteria outlined below:
● Clinical Outlook. In relation to clinical specialties, to organ systems and related vital functions, and to subordinated diseases of each one. We find
biomarkers for oncology profiling, cardiology and hematology profiling, neurology profiling, endocrinology, infectious diseases, immunology, and so
forth. Due to the low degree of specificity, here we usually find large biomarker panels and not single biomarkers.
● Disease and Conditions Outlook. Within each clinical specialty or often overlapping a number of them, the set of biomarkers that make up the profile
of a pathology or set of related pathologies. These categories are usually subsets of each one in the previous criterion, also using panels much more
often than single biomarkers.
● Functional and Structural Outlook. Based on its association with specific functional and structural variables, either physical, anatomical, histological
or physiological. For example, biomarkers for locomotor function, or for strength, balance, bone density, body impedance or waist circumference, in
this case all closely interconnected parameters. This approach is usually subordinate to the previous two. Due to its higher degree of specificity, it
usually allows the use of single biomarkers or small panels, although large panels are more descriptive.
● Source Outlook. By the source of the biological material or data, and its processing methodology. The clinical evaluation usually addresses a small
amount of biomarkers related to one or a few conditions, or to the general state of health. A broad examination of the biomarker network provided by
each test could allow the extraction of a large amount of data about health status.
● Focus Level Outlook. Based on the focus level, or the associated diagnostic or therapeutic depth, biomarkers can be divided by the domain to which
they belong on the organismic scale.There are six categories or levels, Biochemistry, Genomic, Proteins and Cell Signalling, Cellular, Tissue and Organ
markers, each one correlated with a particular set of evaluations, potential interventions, and an order of physical magnitude. Thus, Organ biomarkers
are related to Regenerative medicine, and Biochemical ones include lipid-, glyc- and metabolomics among others.
● Omic Outlook. In relation to the -omic field to which they belong, what will determine the types of technologies and evaluation methods.
● Application Outlook. More typical of the market analysis, according to the activities in which biomarkers are applied, or 'what are they used for’.
● Type Outlook. Indispensable. Classification according to characteristics of its operational definition, or 'how are they used for’.

Biomarker Conventional
Classification Frameworks
Osteoporosis Arthritis
Drug Discovery
COPD Sarcopenia
and Development
Aging-associated
Biological Age
Ophthalmology Metabolic Osteopenia Drug Formulation
measurement
Syndrome
Alcohol/drug Genomic
Gastroenterology Type II Diabetes Obesity Preclinical Trials
treatment Instability
Alzheimer’s Locomotor
Oncology Orthopaedics Cancer Clinical Trials Telomere Attrition
Disease function; Dexterity
Amyotrophic Parkinson’s Bone density; Diagnostic Epigenetic

Cardiology Hematology
Lateral Sclerosis Disease Bone mass hip Development Alterations
Muscle mass;
Cerebrovascular Digital biomarkers Efficacy - Loss of
Neurology Rheumatology Hypertension Body impedance; Biochemistry level Genomics Transcriptomics Diagnostic
Disease + AI Pharmacodynamic Proteostasis
Abdominal fat
Blood pressure;
Mild Cognitive Human Disease Risk Efficacy - Deregulated
Endocrinology Sleep disorders Atherosclerosis Lipid profile; Genomic level Epigenomics Foodomics
Impairment Biomonitoring Assessment Predictive Nutrient Sensing
Glycated Hb
Lung capacities;
Maternal-Fetal Cardiovascular Proteins and Cell Nutritional Efficacy - Mitochondrial
Urogynecology Dementia Transpulmonary Imaging Metabolomics Screening
medicine Disease Signalling level genomics Prognostic Dysfunction
pressure
Laboratory
Processing speed; Efficacy -
Infectious Coronary Artery procedures Pharmaco- Cellular
Dentistry Multiple Sclerosis Working memory; Cellular level Proteomics P4 Medicine Surrogate and
diseases Disease (Blood, Saliva, genomics Senescence
Visual memory Diagnostic
Biopsy)
Deep Vein Coordination Endocrine profile; Pedigree and Pharmaco- Regenerative Stem Cell
Dermatology Otolaryngology Tissue level Lipidomics Validation
Thrombosis impairment HPA axis Family History microbiomics Medicine Exhaustion
Age-related Chronic Routine and Altered
Toxico-
Allergology Immunology Blindness Macular inflammatory Comprehensive Organs level Glycomics Research Safety Intercellular
genomics
Degeneration status Physicals Communication
Functional and Focus Level Application Age Mechanism
Clinical Outlook Diseases and Conditions Outlook Source Outlook Omic Outlook Type Outlook
Structural Outlook Outlook Outlook Outlook
Special mention apart, biomarkers in pharmaceutical industry research and development are predominantly described based on a Type Outlook
classification, the most widely used criterion; that is, as validation, safety and efficacy biomarkers, and likewise also as surrogate and diagnostic,
prognostic, predictive, and pharmacodynamic biomarkers, all categories that are not mutually exclusive since specific clinical setting can determine
how the biomarker is used and interpreted. In the particular sphere of aging, age-related diseases and geriatric syndromes, biomarkers are usually
classified according to an Aging Mechanism Outlook: by the root causes and the mechanisms or phenomena triggered by these causes; for instance,
loss of proteostasis triggers inflammaging mechanisms, although this is not the single cause of age-related low grade inflammation.

Biomarker Conventional
Classification Frameworks
Primary hallmarks of aging

Causes of damage
Antagonistic hallmarks of aging

Root responses to damage
Integrative hallmarks of aging

Root culprits of the phenotype
Aging Mechanism Outlook. The proposed nine hallmarks of aging are grouped into three categories. Those hallmarks considered to be the primary
causes of cellular damage. Those considered to be part of compensatory or antagonistic responses to the damage. These responses initially mitigate
the damage, but eventually, if chronic or exacerbated, they become deleterious themselves. Integrative hallmarks that are the end result of the previous
two groups of hallmarks and are ultimately responsible for the functional decline associated with aging.
Sources Image: López-Otín C., et al. The hallmarks of aging. 2013.

27
Techniques of Biomarker Analysis
In the last two decades, the use of biomarkers in biomedical research and drug discovery and development has seen rapid growth as a result of the
advancement of laboratory techniques and bioanalytical assays, fundamentally:
● Ligand‐Binding Assays (LBA), such as Enzyme‐Linked ImmunoSorbent Assay (ELISA);
● Quantitative Polymerase Chain Reaction (qPCR);
● Mass Spectrometry (MS)‐based technologies.
These and other technologies of biochemical laboratory, analytical chemistry and biophysics, have allowed the identification and characterization of
innumerable genetic, molecular and cellular biomarkers, as well as their direct relationship with mechanism of disease or processes substantially
downstream from the primary disease processes. Despite this, due to economic viability limitations, regulatory or standardization issues, high technical
difficulty or time consumption, excessive specialization skills requirements, or lack of clinical certainty about usefulness in health promotion,
prevention, diagnosis, treatment, or prognosis, many technologies, techniques and biomarkers have been restricted to Research Use Only (RUO), not
taking place the transition or adaptation for Approved Clinical Use (ACU) or taking place in a very slow and limited way.
Because of the substantial risk of adversely affecting the public health if a biomarker is falsely accepted as a surrogate endpoint, robust scientific
evidence is needed to justify qualification of a biomarker for that use. There have been numerous biomarkers that represented plausible surrogate
endpoints, but when tested in outcome trails these have failed to predict the expected clinical manifestation. Qualification of a biomarker as a
surrogate endpoint will inevitably occur far less frequently than qualification of a biomarker for other uses. In this sense, to shorten the translation
delay from RUO to ACU, and for a deep impact on population health care as well as in the field of research and development, it is essential to move
towards the definitive establishment of digital health and P4 Medicine.
The disruptive impact of P4 Medicine is a consequence of the emergence of now well seated technologies of Data Science and AI making
possible the mapping and construction of biomarker networks, giving birth to a new market-ready health care paradigm: deep precision care
along with daily real-time digital monitoring to continuously adjust and set up the optimal state of health, and early stage prevention treatment.

What are Biomarkers of Aging?
Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age
Ten winning business
sample there is considerable variation in the extent of disease and functional impairment risk, revealing a need for archetypes after health’s digital
valid biomarkers to aid in characterizing complex aging processes. The identification of biomarkers is further transformation
complicated by the diversity of biological living situations, lifestyle activities and medical treatments.
Data + platforms
Thus, there has been no identification of a single biomarker or gold standard tool that can successfully monitor
healthy aging, or perhaps not until the recent development of Horvath’s Epigenetic Clock and Glycomic Biomarkers. Data convener
How do we know when a biomarker is a Biomarker of Aging? It depends on how it is sourced. The current approach Science and insights engine
to biomarkers is to take them from people at various stages of a disease’s known progress, which in practice
means sourcing them from hospital patients. Isolating biomarkers of aging, however, means collecting data which Data/platform
infrastructure builder
marks the difference between healthy people only, e.g. between the young and even younger, with no traces of any
officially recognised diseases. Well-being + care delivery
Health products developer

A special focus of Aging Analytics Agency, is the use and recommendation of AI for the Consumer-centric health
development of an optimal Panel of Biomarkers of Aging – a specific niche where the “virtual home + community”
implementation is lagging behind the science. This is one of the most important Specialty care operator
diagnostic services that could be offered, and yet it does not receive the attention it
deserves compared to the amount of tangible benefits it can deliver. Localized health hub
Care enablement
The diagnostic technologies of the future should be anchored to Panels of Aging Biomarkers digitally obtained.
This will enable the current state of health of each patient to be continually and precisely monitored, allowing the Connectors and intermediaries
effectiveness of interventions and micro-adjustments to interventions to be continuously assessed in detail,
enabling an unprecedented degree of precision and prevention in biomedicine, and an unprecedented degree of Individualized financer
prescience in biomedical research. This, in a nutshell is the nature of the aforementioned digital transformation of
the Longevity Industry. Regulator
Sources:Image: Data from Deloitte.

29
Digital Transformation of the Health and Longevity Industry
The future of health will be driven
by digital transformation enabled
by radically interoperable data and
open, secure platforms.
Radically interoperable data and AI

can empower consumers in ways that
are difficult to visualize today. Data
about individuals, populations,
institutions, and the environment will
be at the heart of the future of health.
Sources:Image: Modified from everis.

Biomarkers of Aging are biomarkers that could

predict functional capacity at some later age Validated Biomarkers of Aging would allow for testing interventions to extend lifespan, because
better than will chronological age. Stated another changes in the biomarkers would be observable throughout the lifespan of the organism.
way, biomarkers of aging would give the true Although maximum lifespan would be a means of validating biomarkers of aging, it would not be
Biological Age, which may be different from the a practical means for long-lived species such as humans because longitudinal studies would
Chronological Age. take far too much time.
Ideally, biomarkers of aging should:
● Assay the biological process of aging itself and not only the predisposition to disease,
since the vast majority of the aging process occurs without pathological manifestation;
● Cause a minimal amount of trauma to assay in the organism, thus enabling continuous
measurement and analysis that do not cause morphofunctional damage, which
ultimately results in aging;
Within this frame, Biological Age is intended as a ● Be measurable with high reproducibility during extremely short intervals compared to the
synthetic index constituted by a single marker or lifespan of the organism.
the combination of few biological markers which, With such biomarkers, it should be possible to obtain Trajectories of Aging, where the
alone or integrated with functional markers, not “accelerated” ones would predict unhealthy aging and diseases, while the “decelerated” ones
only correlates with chronological age but is/are would be associated with healthy aging and longevity. The possibility to draw Trajectories of
capable of identifying individuals “younger” or Aging is a fascinating, far-reaching perspective, especially in consideration of the long
“older” than their chronological age in the same incubation preclinical period that characterizes most of the major age-related chronic diseases,
demographic cohorts; i.e., with a different health being also considered the critical time window for effective treatments. Biomarkers of Biological
status, globally or in relation to a particular vital Age could greatly contribute to identify the subjects characterized by higher risk to develop overt
function or organ system, allowing this index to clinical diseases who would have a major benefit from tailored preventive treatments.
accurately predict future health status and
functional capacity.

AI-Driven Development of
Biomarker Panels of Aging
Artificial Intelligence will use Digital Biomarkers to reality-check the proposed longevity therapies and filter out inappropriate or impractical
biomarkers from those effective.

Precision Prevention, Diagnosis,
Treatment and Prognosis
As the Precision Health industry is grown and developed to scale, we will see an increasing emphasis on the creation and validation of a wide diversity
of Biomarkers of Aging come into use, which will enable the extension of healthspan and the maintenance of optimal health for the majority of citizens'
lifespans via continuous, AI-empowered monitoring of fluctuations in personalized Biomarkers of Aging.
P4 Medicine will be the central platform giving effective usefulness to Aging Biomarkers for healthcare. It is not possible to think about extension of life
expectancy and healthspan without P4 Medicine.
Gathering Aging Biomarkers means collecting data which marks the difference between healthy people only, e.g. between the young and even
younger, with no traces of any officially recognised diseases. The continuous monitoring of small changes in such biomarkers, and the
continuous and commensurate micro-adjustment of treatments in response, allows for some de facto reversal of biological age.

Aging Biomarkers already exist, but they are going through a period of discussion and validation. A major biomedical aim of these biomarkers today is
to identify the subjects at higher risk for each specific age-related disease and syndrome at very early stage; the challenge of precision preventive
medicine.
At present, the combination of last generation effective biomarkers, capable of assessing the deep biological age, with some classical and innovative
biochemical and functional disease-specific ones, represents the best strategy to identify Disease-Specific Aging Trajectories in each individual. This is
the core conclusion and recommendation of our analytical assessment.
Within this perspective, particular attention has to be devoted to the epigenetics, but also the genetics of each individual which is the complex result of
the interaction between nuclear and mitochondrial genetics (stable with the exception of somatic mutations) and microbiomes’ genetics (malleable
and adaptive to the environment), focusing on Gut Microbiota Biomarkers for its capability to be modified by basic habits such as nutrition.
In this sense, we predict that it will be useful enough to combine the above mentioned integrated biomarkers’ assessment (particularly the Horvath’s
Epigenetic Clock with some widely used and conventional routine biomarkers) with established and new genetic risk factors for Aging-Related
Diseases, taking into account some criticalities related to population genetics and demographic birth cohorts.
It must be mentioned; although a number of promising Aging Biomarkers candidates have been proposed in the last years, to date there are no clinically
validated ones. There are three disruptive and non mutually exclusive categories of last generation Biomarkers of Biological Age that have
revolutionized the sector due to its high correlation with chronological age and trajectories of age-related diseases, being of mandatory mention:
● DNA Methylation Biomarkers, especially the Horvath's Clock,
● Glycomic Biomarkers, and
● Gut Microbiota Biomarkers, also called Microbiome Biomarkers.
All of them have presence in the market as informational purpose tests provided by certain companies, but not clinical tests. And each one is up to the
challenge of establishing itself as a self-sufficient metric of Biological Age; particularly the first mention. The integration of any of these into a
Biomarker Panel would not only serve as a reference to evaluate the implication of the remaining, traditional ones like a Lipid Profile, in aging decline;
such a far-reaching and proactive decision would also accelerate the process of their clinical validation both to measure Biological Age and for the
evaluation of specific diseases in any other given context.

Biomarkers of Aging
In summary, research on healthy aging and longevity encompasses the Such research needs measures of Biological Age at the individual level
biological processes contributing to aging per se; the socio-economic and which, in addition to Chronological Age, can characterise and quantify
environmental exposures across life which modulate aging and the risk of important functions which are subject to decline at faster, or slower, rates
age-related frailty, disability and disease; and the development of during individual human aging.
interventions which may modulate the aging trajectory.
Biomarkers of healthy aging could be used as surrogate endpoints or
outcome measures in trials of interventions designed to extend
healthspan, and public health-related population surveys would benefit
from reliable, readily-measured indices of healthy aging. Nevertheless,
there is no criterion reference for assessing healthy aging and this creates
difficulties when conducting and comparing research on aging across
studies. Herein the need for Maximally Actionable Aging Biomarkers
Panels.
Healthy aging and wellbeing are common goals in all modern societies.
The demographic shift towards higher proportions of older people within
the population in practically all countries worldwide, and the recognition
that much of the costs of health and social care in
economically-developed countries is densely concentrated in the last
decade of life, have sharpened globally the research focus on aging and
longevity.
The concept of biological age predictors. A biological age predictor could be defined as a
biomarker correlated with chronological age (black line), which brings additive
information in the risk assessments for age-related conditions on top of chronological
age. Hence, adult individuals of the same chronological age could possess different risks
for age-associated diseases as judged from their biological ages (x's in figure). Usually,
the positive predictive value (red line) of a biological age predictor decreases from
mid-life and onwards due to the increased biological heterogeneity at old age (confidence
interval described by dashed lines increases at old age).
Sources: Image: Juulia Jylhävä, et al. Biological Age Predictors. 2017.

35
The Need for Maximally Actionable Biomarkers of Aging
It is important in technology never to let the perfect be the enemy of good, especially when the technology is of great humanitarian significance. Aging
Analytics Agency has observed a tendency among governments and political strategic bodies to make the error of assuming that because the current
scientific quest for ever more precise biomarkers is not slowing down, that we don’t yet have a set of biomarkers precise enough and actionable
enough to take immediate action.
It is important therefore to develop and promote the widespread use of a panel of biomarkers which are not only comprehensive but also immediately
actionable. A panel of less precise but easily implementable biomarkers of aging would be much better than an extremely precise and comprehensive
panel of biomarkers of aging that is too hard or expensive to translate easily into widespread practical use across nations. As an example of minimum
viable biomarkers, consider that a set of of aging biomarkers was developed recently which is based on Deep Learning analysis of standard blood
biomarkers, which is less accurate than the most precise available biomarkers of aging (DNA Methylation clocks), but which is nonetheless good
enough, and can be implemented by any researcher, doctor and clinician that has access to routine blood tests.
As a further example, consider that biomarkers of aging have been constructed using Deep Learning-based analysis of photographs of mice, which
could quite easily be extended to humans. Their accuracy alone is not enough to make them a research priority, but the increasing video capabilities of
smart-phones means that these rapid development of photographic biomarkers of aging (e.g. of the face or the eye) could now be a very actionable
area of research whose practical level of precision and accuracy will develop quite rapidly in coming years.
However, the use of AI in R&D is lagging behind in its application to geroscience. While there is a small handful of companies that are working at this
frontier, the overall proportion in comparison to the total size of the Longevity industry is still quite small. Deep Knowledge Ventures has been
identifying and supporting companies working on the frontlines of AI for Longevity since 2014, when it provided the seed funding for Insilico Medicine,
now a leader in the application of AI for Longevity research, drug discovery and biomarker development. An MVP panel of biomarkers will make the
biotech sector of Longevity much more lean, and dynamic. It will allow for a more rapid assessment period, which in turn will allow for a rapid
succession of experiments with microdoses of different treatment and drugs.

It is impossible to determine whether biotechnologies for Longevity have been successful if we cannot tell how advanced the aging process is in any
given individual; but at the same time the latter will not be feasible until successfully achieving High Actionability Panels that allow to evaluate the
aging process in broad healthy and less healthy differentiated ranges of the population spectrum. From the above the following two notions emerge.
● It will be impossible to make concrete claims regarding global progress in health biotechnology, and in P4 Medicine in particular, without an
agreed and accessible panel of biomarkers as a tool to standardize results.
● These biomedical markers, measurable indicators of the severity or presence of some disease state, are able to serve as the basis for building
standard metrics for government programs and cost-effective healthcare policies, clinical implementations, and industrial output in global
Longevity Industry.
Biomarkers of aging can be used to predict the biological age, which reflects the state of health, via statistics and machine learning algorithms. A
single class of biomarkers, which is intrinsically a matrix of features, can be used in the prediction. DNA methylation was used to predict age with an
error of about 3.6 years using 8,000 samples. 3D facial images have also been used to predict age with a mean deviation of 6 years. Integration of
multiple biomarkers can be even more powerful.
Given the complex nature of the aging process, the biomarkers of aging are multilayered and multifaceted. Combined and integrated by AI and machine
learning techniques, reliable panels of biomarkers of aging will have major and tremendous potential to improve human health in aging societies.
Identifying and using biomarkers of aging organized in an objective and solidly founded panel to improve human health, prevent age-associated
diseases, and extend healthy life span are now facilitated by this fast-growing AI-driven capacity for multilevel cross-sectional and longitudinal data
acquisition, storage, and analysis, particularly for data related to general human populations.
Is in this sense that Biomarkers are an essential factor in Aging Analytics Agency's strategic agenda, which includes recommendations for the
establishment of AI centres in the United Kingdom, the indispensable medium to nail down the implementation of P4 Medicine and also to guarantee
competitiveness in the new global health market, in the same way that highly specialized advice for the success of longevity-related government
initiatives worldwide.
Sources: Xian Xia, et al. Molecular and phenotypic biomarkers of aging. 2017.
37
The Need for Maximally Actionable Biomarkers of Aging
It is important in technology never to let the perfect be the enemy of good, especially when the technology is of great humanitarian significance.
In the early 2000s, enthusiastic proponents of the application of Regenerative Medicine to aging were urging governments, entrepreneurs and
thought-leaders to make this a priority. They argued that technology was ahead of the science and the funding, and that while a great deal remains to
be discovered about the mechanisms of aging, we already know enough to optimize the existing toolkit of Regenerative Medicine to address the
damage of aging, which is already thoroughly researched. And thus, shift occurred out of this paradigm and the field of Rejuvenation Biotechnology
arose.
Now once again, the technology is ahead of the science, the funding, and the political leadership. And, once again, a paradigm shift is due.
Presently the necessary biotechnologies for the implementation of P4 Medicine technologies and therapies are already in place. What is needed now is
Big Data analytics to develop optimal Panels of Biomarkers of aging and to determine how to optimize their implementation. Thus, this is not a
biotechnology problem, but a data mining, analysis and management problem. In many countries, to various degrees, data mining, analysis and
management problem is a question of political coordination. In that way, there is a risk that governments and governmental or political strategic
bodies may make one or both of the following errors:
● They might assume that missing bridge on the road to HALE-extending P4 Medicine is still biotech progress, rather than a data analysis and
management problem; i.e., an AI and computational problem;
● They might assume that current scientific quest for ever more precise Biomarkers is not slowing down because we don’t have yet a set of Aging
Biomarkers sufficiently actionable and precise, in order to take immediate action.
As such government strategic bodies therefore risk limiting their strategic ambitions with regard to time frames. For example, in the United Kingdom,
Theresa May’s government has announced a commitment to adding 5 extra years on the nation’s HALE by 2035, whereas Aging Analytic Agency has
subsequently advised the UK’s newly formed APPG for Longevity that a much more relevant timeline would be 2025, provided actionable biomarkers
with sufficient accuracy are utilized. This aspiration better reflects real current rate and state of scientific and technological innovation.

The Need for Maximally Actionable Biomarkers of Aging.
Aging Analytics Agency is recommending that government place a strategic emphasis not on
the best Biomarkers of Aging, but on a Panel of Biomarkers that has the highest ratio of
comprehensiveness to actionability and implementability.
Having a panel of less precise but highly implementable Biomarkers of Aging close at hand is
much better than having an extremely precise and comprehensive panel of biomarkers that is
too hard or expensive to translate easily into widespread practical use across nations, as the
beneficiaries of earlier action are likelier to stand a chance of living long enough to
subsequently benefit from more advanced applications based on more precise, more
comprehensive biomarkers.
The past few years have seen a lot of progress in the development of Biomarkers of Aging
that are not as precise as the current leading methods, but that are precise enough, and most
importantly, extremely easy to implement in practice -in particular, those based on
Deep-Learning and AI-driven analysis of routine blood tests, and of photographs. These are
highly viable Biomarker Panels.
Consider that set of Aging Biomarkers developed recently, based on Deep Learning analysis
of standard blood biomarkers; while less accurate than the most precise available Aging
Biomarker, DNA Methylation Clocks, is nonetheless good enough and can be performed by
any researcher, doctor and clinician that has access to routine blood tests.
The increasing video capabilities of smart-phones means that these rapid

developments in Imaging Biomarkers of Aging (for any physical or behavioral trait
correlated with biological age) can now be a very actionable area of research whose
practical level of precision and accuracy will develop quite quickly in coming years.
Sources: Image: Olink. From protein biomarker discovery to precision medicine

39
The Need for Maximally Actionable Biomarkers of Aging.
It should not be assumed that the use of Artificial Intelligence is widely embedded into
biogerontology and geroscience. AI in R&D is lagging behind in its application to the Longevity
industry. While there is a small handful of companies that are working at this frontier, the
overall proportion in comparison to the total size of the Longevity industry is still quite small.
Deep Knowledge Ventures has been identifying and supporting companies working on the
frontlines of AI for Longevity since 2014, when it provided the seed funding for Insilico
Medicine, now a leader in the application of AI for Longevity research, drug discovery and
development, and biomarker development. A MVP Panel of Biomarkers, hand in hand with
highly integrated AI for data processing will make the biotech sector of Longevity much more
lean, and dynamic. It will allow for a more rapid assessment period, which in turn will allow for
a rapid succession of experiments with microdoses of different treatment and drugs, and
then for translation into their parallel clinical applications, like preventive treatment in P4
Medicine or directly rejuvenation therapies in Regenerative Medicine.
It is important to develop and promote the widespread use of a comprehensive enough Panel
of Biomarkers but, primarily, immediately actionable. We have documented many of the Aging
Biomarkers here and identified from among them those which, by the metrics described,
belong to the category we have named Minimum Required: the Most Viable Products for
immediate implementation.
It is our hope that regardless of whether it is adopted wholesale, it may serve as a starting
point for discussion on how best to utilize the deep knowledge we already have to
maximum effect as soon as possible.
Sources: Images: cbinsights.com | Rock Health

40
Report Methodology
Report Methodology in Details
To calculate the final score of a Single Biomarker or a Biomarker Panel, 3 types of Indexes are applied:
Accuracy Index - value expressed within the range [0.0-1.0].

It is a measure of the precision to predict overall biological age, based on the accuracy of each single biomarker scanned by the Panel. Thus, it is
defined with formulas for both, single biomarkers and groups of biomarkers, and the output of the latter as an expression of the values projected by
the first ones. The magnitudes depend not only on the number of biomarkers evaluated by the Panel, but on the nature of those biomarkers, the
experimental background of its association with age-related conditions and processes, and a proposed classification framework that assigns or
removes scores for qualitative characterizations; in this sense, the fundamental parameter used by the index is scientific support mined by
sampling journal publications from specialized literature which successfully correlate each biomarker with temporary progression of aging. As
expected, this framework equals the comprehensiveness of a biomarker or a panel with its precision or accuracy degree.
Availability Index - value expressed within the BAI range [0.0-10.0 BAI].
Value that is calculated by omitting the significance degree of the biomarker as an indicator of age-related health status, assuming the implicit
condition of correlation between the biomarker and temporary progression of aging. It measures only the material capacity of extensive
implementation for the reference character, understood as an expression of the availability of assays or tests, its invasiveness, monetary value, the
proposed classification framework for qualitative characterizations used also in Accuracy Assessments, and so on.
Actionability Index - value expressed within the range [0.0-1.0].

Actionability is estimated as an expression of both the accuracy and availability of a biomarker or a Panel. The Availability Index value is
transferred to the range [0.0-1.0]. Then, an operation is performed combining the previous measurements and converting them into a new metric
that takes into account both factors; this is done by decreasing the absolute contribution of Accuracy Index, since it must be taken into account
along with availability for assessment of actionability but does not contribute equivalently, being of lesser relative relevance in the terms described
in the preceding pages. This comprehensive value allows to evaluate not only the current material capacity of implementation of a biomarker or a
Panel but also its viability for biological age prediction in such an immediate and effective frame of implementation, thus empowering single
biomarker and Panel comparisons with a purely pragmatic sense. It is a weighted expression of a biomarker or a Panel’s individual and effective
availability combined with a mathematical modification of its Accuracy Index that only admits near-real values for extremely high accuracy outputs
of correlation with biological age, minimizing the contribution of said term for medium-high, medium and low magnitude outputs.

Indexes Values for Single Aging Biomarkers and Aging Panels
.6657 .7214 .7771 .8328 .8885 .9442 1.0 ACCURACY VALUES AND SEVEN 3.82 4.85 5.88 6.91 7.94 8.97 10 AVAILABILITY VALUES AND SEVEN
LEVELS SEGMENTATION LEVELS SEGMENTATION
Illustrative only; non-real values. (coming soon) Illustrative only; non-real values. (coming soon)
It is Aging Analytics Agency’s hope that our comparative analytics framework and methodology will serve as a useful long-term analytical tool for aging single
biomarkers and panels assessment to identify the most advanced, available and actionable resources to create, manage, optimize and improve action plans for the
health and Longevity industry, market and public sectors.
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Aging Analytics Agency uses detailed mathematical procedures to assign a value (or numerical factor) to each of the three
variables taken into account in the evaluation of single biomarkers and whole biomarker panels. Many qualitative considerations
are made when assigning scores to these three variables. In first place, the CONDITIONING STAGE CATEGORY of the single
biomarker or the panel; that is, if they are approved or not for clinical use. Second, its OPERATIONAL CATEGORY; if they are
offered in the market as laboratory research kits, as medical tests; if the company gives access to the prices; if it is a theoretical
panel or one employed in epidemiological surveys, in which case it is not materially offered to the market by the entity; if it is a
real-time evaluation technology for a set of biomarkers, which could decrease availability due to the increase in cost but actually
increases it because it allow large-scale assessment of vast amounts of patients, and so on. Thus, the numerical evaluation is to
some extent subordinated to a multiplicity of qualitative factors considered by our highly specialized professionals in the field of
Illustrative only;
biotechnology and pharmaceutical intelligence. non-real values.

COMPANY or CONDITIONING STAGE Accuracy Availability Actionability

NAME OPERATIONAL CATEGORY Actionability Factor
ENTITY CATEGORY Index (*) Index Index (**)
Epidem. or Theoretical Panel
Biomarker Panel UK BIOBANK Approved for Clinical Use 0.66 0 BAI N/A 0
Only (BAI=0; ACTIONAB.=0)
Research Kit or OLPS 2
DiscoveryMAP v. 3.3 Research Use Only (0.65) + 0.1166 =
MYRIAD RBM (Accuracy Index x RKOLPS 0.65 1.166 BAI 0.2695
Panel (-2 Availab. Weight Points) 0.5391
coefficient)
Research Use Only (0.64) + 0.133 =
Metabolism Panel OLINK (Accuracy Index x RKOLPS 0.64 1.33 BAI 0.2713
(-2 Availab. Weight Points) 0.5426
coefficient)
Research Use Only (0.645) + 0.133 =
Inflammation Panel OLINK (Accuracy Index x RKOLPS 0.645 1.33 BAI 0.2745
(-2 Availab. Weight Points) 0.549
coefficient)
Healthy Aging Panel Medical Test 2

LIFE EXTENSION Approved for Clinical Use 0.63 2.708 BAI (0.63) + 0.2708 = 0.3338
(Comprehensive) (+2 Availability Weight Points) 0.6677
InsideTracker Ultimate Medical Test 2

SEGTERRA Approved for Clinical Use 0.663 3.291 BAI (0.663) + 0.3291= 0.3843
Plan + DNA analysis (+2 Availability Weight Points) 0.7686
Medical Test 2
WellnessFX Premium WELLNESSFX Approved for Clinical Use 0.665 3.375 BAI (0.665) + 0.3375 = 0.3898
(+2 Availability Weight Points) 0.7797
Medical Test 2
Aging Theranostic 1.0 OPEN LONGEVITY Approved for Clinical Use 0.66 3.45 BAI (0.66) + 0.345 = 0.3903
Phospho-H2AX (Ser139) Research Use Only (0.72) + 0.279 =
CISBIO (Accuracy Index x RKOLPS 0.72 2.79 BAI 0.3987
Cellular kit (-2 Availab. Weight Points) 0.7974
coefficient)
PhysioAge Biomarkers Medical Test 2

PHYSIOAGE Approved for Clinical Use 0.77 2.416 BAI (0.77) + 0.2416 = 0.4172
of Aging Test (+2 Availability Weight Points) 0.8345

COMPANY or CONDITIONING STAGE Accuracy Availability Actionability

NAME OPERATIONAL CATEGORY Actionability Factor
ENTITY CATEGORY Index (*) Index Index (**)
Medical Test 2
Immune-Frame RGCC Approved for Clinical Use 0.74 3.125 BAI (0.74) + 0.3125 = 0.43
TeloYears + Advanced 2
TELOYEARS Healthcare-Ready Informational Purpose Test 0.83 1.833 BAI (0.83) + 0.1833 = 0.4361
Ancestry 0.8722
InsideTracker Inner Age Medical Test 2

SEGTERRA Approved for Clinical Use 0.61 5.541 BAI (0.61) + 0.5541 = 0.4631
+ DNA analysis (+2 Availability Weight Points) 0.9262
Biomarkers Real-Time 2
Health Reviser Platform HEALTH REVISER Approved for Clinical Use Assessment Technology 0.8 4.4 BAI (0.8) + 0.44 = 0.54
Anti-Aging #4 2
Medical Test (0.69) + 0.87 =
Comprehensive Blood WALK-IN LAB Approved for Clinical Use 0.69 8.7 BAI 0.673
and Urine Test Panel
Biomarkers Real-Time 2
AgeReader test DIAGNOPTICS Approved for Clinical Use Assessment Technology 0.87 7.1666 BAI (0.87) + 0.71666 = 0.7367
INSILICO AI Platform 2
Aging.AI Healthcare-Ready 0.93 10 BAI (0.93) + 1 = 0.9324
MEDICINE (+5 Availability Weight Points) 1.8649
DNAge™ Epigenetic 2
ZYMO RESEARCH Healthcare-Ready Informational Purpose Test 1.0 10 BAI (1.0) + 1 = 1.0
Aging Clock 2
(a) Their respective values presented in this chart are illustrative only; they were not calculated based on their actual availability or accuracy. For real values, access the full Report.

Classification Framework for the Assignment or
Removal of Scores by Qualitative Characterizations
(*) Accuracy results depend on the number of replicates for each biomarker per study and between studies, therefore it is expected that biomarkers
with a lot of empirical support but few background studies (eg, gold standard ones; Horvath's Clock, Gut Microbiome Age Clocks, Advanced
Glycation End-products Clocks) may have lower values than markers less correlated with aging but a large amount of experimental background
(more replicas), like HbA1C, estrogens, testosterone and so on. The results, then, are always weighed against the total empirical support for each
biomarker, which depends on the quality of the publications rather than merely the quantity, this being evaluated by our life sciences team at Aging
Analytics Agency, highly trained in the analysis of Big Data from scientific publications.
(**) The numerical evaluation of Actionability is to some extent subordinated to a multiplicity of qualitative factors considered by our highly
specialized professionals in the field of biotechnology and pharmaceutical intelligence. These qualitative considerations can be summarized in the
following categorical delimitations:
● Research Use Only Panels or Single Biomarkers: Availability Index is reduced in 2 Points, because it negatively conditions the implementation of the panel; there is
little to no implementation of the Panel in healthcare assessment, even less in Longevity assessment.
● Research Kits or Other Laboratory Practice Supplies (OLPS) multiplies Accuracy Index by a RKOLPS coefficient (= 0.5) that causes the total value to fall, unless the
supply is specifically designed for the evaluation of biological age or aging itself: these kits and OLPSs are not usually designed for this purpose, and evaluation of
accuracy becomes highly subjective.
● A Medical Test Panel or Single Biomarker increases availability in 2 Points, but never exceeding the maximum 24 Points: facilitates large-scale implementation.
● A Real-Time Assessment Technology for a Biomarker or a Panel, increases availability in 5 Points, but never exceeding the maximum 24 Points: facilitates ultra
large-scale implementation and analysis.
● AI Platforms for biomarkers inputs, increases availability in 5 Points, but never exceeding the maximum 24 Points: facilitates ultra large-scale implementation and
analysis.
● Epidemiological or Theoretical Panel Only are those not in the market; they are references to scientific articles, or to academic developments or public
developments not necessarily published in journals. The availability is 0 BAI, and in the same way actionability falls to zero (0); they are not part of the practical
recommendations of this report.
● When the company or entity does not share prices, it is immediately assumed x> maximum tolerable in the calculation of Availability Index, thus causing the
magnitude of the Availability Index to fall.

Biomarkers of Longevity Distribution by Operational Category
Research Kit Informational Purpose Epidemiological or

or Other Laboratory Medical Test AI Platform
Test or Platform Theoretical Panel Only
Practice Supplies
Biomarkers Real-Time
Assessment
Technology

Biomarkers of Longevity Distribution by Conditioning Stage
Stage Three: Approved for

Stage One: Research Use Only Stage Two: Healthcare-Ready
Clinical Use

Biomarkers of Longevity Distribution by Amplitude Level
Panels Single Biomarker Digital Panel Platform
Baseline Amplitude Level Maximum Amplitude Level

Classification Framework by Qualitative Characterizations
It will be noted that our core Biomarker Domains Classification Framework is absent in the previously exposed Classification Framework by Qualitative
Characterizations; although the first systematization is applied throughout the entire report, particularly in the profiles of Single Biomarkers and Panels,
it does not affect the scores of Single Biomarkers and Biomarker Panels at the time of its quantitative evaluation. The Biomarker Domains
Classification Framework is related only to characteristics of the selection process of the Panels offered by the market. Those Panels conform to the
Three Spectra Classification Framework exposed in the previous boxes; nevertheless, these three spectra precise and advanced systematization is not
enough, as detailed below.
The vast majority of the Panels offered by the market evaluate characteristics at a molecular level and based on laboratory procedures. For instance,
there are almost no commercial presentations for assessment of Cognitive Function; there are isolated neurological or psychological tests not
addressed by Biomarker Panels in the market. The same applies with Physical or Physiological Function assessments; classic imaging tests,
ultrasound, waist circumference, muscle mass, bone density, grip strength and so on, are almost not included variables in the Panels offered by the
market; in this sense, the only Panel for assessment of those conventional variables is a traditional Physical Examination -or Comprehensive Physical
Exams sensu stricto-; that is, checkups provided by clinical physicians, neurologists, and so on. In those cases, our Panels selection would overlap
entirely with the offer of clinical and specialized medical services related to these specific domains; it should be considered that a physician's service is
a Panel per se, or something similar to that. And which of those "Panels" for Physical, Physiological or Cognitive function would we choose? There are
as many as physicians. It will also be noted that most of the Biomarker Panels cannot be characterized with a Domains Classification Framework, since
the majority include Biomarkers distributed between these three Domains - some of Endocrine Function in conjunction with others of Immune Function
and sometimes with some of our Molecular Level Domain-.
Nor can we omit these Biomarker Domains. In Aging Analytics Agency we propose an exhaustive and advanced evaluation of all the variables that
influence the aging process and Longevity, and for that reason we have included this Biomarker Domains Classification Framework. For this
considerations, it has been decided to recommend a combination of all these categories; the following configuration for the most optimal Panel, the
one with the best availability vs. accuracy ratio: one that includes data from conventional physical, physiological and cognitive exams, offered by the
clinical services - and for which only an accuracy assessment is carried out, since its availability is, with certainty, maximum; or at least in the countries
with access to the minimum expected clinical services-, and additionally data provided by Panels that evaluate Immune, Endocrine and other Molecular
and Cellular Level Biomarkers, the remaining three domains that are satisfied by the offer of Biomarker Panels in the market.

Distribution by Conditioning Stage
● The Conditioning Stage Classification Framework allows to differentiate degrees of availability vs. accuracy in strata or layers according to the current
state of Panels uses.
● Research Use Only Panels and tests, as immunophenotyping of T cells, B cells and so on, could be highly decisive for aging and Longevity
assessments, nevertheless there is virtually no availability for healthcare evaluations. Sometimes they are used, but only in very particular health
conditions and frequently at the cost of making mistakes: the methodology is usually not well standardized, the results are sometimes confusing, the
association with aging conditions and Longevity is not so linear or clear. At the same time, RUO Panels are often very expensive ones; ELISA kits,
chromatographic assays or those involving NMR, and other laboratory kits not usually used in clinical practice. Here, poor availability and poor
accuracy overlap; this is the stratum that worse availability vs. accuracy ratio per Biomarker would have. Aging Analytics Agency does not intend to
exclude these presentations from the practical purposes of its studies; here we consider Panels such as those offered by Olink, BIOLEGEND, Myriad,
all companies and products deeply involved in P4 Medicine as they facilitate the study and assessment of the proteome specifically, and other-omic
levels in general.
● Routine and Approved for Clinical Use tests for our selected Single Biomarkers have usually a high correlation degree with age-related diseases and
aging conditions; they often show good availability and excellent actionability. We could focus mainly on these, but what will provide an increase in
their precision and utility for Longevity assessments is to combine them with the so-called "Healthcare-Ready" Panels.
● Healthcare-Ready tests (or "Used for Informational Purposes" tests) are those RUO sensu lato; although they are not Approved for Clinical Use - as
they lack clinical validity at some degree-, they are offered by companies and clinics to give complementary information on the state of health or
Longevity. Thus, they may or may not provide useful information, which should be analyzed in conjunction with data provided by validated, ACU tests.
This category has good general availability, despite constituting Non-Approved for Clinical Use presentations; so they are considered quantitatively
equivalent to ACU in availability calculations, but without being ACU at a qualitative level. Healthcare-Ready Panels are almost ready for the healthcare
market, although they are not implemented in these terms: they have an informative purpose only. Nevertheless, its continuous use in such
configuration and in conjunction with already validated Panels will allow a better interpretation of the outputs or endpoints, enhanced standardization
of the results, wide access to the products, and therefore its very prompt clinical validation. The increasing access of individuals to this presentation
stratum is an incredible new phenomenon in regard to the health care market; it should be used to introduce health endpoints in Digital Panel
Platforms already conditioning for assessments of biological age, aging itself and Longevity; that is, in a way that other RUO Panels are not yet ready
to achieve.

Distribution by Amplitude Level
● An analytical and comparative approach of aging biomarkers makes it necessary for certain single ones to be considered as equivalent to whole
Panels, since they are strongly and self-sufficiently correlated with chronological age. This is the case regarding some classic examples such as
telomere length assays (Telomere Length Test from Cell Science Systems; Telomere Length and Biological Age Testing from Life Length) or CpGs
dinucleotides Methylation tests (DNAge™ Epigenetic Aging Clock from Zymo Research; Epigenetic Age Analysis Version 2.0 from Osiris Green), among
others. The single biomarkers selected in this report are almost always significantly correlated with chronological age - they are indicators of
biological age on their own-, although not usually with particular pathologies and conditions associated with the progression of aging; thus, its clinical
interpretation or validity is usually limited. The dramatic reduction in costs for most of these advanced assessments allows those biomarkers to be
currently used for informational purposes complementary to clinical validity tests, having good availability. In the other hand, a few single biomarkers
selected as Panels do not present such correlation with chronological age; they would only describe it to some extent, or not, depending on their
calculated accuracy index.
● In the same way, in a market study it can be seen that some of these Single Biomarkers are not integrated in Panels which also justifies this criterion.
These forms of presentation are at an equivalent amplitude level regarding to their correlation with chronological age; in practice, one of these Single
Biomarkers can be equivalent, in terms of Accuracy for biological age assessment, to an entire Panel.
● A Digital Panel is a platform in which data sets from Digital Biomarkers and non-Digital Biomarkers (eg, blood, physical, physiological or other tests
outputs) are introduced and integrated by an algorithm and analyzed to establish a biological age secondary output, allowing a real-time health status
assessment. Note that they include Digital Biomarkers, but are not restricted to them; they also include AI platforms, but not limited to these.
● Real-time monitoring combining Single Biomarkers and entire Panels from different sources provides a much higher level of amplitude (or
comprehensiveness) than the other two presentations; for this case study, highly consolidated Platforms only have been considered, this is, in terms
of their documented precision and reliability. Thus, all of them have comparatively a maximum degree of amplitude, or maximum Accuracy (1.0), with
availability being the conditioning factor of actionability.

Open Access and Proprietary Metrics
Open Access Metrics Proprietary Metrics
The methodology and metrics featured in this teaser for this contracted analytical case study are public and could have been used in a number of
other open-access Aging Analytics Agency reports, whereas a large portion of the analytical frameworks used for the report’s benchmarking are
proprietary, available to potential partners via NDA. These include both absolute values (quantitative or qualitative) and dynamic parameters to
analyze metrics as they change over time. The following are examples of parameters used in assessment of P4 Medicine clinics, so many of
them may concern this report while others may not.

The Role of AI in Biomarker
Discovery and Monitoring
The Increasingly Necessary Role of AI in Longevity Research
● As with the Rejuvenation Biotechnology 10 years ago, today the technology again is ahead of Deep Aging Clocks: deep-learned predictors of
the policy, and the practical healthcare and medical frameworks of developed countries, Biological Age
necessitating a paradigm shift toward greater prevention, personalization, precision and
patient participation, utilizing all available tools and technologies that are market-ready today
to optimize citizens’ Healthy Longevity. Holistic view into Age-adjusted clinical
biological processes trial enrolment
● The layering of paradigms, and the explosion of synergies that Data Aggregation in
Age-personalized
healthcare will produce within a short timeframe, means that by the normal methods of Dementia screening and
staging immuno-oncology
assessment, the science of Longevity will soon be comprised of tens of thousands of monitoring
components, and to predict the effects of all of them on human health is already an
incredibly complex challenge. The major tool for managing this will be AI. Hence why Aging Feature transfer from Age-personalized
Analytics Agency have long considered AI the major engine and driver of future Longevity aging to disease vaccines
science and industry.
Regenerative medicine Health trajectory
● This is especially true of P4 medicine itself. P4 is defined by the fact that its constituent ●Patient age-matching monitoring and
leading-edge technologies have already achieved a state of market-readiness and clinical ●Stem-cell quality control estimations
implementation. As such, when different strands of geroscience R&D reach a state of
validation sufficient for their practical implementation, they cross over from R&D and into the
scope of P4 medicine. Generation of synthetic Mortality prediction
data
● Given that P4 medicine, by definition, consists of those Longevity-relevant technologies and
Immunosenescence
techniques that are in practice today, what remains to be done in terms of actually applying New targets
identification analysis
them for the extension of Healthy Longevity is largely a matter of data mining, analysis and
management, driven by advances in biomedicine, data science and Artificial Intelligence.
P4 Medicine to P6: Digital clinical trial
Intelligent Health Web outcomes predictions
● For example, as AI for R&D in drug discovery becomes more sophisticated, drugs will
Science
become more customized to specific diseases and even specific patients. Drug development
companies will transition from the current form of “blockbuster drugs” (standard drug Reproductive longevity
Age reversal
formulations applicable to many millions of patients) to P4 medicine, tailoring drugs to tracking
specific patient cases based on age, gender, ethnicity, state of health and genetics.

The Increasingly Necessary Role of AI in Longevity Research
The first and second Ps in P4 Medicine are personalized and precision, which refer to the drugs and treatments that will be designed and applied using
precise, individually-tailored methods of dosing, cocktail compositions of micro-dosages, and efficient methods of delivery. Such advances also
represent a move toward greater prevention (the third P in P4 Medicine), and a shift away from reactionary treatments and towards optimized disease
prevention, by the application of micro-dosages of drugs long before the underlying pathology develops into actual chronic disease. Healthy Longevity
means prevention rather than treatment, through the maintenance of optimal states of health via continuous monitoring of Biomarkers, and
micro-adjustments in therapeutic, lifestyle and behavioural regimes to normalize those Biomarkers.
The fourth P in P4 Medicine is participatory, which refers to the increasingly active role that patients are taking in managing their own health,
culminating in a situation where citizens are empowered with the tools, approaches and services capable of enabling continual micro-adjustments to
their behavioural, lifestyle and therapeutic regimens in response to continuous AI-empowered monitoring of micro-changes in Biomarkers that measure
state of health and predict risk of diseases long before their actual onset and progression.
These changes are already being embraced by the medical communities and healthcare systems of progressive countries. In coming years, as P4
becomes the new norm, the new definition of failure will be when patients are forced to get doctors involved. In a world in which P4 Medicine triumphs,
citizens will have no need to engage with doctors until the very end of life. The term “Precision Health” is becoming increasingly common. The term
refers to the idea that the ideal and most comprehensive case of P4 Medicine will naturally and inevitably lead to a state of Precision Health, where
diseases and other sub-optimal forms of health are delayed for as long as possible, until near the very end of life.
The role of AI in P4 Medicine is already remarkably apparent, especially in places such as the UK, USA, Switzerland and Singapore. For example we have
seen very proactive efforts by the UK government, both through their AI Industrial Grand Challenge and their Aging Industrial Grand Challenge, to rapidly
apply AI to preventive medicine, advanced biomedicine and Digital Health, and the recent establishment of the All-Party Parliamentary Group for
Longevity, where Aging Analytics Agency was proactively involved.

Biomarkers and Data Science in the core of P4 Medicine
Small doses of
medications Not only do new methods of
standard industry benchmarking and
forecasting need to be developed to
combat the issues of overcomplexity
and multidimensionality in the
Longevity Industry, but new methods
of testing the basic safety and
efficacy of Longevity and Precision
Personalized
Measurement of Health prevention, diagnostics,
dose
optimization
biomarkers prognostics and therapeutics need
to be adapted as well, moving away
from the use of model organisms,
towards a more human-centric
approach. Digital biomarkers satisfy
all these new industry requirements:
they can be continuously tested on
all users, notifying adverse
micro-effects and ultra-stratifying
Digital avatar patients.
visualization

Precision diagnostics
Collect your data today:

Transcript-
Imaging
omics ● Blood samples
● Biomarker analysis
Pathology
Biomarker
Genomics ● Database of personal biomedical
data stored on blockchain
Cell
Proteomics
Future benefits:
Biology
● Data driven analysis of Biomarkers

Molecular Metabol- dynamics over time
Biology omics
● Analyse the changes in your digital
avatar
Digital avatar visualizes a combination of Biomarkers and other diagnostic results ● Personalized interventions
A large part of health information is digitized, which allows us to compile enormous amount of data, access global servers, and compare
patient information, sort of a dynamic repository of information that is constantly being updated. The massive advance as far as these databases
facilitates doctors in their diagnostic process, their ability to measure, analyze, compare patients, and produce medical reports that are more
accurate and personalized, that will, in turn, lead to the best available therapy or treatment of the time.
The intensive application of AI to all stages of Longevity and Preventive Medicine R&D, and healthcare, has the potential to rapidly accelerate the clinical
translation of experimental, validated and non-validated biomarkers, toward diagnostics, prognostics and therapeutics, to empower patients to
ultimately become the CEOs of their own health through continuous AI-driven monitoring of minor fluctuations in biomarkers, and the rapid
development of the global Longevity Industry to scale.
Sources: Digital Health. Fundación Innovación Bankinter.
59
Data science for Biomarkers
Multi-Omics Sequencing Non-invasive continuous monitoring

of biomarkers
Multi-modal total body
Imaging 3D integration of cross-sectional
The diagnostic technologies of the future
are grounded in colossal bodies of data tissue and organ imaging
Qualitative functional tests which are incomprehensible by current
linear methods, and that will span every Whole-body and organ specific
stage in the development of a pathology, biological age calculation based on
Data from wearable devices from the exposome to the epigenome. biomarkers
To shorten that translation delay from Research Use Only (RUO) and non-validated biomarkers and panels, to an Approved for Clinical Use (ACU)
condition in the field of age-related diseases health care, and for a deep impact on applied health in a world of aging populations, it is an essential
challenge, to obtain a set of biomarkers already Approved for Clinical Use with high availability and actionability, and use it in conjunction with others,
market- and healthcare-ready although less conventional biomarkers gathered in digital real-time monitoring environments. That will enable a
sufficiently accurate assessment of the overall process of aging, calculation of biological age, and analysis of the progression of particular elderly
conditions nested by biomarker networks leading to the creation of a Most Viable Product, or the Minimum Required Panel.
Biomarker networks, which consist of the alignment between interactome and phenome levels, reveals new disease genes and connections between
previously unrelated diseases or traits. Despite a great potential for novel discoveries, this approach is still rarely used in genomics and other omics. A
biomarker network is a group of functionally related units of indicators, of any biological level, that contribute to the same phenotype - understanding by
phenotype a molecular, metabolic, immune, physiological or physical trait, and so on-, pathological or not. The interactome - the whole set of molecular
interactions for a trait, a condition, a disease, a cell or another biological unit-, and the phenome - the set of all phenotypes expressed by that unit-, are
complexly connected at multiple levels. At the root of these networks is the epigenome. Only AI-driven methods can efficiently address such
complexity, those colossal bodies of data that can be currently entered into multiple and different digital platforms.

Data science and AI making Complex Biomarkers available
Unlocking the value of epigenetic data for actionable insights will drive aging research,
Applying AI in Epigenetics Research.
precision medicine, and ultimately population health. Fundamental questions should be
Input Layer
addressed by integrative personal omics profiling with epigenomics at its center,
combining genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles Exposome
from an individual to reveal dynamic molecular changes in health and disease. With the Hidden Hidden
Layer 1 Layer 2
evolution of better technologies and digital capacity, enormous amounts of omics data Metabo-
will be produced and stored in the digital space and researchers will need AI to be able to lome
keep track of it. AI is already transforming the world of medicine and will help healthcare
Proteome
providers make faster and more accurate diagnoses. Based on epigenetic data, deep
learning algorithms will predict the risk of a disease in time to prevent it and will help
scientists understand how interindividual epigenetic variability leads to disease. Epigeno-
me
However, ensuring security and privacy in transmitting and storing personal epigenetic
profiles will require building a new and open multi-omics data ecosystem. Blockchain, an Social
Graph
open-source technology that uses a distributed database for secure transactions, has Output
Layer
the potential to address many of the challenges related to security and privacy with Sensor
personal health information. Blockchain technology enables integrating data from a Data
distributed network of participants in the healthcare value chain on a global scale. We

Trans-
are in the initial stages of a revolution in precision medicine enabled by advanced criptome
technologies such as epigenomics, AI, and blockchain. The pioneering effort by early
adopters from the research space is critical for putting these technologies within reach Imaging
of the broader healthcare ecosystem.
Multilevel artificial neural network to support epigenetics research. At the input layer, multi-omics and demographic data are fed into the network. Each circular node
represents an artificial neuron and each line represents a connection from the output of one neuron to the input of another. Machine learning enables data-driven decision
systems to continuously learn from new epigenetic data and adapt itself to deliver “reliable and repeatable” results.
Sources: Schumacher, A. Epigenetics of Aging and Longevity. 2018.

61
Systems healthcare is a holistic approach to health premised on systems

biology and medicine. The approach integrates data from molecules, cells,
organs, the individual, families, communities, and the natural and
man-made environment. Both extrinsic and intrinsic influences constantly
challenge the biological networks associated with wellness. Such
influences may dysregulate networks and allow pathobiology to evolve,
resulting in early clinical presentation that requires astute assessment and
timely intervention for successful mitigation.
The cornerstone of P4 Medicine, as in systems health, is the evaluation of
dysfunctions of molecular or biomarker networks. The P4 Medicine
paradigm involves a comprehensive understanding of the regulation and
dysregulation of the complex molecular networks that forge the
phenotype of an individual. In this framework, disease is a consequence
of aberrant reconstitution of cellular and molecular networks that lead to
organ and organismal dysfunction (e.g., the patient’s clinical Creation of topological maps of health and disease.
presentation). “Omic” latin suffix, or “ome” = mass or many.
The interaction of the diseased organ within the person produces a cascade of dysregulated networks, resulting in associated comorbidities, some of
which are evident and others that are asymptomatic (preclinical). In the state of wellness, networks are precisely regulated via complex homeostatic
mechanisms. Through one or a series of network (or sub-network) perturbations, wellness is driven toward altered nodal activity. Such nodal
modulation constitutes the at-risk state, and although preclinical, it typically provides systemic signatures, which can be discerned and quantitated, and
enable detection of dysregulation during a preclinical stage. Systems level wellness, disease prevention, and health, therefore, aim to characterize
specific nodal perturbations, some environmentally mediated, others rooted in the complexities of the intrinsic multidimensional networks only
revealed via the aforementioned perturbations.
Sources:: Fiandaca M. S., et al. Systems healthcare: a holistic paradigm for tomorrow. 2017.
Machine and Deep Learning, systems health and multi-omics technologies

Omics profiling and
revolutionize the way we acquire and process data. At their core, AI Data processing
algorithms dissect the data to learn their structure and associations
within, often without the need of specific knowledge on processes and
models that generated them. The strength of AI techniques is proportional
to the size and quality of the data amassed. At the same time, sequencing
and molecular technologies can generate a vast amount of high quality
data in an inexpensive, reproducible way and hence they allow an
unprecedented system-level view of any organism. These datasets, which
can come from a variety of sources, equipment and experimental settings,
are in their majority not ready to serve as training sets to computational
models, Machine and Deep Learning methods, as they have not been
created with that function in mind. As such, there is a clear need for
methods that process, normalize, integrate and transform the plethora of
heterogeneous multi-omics data to cohesive compendia that can be used
as a training grounds for further analysis and learning.
Machine and Deep Learning analytics has been applied in biology to deal
with the intrinsic complexity in omics data with a long history and its Predictive modelling and
Quality Assessment
integration in recent years. The high-level overview of the machine- analytics
learning analytic pipeline for integrated multiomics data consists of data
preprocessing, modeling, and active learning. Once a model is constructed Three major steps involved in AI-driven multi-omics: Data acquisition,
and evaluated, active learning guides what experiments to perform next to multi-omics integration and predictive modeling. An end-to-end
minimize uncertainty in the model. pipeline for multi-omics data as a source of biomarkers for health care,
biological age precise calculation and extension of lifespan.
Sources:: Minseung Kim, et al. Data integration and predictive modeling methods for multi-omics datasets. 2017.
Machine and Deep Learning analytics over integrated multi-omics data have the capacity to make far-reaching impacts across multiple industries. In
biomedical applications, finding therapeutic targets and biomarkers is one of the major issues in human health, and such efforts are being more and
more translated into the real world (e.g. BERG, Eagle Genomics). Antibiotic resistance is of paramount importance as it is considered a global threat
and machine learning methods can be applied for predicting antibiotic resistance from the molecular signature of clinical isolates to select effective
antibiotics. In food and nutrition science, optimizing nutrition treatment for individuals is enabled by machine learning over personal omics data
accompanied with dietary information.
One prominent example of applying deep learning comes from gaming. In 2016, the program AlphaGo beat the world champion Lee Sedol
in four out of five games of Go, a complex ancient Chinese board game. It was a huge victory for AI that came decades earlier than most
experts believed possible. AlphaGo was developed by DeepMind, a subsidiary of Google that focuses on AI. Instead of relying on explicit programming,
DeepMind applies general-purpose learning algorithms to large data set to make predictions. It is this type of advancement in machine learning that is
delivering on the promise of real-time diagnostics and revolutionizing the future of precision medicine. In the same year, the field of machine
learning changed significantly because most of the major information and communication technology (ICT) companies have made their deep learning
codes open source and available to anyone. Consequently, most major machine learning implementations are available for free to use and modify for
everybody. This means it is possible for all researchers to set up a simple machine intelligence with nothing more than a laptop and a web connection.
Already, there are over 50 different deep learning tool sets available and most are already open source.
As a key case study that cannot be omitted, some early approaches to merge epigenetics and deep learning exist already. One of them is DeepCpG,
which was designed to help scientists learn about the connections between genomic data and DNA methylation to make predictions about
DNA methylation in single cells. In particular, DeepCpG is trained to predict binary CpG methylation states from local DNA sequence windows and
observed neighboring methylation states. The trained DeepCpG model can be used for different downstream analyses, including imputation
low-coverage methylation profiles for sets of cells and discovery of DNA sequence motifs that are associated with methylation states and cell-to-cell
variability. The long-term goal of using deep learning algorithms is to predict the effect of epigenetic drift and epimutations on a cell’s
regulatory landscape and how this, in turn, affects disease development. And aging itself.
Sources:: Minseung Kim, et al. 2017. | Schumacher, A. 2018.

AI-driven Biomarkers and P4 Medicine
AI-Driven Precision AI-Driven Advanced Personalised Treatment AI-Driven Preventative

Biomarkers Prognostics Optimization Treatment
● Multi-Omic Sequencing ● AI-driven prognostics ● AI-driven in silico ● Maintenance state of

personalised treatment precision health through
● Continuous monitoring ● Advanced Biomarker-based optimization preventive medicine
powered by Big Data prognostics
Analytics ● AI-driven personalised in ● AI-based predictions of
● AI-driven predictive vivo drug optimization optimal drug combination
● Continuous monitoring of prognostics based on
health state based on personalized multi-omics ● Treatment optimization
changes in Biomarkers of based on patient genetics
aging

Key points:
● As the complexities of Longevity science and technology increase,
and as the volume of data continues to amass, the role of AI in both
analyzing and understanding becomes completely necessary for
continued progress and industry development
● While AI for Longevity is still an emerging and underrepresented
sector within the global Longevity Industry, its extreme disruptive
potential makes its eventual emergence as a core and integral area of
growth and development inevitable
● AI for Longevity will become one of the most impactful sectors within
the industry in the next several years, and make its potential to
accelerate the continue development of the industry apparent in
almost every sector, from Longevity R&D to therapeutic development,
P4 Medicine, biomarker discovery, and even non-biomedical sectors
such as the Longevity Financial Industry.
Awareness of the importance of utilising Artificial intelligence within

aging and longevity research is rapidly increasing in academia and
industry. Modern deep learning techniques used to develop age
predictors offer new possibilities for diverse data types. This will
enable a holistic view to identify novel biomarkers, but it will also
bring novel geroprotectors and will become the core of drug
discovery and healthcare in biotechnological, pharmaceutical and
health industries, integrating them like never before.

Selected Biomarkers by
Comprehensiveness Level
Selected Biomarker Panels List
1. Gait (Walking) Speed 27. Block Design Test 59. TNF-α
2. Timed Get Up and Go 28. Raven’s Progressive Matrices 60. IL-1
3. Chair Rising 29. Rey Auditory Verbal Learning Test 61. IL-6
4. Grip Strength 30. Benton Visual Retention Test 62. IL-10
5. Standing Balance 31. Adiponectin 63. IL-12
6. Purdue Pegboard Test 32. DHEAS:Cortisol Ratio 64. p16INK4a
7. Spirometry: Forced Expiratory Volume in 1 33. DHEAS 65. β-galactosidase
Second (FEV1) 34. Growth Hormone; IGF-1 66. Small Dense Low-Density Lipoprotein (sdLDL)
8. Bone Density, Bone Mass Hip: Dual X Ray 35. Leptin 67. High Density Lipoprotein (HDL)
Absorptiometry for Bone Health 36. Ghrelin 68. AGEs
9. Broadband Ultrasound Attenuation (BUA) at 37. Melatonin 69. NT-proBNP
Heel for Bone Health 38. Estrogens 70. γ-H2A.X
10. Computed Tomography for Bone Health 39. Somatostatin 71. Protein Carbamylation
11. Dual X Ray Absorptiometry for Estimated Leg 40. Testosterone 72. Mitochondrial DNA Copy Number
Muscle Mass 41. Thyroid Hormones 73. Cell-Free DNA
12. Bioelectrical Impedance Analysis for Muscle 42. B Cells 74. Telomere Length Aging Clock
Mass 43. CMV Seropositive 75. Biomarkers of Oxidative Stress
13. Computed Tomography for Muscle Mass 44. C-Reactive Protein 76. Gut Microbiome Transcriptome
14. Magnetic Resonance Imaging for Muscle Mass 45. Dendritic Cells
15. Body Potassium for Muscle Mass 46. Natural Killer Cells
16. Abdominal Fat; Waist Circumference 47. Neutrophils
17. Body Mass; Body Mass Index; Body Weight 48. Lymphocyte/Granulocyte ratio
18. Blood Pressure; Sphygmomanometry 49. Immune Risk Profile
19. Standard Lipid Profile: Total Cholesterol; LDL-C; 50. Telomere Length in Leukocytes
HDL-C; Triglycerides 51. T Cell Phenotype
20. Glycated haemoglobin (HbA1C) 52. CpGs Dinucleotides
21. Fasting Plasma Glucose 53. miR-34a
22. Verbal Fluency 54. miR-1, miR-133a, miR-499 and miR-208a
23. Digit-Symbol Coding 55. miR-137, miR-181c, miR-9, and miR-29a/b
24. Digit Span Backward 56. IFN-γ
25. Boston Naming Test 57. High-Sensitivity C-Reactive Protein (hs-CRP)
26. Stroop Task 58. Lipoxins
Biomarker Domains Classification Framework.
Biomarkers of Physical Function and Physiology. Complex changes affecting the structure and
function of cells, tissues and organ systems
are a hallmark of aging and can be detected
Biomarkers of by the third or fourth decade of life. These
Physical Function may translate, eventually, into functional loss,
chronic disease and finally death.
and Physiology
2
Body Composition.
Muscle mass: Bioelectrical Impedance
Analysis; Computed Tomography; Dual-energy
1 3 X-ray Absorptiometry; Magnetic Resonance
AGING Physiological
Imaging; Body Potassium.
BMI.
BIOMARKERS function
Body Weight.
Waist Circumference and abdominal fat.
Validated Biomarkers of aging would Bone Health.
allow for testing interventions to extend
Broadband Ultrasound Attenuation.
lifespan; effective lifespan would not be
Computed Tomography.
a practical means for long-lived species
6 such as humans because longitudinal 4 Dual-energy X-ray Absorptiometry.
All have been used extensively to measure
studies would take far too much time.
bone health.
Cardiovascular Function.
*Standard Lipid Profile.
5 Physical Blood Pressure.
*(Ideally: Advanced Lipoprotein Testing like
function VAP test).
Lung Function.
FEV1.
Glucose Metabolism.
HbA1C.
Fasting Glucose.
*(Ideally: Skin Autofluorescence Tests like
AGE-Reader mu ones).

Biomarkers of Physical Function and Physiology.
Biomarkers of
Physical Function
and Physiology
2
1 3
AGING Physiological
There is strong evidence supporting
the validity and reliability of these
BIOMARKERS function
measures, and their use in healthy
aging studies have key advantages.
Validated Biomarkers of aging would

lifespan; effective lifespan would not be Strength.
a practical means for long-lived species Grip Strength.
6 such as humans because longitudinal 4
Balance.
Standing Balance.
Dexterity.
Physical Purdue Pegboard Test.
5 Locomotor Function.
function Chair Rising.
Gait Speed.
Timed Get Up and Go.

Blood-based Biomarkers. Whilst the field of immunology is well developed, the study of
age-related decline in immunity, termed immunosenescence, is more
Blood-based recent. Susceptibility to both bacterial and viral pathogens, incidence
Biomarkers of cancer and loss of tolerance to one’s own tissues evidenced by
increased autoimmunity are clearly related to aging. Studies assessing
age-related immune and inflammatory function, including T-cell
2 phenotype, cytomegalovirus serostatus and pro-inflammatory cytokine
status (inflammaging), have been the basis for the development of the
Immune Risk Profile (IRP).
1 3
AGING IRP.
BIOMARKERS Defined by an inverted CD4/CD8 ratio and
associated with increased numbers of CD8 +
CD28 cells.
allow for testing interventions to extend Lymphocyte/Granulocyte ratio.
lifespan; effective lifespan would not be Neutrophils.
a practical means for long-lived species
6 such as humans because longitudinal
4 B Cells.
studies would take far too much time. NK Cells.
T Cells phenotype.
Dendritic Cells.
5 CMV serostatus.
CRP.
Telomere Length in Leukocytes.
Physiological Physical
function function

Blood-based Biomarkers.
Blood-based
Biomarkers Age-related changes in the endocrine system,
particularly among the sex hormones, are well
2 recognized and studies have established causal links
with health outcomes. For most of these Biomarkers,
there is strong consensual evidence that changes are
linked with risk of physical frailty and premature
1 3
AGING mortality, despite the non-linear relationship between
some Biomarkers and aging.
BIOMARKERS
lifespan; effective lifespan would not be Adiponectin.
6 a practical means for long-lived species
4 Ghrelin.
such as humans because longitudinal
studies would take far too much time. Leptin.
DHEAS.
DHEAS:Cortisol ratio.
5 Growth Hormone, IGF-1.
Estrogens.
Testosterone.
Somatostatin.
Melatonin.
Physiological Physical
Thyroid Hormones.
function function

Blood-based Biomarkers. Common theories of aging, where age linearly correlates with ROS, DNA
damage, mitochondrial dysfunction and shortening of the telomeres, are well
Blood-based established in humans. New approaches contemplate the role of epigenetics,
cellular senescence, inflammaging, genomic instability, translational
Biomarkers regulation and proteome changes. Taken together, very old humans
demonstrate a different picture of aging regarding the accumulation of DNA
2 damage, antioxidant defense capacity, genome instability and telomere
shortening by evidenced better DNA repair capacity and higher telomerase
activity.
1 3
AGING
BIOMARKERS
lifespan; effective lifespan would not be DNA Methylation.
a practical means for long-lived species CpGs dinucleotides.
4
Translational Regulation.
miR-34a.
miR-1, miR-133a, miR-499 and miR-208a.
miR-137, miR-181c, miR-9 and miR-29a/b.
5 Inflammaging.
IL-1β, IL-6, IL-10, IL-12.
TNF-α.
IFN-γ.
hs-CRP.
Lipoxins.
Cellular Senescence.
Physiological Physical β-galactosidase.
function function p16INK4a.

Blood-based Biomarkers. Common theories of aging, where age linearly correlates with ROS, DNA
damage, mitochondrial dysfunction and shortening of the telomeres, are well
Blood-based established in humans. New approaches contemplate the role of epigenetics,
cellular senescence, inflammaging, genomic instability, translational
Biomarkers regulation and proteome changes. Taken together, very old humans
demonstrate a different picture of aging regarding the accumulation of DNA
2 damage, antioxidant defense capacity, genome instability and telomere
shortening by evidenced better DNA repair capacity and higher telomerase
activity.
1 3
AGING
BIOMARKERS Proteome Changes.
HbA1C.
lifespan; effective lifespan would not be AGEs.
a practical means for long-lived species NT-proBNP.
4 DHEAS.
studies would take far too much time. γ-H2A.X.
Protein Carbamylation.
Lipoproteins.
sd-LDL (Advanced Lipoprotein Testing).
5 HDL (Advanced Lipoprotein Testing).
Genome Instability.
cfDNA.
mtDNAcn.
Telomere Length Aging Clock.
Biomarkers of Oxidative Stress.
Physiological Physical Gut Microbiome Aging Clock.
function function Gut Microbiome Transcriptome.

Cognitive Biomarkers.
Cognitive
Biomarkers
2 Executive Function.
Verbal Fluency.
1 3 Processing Speed.
AGING Digit-Symbol Coding.
Working Memory.
BIOMARKERS Digit Span Backward.
Crystallized Ability.
Boston Naming Test.
lifespan; effective lifespan would not be Cognitive Attention.
6 a practical means for long-lived species
such as humans because longitudinal 4 Function Stroop Task.
studies would take far too much time. Non-Verbal Reasoning.
Raven's Progressive Matrices.
Visual Memory and
5 Cognitive decline is a well documented Visuospatial Ability.
process common to old age. Structural and
function changes in the brain correlate with
Benton Visual Retention Test
cognitive decline, including alterations in and Block Design Test.
neuronal structure, neuronal loss, loss of Verbal Memory &
synapses, and dysfunction of neuronal
networks. Age-related diseases are directly Learning
connected with these processes since they Rey Auditory Verbal
Physiological Physical increase the rates of changes at brain level. Learning Test.
function function

Minimum Required Biomarkers List
1. Gait (Walking) Speed 21. Fasting Plasma Glucose

2. Timed Get Up and Go 22. Verbal Fluency
3. Chair Rising 23. Digit-Symbol Coding
4. Grip Strength 24. Digit Span Backward
5. Standing Balance 25. Boston Naming Test
6. Purdue Pegboard Test 26. Stroop Task
7. Spirometry: Forced Expiratory Volume in 1 Second (FEV1) 27. Block Design Test
8. Bone Density, Bone Mass Hip: Dual X Ray Absorptiometry for 28. Raven’s Progressive Matrices
Bone Health 29. Rey Auditory Verbal Learning Test
9. Broadband Ultrasound Attenuation (BUA) at Heel for Bone 30. Benton Visual Retention Test
Health 31. Adiponectin
10. Computed Tomography for Bone Health 32. DHEAS:Cortisol Ratio
11. Dual X Ray Absorptiometry for Estimated Leg Muscle Mass 33. DHEAS
12. Bioelectrical Impedance Analysis for Muscle Mass 34. Growth Hormone; IGF-1
13. Computed Tomography for Muscle Mass 35. Leptin
14. Magnetic Resonance Imaging for Muscle Mass 36. Ghrelin
15. Body Potassium for Muscle Mass 37. Melatonin
16. Abdominal Fat; Waist Circumference 38. Estrogens
17. Body Mass; Body Mass Index; Body Weight 39. Somatostatin
18. Blood Pressure; Sphygmomanometry 40. Testosterone
19. Standard Lipid Profile: Total Cholesterol; LDL-C; HDL-C; 41. Thyroid Hormones
Triglycerides 42. C-Reactive Protein
20. Glycated haemoglobin (HbA1C) 43. Neutrophils

Most Comprehensive Biomarkers List
1. B Cells 18. IL-6

2. CMV Seropositive 19. IL-10
3. Dendritic Cells 20. IL-12
4. Natural Killer Cells 21. p16INK4a
5. Lymphocyte/Granulocyte ratio 22. β-galactosidase
6. Immune Risk Profile 23. Small Dense Low-Density Lipoprotein (sdLDL)
7. Telomere Length in Leukocytes 24. High Density Lipoprotein (HDL)
8. T Cell Phenotype 25. AGEs
9. CpGs Dinucleotides 26. NT-proBNP
10. miR-34a 27. γ-H2A.X
11. miR-1, miR-133a, miR-499 and miR-208a 28. Protein Carbamylation
12. miR-137, miR-181c, miR-9, and miR-29a/b 29. Mitochondrial DNA Copy Number
13. IFN-γ 30. Cell-Free DNA
14. High-Sensitivity C-Reactive Protein (hs-CRP) 31. Telomere Length Aging Clock
15. Lipoxins 32. Biomarkers of Oxidative Stress
16. TNF-α 33. Gut Microbiome Transcriptome
17. IL-1

Age-Related Diseases and Molecular Links Oxidized proteins Age-Related Disease
Lipid peroxidation
with Root Causes of Aging. IL-1β, IL-6, IL-12, IL-18, TNF-α, TGFβ, IFN-γ
8-hydroxyguanosine Alzheimer’s disease
1 8-hydroxy-2’-deoxyguanosine
20S core reduced activity
The longstanding question if old age is itself a disease has p21CIP1/WAF1 Senescent cells
been addressed since ancient times, starting from the p16INK4A Senescent cells Parkinson’s disease
Activation of pro-inflammatory cytokines
Roman playwright Terentius, who claimed senectus ipsa est β-galactosidase activity Increased intestinal permeability Activation of pro-
morbus, "old age itself is a disease", and Cicero who some SASP inflammatory cytokines
decades later argued in De Senectute pugnandum, tamquam IL-1β, IL-6, IL-18 Cancer
contra morbum sic contra senectutem, "we have to fight Inflammatory cells (astrocytes)
Chemokines (CXCL8 and CCL2) Mitochondrial dysfunction Increased intestinal permeability
against aging, as we do against a disease". These quotations 2 Metalloproteinases Serotonin system alteration
elegantly summarize a long-held view of aging and old age
Stress markers such as Inflammation Chronic Obstructive
addressed by several scholars. 1
Parkin, and Phosphatase and Oxidative stress Pulmonary disease
Notwithstanding, with the birth of modern medicine in the tensin homolog-induced Autophagy
nineteenth century, this discussion suddenly ended up in protein kinase 1 dysregulation
Cellular senescence
considering aging and diseases as separate phenomena. 2 Maculophaty
Stem cell IL-6
Age-Related Diseases, Geriatric Syndromes and Aging itself exhaustion Senescent cells
Inflammasome activation
are not separate entities, both should be considered as Loss of proteostasis
Abs vs self-epitopes 3
parts of a continuum and, to support this hypothesis, we at Decreased Periodontitis
Heat shock proteins
Aging Analytics Agency highlight the meeting points proteasome activity
NT-proBNP, hsTnT, IL-6, IL-15
between these phenomena and the need to focus on their
basic and shared molecular and cellular mechanisms.
Aging Protein aggregation Apolipoprotein B, Apolipoprotein C-III
Soluble receptor for AGE Cardiovascular diseases
Dysregulated
Advanced glycation and Diabetes
nutrients sensing Cell disruption end-products (AGEs)
Pro-inflammatory cytokines
Osteopontin, Osteoprotegerin
Porphyromonas gingivalis Matrix metalloproteinase 3
Cell death
To establish the links between these basic mechanisms express peptidylarginine Angiopoietin 2, Chromogranin A Rheumatoid arthritis
deiminase generating NLRP3 activation LDL, sdLDL
shared by Aging, Age-Related Diseases and Geriatric
citrullinated epitopes Telomere HbA1C, Blood glucose
Syndromes, international experts identified nine pillars or
shortening Growth/differentiation factor 15
root-causes which actually include adaptation to stress, Sarcopenia
Lipofuscinogenesis Hepatocyte growth factor receptor
loss of proteostasis, stem cell exhaustion, metabolism Glutathione S transferase α
IL-6 PI3 kinase-mTOR
derangement, macromolecular damage, inflammation, α-2-Macroglobulin
signal activation
epigenetic modifications and senescence, among others. TNF-α Trefoil factor 3
Many chronic diseases and pathological conditions, some IL-1β, IL-6 Osteopenia and Osteoporosis
CRP Gut microbiota alterations HGMB1, TNF-α
of which are considered here, are at least in part determined
by (some of) these root-causes or shared mechanisms. Inflammatory markers Matrix metalloproteinases
3 Abs vs modified 4 Osteoarthritis
self-epitopes
IL-8
IL-1
HGMB1
4 IL-6 5
HGMB2
TNF-α
CRP
Biomarkers 5 Mechanisms shared with Aging Process

The Increasing Role of Digital Biomarkers
The continuous monitoring of small changes in health, and the continuous and commensurate micro-adjustment of treatments in response, requires an
agreed panel of biomarkers. Biomarkers are typically classified as molecules which have properties that allow them to be measured in biological
samples in clinical settings. But what if we measure people's health outside the clinic with the help of everyday devices such as a phone?
Thanks to advances in digital technology we now have access to a whole new form of measurable indicator: Digital Biomarkers. Digital Biomarkers
are like any other biomarker, but measured through gadgets.
Now we have access to a whole new form of measurable indicator:

Digital Biomarkers.
We can measure people's health outside the clinic with the help of everyday devices such as a phone. Digital biomarkers are defined as objective,
quantifiable physiological and behavioral data that are collected and measured by means of digital devices such as portables, wearables, sensors,
implantables and digestible devices.
"Digital" expresses the data collection methodology as using sensors and computational tools, and across multiple layers of hardware and software.
This data can be used not only to confirm the presence of any kind of disease but to predict and, moreover, prevent all possible pathologies.
A currently in development Digital Biomarker of aging that also use Deep Learning-driven analysis, for instance, involve the aggregation of photographs
continuously taken to mice under the MouseAGE Project; these images associate behavior and other traits with a biological age endpoint. These also
can be quite easily extended to humans and similar developments are taking place, involving algorithms designed to operate from mobile phone
applications or wearable devices. The precision of this electronic devices alone is still not enough to make these implementations a research priority,
but the increasing video capabilities of smart-phones means that the accelerated developments in Digital Imaging Biomarkers (e.g., for the face or eye,
collecting data about ocular or neurological diseases) may be implemented sooner rather than later.

The Increasing Role of Digital Biomarkers
Quantified in ones and zeros, the Digital Biomarkers or their related Digital Panel Platforms can support continuous measurements outside the physical
confines of the clinical or the hospital environment, using home-based connected products. These products have created new opportunities, enabling
remote monitoring for biomedical research, decentralized clinical trial designs, and routine patient care. These are components already well integrated
into the market, but still waiting to be used to good advantage by the world's health systems.
Nowadays Digital Biomarkers are widely studied in order to reveal the broad spectrum of possible uses, and to revolutionize current methods of patient
health state monitoring and disease outcomes prediction. According to Digital Biomarkers Journal, a multidisciplinary-by-design open access journal
that bridges the disciplines of computer science, engineering, biomedicine, regulatory science and informatics, Digital Biomarkers represent an
opportunity to capture clinically meaningful, objective data.
Digital Biomarkers could be the breakthrough bioscience has been waiting for, which is why not only individuals and health care providers but also
many companies have grabbed the opportunity with both hands. Breathometer, Xsensio, Scailyte AG, Nightingale Health, FEET ME, xbird, Mindstrong
Health, Serimmune, IXICO, etc., are top private companies that successfully carry out the mission of Digital Biomarker popularization. They are known
for the development of unique sensing platforms and chips, human liquid testing systems, devices for health monitoring, single-cell profiling devices,
and providing unique information that fuels development of new diagnostics, vaccines, and therapeutics. All of these enable novel approaches for
preventing and treating a great many diseases; not only pathologies and conditions of aging, but the vast majority associated without any doubt with
age and Longevity.
Digital Biomarkers span a broad range of preventive, diagnostic and prognostic measurements, with opportunities and challenges associated with their
use. Some Biomarkers are immediately familiar to patients or physicians as they are digitized versions of well-established metrics—for example,
glucometer readings transmitted by Bluetooth, or the timed six-minute walk test measured with the smartphone’s built-in gyroscope and accelerometer.
Others, such as the smartphone-derived tapping test for Parkinson’s disease severity, are entirely novel and evolving. They are able to detect eye
diseases from scans as accurately as experts, or to predict patient deterioration up to 48 hours earlier than currently possible, developments carried
out by DeepMind Technologies, now belonging to Alphabet. Also, Digital Biomarkers can be components in autoregulated closed loop systems; for
instance, a continuous glucose sensor linked to an insulin pump in a pancreas can automatically dose or micro-dose insulin in patients with diabetes.

Developing and adopting safe and effective digital
biomarkers to improve patient outcomes.
Category (a) Definition (a) Example (a) Corresponding Digital Biomarker Examples
[*] Detect cognitive changes in healthy subjects at risk of developing Alzheimer's

disease using a video game platform.
Source: Gold, M. et al. Digital technologies as biomarkers, clinical outcomes assessment, and
A biomarker that recruitment tools in Alzheimer's disease clinical trials. Alzheimers Dement. 4, 234–242 (2018).
Breast Cancer genes 1 and 2
indicates the potential for
developing a disease or
(BRCA1/2) mutations may be [**] Classify adults at high risk of late-onset Alzheimer's disease using computerized
used as a susceptibility/risk cognitive testing.
Susceptibility/Risk medical condition in an
biomarker to identify Source: Ritchie, K. et al. The midlife cognitive profiles of adults at high risk of late-onset Alzheimer's
Biomarker individual who does not
individuals with a disease: the PREVENT study. Alzheimers Dement. 13, 1089–1097 (2017).
currently have clinically
predisposition to develop
apparent disease or the [*] Reduce key risk metrics for anterior cruciate ligament injury during jump landings
breast cancer.
medical condition. using inertial sensor-based feedback.
Source: Dowling, A. V., Favre, J. & Andriacchi, T. P. Inertial sensor-based feedback can reduce key
risk metrics for anterior cruciate ligament injury during jump landings. Am. J. Sports Med. 40,
1075–1083 (2012).
[*] Diagnose ADHD in children using eye vergence metrics.

Source: Varela Casal, P. et al. Clinical validation of eye vergence as an objective marker for
diagnosis of ADHD in children. J. Atten. Disord.
[*] Detect arrhythmias using convolutional neural networks and a wearable single-lead
Repeated blood pressure
A biomarker used to heart monitor.
readings obtained outside the
detect or confirm the Source: Rajpurkar, P., Hannun, A., Masoumeh, H., Bourn, C. & Ng, A. Cardiologist-level arrhythmia
clinical setting in adults 18
Diagnostic presence of a disease or detection with convolutional neural networks. arXiv preprint arXiv:1707.01836
years and older may be used
Biomarker condition of interest or to
as a diagnostic biomarker to [*] Detect depression and Parkinson’s disease using vocal biomarkers.
identify individuals with a
identify those with essential Source: Gosh, S. S. & Ciccarelli, G. Speaking one's mind: vocal biomarkers of depression and
subtype of the disease.
hypertension. Parkinson disease. J. Acoust. Soc. Am. 139, 2193 (2016).
[*] Diagnose asthma and respiratory infections using smartphone-recorded cough
sounds.
Source: RespApp. Diagnosing Respiratory Disease in Children Using Cough Sounds 2
(SMARTCOUGH-C-2).

[**] Monitor signs of Parkinson's disease using smartphone-based measurements.

Source: Sage Bionetworks. Sage Bionetworks in Collaboration with The Michael J. Fox Foundation
Announce Winners in the DREAM Parkinson’s Disease Digital Biomarker Challenge.
[*] Quantify Parkinson’s disease severity using smartphones and machine learning.
Source: Zhan, A. et al. Using smartphones and machine learning to quantify Parkinson disease
severity: the mobile Parkinson disease score. JAMA Neurol. 75, 876–880 (2018).
A biomarker measured
serially for assessing the [**] Track time and location of short-acting beta-agonist inhaler use using an attached
Prostate-specific antigen (PSA) wireless sensor.
status of a disease or
may be used as a monitoring Source: Barrett, M. A. et al. Effect of a mobile health, sensor-driven asthma management platform
Monitoring medical condition or for
biomarker when assessing on asthma control. Ann. Allergy Asthma Immunol. 119, 415–421 (2017).
Biomarker evidence of exposure to
disease status or burden in
(or effect of) a medical
patients with prostate cancer. [*] Predicting sleep/wake patterns from a 3-axis home-based accelerometer using
product or an
environmental agent.
deep learning.
Source: Wolz, R., Munro, J., Guerrero, R., Hill, D. L. & Dauvilliers, Y. Predicting sleep/wake patterns
from 3-axis accelerometry using deep learning. Alzheimer Dement. 13, P1012 (2017).
[*] Detection of nocturnal scratching movements in patients with atopic dermatitis

using accelerometers and recurrent neural networks.
Source: Moreau, A. et al. Detection of nocturnal scratching movements in patients with atopic
dermatitis using accelerometers and recurrent neural networks. IEEE J. Biomed. Health Inform. 22,
1011–1018 (2018).
A biomarker used to Increasing prostate-specific Stratify mental health conditions and predict remission using passively collected
identify the likelihood of a antigen (PSA) may be used as smartphone data.
clinical event, disease a prognostic biomarker when Source: Mindstrong Health. Mindstrong Health and Takeda Partner to Explore Development of
Prognostic recurrence, or evaluating patients with Digital Biomarkers for Mental Health Conditions (2018)
Biomarker progression in patients prostate cancer during
who have the disease or follow-up, to assess the Detect post-acute care deterioration in patients at home, applying machine learning to
medical condition of likelihood of cancer multi-sensor digital ambulatory monitoring.
interest. progression. Source: physIQ (http://www.physiq.com/resources/)

A biomarker used to Predict autism risk in the siblings of children with autism, using an EEG biomarker.
Human leukocyte antigen allele
identify individuals who Source: Bosl, W. J., Tager-Flusberg, H. & Nelson, C. A. EEG analytics for early detection of autism
(HLA)–B*5701 genotype may
are more likely than spectrum disorder: a data-driven approach. Sci. Rep. 8, 6828 (2018).
be used as a predictive
similar individuals without
biomarker to evaluate human
Predictive the biomarker to
immunodeficiency virus (HIV)
Biomarker experience a favorable or
patients before abacavir Detect asymptomatic atrial fibrillation (AF) as a stroke risk factor, remotely through a
unfavorable effect from
treatment, to identify patients connected device.
exposure to a medical
at risk for severe skin Source: Halcox, J. P. J. et al. Assessment of remote heart rhythm sampling using the AliveCor
product or an
reactions. Heart Monitor to screen for atrial fibrillation: The REHEARSE-AF Study. Circulation 136,
environmental agent.
1784–1794(2017).
Measure cognitive performance with the Cambridge Neuropsychological Test

A biomarker used to show Blood pressure may be used as Automated Battery (CANTAB) to test the effects of erythropoietin.
that a biological response a pharmacodynamic/response Source: Kessing, L. V. Effects of Erythropoietin on Cognition and Neural Activity in Bipolar Disorder
Pharmacodynamic has occurred in an biomarker when evaluating (PRETEC-EPO). https://clinicaltrials.gov/ct2/show/NCT03315897 (2017).
/Response individual who has been patients with hypertension, to
Biomarker exposed to a medical assess response to an Measure blood pressure using a digital sphygmomanometer to assess response to
product or an antihypertensive agent or antihypertensive therapy.
environmental agent. sodium restriction. Source: Padwal, R. S. Validation of the Omron HEM-9210T by the ANSI/AAMI/ISO 81060-2 with two
novel cuffs: wide range and extra-large. Blood Press Monit. 22, 379 (2017).
(a) Selected from the FDA-NIH “Biomarkers, EndpointS, and other Tools” (BEST) classification for traditional biomarkers
[*] Digital biomarker under development
[**] Digital biomarker in use (in a clinical trial or an FDA cleared/approved digital health product, or a digital health app in use not requiring approval)
Sources Coravos A., et al. Developing and adopting safe and effective digital biomarkers to improve patient outcomes. 2019.
83
Digital Biomarkers, Pharma Industry, Translational Medicine and P4 Medicine.
Digital Biomarkers could potentially reorganize the whole pharma industry and become an integral part of the drug development process. Due to the
sensitivity and precision they provide, digital biomarkers can be used to improve clinical trials of drugs. While testing a treatment, finding the
appropriate dosage, and looking for side effects, this new form of indicator reveals a drug's efficacy and toxicity for individual patients.
In 2017 the Digital Biomarkers Journal provided a deep analysis of the modern pharmaceutical business model and how it implements digital
biomarkers. According to the article, in the case of some illnesses, Digital Biomarkers can improve the understanding of the natural history of a disease
through more continuous measurement of objective health data. Such information may become priceless in situations where symptom presence and
severity is more variable and disease prevention and treatment necessitates a more individualized approach to each patient.
As Digital Biomarkers are increasingly used as endpoints in drug discovery and development, translational research and clinical trials, we anticipate that
clinicians will have a growing number of validated means of gathering deep insights on patients health status remotely. Digital Biomarkers allow deep
collection of data on individual trial participants as well as patients in clinical settings, thereby providing an opportunity for “N of 1” clinical
investigations, the cornerstone of evidence generation for personalization of care. And with more data, an algorithm’s accuracy improves. This strong
feedback between massive amounts of data and improvement of interpretive algorithms is sufficient to consider that the amplitude levels of the Digital
Biomarkers and the Digital Panel Platforms are much higher than those of conventional biomarkers and panels - and will be even more, as the latter join
one by one to this emerging system, establishing a new paradigm of daily overall health assessment. This will trigger excessive accuracy in the
measurement of biomarkers; process that is already underway and can be seen in multiple market-ready products, such as the AgeMeter, developed by
Centers for Age Control, a functional or biological age test system using digital health inputs for improve personalized health parameters.
Availability of contextual information will enable more precise personalized algorithms, as a blood pressure fluctuation algorithm designed for a
population with a late-stage cardiovascular disease, and also providing opportunities to combine data sources to create novel measures for conditions
that have historically struggled to have meaningful endpoints, as the brain and nervous system disorders. Nevertheless, validation of digital biomarkers
require a uniquely collaborative effort, with translational science, engineering, data science and health information technology functions tightly
coordinated as a highly integrated multidisciplinary unit.

Digital Biomarkers, Pharma Industry, Translational Medicine and P4 Medicine.
As previously stated, there are many Personalization and precision of diagnostics,

examples of Digital Biomarkers in use or prognostics and treatment for individual patients
actively under development today, as well as
computational algorithms with potential for
development into Digital Biomarkers. The
Access to advanced preventive
time is now to give forethought to strong 01 restorative medicine technologies
incentive structures to promote the safe and
effective use of Digital Biomarkers. The ● Safe testing of novel therapies on
verification and validation of a Digital individual`s stem cells, skin and
Biomarker should be not construed as a other organs
one-time process, but rather, a learning

digital health system should continuously
collect data and handle modifications and 02 Personalized Longevity programs
updates over time.
Industry, researchers, policy regulators, ● Personalised diagnostics,

prognostics and therapeutics
clinicians, and patients have a joint ● Virtual human body for health
responsibility to design such a learning monitoring
system that can improve Digital Biomarker
products, empower patients, and improve 03 Health management by
world leading experts
global health and healthcare delivery for
everyone. That is the challenge, and the Healthy lifespan extension and ageing ● Continuous health monitoring by
opportunity. processes reversal to a young state the world leading experts
Sources: Coravos A., et al. Developing and adopting safe and effective digital biomarkers to improve patient outcomes. 2019.
85
Preventive Treatment
This eclectic range of biotechnologies owe their

“preventive medicine” status to the fact that each
can be applied (and micro-adjusted) in response
to continuous monitoring of Biomarkers. Early pre-symptomatic preventive intervention
In order to achieve an optimal panel of aging
Biomarkers for precision prevention, diagnosis, ● Natural mimetics of
● Gene therapies
treatment and prognosis, data must be taken validated geroprotectors
using multiple health variables from people who ● Cell therapies (e.g. metformin, rapamycin)
are not currently patients. This is an almost ● Tissue engineering ● Genetically engineered
entirely impractical task to do manually; ● Small molecules cell therapies
automated platforms have already loaded the and biologics ● 3D bioprinting
future, they will be the environment of the massive
● Microbiome engineering
and deep data flow; artificial intelligence is
revealing the fine reticular patterns that will give
sense and actionability to that future; frontier
technology and treatments, awaiting for clinical
validation but almost market-ready, are the skilled
and precise hand that will deliver radical
prolongation of health and wellness to the
societies of the next decade and the economies
that guide their efforts to remain competitive and
at the forefront of the next Biggest and Most
Complex industry in human history.

Digital Avatar - Virtual You
A virtual profile of all health data can be generated through collection of multiple types
What is an Avatar? of data, some of which are visualised also in 3D through devices or augmented reality.
Biomarkers serve not only to diagnose issues, but also to evaluate overall health status
An avatar is a graphic representation that is associated
and predict aging rates of each individual. Gathering more of this type of data e.g.
with a user to serve as their identification. Avatars can
periodic blood tests, will enable a complex, highly personal picture of each person,
be a picture, artistic drawing, or a three dimensional
whose predictive power will be proportional to the quantities of input classes and the
representation. With the advent of the digital revolution,
intrinsic capabilities of the AI-driven analysis aimed at recreating biomarker networks.
its use has spread to a large number of fields including
The added accuracy and size of the data sets means it will inevitably provide an
medicine. Currently, the digital avatar is being used in
invaluable source for AI to pick out key trends for each kind of patient cohort, or indeed
medical education such as for training models using
work out the cohorts itself.
augmented reality in order to explain anatomy to
students with a three-dimensional human body. Despite being a trove of knowledge for health practitioners and researchers, individuals
will still be the sole proprietors of their own health data, allowing them to control who
A good example for its usefulness within the context of
sees what, and how this data is used for various monetisation purposes. This is enabled
health is the projection of the effects of tobacco in a
by blockchain storage of patient data. In addition to biomarkers, all other types of data
patient who is a smoker, which allows us to visualize
relevant to healthcare will be integrated into the digital avatar. Health records,
their body within 5 years and analyze the consequences
medication, lifestyle will be fed into the profile. The ability to process patient data on a
to their health in the near future if they continue to
bigger scale compared to traditional medicine enables truly personalised
smoke. The challenge is keeping in mind the quantity of
healthcare, and removes the difficulties of identifying individual patient backgrounds
information that exists regarding pathological
and needs, that doctors may fail to obtain in time. With the technologies of healthcare
conditions and the consequences. How can we motivate
advancing, the digital avatar will evolve from a data collection and disease focused tool
people to adopt good habits? The digital avatar in health
to a truly longevity focused tool. Instead of looking at unidimensional, disease-linked
allows us to plan a path and observe the body of a
biomarkers, it will be able to look at the whole organism in an overarching health point of
patient in alternate scenarios.
view, and focus mainly on prevention and extending patient healthspan.
Sources: Digital Health. Fundación Innovación Bankinter.

87
The Anatomy and Evaluation of Digital Biomarkers
Measurements Verification
An input layer such as a camera, Analytical verification uses engineering
microphone, or sensor captures a digital bench tests to ensure that the product is
biomarker signal. For example, measuring and storing values accurately by
photoplethysmographs measure blood confirming the tool’s accuracy, precision, and
volume changes in the microvasculature reliability. Confidence in the performance of
using an optical sensor placed on the skin digital biomarkers is an important
surface. A signal processing layer, typically consideration for researchers, clinicians, and
an algorithm, converts the input signal into patients. For example, the verification step
actionable metrics (e.g., oxygen saturation ensures that the translation from raw data,
and/or heart rate), or digital biomarkers. e.g., that a heart rate sensor measuring
Although measuring blood volume changes electrical potential in millivolts, faithfully
using photoplethysmography is widely converts that signal into an accurate heart
accepted in medical practice, the interplay rate, expressed in beats per unit of time.
among hardware, sensors, and algorithms
can make the evaluation of emerging digital
biomarkers difficult. There are several Validation
challenges in deciding not only whether a
As with diagnostics, the performance of digital biomarker algorithms may vary across different
digital biomarker is valid, but equally
patient populations, producing different rates of false-positive or false-negative outputs in
important, whether it is “fit-for-purpose”,
different groups. Validation addresses whether the measurement is applicable in the target
meaning that the product has an explicit
population and context of use,6 which would render digital biomarker “fit for purpose”. For
context of use, meets appropriate
example, a tool measuring sleep and waking periods perform against polysomnography may
requirements for accuracy and precision,
perform differently in a patient population with insomnia versus sleep apnea versus healthy
and is accompanied by the metadata needed
volunteers.
for analysis and interpretation.
Sources: Andrea Coravos, et al. Developing and adopting safe and effective digital biomarkers to improve patient outcomes. 2019.
88
Biomarkers of
Physical Function and Physiology
Biomarkers of Physical Function Domain Overview
Measures of physical capability, that is, a person’s ability to perform the physical tasks of everyday living, are useful markers of current and future
health. Poor performance in tests of grip strength, walking speed, chair rise time and standing balance, and so on, are associated with higher mortality
rates. In addition, lower levels of physical capability are associated with higher risk of cardiovascular disease (CVD), dementia, institutionalisation and
difficulties performing activities of daily living (ADLs). Locomotor function, strength, balance and dexterity, are considered to capture underlying
functions that are used most commonly as objective measures of physical capability in longitudinal studies.
Objective, standardised tests of physical capability have been developed and are used increasingly in population-based studies. These objective
measures complement self-reports, improve validity and reproducibility, capture change over time, and may reduce the influence of cognitive function,
culture, language and education that can affect self-reported assessments and so limit comparability across studies. From the perspective of healthy
ageing, these objective tests have two key advantages. Firstly they enable the study of variation in functioning across the full spectrum. Secondly, they
facilitate identification of those people performing best who cannot be distinguished by self-reported measures which aim to identify people who have
difficulty in performing the tasks of everyday living.
There is considerable variability in the protocols of assessment for these measures, but attempts at standardisation across studies are now being
made through initiatives such as the NIH toolbox [intro]. All tests of physical capability are relatively quick, easy and inexpensive to perform with only
grip strength and the pegboard test requiring special instruments. An exception is the use of an accelerometer to measure swaying during balance
tests which is recommended by the NIH toolbox. There is strong evidence supporting the validity and reliability of these measures.
However, all the physical capability tests have exclusion criteria and an important consideration, not well addressed in the literature, is how to handle
the increasing proportion of people unable to perform these tests at older ages. Grip strength is the most comprehensively studied physical capability
test. Longitudinal studies show that grip strength peaks in the late thirties for both sexes, while longitudinal and cross-sectional studies show declines
in both sexes from the fifties and sixties. At all ages, grip strength is higher in men than women and there is some evidence for faster decline in men
than in women.
Sources: Jose Lara, et al. A proposed panel of biomarkers of healthy ageing. 2015.
90
Measures of physical Risks and threats
capability
Disadvantages
Poor
Higher mortality rates
performance
Grip strength
Cardiovascular disease
Increasing proportion of people
Walking speed Considerable variability in the
unable to perform these tests at
Dementia protocols of assessment
older ages
Chair rise time
Institutionalisation and
difficulties performing
Standing balance
activities of daily living Facilitate identification of those people performing best who
(ADLs) cannot be distinguished by self-reported measures
Types of measures of
physical capability Validity and
reproducibility
improvement 2 Key
Locomotor function 2 Key
Advanta
Advantages
Self-reports Capturing changes over ges
Strength time
Balance Reducing the influence

Enable the study of variation in
of cognitive function,
functioning across the full
Dexterity culture, language and
spectrum
education

Evidence for age-related change in other measures of physical capability is more limited
Higher mortality rates prediction
because it is restricted largely to cross-sectional data from relatively small studies.
However this limited evidence is consistent in suggesting that physical capabilities
decline progressively in later life and that men perform better than women at all ages. Weaker grip strength
A systematic review has shown that weaker grip strength, slower walking speed, longer Slower walking speed
chair rise time and poorer standing balance performance are associated with higher
mortality rates, independent of age in older community-dwelling populations.
Longer chair rise
Meta-analyses of data from several American studies of older people have also revealed
a strong association between slower walking speed and higher mortality rates. More
Poorer standing balance performance
recent studies indicate that, in addition to grip strength and walking speed, standing
balance and chair rise speed in middle age predict mortality rates over 13 years of
follow-up.
In another recent systematic review, weaker grip strength was found to be associated Weaker grip strength was found to be
with functional decline as assessed by self-reported difficulties performing activities of associated with functional decline as
daily living (ADLs). Three other systematic reviews evaluating risk for subsequent assessed by self-reported difficulties
disability (assessed using ADLs) showed that older adults performing poorly in tests of performing activities of daily living (ADLs)
physical capability are more likely to become disabled.
There is also some evidence that poorer performance in grip strength, walking speed, Older adults performing poorly in tests of
chair rise times and standing balance, is associated with higher risk for cardiovascular physical capability are more likely to become
disease (CVD), dementia and institutionalisation (as a marker of loss of independence), disabled
but none of these associations has been studied sufficiently often to allow definitive
conclusions to be drawn.

Weaknesses in the Physical Function Biomarker Domain
Recent work suggests that there is added value, for the prediction of mortality, Physical Well-being and Exercise Effects
in assessing different measures of physical capability in midlife. However,
there is currently insufficient evidence, from the perspective of studying Genomic instability Telomere attrition
healthy aging, to establish the added value of assessing any one additional ↑ Systemic antioxidant
specific measure, if other measures have been assessed already, to defense and DNA repair ↑ Telomerase activity; TERT
activity and expression;
recommend an order of priority for these measures or to define with
↓ DNA and mtDNA damage Shelterin complex
confidence the minimum number of measures that should be made across the
full range of older ages and for different research questions. Some studies
consider each measure of physical capability separately, and some have used Epigenetic alteration Loss of Proteostasis
a set of tests of several aspects of physical capability interpreted as a total
↑ Histone PTMs (HATs, Induces autophagy in brain,
performance score, such as the short physical performance battery (SPPB) or HDACs, jmjC, LSD); miRNA hearth, skeletal muscle,
the index of physical fitness age. Further work should establish whether regulation (e.g. miR-33, 1, liver, pancreatic β cells and
deriving an overall score of physical capability is of greater predictive value 133a, 499-5p, 208a, 126) adipose tissue through
than considering each measure separately and the most appropriate approach several mechanisms (IGF-1,
AKT/mTOR, beclin1) and
is likely to depend on the specific research question being addressed. Deregulated nutrient sensing modulates ubiquitin-
proteasome system
↑ mTOR; AMPK; SIRT; Glut 4;
There is a need for more studies with longitudinal data on change in physical Testosterone; GH; IGF-1
capability, and a need to assess physical capability in relation to other positive
Mitochondrial dysfunction
aspects of health, such as quality of life, that may be important criteria for
Cellular senescence
healthy aging. Significant variability in the protocols used to assess any one ↑ PGC-1; SIRT; Antioxidant
measure of physical capability makes comparisons between, and combination ↑ NK-Cell activity; defense; mtDNA shifting
of findings from, different studies difficult. In addition, few studies have Antigen-presentation
compared formally the different measures of physical capability and, as with Stem cell exhaustion
Altered intercellular
measures of cognitive function, performance in any one measure of physical communication Stimulates proliferation and
capability is likely to be correlated with performance in other such measures.
↑ IL-4, 6, 10, 13, 1β; AUF1 migration of stem cells

Weaknesses in the Physical Function Biomarker Domain
There is also a need for larger longitudinal Physical Well-being and Exercise Effects
studies in which these age-related
patterns, as well as variations in Lung Function Brain Function
within-individual changes over time, can be
investigated further. Declines in mean ↑ Neurogenesis
↑ Ventilation;
levels of physical capability at the Gas exchange ↓ Neurodegeneration;
population level hide substantial Cognitive alterations
inter-individual variation in rate of decline.
For example, being able to identify people Muscle Function Cardiovascular Function
who maintain, or improve, their physical
capability despite increasing age will be ↑ Regional blood flow; Blood volume;
↑ Muscle strength/power; Muscle Body fluid regulation; Endothelial
important when studying healthy aging. endurance; Muscle quality; Balance function; Autonomic function; Vagal
More research is also needed on the utility and mobility; Motor performance and tone and HRV; Cardiac pre conditioning
of some measures such as dexterity control; Flexibility and joint ROM;
Oxygen arterio-venous difference
performance in the pegboard test ↓ Blood Pressure
(dexterity), which has been understudied;
this in addition to the aforementioned Body Composition Metabolism
dearth of evidence on the associations of
physical capability with measures of ↑ Fat-free mass; Muscle mass; Bone
density
positive aspects of health that may be ↑ Resting metabolic rate; Muscle
protein synthesis; Fat oxidation
important criteria for healthy aging. ↓ Weight; Regional adiposity

Biomarkers of Physiology Domain Overview
Complex molecular changes affecting the structure and function of most cells, tissues and organ systems are a hallmark of aging, and changes in their
function can be detected by the third or fourth decades of life. Such loss may translate, eventually, into metabolic dysregulation leading to the
development of early signs of pre-disease which, if not identified and managed, will result eventually in functional loss, chronic disease and finally
death. A well-recognised example is age-related loss of skeletal muscle mass and strength potentially leading to sarcopenia. However, subtle changes
in the function of most organs can occur by the third or fourth decades of life.
This domain includes biomarkers of lung function, body composition (including bone mass and skeletal muscle), cardiovascular (CV) function and
glucose metabolism.
Body mass and body composition. Aging is associated with body composition changes including increased body fat, reduced muscle mass and, with
exception of the heart, reduced organ mass. Greater abdominal adiposity is a risk factor for aging and for age-related diseases with the lowest
mortality risk for those with waist circumferences (WC) below 94 and 77 cm for men and women, respectively. The relative risk (RR) of mortality is
doubled for those with WCs above 132 and 116 cm in men and women, respectively.
Body mass index (BMI) is a useful measure of overall adiposity, since each 5 kg/m2 Increase in BMI is associated with 30% higher overall mortality,
40% higher vascular mortality, 60–120% higher diabetic, renal, and hepatic mortality. High BMI, independent of gender and other confounding factors, is
a risk factor for cognitive decline. In addition, weight gain in middle age is associated with substantially reduced likelihood of healthy survival after age
70 years in women.
Muscle mass can be assessed using CT, magnetic resonance imaging (MRI), DXA, bioimpedance analysis (BIA), and body potassium. Evidence shows
that muscle mass, such as leg muscle mass, declines with age. Cross sectional and prospective studies that have examined the relationship between
regional muscle mass per se and health outcomes have reported that low skeletal muscle index (skeletal muscle mass/body mass percent) is
associated with increased likelihood of functional impairment and disability. Recent developments from the FNIH Sarcopenia Project may help to
establish universal cut-points for low muscle mass and weakness.

Cardiovascular function. Aging of the cardiovascular system is associated with aging of both cardiac muscle and the vascular wall. Although there are
many inflammation and haemostasis-related biomarkers of cardiovascular function, the classical, widely measured, and well documented physiological
markers of risk of cardiovascular-related diseases remain the strongest biomarkers of aging. Systematic reviews and meta-analyses provide strong
evidence that blood pressure (BP), lipid profile (including total cholesterol, low- and high-density lipoprotein cholesterol, and triglycerides
concentrations) are predictors of morbidity and mortality. A difference of 20 mmHg in systolic BP (or 10 mmHg in diastolic BP) is associated with > two
fold difference in death from several vascular causes. High BP in midlife is associated with lower cognitive function in later life. Among the
components of the Metabolic Syndrome, high-BP and impaired fasting glucose are significant predictors of greater CV-morbidity and mortality. There is
a lack of evidence on the age-related changes in most cardiovascular biomarkers but, using data from eight UK cohorts, a recent study evaluated the
life course trajectories in BP and confirmed age-related changes in BP, independent of BMI.
Systolic increased from childhood, with a markedly midlife acceleration beginning at 40 years of age, and deceleration and reversion of these increases
in late adulthood.
Lung function. From age 25, lung function assessed through forced expiratory volume (FEV1; the most common measure documented in
epidemiologic studies) declines at approximately 32ml/year in men and 25 ml/year in women. Numerous population studies have documented an
inverse association between FEV1 and aging-related endpoints including future total and cardiovascular mortality, cognitive function and fractures.
Bone health. Bone mass declines with age in both men and women although whether the decline is greater in women is debated. Techniques for
measuring bone mass include dual x-ray absorptiometry (DXA), broadband ultrasound attenuation (BUA), and quantitative computed tomography (CT)
and both site specific (hip or spine) DXA and heel BUA have been used extensively in epidemiologic studies. DXA is the most widely used method to
assess bone mineral density and is the method of choice to diagnose osteoporosis. Bone mass or density (measured using DXA or BUA) predicts
future fracture risk as well as mortality and other age-relevant health outcomes. BUA is an attractive alternative to DXA given its portability, lower cost,
and no exposure to ionising radiation. A recent meta-analysis showed that BUA predicted fracture risk similarly to DXA.

Glucose metabolism. Aging is associated

with alterations in several aspects of Glucose metabolism Insulin receptors
glucose metabolism, including insulin
receptors and glucose transporters, Glucose transporters
leading to decreased glucose oxidation
and increased liver gluconeogenesis Glucose oxidation
Biomarkers of dysregulated glucose

metabolism including fasting blood
Glucose metabolism
Impact of aging Increased liver gluconeogenesis
glucose concentration and glycated
haemoglobin (HbA1C) (an indicator of
long-term average blood glucose
concentration), are associated with age Fasting blood glucose concentration and glycated haemoglobin (HbA1C) features:
and predict future cardiovascular events
and mortality, cognitive impairment and Associated with age
dementia in non-diabetics. A difference of
1% in HbA1C levels is associated with a Predicts future cardiovascular events and mortality, cognitive impairment and dementia in non-diabetics.
20% and 26% difference in risk of
A difference of 1% in HbA1C levels is associated with a 20% and 26% difference in risk of coronary heart
coronary heart disease (CHD) and total
disease (CHD) and total mortality, respectively.
mortality, respectively. Favourable
glucose metabolism has been identified Favourable glucose metabolism has been identified as a central factor for familial longevity.
as a central factor for familial longevity.

Weaknesses in the Physiology Biomarker Domain
Emerging biomarkers, for example fibrinogen,

plasma cystatin C and brain natriuretic
peptide, have been associated with increased
risk of CV events and mortality, but it is
uncertain if these offer advantages over
well-established biomarkers. More research is
needed on whether monitoring biomarkers
over longer time periods, for example glucose
concentration and ambulatory BP over 24
hours, or in response to a challenge, improves
their predictive value.
The long-established age-related physiological

biomarkers are usually measured at single
points in time and it has been suggested that
monitoring some of these biomarkers over
longer time periods, e.g. glucose
concentration and ambulatory blood pressure
over 24h, may improve their predictive value From Continuous Glucose Monitoring (CGM) to cutting-edge insulin pumps, diabetes technology has come
but this needs to be tested in appropriate a long way. Health devices are becoming progressively less to non-invasive, and offer more options so that
prospective cohort studies. The lack of you can find what works best for you. CGM is an advanced way to check glucose readings in real-time or
evidence on the age-related changes of monitor glucose readings over indefinite periods of time. The CGM system works through a sensor placed
biomarkers could be addressed by in contact with your skin. It transmits readings to a recording device that could sounds an alarm if your
blood sugar gets too high or low.
mathematical modelling of longitudinal data.
Sources Images: PKvitality.

99
Blood-based
Biomarkers
Blood-based Biomarkers Overview
Most aging biomarkers measured within blood samples are related to cardiovascular function, glucose metabolism, inflammation, nutritional status,
endocrinology and simply hematology. As already said, although there are many less well understood inflammation- and hemostasis-related
biomarkers of cardiovascular function, the classical, widely measured, and well-documented physiological markers of risk of cardiovascular-related
diseases remain some of the strongest biomarkers of aging: systematic reviews and meta-analyses provide strong evidence that the lipid profile is a
predictor of morbidity and mortality; but there is a wide margin of error. Approximately 50% of the negatives for cholesterolemia and coronary heart
disease risk through a conventional lipid profile are false negatives; implementing timely access to advanced lipid testing for the population would
result in the effective prevention of at least a quarter of the prevalence of cardiovascular diseases, quite possibly much more.
Amongst the best studied aspects of immunosenescence is the age-related increase in inflammatory peptide biomarkers (Interleukins 6, 1β, Tumor
Necrosis Factor-α and C-Reactive Protein), collectively termed inflammaging. Higher plasma concentrations of inflammatory factors such as IL-6 and
TNF-α have been associated with lower grip strength and gait speed in older adults, demonstrating the interconnection between immune and functional
status. CRP has been related to all-cause and specific causes of mortality and IL-6 was found to be a strong predictor of mortality.
Measurement of inflammatory markers has been conducted in centenarians. Centenarians demonstrate fewer signs of inflammaging. Whilst
inflammatory peptides are either absent or lowered than that evident in younger cohorts, there is a corresponding increase in the levels of
anti-inflammatory cytokines, such as IL-10. Importantly, much yet is to be understood with respect to the interactions between cytokines, the immune
system and target organs. It is apparent that these inflammatory markers have many non-classical functions, including the modulation of metabolic
functions, well beyond the classically described impact on inflammatory function.
Aging is associated with alterations in many aspects of metabolic and hormonal function, including altered expression of cellular insulin receptors and
glucose transporter units in target tissues. Within these tissues there is corresponding changes in carbohydrate metabolism including decreased
cellular glucose oxidation. These alterations result in a lowered glucose tolerance as measured by impaired ability to lower blood glucose after a
standard glucose load. There are several measures of glucose tolerance with the clinically accepted measures for diagnosis of diabetes mellitus being
the fasting and postprandial blood glucose concentration. Glycated hemoglobin, a measure of usual glucose concentrations over the preceding few
months, which does not require fasting or a glucose challenge, has also been suggested as a feasible indicator of glucose metabolism.

Main Predictors of Morbidity in the Lipid Profile
The Standard Lipid Profile (image) test is used as part of a cardiac risk assessment to help identify an individual’s risk of heart disease and to help make decisions about suitable
treatment if there is a borderline or high risk. The results of a standard lipid profile test are considered along with other risk factors of heart disease such as lifestyle, family health
history of a heart attack before the age of 50, family history of elevated cholesterol level, obesity, etc., to develop a plan of treatment and follow-up.
However, there are serious limitations to relying solely on the standard cholesterol panel. The well-known Framingham Study illustrated that the higher the cholesterol, the higher
the statistical risk of a heart attack; nonetheless, a frightening number of heart attacks still occur every day in people whose cholesterol values are seemingly normal. In fact, the
American Heart Association reports that 50% of men and 64% of women who died suddenly of coronary heart disease had no previous symptoms. Scientists, on the other hand,
have developed more advanced blood tests that can far more accurately gauge risks of heart disease. An Advanced Lipid Test augments the standard cholesterol profile with
additional measurements that can identify several risks related to cardiovascular disease. These tests not only offers a comprehensive assessment of cardiovascular risk, but
also supplies vital information that can help patients and clinicians formulate a customized disease-prevention program and measure its progress over time. This powerful
diagnostic tool can help take the steps necessary to avoid preventable health catastrophes — like heart attack and stroke— today. An Advanced Lipid Test is performed just like a
traditional cholesterol panel: a technician or nurse draws blood and submits it to a laboratory. At reasonable cost, the test provides a lot more data than routine cholesterol tests
and expands on this information. The comprehensive information derived from an advanced test enables physicians to more accurately predict their patients’ risk of heart
disease, and to customize more aggressive, patient-specific treatment plans.
Sources Life Extension.

102
Recently it was shown that markers related to red blood cells, more specifically
Markers related to red blood cells
hematocrit, hemoglobin and the red blood cell count are associated with
significantly higher chances of adverse health-status measures such as Hematocrit
multi-morbidity, cognitive impairment, disability and mortality. Age-related
Hemoglobin
changes in the endocrine system are very well established including a decline in
the sex hormones testosterone and estrogens due to andropause and Red blood cell count
menopause, and the reduced production of Growth Hormone and Insulin-Like
Growth Factor-1 (Somatopause). Multi-morbidity
The more recently discovered adipokines such as adiponectin, ghrelin, leptin and Adverse status Cognitive impairment
visfatin are key regulators of inflammation, insulin resistance as well as of central measures Disability
functions such as appetite regulation. Alterations in serum adipokine levels have Mortality
been linked with an increased risk of obesity and metabolic syndrome.
Interestingly, the concentration of adiponectin appears to change with age and is
Key regulators of inflammation. Key role in the development of
linked with age-related health outcomes, however further research on the insulin resistance and atherosclerosis.
association between aging and adipokines is required.
Other hormonal changes including thyroid-stimulating hormone (TSH), free

thyroxine (FT4) and triiodothyronine (FT3) have also been evaluated on their link Adipo-
Leptin Ghrelin Visfatin
to health outcomes in elderly, but only low FT3 levels were associated with an nectin
increased risk for morbidity and mortality. These findings are consistent with
other studies investigating aged populations, showing an association of low
serum FT3 with reduced parameters of physical performance and muscle Other hormonal changes including thyroid-stimulating hormone (TSH), free
strength, as well as an increased disease-burden and mortality. thyroxine (FT4) and triiodothyronine (FT3) have also been evaluated on their
link to health outcomes in elderly

Nutrition-related parameters are diverse, although studies have tended to

focus primarily on a small subset of micronutrients including the vitamins
D, B12, B6 and folic acid. However, data are not convincing, with limited
evidence that suppressed vitamin D levels are associated with increased
overall morbidity and cognitive impairment.
Other very interesting aging markers are N-terminal pro-B-type natriuretic

peptide (NT-proBNP) and cardiac troponin, both of which are highly linked
to myocardial damage. Recently it has been shown that NT-proBNP, which
is elevated in the presence of heart failure, is associated with
multi-morbidity, cognitive impairment and mortality, which makes
NT-proBNP an informative general marker of age-related myocardial
dysfunction. Cardiac troponin is associated with physiological renewal or
remodeling of the myocardium. It is significantly correlated to NT-proBNP .
Despite their validity as predictors for cardiac damage and cardiovascular
diseases, both markers increase with age, importantly until very old age, in
both male and female healthy subjects, which successfully qualifies them
as biomarkers for human aging.
Despite the apparent relevance of many of these blood-borne measures,

longitudinal data to precisely identify the predictive value of these markers
prior to the onset of ill health are scarce. There is, however, substantial
evidence that the timely analysis of blood borne biomarkers should be a
common feature of geriatric care, with the need to establish normative
standards and appropriate age-related reference ranges.

Biomarkers of Endocrine Function
Age-related changes in the endocrine system,

particularly the sex hormones, are well recognised
and have established causal links with health
outcomes. This area includes on sex hormones, the
HPA axis, growth hormone, IGF-1, melatonin,
adipokines and thyroid hormones, etc
The strongest evidence supporting relationships

with aging emerged for testosterone, estrogen,
DHEAS, and GH/IGF-1. For each of these markers
there was strong consensual evidence from
longitudinal studies that changes were linked with
risk of premature mortality and/or physical frailty.
For some endocrine biomarkers, the relationship
with aging appears to be non-linear. For example,
the limited available evidence has shown that both
high and low IGF-1 is related to mortality risk. Whilst
DHEAS declines with aging, it is worth noting that a
few studies reported no association with mortality;
however, low serum DHEAS is almost always
associated with increased mortality and, in the
aforementioned few studies, generally associated
with increased mortality in older women with
concurrent frailty and also with frailty in men.

Hormone replacement studies add to the evidence for a causal link to age-related physical and psychosocial decline. In this respect, the strongest
associations are for both testosterone and estrogen and risk of physical frailty and bone health. There is evidence that circulating concentrations of
melatonin and of adiponectin decline with age but these relationships have been investigated in only a few longitudinal studies. Adiponectin shows the
strongest association with mortality even after controlling for BMI or change in BMI. Cortisol, a stress hormone produced in the adrenal cortex and a
component of the HPA axis, has been associated with age-related disease and disability. There is evidence from longitudinal studies that abnormal
cortisol secretion patterns are associated with increased BP, impaired glucose metabolism (fasting insulin and insulin/glucose ratio), and increased
incidence of CVD and type 2 diabetes in men. Recently, associations between heightened cortisol reactivity to stress and coronary artery calcification
have been identified which may influence the risk of coronary heart disease and hypertension.
Strong consensual evidence from longitudinal studies indicates that testosterone,
estrogen, DHEAS growth hormone and IGF-1 are linked with risk of premature mortality and
physical frailty. For some biomarkers, the relationship with aging appears to be non-linear,
for example both high and low IGF-1 are related to greater mortality rates. DHEAS declines
with age from the third decade onwards and low DHEAS is associated with increased
mortality in older subjects with concurrent frailty. Hormone replacement studies suggest
causal links for both testosterone and estrogen and risk of physical frailty, bone and
muscle health. Cortisol is associated with age-related disease and disability, and abnormal
cortisol secretion patterns with increased blood pressure, impaired glucose metabolism,
insulin resistance and increased incidence of CVD and type 2 diabetes in men. The
Cortisol:DHEAS ratio is even more precise in this regard.
Regarding the weaknesses of endocrine biomarker, longitudinal evidence is needed to

enhance understanding of the relationships between cortisol, DHEAS, cortisol:DHEAS ratio,
adipokines (adiponectin, leptin, ghrelin), somatostatin, and ageing, frailty and mortality.

For these reasons, we conducted what may be the first human clinical trial
designed to reverse aspects of human aging, the TRIIM (Thymus
Regeneration, Immunorestoration, and Insulin Mitigation) trial, in
2015–2017. The purpose of the TRIIM trial was to investigate the possibility
of using recombinant human growth hormone (rhGH) to prevent or reverse
signs of immunosenescence in a population of 51‐ to 65‐year‐old putatively
healthy men, which represents the age range that just precedes the collapse
of the TCR repertoire. rhGH was used based on prior evidence that growth
hormone (GH) has thymotrophic and immune reconstituting effects in
animals and human HIV patients. Because GH‐induced hyperinsulinemia is
undesirable and might affect thymic regeneration and immunological
reconstitution, we combined rhGH with both dehydroepiandrosterone
(DHEA) and metformin in an attempt to limit the “diabetogenic” effect of GH.
DHEA has many effects, in both men and women, that oppose deleterious
effects of normal aging. Metformin is a powerful calorie restriction mimetic
in aging mice and has been proposed as a candidate for slowing aging in
humans. Neither DHEA nor metformin are known to have any thymotrophic
effects of their own.
Obvious qualitative improvements in thymic MRI density were observed.

Quantitatively, the overall increase in the thymic fat‐free fraction (TFFF) was
significant, implying a restoration of thymic functional mass. Bone marrow,
similar to thymus, showed a pattern of increased BMFFF with increased
baseline fat content. This difference plus the more robust replacement of
thymic vs. bone marrow fat is consistent both with a specific reversal of
thymic involution and with possible stimulation of bone marrow T‐cell
progenitor production by GH. Trial volunteer epigenetic ages were lower than
their chronological ages at baseline, and epigenetic age was significantly
decreased by treatment based on the results of all four epigenetic clocks,
with a mean reversion after 12 months of about 2.5 years in each subject.
Sources Steve Horvath, et al. Reversal of epigenetic aging and immunosenescent trends in humans. 2019.
107
Biomarkers of Immune Function Overview
Whilst the field of immunology is well developed, the study of Chronic Challenges (lifelong immune history)
age-related decline in immunity, termed immunosenescence, is more
recent. Here we focused on age-related immune function and Infections Cellular Debris
inflammatory factors. Longitudinal studies comparing immune cells or
Tumor Antigens Modified Proteins
function with mortality, or with age-related functions such as infection
rates or vaccination responses, are scarce.
Two octogenarian and nonagenarian studies assessing immune

markers (T-cell phenotype, cytomegalovirus serostatus and Inflamm-ageing
pro-inflammatory cytokine status) with subsequent mortality have been
the basis for the development of the Immune Risk Profile (IRP; defined Innate immune system activation/activity
by an inverted CD4/CD8 ratio and associated with increased numbers of Senescence associated secretory phenotype
CD8 + CD28 cells), which is associated with mortality in those over 60
years. A limitation of the IRP is its narrow scope since it does not
consider innate immune factors such as natural killer cell (NK Cell) Main changes in the adaptive immune
system phenotypes and functions
function, which is linked with infection rates and mortality. The best
(T and B cells)
studied aspect of immunosenescence is the age-related increase in
systemic inflammatory cytokines, termed inflammageing. Higher Immunosenescence/adaptation
plasma concentrations of IL-6 and TNF-α are associated with lower grip
strength and gait speed in older adults. Centenarians show fewer signs
of aging of the immune system although some inflammageing is seen.
Age-related chronic inflammatory diseases
Metabesity; Aging itself
Sources Image data: Tamàs Fulop, et al. From Inflamm-Aging to Immunosenescence. 2019.
108
Biomarkers of Immune Function Weaknesses
Longitudinal studies should examine relationships between number and function of T cells, neutrophils, NK cells, B cells, and mortality, risk of
age-related disease and wellbeing in later life. Given the switch from lymphoid to myeloid cell production with age, the lymphocyte/granulocyte ratio is a
potentially useful biomarker of healthy aging. The Immune Risk Profile needs validation in younger people and should be expanded to include measures
of immune function such as infection incidence or vaccination response.
Telomere length in leukocytes, including lymphocytes and monocytes, has received much attention. Despite its association with aging in several cohort
studies, it is likely that shortened telomeres are also a marker of infection frequency so that leukocyte telomere length may not be a reliable index of
biological aging. Lymphocytes proliferate rapidly in response to their cognate antigen and unlike most somatic cells have the ability to extend their
telomeres by inducing telomerase expression but, eventually, this is insufficient to prevent lymphocyte telomere length shortening with age. Further
studies of telomere length and aging should include investigation of exposure to infections and CMV seropositivity as possible confounders. In the
Newcastle 85+ Study and other studies thus far leukocytes’ telomere length was uninformative about health status.
The immune system protects the organism from pathogens and also from damaged or altered tissues, cells (as occurs with cancer or traumatic injury)
and molecules (as happens in phenomena such as loss of proteostasis, characterized by the loss of structural integrity of proteins, particularly
long-lived proteins or LLP), whilst not damaging the organism’s own tissues. In humans, the immune system develops a memory of exposure to a
pathogen or particular environmental molecules, so that when those threats are encountered a second time the response is rapid and specific to that
agents. This so-called adaptive immune system, based on lymphocytes activity, is also the basis of the vaccination response.
It is clear that each of these aspects of immune function declines with age; e.g. susceptibility to both bacterial and viral pathogens increases with age,
the incidence of cancer is age-related as is loss of tolerance to one’s own tissues, evidenced by increased autoimmunity. In addition, the ability to
mount an adequate, protective vaccination response also deteriorates with age. This age-related decline in immunity is termed immunosenescence
and, whilst the field of immunology is well developed, the study of immunosenescence is more recent, with papers beginning to appear in the 1980’s.

Biomarkers of Immune Function Weaknesses
The best studied aspect of immunosenescence is the age-related increase in inflammatory cytokines (IL6, IL1β, TNFα and CRP) which is termed
inflammageing. Higher plasma concentrations of inflammatory factors such as IL-6 and TNF-α have been associated with lower grip strength and gait
speed in older adults. Measurement of inflammatory cytokines has been incorporated into longitudinal studies and have also been studied in
centenarians. The latter group shows fewer signs of aging of the immune system, including the Immune Risk Profile, and inflammageing is absent or
much reduced, being counteracted in part by high levels of anti-inflammatory cytokines such as IL-10.
Although there is no exact understanding about the causes of inflammaging and the key aspects of their feedback with immunosenescence, a common
finding seems to involve a dysregulation of the cytokine network and its homeostasis. Several common molecular pathways have been identified that
seem to be associated with both aging, low-grade inflammation and immunosenescence, but these relationships are not yet sufficiently clarified.
HOMEOSTASIS
Control of Infection
Immunoregulation
Tumor Surveillance
Pathogen Responses Inflammageing
Memory Formation Immunosenescence

Molecular-Level Biomarkers Overview
Common theories of aging, where age linearly correlates with and/or is caused by the accumulation of reactive oxygen species (ROS), DNA damage,
mitochondrial dysfunction, impaired antioxidant defense and shortening of the telomeres, are well established in humans. However it has been
reported that many of these markers increase up to a certain age, most commonly coinciding with the statistical life-expectancy. Thereafter, a plateau
or even a decrease in the level of some of these biomarkers has been described.
Supported by the free radical theory of aging, it is widely accepted that the production of ROS by mitochondria accumulates over the lifespan and leads
to a state of chronic oxidative stress at old age. As antioxidant defense mechanisms and DNA repair capacity seem to be impaired in the elderly, or at
least be overwhelmed by the damage occurrence rate, DNA damage has been proposed to be a consequence of aging. Impaired DNA stability and
genome instability increase the frequency of cytogenetic aberrations, which in turn is highly linked to age-related diseases such as cancer, diabetes,
cardiovascular diseases and cognitive decline. However, after linearly increasing until the age of 60–70 years, chromosomal damage tapers and the
rate of damage diminished with increasing age (over 85 years). Notably, the same seems to be true for telomeres, the protective ends of the
chromosomes. Longer telomeres and higher telomerase activity contribute to the stability of the genome, to DNA integrity and are positively correlated
with the aging process. These are evidently adaptive-based processes that have been consolidated and deepened throughout the pathway of evolution
by natural selection, cushioning the effects of aging on the human species.
Both, the “regular” aging process and the development of chronic diseases are accompanied by increased DNA damage, chromosomal damage, and
telomere shortening. Importantly, people exceeding the statistical life-expectancy, and especially the very oldest age-groups including nonagenarians
(90–99 years), centenarians (100–109 years) and super-centenarians (110 years and older), demonstrate a different picture of age-related diseases
compared to study cohorts at or below life-expectancy. Furthermore, an increasing amount of data suggests that chromosomal stability, DNA repair
activity, and antioxidant defense capacity in successfully aged subjects is comparable to younger cohorts.
Taken together, very old humans seem to contradict traditional theories of aging regarding the age-related accumulation of DNA damage, genome
instability and telomere shortening by demonstrating better DNA repair capacity and higher telomerase activity, even comparable to much younger
cohorts. Whether the superior resilience of “successful” agers originates from hereditary factors or an outstanding healthy lifestyle remains a field for
future research. Conclusively, markers of DNA integrity, genome stability, antioxidant defense or telomere length based on current evidence do not meet
the criteria for a valid biomarker for aging.
Bilirubin, the principal tetrapyrrole, bile pigment and catabolite of haem, is an emerging biomarker to monitor resistance against chronic
non-communicable diseases. Mildly elevated serum bilirubin levels have been reported to be strongly associated with reduced CVD-related mortality
and associated risk factors. Recent data also link bilirubin to all-cause mortality and to other chronic diseases, including cancer and type 2 diabetes
mellitus. Therefore, there is evidence to suggest bilirubin as a biomarker for reduced chronic disease prevalence and for the prediction of all-cause
mortality, but also as a novel biomarker for successful aging.
Advanced Glycation End-products (AGEs) represent further biomarkers with incredible potential to monitor healthy aging. Protein modifications such as
the non-enzymatic protein glycation are common posttranslational modification of proteins resulting from reactions between glucose and the amino
groups of proteins. This process, better known as “Maillard reaction”, leads to the formation and accumulation of AGEs throughout life. Interestingly, the
AGEs of long-lived proteins (LLPs) such as collagens and cartilage accumulate during normal aging; these are proteins that barely experience or do not
experience replacement throughout life, some with a half-life of more than 100 years. AGEs are involved either directly or through interactions with
AGE-receptors in the pathophysiology of numerous age-related diseases including cardiovascular diseases, amyloidosis, neurodegeneration, diabetes
and renal disease, among multiple others.
Metallothioneins (MTs) are low molecular weight, cysteine rich, zinc-binding proteins, which are down-regulated in older age groups. MTs exert an
essential role in zinc-mediated transcriptional regulation of genes involved in growth, proliferation, differentiation, and development, pathways of
importance in neural function. There is experimental evidence that MTs are induced in the aging brain as a defensive mechanism to attenuate oxidative
and nitrative stress. MTs may also act as free radical scavengers by inhibiting Charnoly body formation, thus contributing to protecting mitochondrial
function as a mechanism of neuroprotection in the aging brain.
Very recently the interesting model of the epigenetic clock has been advanced with the analysis of peripheral blood mononuclear cells isolated from
semi-supercentenarians and their offspring. The epigenetic clock is a multivariate estimator of chronological age based on DNA methylation levels of
353 dinucleotide markers known as Cytosine phosphate Guanines (CpGs). These cytosines experience methylation selectively throughout life, they are
hot spots of greater probability and incidence of methylation. Extent and patterns of CpGs are independently associated with chronological age and
mortality; further data is required to understand whether these changes are causal or a consequence of aging, but it is almost unquestionable that the
first is true.
Epigenetic changes are but one of a number of emerging molecular biomarkers of
altered molecular function in aging that may be predictive of health status. Recent
studies have examined the novel molecular marker p16INK4a, which is classically
known for its capacity to inhibit cyclin-dependent kinase activity. Long-term p16INK4a
expression is a promoter of cellular senescence, a process of irreversible cell-cycle
arrest and the loss of regenerative capacity. Therefore, precise regulation of p16INK4a
is essential to tissue homeostasis, maintaining a coordinated balance between tumor
suppression and aging. As yet, studies in human populations and differing cell types
have yet to be conducted to provide evidence of its potential as a biomarker of healthy
aging.
Finally, microRNAs (miRNAs), single-stranded and non-coding RNA molecules of

21–23 nucleotides that regulate a broad spectrum of biological activities, have been
proposed as signatures of aging. These small RNA molecules were initially
demonstrated to contribute to aging in the worm Caenorhabditis elegans and show
differential expression levels in tissues of young and old animal models. Most
interestingly miRNAs are stable molecules even in serum and/or plasma, hence are
regarded as promising biomarkers in the clinical setting.
Studies also demonstrate a specificity of age-related health loss, with the ability to
differentiate the onset of Alzheimer’s disease and/or mild cognitive impairment from Overexpression/knockout/knockdown
cognitively normal age-matched controls with some degree of accuracy utilizing a studies suggest that the wild-type
activity of the miRNA is:
miRNA signature analysis. Furthermore, miRNAs might also serve as circulating Anti-aging / lifespan-extending
biomarkers for cardiovascular aging or aging-associated diseases, but further Pro-aging / lifespan-shortening
research needs to be conducted to evaluate their sensitivity, selectivity and potential Unclear or unknown.
as predictive biomarkers for discriminating successful from non-successful aging.
Sources Image: Holly E. Kinser, et al. MicroRNAs as modulators of longevity and the aging process. 2019.
113
Accumulation of Bilirubin
DNA damage and
reactive oxygen Many of these markers
shortening of telomeres
species (ROS)
2 Key increase up to a certain Principal tetrapyrrole, bile pigment and
Aging
Advanta age, most commonly catabolite of haem, is an emerging
ges coinciding with the biomarker to monitor resistance against
Mitochondrial Impaired antioxidant statistical life-expectancy. chronic non-communicable diseases.
dysfunction defense
Advanced glycation end products

(AGEs)
Both, the “regular” aging process and the development
of chronic diseases are accompanied by increased An increasing amount of data suggests that
DNA damage, chromosomal damage, telomere chromosomal stability, DNA repair activity, and Further biomarkers with some potential
shortening and epigenetic changes. antioxidant defense capacity in successfully aged to monitor healthy aging. Protein
subjects is comparable to younger cohorts. modifications such as the non-enzymatic
protein glycation are common
posttranslational modification of proteins
People exceeding the statistical life-expectancy, and
especially the very oldest age-groups including Taken together, very old humans seem to contradict resulting from reactions between glucose
nonagenarians (90–99 years), centenarians (100–109 traditional theories of aging regarding the age-related and the amino groups of proteins.
years) and super-centenarians (110 years and older), accumulation of DNA damage, genome instability and
demonstrate a different picture of age-related diseases telomere shortening by demonstrating better DNA
compared to study cohorts at or below life-expectancy. repair capacity and higher telomerase activity, even Metallothioneins
comparable to much younger cohorts.
Low molecular weight, cysteine rich,
Conclusively, markers of DNA integrity, genome stability, antioxidant defense or telomere length based on current zinc-binding proteins, which are
evidence do not meet all the criteria for a valid biomarker for aging. And epigenetic marks do. down-regulated in older age groups.

Cognitive
Biomarkers
Cognitive Biomarkers Overview
Cognitive decline may limit independence and

signal dementia, and, although debated, Cognitive decline Computer-based tests
evidence indicates that the onset of cognitive
Imperative to increase
decline is detectable relatively early in Limiting independence
cost-effectiveness
adulthood, for example from around 45 years of
Availability of tools such as the NIH
age or earlier in some functions. Signaling dementia
Toolbox
Executive function, processing speed and
Is detectable relatively early in Technical development to
episodic memory – are a possible minimum set adulthood ‘future-proof’ operating systems
of domains to be assessed in aging studies. If
assessment time allows, tests of crystallised
cognitive ability and non-verbal reasoning would
Executive function Processing speed
be useful additions. Executive function is
markedly affected by aging, exhibiting an
2 Key
inverted U-shape pattern across the lifespan. Aging
Advanta
Processing speed declines progressively with studies
ges
age and is associated with greater mortality
risk, cardiovascular and respiratory diseases. In
addition, episodic memory is sensitive to brain
Episodic memory Long-term memory
aging and declines in individuals with mild
cognitive impairment and neurodegenerative
diseases. A standard deviation advantage in The issue of covariance among cognitive tests needs more attention because those who score well on one
memory is associated with 21 % reduction in test tend to score well on others. The causes of cognitive aging might affect the variance shared by tests
or domains or the variance in a specific test or domain.
mortality risk among older individuals.

Cognitive Biomarkers Weaknesses
To date, computer-based tests are not widely used in major cohorts; availability of tools such as the NIH Toolbox and the imperative to increase
cost-effectiveness are likely to drive the migration to digital methodologies. This will require that tests are supported by ongoing technical development
to ‘future-proof’ operating systems and hardware. Where tests are administered repeatedly in the same individuals problems associated with practice
and familiarity need to be addressed. The issue of covariance among cognitive tests needs more attention because those who score well on one test
tend to score well on others. Timothy A. Salthouse and others have highlighted that the causes of cognitive aging might affect the variance shared by
tests or domains or the variance in a specific test or domain.
Passive biomarkers are a hot topic at the moment with

the rise of digital phenotyping and the prospect of being
able to monitor a person’s health status non-invasively
without the participant having to engage in specific
tasks. To facilitate these passive biomarkers, large
datasets are required with extensive validation in healthy
and clinical populations.
Passive data sources can be combined to create

complex phenotypic signatures or digital avatars which
relate to a person’s health or disease status. These can
be enhanced by coupling passive data sources with
active cognitive assessments to determine relationships
with health.
Active cognitive biomarkers serve as both the

immediate gold-standard endpoints for cognitive
function, but also as the benchmark for training and
validating novel passive measurements against.
Sources Cambridge Cognition | Jose Lara. 2015.

117
Sources Images: Mindstrong
Panels of Biomarkers of Aging
1. WellnessFX Premium, WELLNESSFX 30. NeuroGenomic™ Profile, GENOVA DIAGNOSTICS

2. Anti-Aging #4 Comprehensive Blood and Urine Test Panel, WALK-IN LAB 31. CardioGenomicPlus™ Profile, GENOVA DIAGNOSTICS
3. Aging Theranostic 1.0, OPEN LONGEVITY 32. PhysioAge Biomarkers of Aging Test, PHYSIOAGE
4. InsideTracker Ultimate Plan, SEGTERRA 33. DiscoveryMAP v. 3.3 Panel, MYRIAD RBM
5. InsideTracker Inner Age, SEGTERRA 34. Explorer MAP™ v. 1.0, MYRIAD RBM
6. Biomarker Panel, UK BIOBANK 35. HumanMAP® v. 2.0, MYRIAD RBM
7. Healthy Aging Panel (Comprehensive), LIFE EXTENSION 36. CardiovascularMAP® v. 3.0, MYRIAD RBM
8. Female/Male Saliva Profile II - Test Kit For 6 Hormone Level Imbalances, 37. InflammationMAP® v. 1.0, MYRIAD RBM
ZRT LABORATORY 38. ImmunoMAP® v. 1.0, MYRIAD RBM
9. 10 Hormone Saliva Test Kit, LABRIX 39. NeuroMAP™ v. 1.0, MYRIAD RBM
10. Adrenal Stress Profile, CELL SCIENCE SYSTEMS 40. MetabolicMAP® v. 1.0, MYRIAD RBM
11. Adrenal Check, FLUIDS iQ® 41. CytokineMAP A, MYRIAD RBM
12. Comprehensive Adrenal Stress Profile, GENOVA DIAGNOSTICS 42. CytokineMAP B, MYRIAD RBM
13. Oxidative Stress Analysis 2.0, GENOVA DIAGNOSTICS 43. AngiogenesisMAP® v. 1.0, MYRIAD RBM
14. Metabolic Analysis Profile (Organic Acids), GENOVA DIAGNOSTICS 44. LEGENDScreen™ Human PE Kit, BIOLEGEND
15. Immune-Frame, RGCC 45. LEGENDplex™ Human B Cell Panel (13-plex), BIOLEGEND
16. Cytokine Panel, MAYO CLINIC LABORATORIES 46. LEGENDplex™ Human CD8/NK Panel (13-plex), BIOLEGEND
17. Salivary Cytokine Panel, SALIMETRICS 47. LEGENDplex™ Human Th Cytokine Panel (13-plex), BIOLEGEND
18. Advanced MethylDetox Profile, CELL SCIENCE SYSTEMS 48. Regulatory T-Cell Panel, ARUP LABORATORIES
19. Advanced MethylDetox Profile plus Telomere Length Test, CELL SCIENCE 49. Cytokine Panel, ARUP LABORATORIES
SYSTEMS 50. Cytokine Panel, TH1, ARUP LABORATORIES
20. Genetic Age Test, CERASCREEN 51. Carnitine Panel, ARUP LABORATORIES
21. AGE-Reader mu Test, DIAGNOPTICS 52. Hepatic Function Panel, ARUP LABORATORIES
22. GlycanAge Test, GLYCANAGE 53. B-Cell Memory and Naive Panel, ARUP LABORATORIES
23. Viome Gut Intelligence™ Test, VIOME 54. Natural Killer Cell and Natural Killer T-Cell Panel, ARUP LABORATORIES
24. SmartGUT™ Microbiome Test, SMARTDNA 55. OMIP-004: In-Depth Characterization of Human T Regulatory Cells
25. Microba Insight™, MICROBA 56. OMIP-007: Phenotypic Analysis of Human Natural Killer Cells
26. Gut Microbiota Biohacker, TFTAK CENTER OF FOOD AND 57. OMIP-018: Chemokine Receptor Expression on Human T Helper Cells
FERMENTATION TECHNOLOGIES 58. OMIP-027: Functional Analysis of Human Natural Killer Cells
27. Health plus Ancestry Service, 23ANDME 59. OMIP-029: Human NK-Cell Phenotypization
28. Array Comparative Genomic Hybridisation (aCGH) RGCC, RGCC 60. OMIP‐039: Detection and analysis of human adaptive
29. ImmunoGenomic® Profile, GENOVA DIAGNOSTICS NKG2C+ natural killer cells
61. Cardiometabolic Panel, OLINK 92. CD57+ NK Cells, Peripheral Blood by Flow Cytometry, ARUP LABORATORIES
62. Cell Regulation Panel, OLINK 93. Phospho-H2AX (Ser139) Cellular Kit, CISBIO
63. Cardiovascular II Panel, OLINK 94. Senescence Detection Kit, ABCAM
64. Cardiovascular III Panel, OLINK 95. SPiDER-ßGal, DOJINDO MOLECULAR TECHNOLOGIES
65. Immune Response Panel, OLINK 96. Young.AI, INSILICO MEDICINE
66. Inflammation Panel, OLINK 97. Aging.AI, INSILICO MEDICINE
67. Metabolism Panel, OLINK 98. PhotoAgeClock, HAUT.AI
68. Neurology Panel, OLINK 99. Haut.AI Skin Health, HAUT.AI
69. Neuro Exploratory Panel, OLINK 100. AgeMeter, CENTERS FOR AGE CONTROL
70. Oncology II Panel, OLINK 101. Health Reviser Platform, HEALTH REVISER
71. Oncology III Panel, OLINK 102. MEDIAGE™ Biological Age Measurement System, MEDIAGE
72. Organ Damage Panel, OLINK 103. CarePredict Platform, CAREPREDICT
73. Human v3 miRNA Assay, NANOSTRING 104. Enlitic Platform, ENLITIC
74. MiRXES ID3EAL miRNA Assay, MiRXES 105. Freenome Platform, FREENOME
75. OsteomiRTM - Validated Bone Biomarkers, TAmiRNA 106. AI-Powered Radiology Assistant, ZEBRA MEDICAL VISION
76. ThrombomiRTM - Biomarkers of Platelet Function, TAmiRNA 107. PathAI Platform, PATHAI
77. ToxomiRTM - Biomarkers of Toxicity, TAmiRNA 108. Buoy Health Platform, BUOY HEALTH
78. DNAge™ Epigenetic Aging Clock, ZYMO RESEARCH 109. BenevolentAI, BENEVOLENT
79. Epigenetic Age Analysis Version 2.0, OSIRIS GREEN 110. Tempus Platform, TEMPUS
80. DNAge® Test, BIOVIVA 111. KenSci Platform, KENSCI
81. EpiHealth, CHRONOMICS 112. Proscia Platform, PROSCIA
82. EpiAging, HKG EPITHERAPEUTICS 113. Google’s DeepMind Health AI Platform, DEEPMIND TECHNOLOGIES
83. EpiSocialpsych, HKG EPITHERAPEUTICS 114. ICarbonX Platform, ICARBONX
84. Targeted Sequencing For DNA Methylation Analysis, HKG 115. Blood Chemistry Calculator, NOURISH BALANCE THRIVE
EPITHERAPEUTICS 116. Ada - Symptom Checker App, ADA HEALTH GMBH
85. EpiLiver, HKG EPITHERAPEUTICS 117. Babylon Health Platform, BABYLON HEALTH
86. EpiBreast, HKG EPITHERAPEUTICS 118. Digital Nutrition Platform, ZIPONGO
87. TeloYears plus Advanced Ancestry Tests, TELOYEARS 119. Better Therapeutics Platform, BETTER THERAPEUTICS
88. Telomere Length and Biological Age Testing, LIFE LENGTH
89. Telomere Length Test, CELL SCIENCE SYSTEMS
90. CD4+ T-Cell Recent Thymic Emigrants (RTEs), ARUP LABORATORIES
91. CD21 (Dendritic Cell) by Immunohistochemistry, ARUP LABORATORIES
Biomarker Panels
Given the heterogeneity and variability in any disease, a single biomarker may not be able to sufficiently reflect the pathological phenomenon itself or
its underlying complexity. Almost all single biomarkers have considerable fallibility. This reason, coupled with the disruptive burst of biotechnology, the
massive capture and aggregation of data and deep biomedical knowledge facilitated by frontier tech in the field of research and development, has
kindled interest in and accelerate progress toward Biomarker Panels design.
A Biomarker Panel is a group of biomarkers that reflect different interconnected processes or parameters of a disease or health status, creating
complex networks of biomedical outputs. In the particular context of aging biomarkers, a biomarker panel is some integrated composition of those
biological indicators predicting functional capacity at a certain time in the future in more optimal ways than single biomarkers and chronological age
itself.
Noonan with multiple Musculo- Body and

Neuro- skeletal limbs
lentigines logic
d d d d
fiel fiel fiel fiel HRAS NF1
Physical
Deve- Head
ic ic ic ic Legius Skin lopment
m m m m
-o -o -o -o Gastro-
Intesti-
Prenatal
Deve-
SOS1 Cardio-
nal lopment
Noonan vascular
Mouth
Puberty And
Hema-
RAP1 NF1 tologic voice
KRAS Mental
Develo- Eyes
Lymph- pment
MAP2K2 CFC atic
MAP2K1
Hair
Genito- Nose
urinary
Costello
Tumors
Ears and
hearing
Sources: Image: T. Kunej, et al. RASopathies: Presentation at the Genome, Interactome, and Phenome Levels. 2016.
122
Biomarker Panels
Genome Genomics, metabolomics, proteomics, microbiomics and so forth, but

fundamentally novel multi-omics approaches, are offering thumping amounts of
biological data and ultra-modern insights on disease trajectories. These are all
concise examples of Comprehensive Panels of Biomarkers.
These uses of numerous biomarkers assembled in Panels including multi-omics

data and their deep analysis by AI platforms push back the boundaries of
biomedical knowledge, health status characterization, diagnosis and early
detection, and opens new doors for Precision, Preventive, Personalized and
Participatory interventions; for P4 Medicine.
We aim to build an objective panel of biomarkers of the aging trajectory and

healthy aging in humans, where healthy aging is defined as the maintenance of
function for the maximal period of time. In a clear example of its usefulness, the
inclusion of the same common biomarker panel of aging in diverse study
designs and epidemiological surveys can enhance the value of those studies by
allowing the standardization and validation of the surrogate endpoints, thus
facilitating enhanced comparisons between studies and the pooling of data
across studies.
The use of Biomarker Panels means more granular data, and more granular data translates into more finely tuned ways of performing risk and disease
progression stratification for assignment to different care regimens and shift from late stage care to preventive medicine. This shift from treatment to
prevention is ultimately leading to a coming age of Preventive Treatments and Precision Health, where patients are empowered with the tools
necessary to become the drivers and engineers of their own health status; i.e., through the application of P4 Medicine in response to continuous
monitoring of fluctuations in these aging biomarkers.
Biomarker Panels
Complex Biomarker Network.

It has previously been reported that gene/protein and
phenotype networks could be assembled into an
integrated network. The different units of all the omic
levels are interconnected, weaving a complex network Noonan with Musculo- Body and
multiple skeletal limbs
of biomarkers highly correlated with a disease, Neuro-
lentigines
logic
condition or biological trait or state: the Interactome. Physical
Thus, a pathology can be identified and corrected in HRAS NF1 Deve- Head
multiple levels. More network data, greater predictive Legius Skin lopment
SPRED1
power and controllability of the biological state. Gastro- Prenatal
SOS1 PTPN11 Intesti- Deve-
Clinical symptoms can be correlated with mutated NRAS
Noonan
Cardio-
nal lopment
vascular
proteins. According to T. Kunej et al., alignments RAF1
between interactome and phenome levels can reveal RIT1
Mouth
KRAS Puberty And
new links between diseases, symptoms, -omes and BRAF
NF1
Hema-
voice
tologic
knows genes, as well as connections between MAP2K2
MAP2K1 Mental
previously unrelated diseases, as in the illustration: a Develo- Eyes
network model for 6 syndromes belonging to the CFC
Lymph- pment
RASopathy class of disorders; Noonan syndrome with atic
multiple lentigines, Legius, Noonan, NF1,

Hair
cardiofaciocutaneous and Costello syndromes, and the Genito- Nose
urinary
string associations between different levels of Costello
biomarkers for this set of disorders. This biomarkers Tumors
Ears and
network approach is rarely used in genomics, despite its hearing
potential for novel discoveries and medical
interventions.
Sources: Image: T. Kunej, et al. RASopathies: Presentation at the Genome, Interactome, and Phenome Levels. 2016.
124
Selected Biomarker Panels
NAME COMPANY or ENTITY AMPLITUDE LEVEL CONDITIONING STAGE CATEGORY OPERATIONAL CATEGORY
Medical Test
WellnessFX Premium WELLNESSFX PANEL Approved for Clinical Use
(+2 Availability Weight Points)
Anti-Aging #4 Comprehensive Blood and Medical Test

WALK-IN LAB PANEL Approved for Clinical Use
Urine Test Panel (+2 Availability Weight Points)
Medical Test
Aging Theranostic 1.0 OPEN LONGEVITY PANEL Approved for Clinical Use
Medical Test
InsideTracker Ultimate Plan SEGTERRA PANEL Approved for Clinical Use
Medical Test
InsideTracker Inner Age SEGTERRA PANEL Approved for Clinical Use
Epidem. or Theoretical Panel Only

Biomarker Panel UK BIOBANK PANEL Approved for Clinical Use
(BAI=0; ACTIONAB.=0)
Medical Test
Healthy Aging Panel (Comprehensive) LIFE EXTENSION PANEL Approved for Clinical Use
Female/Male Saliva Profile II - Test Kit Medical Test

ZRT LABORATORY PANEL Approved for Clinical Use
For 6 Hormone Level Imbalances (+2 Availability Weight Points)
Medical Test
10 Hormone Saliva Test Kit LABRIX PANEL Approved for Clinical Use
CELL SCIENCE Medical Test

Adrenal Stress Profile PANEL Approved for Clinical Use
SYSTEMS (+2 Availability Weight Points)

Medical Test
Adrenal Check FLUIDS iQ® PANEL Approved for Clinical Use
GENOVA Medical Test

Comprehensive Adrenal Stress Profile PANEL Approved for Clinical Use
DIAGNOSTICS (+2 Availability Weight Points)
GENOVA Medical Test

Oxidative Stress Analysis 2.0 PANEL Approved for Clinical Use
Metabolic Analysis Profile (Organic GENOVA Medical Test

PANEL Approved for Clinical Use
Acids) DIAGNOSTICS (+2 Availability Weight Points)
Medical Test
Immune-Frame RGCC PANEL Approved for Clinical Use
MAYO CLINIC Medical Test

Cytokine Panel PANEL Approved for Clinical Use
LABORATORIES (+2 Availability Weight Points)
Research Use Only

Salivary Cytokine Panel SALIMETRICS PANEL Informational Purpose Test or Platform
(-2 Availab. Weight Points)
CELL SCIENCE Medical Test

Advanced MethylDetox Profile PANEL Approved for Clinical Use
SYSTEMS (+2 Availability Weight Points)
Advanced MethylDetox Profile CELL SCIENCE Medical Test

PANEL Approved for Clinical Use
plus Telomere Length Test SYSTEMS (+2 Availability Weight Points)
Genetic Age Test CERASCREEN PANEL Healthcare-Ready Informational Purpose Test or Platform

Biomarkers Real-Time Assessment

AGE-Reader mu Test DIAGNOPTICS PANEL Approved for Clinical Use Technology
GlycanAge Test GLYCANAGE PANEL Healthcare-Ready Informational Purpose Test or Platform
Viome Gut Intelligence™ Test VIOME PANEL Healthcare-Ready Informational Purpose Test or Platform
SmartGUT™ Microbiome Test SMARTDNA PANEL Healthcare-Ready Informational Purpose Test or Platform
Microba Insight™ MICROBA PANEL Healthcare-Ready Informational Purpose Test or Platform
TFTAK CENTER OF
FOOD AND
Gut Microbiota Biohacker PANEL Healthcare-Ready Informational Purpose Test or Platform
FERMENTATION
TECHNOLOGIES
Medical Test
Health plus Ancestry Service 23ANDME PANEL Approved for Clinical Use
Array Comparative Genomic Medical Test

RGCC PANEL Approved for Clinical Use
Hybridisation (aCGH) RGCC (+2 Availability Weight Points)
GENOVA Medical Test

ImmunoGenomic® Profile PANEL Approved for Clinical Use
GENOVA Medical Test

NeuroGenomic™ Profile PANEL Approved for Clinical Use

GENOVA Medical Test

CardioGenomicPlus™ Profile PANEL Approved for Clinical Use
Medical Test
PhysioAge Biomarkers of Aging Test PHYSIOAGE PANEL Approved for Clinical Use
Research Use Only Research Kit or OLPS

DiscoveryMAP v. 3.3 Panel MYRIAD RBM PANEL
(-2 Availab. Weight Points) (Accuracy Index x RKOLPS coefficient)

Explorer MAP™ v. 1.0 MYRIAD RBM PANEL

HumanMAP® v. 2.0 MYRIAD RBM PANEL

CardiovascularMAP® v. 3.0 MYRIAD RBM PANEL

InflammationMAP® v. 1.0 MYRIAD RBM PANEL

ImmunoMAP® v. 1.0 MYRIAD RBM PANEL

NeuroMAP™ v. 1.0 MYRIAD RBM PANEL

MetabolicMAP® v. 1.0 MYRIAD RBM PANEL


CytokineMAP A MYRIAD RBM PANEL

CytokineMAP B MYRIAD RBM PANEL

AngiogenesisMAP® v. 1.0 MYRIAD RBM PANEL

LEGENDScreen™ Human PE Kit BIOLEGEND PANEL
LEGENDplex™ Human B Cell Research Use Only Research Kit or OLPS

BIOLEGEND PANEL
Panel (13-plex) (-2 Availab. Weight Points) (Accuracy Index x RKOLPS coefficient)
LEGENDplex™ Human CD8/NK Research Use Only Research Kit or OLPS

BIOLEGEND PANEL
LEGENDplex™ Human Th Cytokine Research Use Only Research Kit or OLPS

BIOLEGEND PANEL
Medical Test
Regulatory T-Cell Panel ARUP LABORATORIES PANEL Healthcare-Ready
Medical Test
Cytokine Panel ARUP LABORATORIES PANEL Healthcare-Ready
Medical Test
Cytokine Panel, TH1 ARUP LABORATORIES PANEL Healthcare-Ready

Medical Test
Carnitine Panel ARUP LABORATORIES PANEL Healthcare-Ready
Medical Test
Hepatic Function Panel ARUP LABORATORIES PANEL Healthcare-Ready
Medical Test
B-Cell Memory and Naive Panel ARUP LABORATORIES PANEL Healthcare-Ready
Natural Killer Cell and Natural Killer Medical Test

ARUP LABORATORIES PANEL Healthcare-Ready
T-Cell Panel (+2 Availability Weight Points)
OMIP-004: In-Depth Characterization of Research Use Only Epidem. or Theoretical Panel Only
N/A PANEL
Human T Regulatory Cells (-2 Availab. Weight Points) (BAI=0; ACTIONAB.=0)
OMIP-007: Phenotypic Analysis of Research Use Only Epidem. or Theoretical Panel Only
N/A PANEL
Human Natural Killer Cells (-2 Availab. Weight Points) (BAI=0; ACTIONAB.=0)
OMIP-018: Chemokine Receptor Research Use Only Epidem. or Theoretical Panel Only
N/A PANEL
Expression on Human T Helper Cells (-2 Availab. Weight Points) (BAI=0; ACTIONAB.=0)
OMIP-027: Functional Analysis of Human Research Use Only Epidem. or Theoretical Panel Only
N/A PANEL
Natural Killer Cells (-2 Availab. Weight Points) (BAI=0; ACTIONAB.=0)
OMIP-029: Human NK-Cell Research Use Only Epidem. or Theoretical Panel Only
N/A PANEL
Phenotypization (-2 Availab. Weight Points) (BAI=0; ACTIONAB.=0)
OMIP‐039: Detection and analysis of

Research Use Only Epidem. or Theoretical Panel Only
human adaptive NKG2C+ natural killer N/A PANEL
(-2 Availab. Weight Points) (BAI=0; ACTIONAB.=0)
cells


Cardiometabolic Panel OLINK PANEL

Cell Regulation Panel OLINK PANEL

Cardiovascular II Panel OLINK PANEL

Cardiovascular III Panel OLINK PANEL

Immune Response Panel OLINK PANEL

Inflammation Panel OLINK PANEL

Metabolism Panel OLINK PANEL

Neurology Panel OLINK PANEL

Neuro Exploratory Panel OLINK PANEL

Oncology II Panel OLINK PANEL


Oncology III Panel OLINK PANEL

Organ Damage Panel OLINK PANEL

Human v3 miRNA Assay NANOSTRING PANEL

MiRXES ID3EAL miRNA Assay MiRXES PANEL
OsteomiRTM - Validated Bone

TAmiRNA PANEL Healthcare-Ready Informational Purpose Test or Platform
Biomarkers
ThrombomiRTM - Biomarkers of
TAmiRNA PANEL Healthcare-Ready Informational Purpose Test or Platform
Platelet Function
ToxomiRTM - Biomarkers of Toxicity TAmiRNA PANEL Healthcare-Ready Informational Purpose Test or Platform
DNAge™ Epigenetic Aging Clock ZYMO RESEARCH SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
Epigenetic Age Analysis Version 2.0 OSIRIS GREEN SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
DNAge® test BIOVIVA SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform

EpiHealth CHRONOMICS SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
HKG
EpiAging SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
EPITHERAPEUTICS
HKG
EpiSocialpsych SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
EPITHERAPEUTICS
Targeted Sequencing For DNA HKG

SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
Methylation Analysis EPITHERAPEUTICS
HKG
EpiLiver SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
EPITHERAPEUTICS
HKG
EpiBreast SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
EPITHERAPEUTICS
TeloYears plus Advanced Ancestry Tests TELOYEARS SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
Telomere Length and

LIFE LENGTH SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
Biological Age Testing
CELL SCIENCE
Telomere Length Test SINGLE BIOMARKER Healthcare-Ready Informational Purpose Test or Platform
SYSTEMS
CD4+ T-Cell Recent Thymic Medical Test

ARUP LABORATORIES SINGLE BIOMARKER Healthcare-Ready
Emigrants (RTEs) (+2 Availability Weight Points)

CD21 (Dendritic Cell) Medical Test

by Immunohistochemistry (+2 Availability Weight Points)
CD57+ NK Cells, Peripheral Blood Medical Test

by Flow Cytometry (+2 Availability Weight Points)

Phospho-H2AX (Ser139) Cellular Kit CISBIO SINGLE BIOMARKER

Senescence Detection Kit ABCAM SINGLE BIOMARKER
DOJINDO MOLECULAR Research Use Only Research Kit or OLPS

SPiDER-ßGal SINGLE BIOMARKER
TECHNOLOGIES (-2 Availab. Weight Points) (Accuracy Index x RKOLPS coefficient)
AI Platform
Young.AI INSILICO MEDICINE DIGITAL PANEL PLATFORM Healthcare-Ready
AI Platform
Aging.AI INSILICO MEDICINE DIGITAL PANEL PLATFORM Healthcare-Ready
AI Platform
PhotoAgeClock HAUT.AI DIGITAL PANEL PLATFORM Healthcare-Ready
AI Platform
Haut.AI Skin Health HAUT.AI DIGITAL PANEL PLATFORM Healthcare-Ready

CENTERS FOR AGE
AgeMeter DIGITAL PANEL PLATFORM Approved for Clinical Use Technology
CONTROL

Health Reviser Platform HEALTH REVISER DIGITAL PANEL PLATFORM Approved for Clinical Use Technology
MEDIAGE™ Biological Age
MEDIAGE DIGITAL PANEL PLATFORM Approved for Clinical Use Technology
Measurement System
AI Platform
CarePredict Platform CAREPREDICT DIGITAL PANEL PLATFORM Approved for Clinical Use
AI Platform
Enlitic Platform ENLITIC DIGITAL PANEL PLATFORM Healthcare-Ready
Research Use Only AI Platform

Freenome Platform FREENOME DIGITAL PANEL PLATFORM
(-2 Availab. Weight Points) (+5 Availability Weight Points)
ZEBRA MEDICAL AI Platform

AI-Powered Radiology Assistant DIGITAL PANEL PLATFORM Healthcare-Ready
VISION (+5 Availability Weight Points)
AI Platform
PathAI Platform PATHAI DIGITAL PANEL PLATFORM Healthcare-Ready
AI Platform
Buoy Health Platform BUOY HEALTH DIGITAL PANEL PLATFORM Healthcare-Ready

BenevolentAI BENEVOLENT DIGITAL PANEL PLATFORM

Tempus Platform TEMPUS DIGITAL PANEL PLATFORM

KenSci Platform KENSCI DIGITAL PANEL PLATFORM Healthcare-Ready Technology
Research Use Only
Proscia Platform PROSCIA DIGITAL PANEL PLATFORM Technology
(-2 Availab. Weight Points)
DEEPMIND AI Platform
Google’s DeepMind Health AI Platform DIGITAL PANEL PLATFORM Approved for Clinical Use
TECHNOLOGIES (+5 Availability Weight Points)

ICarbonX Platform ICARBONX DIGITAL PANEL PLATFORM
NOURISH BALANCE AI Platform

Blood Chemistry Calculator DIGITAL PANEL PLATFORM Healthcare-Ready
THRIVE (+5 Availability Weight Points)
AI Platform
Ada - Symptom Checker App ADA HEALTH GMBH DIGITAL PANEL PLATFORM Approved for Clinical Use
AI Platform
Babylon Health Platform BABYLON HEALTH DIGITAL PANEL PLATFORM Approved for Clinical Use
AI Platform
Digital Nutrition Platform ZIPONGO DIGITAL PANEL PLATFORM Healthcare-Ready
BETTER Research Use Only AI Platform

Better Therapeutics Platform DIGITAL PANEL PLATFORM
THERAPEUTICS (-2 Availab. Weight Points) (+5 Availability Weight Points)

Approved for Clinical Use - 41
Biomarkers of Longevity Research Use Only - 45
Healthcare-Ready - 33
1st edition. Selection

and Current Status, Biomarker Panels Digital Panel Platforms Single Biomarkers
2019
Approved for Clinical Use
Healthcare-Ready
(waiting for clinical approval)
Research Use Only

Most Viable Panels
.6657 .7214 .7771 .8328 .8885 .9442 1.0 ACCURACY VALUES OF 3.82 4.85 5.88 6.91 7.94 8.97 10 AVAILABILITY VALUES OF
MOST VIABLE PANELS MOST VIABLE PANELS
(coming soon) (coming soon)

Most Comprehensive Panels
.6657 .7214 .7771 .8328 .8885 .9442 1.0 ACCURACY VALUES OF 3.82 4.85 5.88 6.91 7.94 8.97 10 AVAILABILITY VALUES OF
MOST COMPREHENSIVE PANELS MOST COMPREHENSIVE PANELS
(coming soon) (coming soon)

Conclusions
Conclusions
The use of biomarkers is an indispensable component of industry analytics and assessment. It is the foundation upon which measurement of Healthy
Longevity and the effectiveness of P4 (Precision, Preventive, Personalized, Participatory) Medicine and Longevity therapeutics is built. This special
analytical case study is designed as an in-depth review of the state of the art in biomarkers of biological age to advise private and public sector
participants effectively.
It was produced to offer a panoramic review of the global landscape of aging and Longevity biomarkers, containing selected lists, rankings and
enhanced profiles of more than 50 single biomarkers directly correlated with the trajectories of age-related diseases and syndromes, and exceeding
100 diverse biomarker panels for analytical data-driven comparisons that allow for an optimal integration of multiple biomarkers for practical use,
achieving highly actionable monitoring systems for healthcare, clinical practice, translational research, frontier developments that exploit the current
conditions of the rising Longevity industry, and the execution of public policies aiming to increase National Healthy Longevity that will result in a
renaissance never seen before in economic and social dynamics.
In addition to their purely descriptive and analytical approaches, the report is designed to make key strategic recommendations, and to offer guidance
regarding biomarker implementations, technologies and techniques within the reach of companies and nations today, in order to equip them with the
tools necessary for optimizing their strategy and action plans, providing specialized guidelines for business, investment and policy decision making.
The report delivers a most comprehensive list of single biomarkers and biomarker panels of biological age together with extensive and enhanced
profiles: their advantages, disadvantages, future perspectives, challenges and opportunities, with a focus on technologies currently used for
assessment; concrete analysis of routine, advanced and novel biomarkers of aging, emerging tools and platforms, and insights about the impact of
these biomarkers on health systems and clinical practice. A special treatment tracing the role of Digital Biomarkers and AI platforms as necessary and
indispensable components of the Longevity biomarker industry is also delivered, highlighting the fact that AI and data science are increasingly
necessary to handle the increasing volume of biomarker, life and health data.

Conclusions
The report’s central conclusion is that as the scope of P4 Medicine broadens actively and healthily, the number of biomarkers, measurement technologies and
platforms will increase rapidly to the thousands in the coming years. This will provide the opportunity to improve medical stratification to its maximum degree,
enabling the adoption of Personalized, Participatory, Precision and Preventive Medicine for both the young, the middle aged and the old.
This will also enable the conditions necessary for conducting more exhaustive and precise studies with samples of only one individual, and a shift away from
testing therapies using conventional model organisms and toward a more human-centered approach, due to the enormous flow of biological digital data that
will be extracted continuously, individual to individual.
These vast amounts of continuous biomarker data will make impractical the implementation of P4 Medicine by current, manual means without the use of AI
and advanced data science techniques and technologies.
Aggregation of biomarkers of Longevity, rather than biomarkers of disease only, and from healthy populations (e.g. the young, middle aged and healthy elderly),
rather than bedside data from hospital populations, will be part of everyday life due to the novel digital health platforms capable of extracting truly massive
amounts of relevant clinical data from single patients.
It is impossible to determine whether biotechnologies for Longevity have been successful if we cannot tell how advanced the aging process is in any given
individual; but at the same time the latter will not be feasible until successfully achieving highly actionable panels that allow for evaluating the aging process in
broad healthy and less healthy differentiated ranges of the population spectrum.
It in this sense that biomarkers are an essential factor in Aging Analytics Agency's strategic agenda, which includes policy proposals to national and
international governance bodies on how to effectively increase National Healthy Longevity via practical implementation of P4 medicine technologies. It is
important to develop and promote the widespread use of a panel of biomarkers that is precise enough and immediately actionable.
The report documents many aging biomarkers, and identifies from among them those which, by the metrics described (and which have never been reported in
pre existing literature), belong to the category we have named Minimum Required: the Most Viable Products for immediate implementation.
It is our hope and commitment that regardless of whether it is adopted wholesale, the results of the report’s analysis can guide relevant counterparties on
how to optimally utilize existing technologies to maximize the health of aging populations and aging economies, as soon as possible.

Conclusions
● Biomarkers of Physical ● The number of biomarkers,

Emergence on integrative
Function and Physiology measurement technologies and
platforms and complex
● Blood-based biomarkers platforms will increase rapidly to
biomarker analysis tools
● Cognitive biomarkers the thousands in the coming years.
● This will provide the opportunity to
improve medical stratification to its
maximum degree, enabling the
2 Key 2 Key adoption of Personalized,
Biomarkers Future Participatory, Precision and
Advanta
Types Advanta
Trends Preventive Medicine for both the
ges ges young, the middle aged and the old.
● This will also enable the conditions
Biomarkers necessary for conducting more
exhaustive and precise studies with
samples of only one individual, and
2 Key 2 Key a shift away from testing therapies
Biomarkers Biomarkets using conventional model
Advanta
for Longevity Advanta
Products
organisms to a more human
ges ges approach.
● Prediction
● Prevention Novel applications in medicine ● Biomarker panels
● Personalization and integration with other ● Digital biomarker platforms
● Participation biotech sectors ● Single biomarkers
● Diagnostics

Major Deliverables and Conclusions
1. What are the current most comprehensive biomarkers and panels to follow the aging trajectory and its related conditions and the most
viable or minimum required ones, and how they can be implemented in the most ideal and useful manner?
2. What leading personalised and preventive market-ready health assessments can aging biomarkers and panels bring to the existing
pipeline of healthcare entities to maximize their competitive advantage?
3. What novel updates and advances in biomarker-related research and development will impact the health industry in the next years?
Which of those should be watched closely for integration into clinics and biomedical or healthcare companies’ existing pipelines as soon
as their conditioning is achieved?
We feel that our efforts over the course of the past five years have established a solid foundation of knowledge and expertise upon which we intend
to summarize the entire landscape of aging and Longevity biomarker utilities in the health industry: the production of this new report entitled
Biomarkers of Longevity Landscape Overview 2019: Current State, Challenges and Opportunities.
This upcoming version will be a 300 page report aiming to answer these three specific questions, to be produced over the next 3-6 months, with
a new edition of this report during each financial quarter, incrementally increasing its breadth and depth as we go along, and with each edition
providing a deeper, more comprehensive and more precise understanding of the landscape. It will deliver:
● Concrete deep analysis of which biomarkers and biomarker panels are available today, its strengths and weaknesses, their accuracy,
availability and current actionability, and the opportunities and challenges related to its uses for real-time and precision monitoring of
health status, and ultimately the reversal of biological age;
● Tangible estimations of which biomarkers of aging, health and Longevity are market ready and at the stage of development necessary for
precision assessment of health status and endpoints of clinical trials and therapies;
● Highlights regarding the role of digital biomarkers and AI platforms and how they will become necessary and indispensable components of
aging and Longevity biomarker discovery, research, development and practical use.

Link to the Report: www.aginganalytics.com/biomarkers-of-longevity
E-mail: info@aginganalytics.com Website: www.aginganalytics.com
Aging Analytics Agency (AAA) Disclaimer.
The information and opinions in this report were prepared by Aging Analytics Agency. The information herein is believed by AAA to be reliable but AAA makes no representation as to the
accuracy or completeness of such information. There is no guarantee that the views and opinions expressed in this communication will come to pass. AAA may provide, may have provided
or may seek to provide advisory services to one or more companies mentioned herein. In addition, employees of AAA may have purchased or may purchase securities in one or more
companies mentioned in this report. Opinions, estimates and analyses in this report constitute the current judgment of the author as of the date of this report. They do not necessarily reflect
the opinions of AAA and are subject to change without notice. AAA has no obligation to update, modify or amend this report or to otherwise notify a reader thereof in the event that any matter
stated herein, or any opinion, estimate, forecast or analysis set forth herein, changes or subsequently becomes inaccurate. This report is provided for informational purposes only. It is not to
be construed as an offer to buy or sell or a solicitation of an offer to buy or sell any financial instruments or to participate in any particular trading strategy in any jurisdiction.

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What is the purpose of the report?

What is the purpose of the report?

What types of biomarkers are discussed in the report?

What types of biomarkers are discussed in the report?

Biomarkers of Longevity

Current State, Challenges and Opportunities

Deep Knowledge Group: Scope of Activities 13 - Biomarkers of Endocrine Function 105

Introduction 19 - Biomarkers of Immune Function 108

Report Methodology 41 - Molecular Level Biomarkers 111

The Role of AI in Biomarker Discovery and Monitoring 55 Cognitive Biomarkers 115

Selected Biomarkers by Comprehensiveness Level 67 Panels of Biomarkers of Aging 119

- Minimum Required Biomarkers 76 - Most Viable Panels 138

- Most Comprehensive Biomarkers 77 - Most Comprehensive Panels 139

- Digital Biomarkers 79 Conclusions 140

Biomarkers of Physical Function and Physiology 89 Disclaimer 145

The use of biomarkers is an indispensable component of industry analytics and assessment. It is

Aging Analytics Agency 4

Aging Analytics Agency 5

Aging Analytics Agency 6

Accuracy Assessment Availability Assessment Actionability Assessment

Aging Analytics Agency 8

1st edition. Selection

Approved for Clinical Use

Research Use Only

Research Kit Informational Purpose Epidemiological or

Stage Three: Approved for

Panels Single Biomarker Digital Panel Platform

Baseline Amplitude Level Maximum Amplitude Level

Deep Knowledge Analytics Pharma Division GovTech Division

Aging Analytics Agency Innovation Eye

Aging Analytics Agency 14

Aging Analytics Agency 15

The company has been involved in charting the

Many of these efforts are currently focused on the

Published / Q1 2019 Published / Q2 2019

Longevity Industry in Longevity Industry in Top-50 Women Top-100

Longevity Industry in Israel Longevity Industry in UK FemTech Healthcare National Longevity

Aging Analytics Agency 17

Aging Analytics Agency 18

Aging Analytics Agency 20

Aging Analytics Agency 21

Aging Analytics Agency 22

Aging Analytics Agency 23

Increased knowledge around the human

Aging Analytics Agency 24

Aging Analytics Agency 25

Amyotrophic Parkinson’s Bone density; Diagnostic Epigenetic

Aging Analytics Agency 26

Primary hallmarks of aging

Antagonistic hallmarks of aging

Integrative hallmarks of aging

Sources Image: López-Otín C., et al. The hallmarks of aging. 2013.

● Ligand‐Binding Assays (LBA), such as Enzyme‐Linked ImmunoSorbent Assay (ELISA);

● Quantitative Polymerase Chain Reaction (qPCR);

● Mass Spectrometry (MS)‐based technologies.

Aging Analytics Agency 28

Health products developer

Sources:Image: Data from Deloitte.

Radically interoperable data and AI

Sources:Image: Modiﬁed from everis.