STUDY OF AGING

• All human adults are aging; initial signs in early

decades typically minimal
• Individual tissues/ organs age at different rates within
and between individuals
• Individuals of same chronological age can have
different physiological/biological age
• Studies on humans: retrospective or prospective, at
a specific point in time in defined populations or
assessing participants long-term
• Humans have long life-span – some studies examine
aging in non-human animals and plants
 Haupt et al (2022) Cells. 11:153.

Evidence-based aging research divided into biology of aging &

age-related diseases
Studies focus on model organisms, humans in the clinic & aging
populations (public health and socioeconomic context)
SOME METHODS USED TO STUDY AGING

POPULATION STUDIES INDIVIDUAL STUDIES

• Life tables -Cross-sectional studies
• Survival curves -Longitudinal studies
• Incidence/prevalence -Environmental impact on
curves aging/disease
-Genetics and aging/
disease
-Functionality tests
-Biomarkers
LIFE TABLES
Aka: mortality or actuarial tables

• Generally constructed from census data

• Estimates survival probability for a
population: at each age what is the
probability you will die before your next
birthday?
• Information obtained: probability of
surviving a particular age, remaining life
expectancy, longevity characteristics of a
particular cohort
First examples of
Life tables
developed in 1600s
Edmond Halley
(1693)

Based on 1238
births in Breslau
(now called
Wrocław), Poland

www.halley.pl
 SURVIVAL CURVES

Graphical representation of survival data

Arking, Biology of Aging

 AGE-INCIDENCE CURVES

Cause of death in individuals

 85 years of age

National center for health statistics USA

http://www.biomedcentral.com/content/figures/1472-6874-4-S1-S14-6-l.jpg

Incidence rates for

invasive ovarian cancer

Statistics Canada
 SURVIVAL AND INCIDENCE CURVES
OVER GENERATIONS
CDC 2010 National
Vital Statistics

Figure 18.35, Arking

Biology of Aging
Survival curves for U.S.
females

Study of aging and age-related

diseases relatively recent
The aging paradox: The older we get, the happier we are
By DEBORAH NETBURN
LA TIMES AUG 24, 2016 | 10:05 AM

In a recent survey of more than

1,500 San Diego residents aged 21 to
99, researchers report that people in
their 20s were the most stressed out
and depressed, while those in their
90s were the most content.
Scientists found a clear, linear relationship between age and
mental health: The older people were, the happier they felt.

"The consistency was really striking," said Dilip Jeste, director of

the UC San Diego Center for Healthy Aging and senior author of
the study.

The results were published Wednesday in the Journal of Clinical

Psychology.
 CROSS-SECTIONAL STUDIES

Observational – measurement(s) taken at the

same point in time
Different age groups are compared
“Snapshot” of study measurement(s)
Advantages: simple, inexpensive, can look at
multiple variables, consistent sampling, convenient
for species with long life expectancy
Disadvantages: no guarantee the data collected at
specific time are representative, confounding
variables, no good estimate of cause/effect or rate
of change
 LONGITUDINAL STUDIES

Observational - measurement of aging variable(s)

repeated on the same subjects as they age
Advantages: data more reliable, subjects from same
birth cohort, can detect individual and population
changes, cause and effect, rate of change and
cross-sectional data can be obtained
Disadvantages: expensive and time-consuming,
long-term commitment of test subjects, some
assessments (eg. psychological): altered
performance due to practice, methodologies for
measurements could change
The Canadian Longitudinal Study on Aging (CLSA)
A large, national, long-term study that is following 51,338
men and women between the ages of 45 and 85 for at
least 20 years.
The study is collecting information on the changing
biological, medical, psychological, social, lifestyle and
economic aspects of people’s lives. These factors will be
studied to understand how, individually and in
combination, they have an impact in both maintaining
health and in the development of disease and disability as
people age.
The CLSA will be one of the most comprehensive studies
of its kind undertaken to date, not only in Canada but
around the world.
The CLSA Report on Health and Aging in Canada tells
us that:

• Almost 90% of CLSA participants aged 45-85 rated their

general health as good, very good or excellent.

• 95% of older Canadians rate their own mental health as

excellent, very good or good.

• Women are more likely than men to express feelings

of loneliness and social isolation, and that there is a notable
correlation between feelings of loneliness and the prevalence
of depression among older Canadians

• 44% of older Canadians report that they provide some level of

care to others, and caregiving rates are at their highest
(almost 50%) among individuals aged 55-64
STUDIES OF ENVIRONMENTAL IMPACT
ON AGING & DISEASE
Cumulative exposure to an environmental component
can alter physiological function.
All else being equal, older individuals have longer
exposure
Identification/study of “gerontogens“ - substances in
the environment that can accelerate the aging
process. http://www.allhealthsite.com/wp-content/uploads/2009/01/smoking-cause-wrinkles.gif

Eg. Smoking causes

premature aging in several
organs and tissues

www.allhealthsite.com
Nabi and Tabassum (2022) Role of Environmental Toxicants on Neurodegenerative Disorders Front. Toxicol. 4:837579.
 GENETICS, AGING & DISEASE
Linkage analysis studies and genome sequencing;
genetic polymorphisms and mutations linked with
physiological changes/diseases associated with aging
E.g. Alzheimer’s disease & apolipoprotein E (APOE)

↓ risk

↑ risk
Physiopedia
 GERIATRIC ASSESSMENT
-involves multi-dimensional, comprehensive
diagnostic assessment of physical, mental and
psycho-social health
- ability to function well and independently perform
activities of daily living (ADL)
Severity of a disability may be measured in terms of:
Does not perform the activity at all
Can only perform the activity with help of
another person
Can only perform the activity with the help of
specialized equipment
Geriatric assessment → individual care plan
 ACIVITIES OF DAILY LIVING (ADL)

ADL: routine activities fundamental for an individual

to be able to care for themselves on their own.
eg: feeding, bathing, toileting, transfer (sitting to
standing), dressing, ambulation, visual acuity

Instrumental ADL: activities not necessary for

fundamental functioning but allow an individual to
live independently
eg: cooking, cleaning, telephoning, writing, reading,
laundry, driving
http://www.aoa.acl.gov/Aging_Statistics/Profile/2012/16.aspx
MEASURING PHYSIOLOGICAL CHANGES IN
AGING

Why are some people more susceptible to

physical and mental deterioration as they get
older, while others remain healthy and sharp to
an older age?
Is it possible to measure biological age?
Researchers are trying to identify age-related
changes that gauge physical age and predict
the future onset of age-related diseases more
accurately than by counting years.
These changes = biomarkers of aging.
 BIOMARKERS

An age-related alteration in a biological parameter

is not necessarily a biomarker of aging

Current research focused on identifying age-

related changes that are not merely expressions of
aging, but also have some causal link to aging.

Challenges: how to define aging; what extraneous

and confounding variables must be controlled for;
the degree of generalization that is intended to
apply to a candidate biomarker
 BIOMARKERS

1. Predict physiological, cognitive, or physical function

in an age-related way
2. Should be a measure of an important process
3. Must be able to be tested repeatedly with minimal
invasiveness or trauma
4. Reproducible, reliable and inexpensive
5. Cross-species correlations
6. Should work as predictor of aging, disease, life-span
and/or measure of successful treatment
Can biological aging be determined by measuring
multiple biomarkers?
 PHYSIOLOGICAL CARTOGRAPHY

Method proposed to determine physiological age

and the speed of aging by measuring many
biological and physical characteristics that have a
proven link to the aging process
Examples of tests:
LDL cholesterol
Body composition (fat, muscle, bone, water)
Heart rate
Lung function (VO2max; forced vital capacity)
Blood glucose
Balance
PACE OF AGING STUDY: PROMISING
SET OF BIOMARKERS?
Longitudinal study following a population of more
than 1,000 individuals in New Zealand (Belsky et al,
2015; PNAS). Identified correlations between function
(physical, cognitive) and biomarker score.
 BIOMARKERS AND CELLULAR
SENESCENCE

Senescence is a specific cellular condition

associated with permanent growth arrest.
It is believed that senescent cells accumulate with
aging and may even cause aging.
Potential markers of cellular senescence:
Telomere length
-galactosidase
What are the links between currently proposed
biomarkers and the proposed causes or
consequences of aging?
 THEORIES (CAUSES) OF AGING

We know much more about what happens than why

Determining cause vs. effect often difficult
One underlying mechanism or several?
THEORIES
Stochastic: based on environmental factors or small
random changes that result in accumulated damage
eg. gene mutation, oxidative damage
Systemic: sequence of interconnected events
(cascade) that → one or more aging phenotypes
Intrinsic (programmed) vs. Extrinsic
Theories of Aging – Nursing Collection
From Biology of Aging, Arking
 WEAR AND TEAR THEORY

Molecules, cells and tissues cannot forever renew

themselves
Everyday life → cumulative damage → biochemical
changes in vital systems → without repair, functional
failure occurs
Many intracellular stochastic theories appear to
support “wear and tear” theory BUT “wear and tear” is
not always related to fundamental aging changes
Eg. use can increase function, negligible senescence,
we do not start at peak performance, mammals made
of similar molecules age at dramatically different rates
Anisimova et al. (2018) Protein
ALTERED PROTEINS
synthesis and quality control in
aging. Aging 10:4269-4288
 PROTEIN SYNTHESIS
-age-related ↓ in genes that regulate protein synthesis
-overall, 40 to 70 % decline in synthesis over life span
-variability between proteins and tissues

Exercise and Nutrition to Target Protein Synthesis

Impairments in Aging Skeletal Muscle (2013)
DICKINSON, J.M., E. VOLPI, and B.B. RASMUSSEN.
Exerc. Sport Sci. Rev., Vol. 41, No. 4, pp. 216-223

The loss of skeletal muscle size and function with aging and
sarcopenia may be related, in part, to an age-related muscle
protein synthesis impairment. In this review, we discuss to
what extent aging affects skeletal muscle protein synthesis and
how nutrition and exercise can be used strategically to
overcome age-related protein synthesis impairments and slow
the progression of sarcopenia.
Dickinson et al 2013
 POST-TRANSLATIONAL CHANGES

Reduced efficiency in protein degradation/removal

 https://medicaldetectivemd.com/

AGEs = advanced glycation end products

AGE levels ↑ in older individuals & those with type I diabetes

 Accumulation of proteins within or between cells → toxicity
and dysfunction
http://www.sciencedaily.com/images/2008/06/080609170803.jpg

Eg. Amyloid Plaques

Beta-amyloid (A) = normal
cleavage product of amyloid
precursor protein (APP)
If A levels elevated →
aggregation → plaques outside
of neurons
www.sciencedaily.com

Elevations in A could result from  synthesis (APP cleavage)

and/or  clearance or degradation
Plaques seen in aging brain and in disease (eg. Alzheimer’s)
Protein accumulation also part of waste accumulation theory
WASTE ACCUMULATION
THEORY
Aging caused by the
accumulation of harmful
substances and waste products.

Consequence of cellular
metabolic processes or the
uptake of exogenous
compounds.

Waste products interfere with

cellular function, gradually
destroying the cell.
Cell Injury, Aging, and Death Jacquelyn L. Banasik
 DNA DAMAGE AND REPAIR
Mutations: change in base sequence
-often more important in disease than aging
-increase in mutation frequency not usually
observed in aging tissue
DNA damage: strand breaks, oxidative damage,
DNA adducts
-usually repaired by
enzymes

-efficiency  with age

 Modified from Maynard et al. Cold Spring Harb Perspect Med 2015

-Linked with other aging theories (cause versus effect?)

-Individuals with diseases associated with mutations/
polymorphisms resulting in altered DNA repair or nuclear
structure exhibit premature aging eg. Werner syndrome,
Hutchinson-Guilford Progeria
 ERROR CATASTROPHE

Errors in DNA → faulty transcription or translation

processes → altered proteins and cellular efficiency
Accumulation over time → catastrophic breakdown
of tissue, organ or system
No supporting data:
-error rates in tissues from older individuals do not
differ from those obtained from younger individuals
-protein aging primarily due to altered 3-dimensional
structures, rather than altered amino acid sequence
Therapeutic potential – eg. Antiviral therapy
 OXIDATIVE DAMAGE

Reactive oxygen species (ROS)

-chemically reactive oxygen-containing
molecules
-intrinsic: regular cellular metabolism
-extrinsic: eg. ionizing or ultraviolet radiation
Free radicals
-chemical species containing one or more
unpaired electrons
Examples
-thermodynamically unstable O 2• OH•
-highly reactive RS• NO•
TARGETS
DNA
-nuclear and mitochondrial
-hydroxylation, strand breaks
Carbohydrates
-polysaccharide
depolymerization
Lipids
-oxidative degradation
-peroxidation of membrane
fatty acids
Proteins
-oxidation of SH groups
 ANTIOXIDANTS

Intercept oxidants before damage occurs

Prevent activation of moderate oxidants to highly
reactive products
Reacts with oxidant to produce harmless product
Dietary: vitamin E and C (tocopherol and ascorbic
acid)
Endogenous: catalase (mitochondrial); glutathione
peroxidase (cytosolic); super oxide dismutase
(SOD; mitochondrial, cytoplasmic, nuclear)
Alterations in ROS and/or antioxidants found in some
diseases.
Role in aging process?
 ROS, ANTIOXIDANTS AND AGING
Most information derived from animal studies:
Drosophila:  antioxidants →  life span
Mice: ROS and aging – conflicting evidence
Mice expressing  mitochondrial catalase →
 life span,  cataracts and cardiac disease
(Schriner et al, 2005)
Transgenic mice overexpressing antioxidants →
no change in life span (Perez et al, 2009)
Mice deficient in antioxidants →  ROS &
pathology → no change in life span
(Zhang et al 2009)
Are there differences in different areas of the body?
Brain: vulnerable to oxidative stress
high oxygen use (20 % of body supply)
high levels of oxidizable substrates
some neurodegenerative diseases associated
with alterations in oxidative stress and/or
antioxidant activity

Abstract on subsequent slide from:

Mitochondrial Decay in the Brains of Old Rats: Ameliorating
Effect of Alpha-Lipoic Acid and Acetyl-L-carnitine
Jiangang Long, Feng Gao, Liqi Tong, Carl W. Cotman, Bruce N. Ames, Jiankang Liu
Neurochem. Res 2009
Abstract: To investigate the mitochondrial decay and oxidative
damage resulting from aging, the activities/ kinetics of the
mitochondrial complexes were examined in the brains of young
and old rats as well as in old rats fed alpha-lipoic acid plus
acetyl-L-carnitine (LA/ALC). The brain mitochondria of old rats,
compared with young rats, had significantly decreased
endogenous antioxidants and superoxide dismutase activity;
more oxidative damage to lipids and proteins; and decreased
activities of complex I, IV and V. Complex I showed a decrease
in binding affinity (increase in Km) for substrates. Feeding
LA/ALC to old rats partially restored age-associated
mitochondrial dysfunction to the levels of the young rats. These
results indicate that oxidative mitochondrial decay plays an
important role in brain aging and that a combination of nutrients
targeting mitochondria, such as LA/ALC, could ameliorate
mitochondrial decay through preventing mitochondrial oxidative
damage.
Endothelial aging associated with
oxidative stress can be modulated
by a healthy Mediterranean diet.
Marín C, Yubero-Serrano EM, López-Miranda J,
Pérez-Jiménez F. Int J Mol Sci. 2013;14:8869-89.

The consumption of a Mediterranean diet improves endothelial

regenerative capacity as a result of a balance between cellular
damage and repair. The mechanisms involved in this process can
be associated with a decreased release of free radicals and a
reduction in oxidative stress, due to the protective effects of both
the monounsaturated fat and antioxidants present in this diet.
Moreover, a Mediterranean diet may protect against endothelial
cell senescence, generating a decrease in intracellular oxidative
stress, telomere shortening and cellular apoptosis. All these
mechanisms may be involved in an increased lifespan and a
lower incidence of the diseases associated with aging present in
populations which consume a Mediterranean-type diet.
 CALORIC RESTRICTION & AGING

Caloric restriction (20 to 30 %) with optimal nutrients

has been found to:
Rodents: Increase life span
Humans:  LDL and triglycerides
 HDL
 BP
 BMI
improve memory
How?  calorie intake associated with  oxidative
stress, cell stress and inflammation
DOES IT REALLY SLOW DOWN AGING?
Duan (2013). Sirtuins: from metabolic regulation to brain aging. Frontiers in aging neuroscience, 5, 36.
 semanticscholar.org

thelifegreek.com
IMMUNE SYSTEM THEORY OF AGING

Proposes that rate of aging controlled by immune

system
With age: thymus size and production of T& B
cells
Alterations in immunity change ability to protect
against invading organisms and destroy
abnormally proliferating cells
Immune response implicated in atherosclerosis &
reduction in connective tissue
 INTEGRATION OF THEORIES

Stochastic damage diverse, not always age-

dependent
Repair mechanisms less efficient with age
Abnormalities increase with time
Abnormalities could alter cellular homeostasis
Alterations in cell function → changes in functional
capacity of tissues, organs and systems
 Ability to cope with environmental demands is
diminished
Dr. Alexey Podcheko, 2015
 CELLULAR SENESCENCE

-Also called replicative senescence (RS)

-Cells do not divide indefinitely
Hayflick’s Limit – normal human cells in culture have
limited capacity to replicate (40 to 60 cell divisions)
-Cellular senescence thought to be determined by
telomeres
-Senescent cells associated with aging & longevity as
well as certain age-related diseases
Hayflick’s Limit – first described in fibroblasts by
Moorehead & Hayflick in 1961
CELLULAR SENESCENCE & AGING

-Cells from old donors divide fewer times than cells

from younger donors
-Cells from short-lived species senesce sooner
than cells from long-lived species
-Cells from donors with premature aging
syndromes senesce more rapidly than cells from
donors without these syndromes
-Cells expressing markers of senescence
accumulate in aging tissue
Based on data from Martin et al, 1970
Biology of Aging, Arking
CAUSES OF CELLULAR SENESCENCE

Meng et al. ajpath.2014

What keeps track of number of cell divisions?

Telomeres = genetic clock
Telomere length decreases with age – at critical length,
cellular senescence is triggered

CD31+ T-cell telomere length in men.

Kushner et al 2010, J. Applied Physiol.
Telomere length is differentially regulated in different
cell types www.bioscience.org
www.hubpages.com
DNA damage response
→ activation of p53 which
activates p21
P21 inhibits CDK’s
(cyclin-dependent
kinases) which decreases
Rb phosphorylation.
Lack of phosphorylated
Rb results in the failure of
expression of several
critical genes involved in
cellular division. Cellular
division stops.
 TELOMERES

From the Greek: telo = end & meros = part

Located at the ends of chromosomes
Nucleotide repeats – TTAGGG
Vary in length – 5 to 15 kb
in humans
Associated with specific
proteins to form
nucleoprotein complex

www.diseasefreeto100.com
 TELOMERE FUNCTION

Protect & stabilize chromosome ends

Prevent: DNA loss, end to end fusion,
rearrangement, DNA degradation
Facilitate complete DNA replication
Contribute to DNA positioning & pairing
Prevent cell from recognizing chromosome
ends as DNA strand breaks for
repair/apoptosis
 DNA
polymerase
only replicates
5’ to 3’
direction
RNA primers
fill in gaps,
DNA ligase
joins DNA
How are the
ends
completed?
www.uic.edu
 Telomeres form complex
secondary and tertiary structures
- capping structures (shelterins)

www.departments.oxy.edu

Denham et al, 2016

 Kim et al 2016, Aging and Disease

Patients with obstructive sleep apnea:

-higher levels of oxidative stress
-shorter telomeres
 TELOMERASE

Expressed in embryonic cells & germ cell lines

Low levels in somatic cells (cell cycle
dependent)
Reverse transcriptase and RNA component
RNA component = template for telomeric DNA
Telomerase activity – telomere length
maintained
Lack of telomerase activity – shortening of
telomeres, cellular aging and senescence
Expressed in most cancer cells
 Epel et al 2004, PNAS

Telomerase activity in peripheral blood

mononuclear cells in female caregivers
TELOMERES AND CANCER
IMPORTANCE OF CELLULAR SENESCENCE

Limiting the number of cell divisions could reduce

the likelihood of tumor formation and cancer
development
Functional changes occur as cells approach
senescence – studying these processes may
contribute to our understanding of functional losses
that occur in organs and tissues
Cellular senescence may determine maximum
longevity
Telomeres as biomarkers of aging?
 You may have more control over aging
than you think, say ‘The Telomere
Effect’ authors
• By Karen Weintraub

Molecular biologist Elizabeth Blackburn shared a

Nobel Prize for her research on telomeres —
structures at the tips of chromosomes that play a
key role in cellular aging. But she was frustrated
that important health implications of her work
weren’t reaching beyond academia.

So along with psychologist Elissa Epel, she has published her findings in a new
book aimed at a general audience — laying out a scientific case that may give
readers motivation to keep their new year’s resolutions to not smoke, eat
well, sleep enough, exercise regularly, and cut down on stress.

The main message of “The Telomere Effect,”is that you have more control
over your own aging than you may imagine. You can actually lengthen your
telomeres — and perhaps your life — by following sound health advice, the
authors argue, based on a review of thousands of studies.
 AGING IN NON-DIVIDING CELLS

Eg. Cardiac muscle cells, neurons, differentiated

cells derived from stem cells
Waste accumulation theory: ie. lipofuscin
(accumulation of lipid-rich yellowish granules in
cytoplasm)
Phagocytosis by other cells: presence of senescence
cell antigen (ie. on surface of red blood cells)
Programmed cell death (apoptosis): genome-
encoded mechanism of cell destruction due to
variety of extra- or intracellular signals
www.basis.ncl.ac.uk
 https://jakabniki.wordpress.com/

CARDIOVASCULAR
AGING

AGE IS ONE OF THE

BIGGEST RISK FACTOR
FOR CARDIOVASCULAR
DISEASE
CARDIOVASCULAR SYSTEM ANATOMY

www.newhealthadvisor.com

www.shands.org www.ottawaheart.ca
 Endothelium
Smooth muscle
Connective/elastic
tissue

https://jakabniki.wordpress.com/
 Diastolic Systolic

Blood Venous Heart Peripheral

Contractility
volume tone rate resistance

Preload Afterload

Myocardial O2 Requirement

Delivers and requires O2

Transports nutrients, cells and hormones
Removes waste
Protects the body (immune, clotting)
Regulates pH, water/ions, body temperature
 Blood pressure Vasomotor center

regulation

Veins
Heart

Sympathetic nerve
terminals

Arterioles

Kidney

Aldosterone Angiotensinogen

ACE Renin

Angiotensin II Angiotensin I
The Framingham Heart Study:
The Town That Changed America's Heart

Approximately 75 years ago, the town of Framingham

was selected by the U.S. Public Health Service as the study
site, and 5,209 healthy residents between 30 and 60 years of
age were enrolled as the first cohort of participants. It was
the first major cardiovascular study to recruit women.

In 1971, the study recruited 5,124 children (and their

spouses) of the original cohort for a second study, the
"Offspring Study." With a ‘Second Generation’ worth of data,
the Framingham Heart Study acquired an unmatched base
of scientific riches.

In 2002, 4095 participants were included in the ‘Third

Generation’ cohort of the study.
 CARDIOVASCULAR DISEASE RISK
FACTORS
Studying the impact of
multiple predictors of/
contributors to cardio-
vascular disease led to
the development of risk
calculators
 AGING AND THE VASCULATURE
Change in shape and size of endothelial cells
→ function
Major arteries:  thickness of smooth muscle (ie.
abdominal aorta) and elastic layers (ie.
thoracic aorta) →stiffening of arteries →
 systolic pressure
Contributors: accumulation of cellular debris,
disintegration of the elastic membrane,
 cross-linked collagen
Capillaries:  wall thickness,
decline in number/
density
Impairment of an Endothelial NAD+-H2S Signaling
Network Is a Reversible Cause of Vascular Aging
Das et al 2018, Cell
(Experiments carried out in mice)
https://www.physio-
pedia.com/Cardiovascular_Considerations_in_the_Older_Patient

Tanaka et al. Journal of the American College of

Cardiology; 2001; Vol. 37; pages 153-156.
 AGING AND THE HEART
Structural changes observed in the aging
heart when no disease present
- Enlarged left atrium and/or ventricle
- Size and  number of myocytes
-Left ventricular wall thickening
-Thickening or degenerating heart valves
-Lipofuscin deposits
-More dramatic changes can be observed in
individuals with kidney or liver damage
FUNCTIONAL CHANGES ASSOCIATED
WITH AGING
At rest – slight  in systolic blood pressure
When stressed or exercising –  maximal heart rate
and oxygen uptake   maximum workload
Additional changes identified:
 norepinephrine (NE) levels in the heart,  β-
receptor sensitivity, prolonged relaxation phase,
 response to renin-angiotensin-aldosterone
system,  blood volume and red blood cells,
 baroreceptor sensitivity
Changes in heart & blood vessels can  blood flow
to organs and tissues
 HEART AND STROKE FOUNDATION REPORT WARNS:
A "PERFECT STORM" OF HEART DISEASE LOOMING ON
OUR HORIZON

"In a very short time, the face of heart disease in Canada has
changed to include groups that have historically been immune
to the threats of heart disease," says Dr. Beth Abramson,
cardiologist and spokesperson for the Heart and Stroke
Foundation. "But the combination of new groups at-risk of heart
disease and the explosion of unhealthy habits across Canada
have accelerated the impact of these threats which are now
converging and erasing the progress we've made in treating
heart disease over the last 50 years.”

The signs of this impending crisis are clearly evident. Between

1994 and 2005, rates of high blood pressure among Canadians
young and old skyrocketed by 77%, diabetes by 45% and
obesity by 18% - all major risk factors for heart disease.
 The shape of things to come

As our population ages, the number of deaths and

hospitalizations due to heart disease and stroke will
rise significantly. Authored by Professor David Foot
from the University of Toronto, The Shape of Things
to Come: A National Report on Heart Disease and
the Challenges Ahead, predicts that within the next
25 years – by the time most baby boomers are in
their 70s –the number of deaths due to heart
disease and stroke will increase seven times faster
than Canada’s population. Furthermore, the number
of people hospitalized due to heart disease and
stroke will increase three times faster than the
population over the next 45 years.
 HYPERTENSION
Most common cardiovascular disease
•Arteries progressively stiffen with age
• genetics, stress, high salt in-take, smoking, lack
of aerobic exercise, hypercholestremia, diabetes,
influence rate of change of arterial properties
Approximately 23 % of Canadians have hypertension,
many require treatment (Statistics Canada)
•If left untreated: damage to blood vessels, renal
failure, coronary disease, stroke.
•Treatment slows blood vessel damage &
decreases morbidity & mortality
 Blood Pressure Threshold Values for
Initiation of Pharmacological Treatment
of Hypertension
Condition Initiation
SBP / DBP mmHg

Diastolic ± systolic hypertension 140/90

Isolated systolic hypertension 160

Diabetes 130/80
Renal disease (130/80)

Canadian Hypertension Society

 HYPOTENSION

Low blood pressure: Systolic/diastolic blood

pressure ≤ 90/60 mmHg
Common symptoms: dizziness, confusion, lethargy
and fainting spells
Common causes: medical and surgical conditions
(cardiovascular problems, hormonal imbalances),
dehydration, medication (anti-hypertensives)
Types: orthostatic
post-prandial
vasovagal syncope
HYPOTENSION IN THE
ELDERLY
Implicated in falls and injury
(Gangavati et al 2011, J. Am. Gertiatr. Soc.)

2010 study in Leuven, Belgium

by Fagard and De Cort:
Orthostatic hypotension is a predictor of subsequent
cardiovascular events – systolic drop of 20 mmHg or
more.
Treatment: modification of activity, replacement of lost
fluid or blood, medication adjustment, increased salt
intake, vasopressors, compression stockings
 ANGINA PECTORIS
Coronary blood vessels supply
heart with O2 & nutrients
Local blood flow regulated by
needs of heart (O2 demand)
Coronary blood flow insufficient → O2 deprivation
→  muscle strength → acute heart failure
O2 deprivation = muscle pain = angina
Pectoris = thorax
Angina pectoris → chest pain
Angina pectoris caused by imbalance between O2
supply and demand
 HEART FAILURE
Delivery of blood (cardiac output) inadequate for O2
and nutritional needs of body
 ANEURYSMS
Enlargement of a blood vessel
(usually an artery) due to
weakening of the vessel wall
(collagen and elastin
breakdown, atherosclerosis,
trauma, infection).

Rupture can be fatal.

Occur most commonly in males over 60 years of age

Risk factors: diabetes, obesity, hypertension, tobacco

use, alcoholism, high cholesterol, copper deficiency,
increasing age, syphilis infection
 NORMAL CARDIAC RHYTHM

SA node

AV node

Purkinje

Katzung Fig 14-1

Normal heart rate 60 - 80 beats/min

 ARRHYTHMIAS
Atrial arrhythmias do not always → ventricular
arrhythmias  may not affect CO
Atrial flutters: 200 - 350 beats/min
Atrial fibrillation: 300-500 beats/min
irregular and disorganized
Ventricular fibrillation: irregular rapid contraction of
ventricles → cannot pump blood properly

Semanticscholar.org

If not treated immediately - FATAL

Bonato and Canziano (2017)
Jornal Brasileiro de Nefrologia

Additional age-related risk factors for arrhythmias:

vascular stiffness, β-receptor response, valve
degeneration, cumulative effects of lifestyle choices,
medications, other diseases and disorders
 ORGANIZATION OF THE NERVOUS
SYSTEM

https://aslforhealthprofessions.com/meningitis/

www.higheredbcs.wiley.com
Spinal Cord
Sensory input, motor
output
Voluntary and autonomic
Reflex and relay pathways

Medulla, Pons and

Cerebellum
Medulla + pons regulate blood pressure and
respiration
Pons relay between cortex and cerebellum
Cerebellum controls posture, co-ordinates
movement
Midbrain
Relays information for auditory and visual systems
Involved in eye movement and motor control of skeletal
muscles
Diencephalon
Thalamus + hypothalamus
Thalamus relays information to the cortex
Hypothalamus regulates hormone secretion (pituitary)
and autonomic activity

Cerebral Hemisphere
Cerebral cortex + hippocampal formation + amygdala + basal
ganglia
Cerebral cortex : perception, cognition,
emotion, memory and motor function
Hippocampus: memory
Amygdala: emotions, autonomic and
endocrine control

Basal Ganglia: group of nuclei involved in

movement, procedural memory,
automatic/habitual behaviours,
cognition, emotion
 • Structural (brain size,
number of neurons,
AGING number of synapses)
AND THE • Electrical/biochemical
NERVOUS
SYSTEM • Metabolic and Circulatory

• Large variability between

individuals
• Additional or more
dramatic changes when
pathology present
 Few structural changes in peripheral nerves
Somatic nervous system:
1. Loss of motor neurons from spinal cord & 
number of endplates at skeletal muscle
2. Loss of sensory nerve endings in skin and
visceral organs

Autonomic nervous system:

1.  in number of SNS neurons supplying pelvic
region
2.  muscarinic receptors in bladder
3.  in β receptor number/sensitivity heart
 Conduction/sensation changes

Thresholds for the perception

of or autonomic response to
sensory afferent input
increase with age.

S. Muravchick (2000) Anesthesia for the Elderly

Conduction velocity in peripheral nerves

decreased with age

Influenced by gender, inflammation and

impaired glucose metabolism
 STRUCTURAL CHANGES

Brain Size (healthy aging)

-slight decrease in brain volume
-not correlated with change in mental ability
Species differences eg. human brain size
changes but rat brain size does not.

Brain Size
(pathology present)
Eg. Alzheimer’s disease
-large decrease in
brain volume
 CELLS OF THE NERVOUS SYSTEM
• NEURONS communicate
Number of Neurons

Some loss of neurons

in discrete areas in
healthy aging
•GLIA support
Major loss of specific
populations of
neurons → symptoms
of neurodegenerative
diseases
Spinal Cord
Some loss of motor neurons in the
spinal cord during aging – can
contribute to muscle weakness

Substantial degeneration in
amyotrophic lateral sclerosis (ALS) –
muscle weakness → paralysis

Motor Cortex
Some neuron loss with age – due to
 muscle use?

Substantial degeneration in ALS

(can also occur in brain stem)
 Hippocampus, Cortex, Nucleus Basalis

Cholinergic neurons
connect these brain
regions
Involved in learning and
memory, perception,
emotion, cognition
Little or no change in
neuron numbers in
healthy aging
> 80 % loss Alzheimer’s
disease
Basal Ganglia

Researchgate.net
Substantia Corpus striatum
nigra

LossNormal
of dopamine neurons from substantia
Dopamine (inhibitory) nigra to striatum:
-healthy aging: < 25 % loss; may contribute to
stooped posture, ACh
slow movement
(excitatory)
GABA

Substantia Corpus striatum

nigra
> 80 % loss in
Dopamine
+ Agonists
Parkinsonism Dopamine individuals with
Parkinson’s disease
ACh GABA

Antimuscarinic
Loss of GABA neurons from striatum
drugs to globus pallidus:

-Huntington’s disease
 STRUCTURAL CHANGES

Number of Synapses

When no CNS pathology present:

Loss of dendrites and
dendritic spines in cortex
(cognition/memory)
Large individual variability
 NEURONAL PLASTICITY
Neurons do not divide
repairing damage and
remodeling of connections
important
Reshaping or formation of new
synapses in response to
stimuli thought to underlie
learning & memory

With age:
Plasticity less effective (takes longer to
learn something new)
Slowing of renewal processes
 CELL PATHOLOGIES

Neuromelanin
Accumulates in locus
ceruleus and
substantia nigra and
decreases when cell
loss occurs
Reported to bind toxic
metals that could
promote
neurodegeneration.
 CELL PATHOLOGIES
Lipofuscin increases in neurons and glia but
interference with cell function controversial

Granular yellow-brown residues of

lysosomal digestion - oxidation of
polyunsaturated fatty acids.

Referred to as ‘wear and tear’

pigment.
http://www.siumed.edu/~dking2/
erg/GI150b.htm
Adaptive response or hazardous
to cellular processes?
 CELL PATHOLOGIES
Made up primarily of
Lewy bodies alpha-synuclein

Dense spherical structures that appear after

age 60

Severity of dementia
correlates with
appearance in cortex

Accumulation in
substantia nigra in
Parkinson’s disease
http://neuropathology-web.org/chapter9/chapter9dPD.html
 CELL PATHOLOGIES
Neurofibrillary tangles and plaques

Tangles = accumulation of twisted fibers (tau) within

cells of the hippocampus also seen in cortex in
Alzheimer’s disease
Plaques = extracellular deposits of amyloid proteins
in hippocampus and cortex

Plaques and/or tangles

present in aging brain
High levels of both in
Alzheimer’s disease
 STRUCTURAL CHANGES
Demyelination:
Loss of myelin or decreased rate of myelin regeneration
in aging → reduction in nerve conduction velocity

Dr. P.M. Kidd, www.thorne.com

 BIOCHEMICAL CHANGES

Some changes in
neurotransmitter Synthesis
levels, Reuptake Nerve terminal
Metabolism
metabolism and Storage

receptor function
during normal Receptor Release
aging but data Degradation

difficult to obtain Post-synaptic cell

Response

Most information obtained from

1. Action potential in presynaptic fiber
neurodegenerative diseases
ptic

2. Synthesis of transmitter
 CHOLINERGIC SYNAPSE

 ChAT in
cholinergic
neurons in
aging and
disease
METABOLIC & CIRCULATORY CHANGES

Blood-brain barrier
Endothelial cells and
astrocytes
Protects brain from
toxins
Function decreases
with age
Energy - The brain uses
glucose and oxygen to
make ATP
Supplied by cerebral
blood flow (CBF) https://healthjade.net/cerebral-circulation/

In aging individuals with no pathology present:

CBF not changed when at rest
Decreased blood flow and glucose
utilization detected in cortex when brain is
stimulated
Some correlation with  memory
Atherosclerosis and CNS
damage
Mild:  CBF compared to
younger adults
Severe:  CBF compared
to age-matched individual
with no atherosclerosis

Atherosclerosis → interruption of blood flow →

infarct
Multiple infarcts → progressive degeneration of
brain tissue (multiple infarct senile dementia)
Stroke – symptoms depend on region affected
OTHER CHANGES THAT MAY INVOLVE
THE NERVOUS SYSTEM
Sleep Apnea (central)
neurological feedback mechanisms that
monitor carbon monoxide do not react
quickly enough to maintain an even
respiratory rate
Senses
hearing, sight, smell
Endocrine functions
thermoregulation
 STRESS RESPONSE

• Stress = psychological or physical event that

alters homeostatic balance
eg. grief, health concerns, trauma, extreme
heat/cold, infection, surgery

• Stress Physiology:
1- initiation of stress response
2- termination of stress response
Neuroendocrine system: neurons regulate
hormones, hormones influence neuron function
 HPA AXIS
Regardless of type of stress, physiological
response is similar
- stress detected by CNS
- stimulation of hypothalamus (H)
to release of corticotropin
releasing hormone (CRH)
- CRH stimulates pituitary (P) to
release adrenocorticotropic
hormone (ACTH) into blood stream www.bl.cymbs.colostate.edu

- ACTH stimulates adrenal gland (A) which

releases glucocorticoids (cortisol, corticosterone)
into blood
 GLUCOCORTICOIDS
Bind to glucocorticoid receptors throughout the
body to enable the body to respond to stress:
1.  gluconeogenesis in liver
2.  mobilization of fat
3.  cardiovascular tone
4.  inflammation and
immunity
5.  anabolic processes
6. Feed back to CNS

https://www.ncbi.nlm.nih.gov/books/NBK279171/
TERMINATION OF STRESS RESPONSE
Level of neuroendocrine response dependent on
accurate detection of feedback systems

Glucocorticoid levels in
blood monitored by
hypothalamus, pituitary
and hippocampus*
Glucocorticoids bind to
glucocorticoid
receptors (GRs) in
these areas to inhibit
CRH release.

*Hippocampus has highest number of GRs in CNS

HIP= hippocampus
GR=glucocorticoid receptors
MR- mineralocorticoid receptors
PVN=paraventricular nucleus
(hypothalamus)
CRH=corticotropin releasing
hormone
AP=anterior pituitary
ACTH=adrenocorticotropic hormone
LC= locus ceruleus
AG=adrenal gland
NE=norepinephrine
E=epinephrine

www.helmholtz-muenchen
 CHRONIC STRESS
Continual or initiation of additional stressful event
prior to return to baseline →  glucocorticoid levels

1.  gluconeogenesis → diabetes
2.  lipid mobilization → dyslipidemia
3.  cardiovascular tone → hypertension
4.  immunity →  risk of disease
5.  anabolic processes →  rebuilding of tissue
(muscle loss, osteoporosis)
6. Feed back to CNS → neuron loss → cognitive
dysfunction
CHRONIC STRESS & THE HIPPOCAMPUS

Chronic stress associated with learning and memory

impairment
Prolonged exposure to
glucocorticoids:
1. Down-regulation of
hippocampal GRs
2. Neuronal and synaptic loss
(could be due to:
 vulnerability to toxins,
 neuroregeneration and/or
 neurogenesis)
Early hippocampal volume loss as a marker of
eventual memory deficits caused by repeated stress, Rahman MM et al 2016
 NEURON VULNERABILITY &
GLUCOCORTICOIDS
Glucocorticoids can:
directly affect neurons

indirectly affect neurons by altering CNS blood flow

ARE GLUCOCORTICOIDS NEUROTOXIC?
Glucocorticoids + neurotoxin → greater neuron loss
than neurotoxin alone
Glucocorticoids + neurotoxin at non-toxic dose →
neuron loss

Glucocorticoids
Enhance Oxidative
Stress-Induced Cell
Death in Hippocampal
Neurons in Vitro

Behl et al 1996

Supports hypothesis that glucocorticoids make neurons

more vulnerable to toxic insults
 CHRONIC STRESS &
NEUROREGENERATION

Damaged neuron → activation of microglia →

remove cell debris & release substances that activate
astrocytes
Activated astrocytes →  growth factor production →
regeneration of neuronal processes
Glucocorticoids inhibit microglia:
 formation of new processes
 removal of cell debris
 CHRONIC STRESS & NEUROGENESIS

Batista et al (2014), BioMed Research International,,

Article ID 438639
 STRESS PHYSIOLOGY

Enhanced glucocorticoid secretion vital

during stressful event
Excess glucocorticoid levels can result in
damage throughout the body
Proper regulation of and response to the
neuroendocrine axis and glucocorticoid
secretion is critical
Chronic stress – affects aging process,
linked with disease & associated with
reduced life-span in aging care-givers
A study of caregivers

The research team, led by Dr. Janice Kiecolt-Glaser,

conducted a 6-year study of elderly people who cared for
spouses with Alzheimer’s disease. The study not only found
a significant decline in the health of the caregivers when
compared to a similar group of non-caregivers, but also
found that the caregivers had a much higher death rate.

The demands on a caregiver result in enormous stress. The

study found that stress creates physiological changes in the
human body. Providing supervision or physical assistance
during many hours a week, and over a period of years, is
extremely stressful. This type of stress often occurs day
after day, week after week. Its long-term effects are more
pronounced in middle-aged and older people — precisely
the group that most often provides long-term care to loved
ones.
 STRESS & AGING

Aging associated with an

impaired capacity to
respond to stress
Stress associated with
accelerating the
degenerative aspects of
aging
Is there a change in
stress response in aging?
 STRESS & AGING IN RATS
Respond to stress normally (activation), delay in
termination of endocrine stress response
Hypothalamus and pituitary function unchanged
Some neuron loss in hippocampus*
*Loss of neurons ~ 20%, loss of glucocorticoid receptors ~ 50%

 Feedback impaired – stress response prolonged

Feng et al (2019). Frontiers in Molecular Neuroscience. 12..

Life experience of rat modulates response to stress
Rats handled frequently in first few weeks of life:
lower basal levels of glucocorticoids & faster stress
response shut-off (many studies – eg. Modification of the
corticosterone response curve as a function of handling
in infancy, Hess et al 1969)

Effects of previous physical exercise to chronic

stress on long-term aversive memory and oxidative
stress in amygdala and hippocampus of rats.
(Dos Santos et al 2016) Findings suggest that physical
exercise during development may protect against
aversive memory impairment and brain oxidative
damage caused by chronic stress exposure later in life.
 STRESS & AGING IN HUMANS
No consistent changes in basal glucocorticoid levels
or neuroendocrine response to stress
However – aging humans generally adapt less well
to stress
1. Require less stressful insult for
homeostasis to be disrupted
2. Body may take longer to turn off endocrine
stress response
Difficult to isolate effects of age – stress influenced
by many factors – eg. coping mechanisms, life
experiences, environment, health, genetics
 www.drsamrobbins.com
www.zrtlab.com

sleep deprived

rested

males 57-79 years of age; Lucertini et al 2015, PLoS one

Buxton et al 2010, Diabetes
In absence of CNS disorders or pathology,
neuroendocrine feedback response to single
stressful event in humans remains intact until
~ 80 years of age
Feedback following subsequent stressful events
reduced compared to younger population
Diurnal variation, levels affected by lifestyle
choices, health status
Individuals with learning/memory impairments
(hippocampus) have higher cortisol levels
Cause versus effect?
GLUCOCORTICOIDS & DEPRESSION
Chronically elevated levels of glucocorticoids
correlated with depression
Thought to be due to CNS-mediated  in
secretion and  in feedback inhibition
Patients treated successfully with antidepressants:
→↓ glucocorticoid levels & recovery of stress
response (neurogenesis and neuroplasticity?)
Some evidence supports
hippocampal damage in
patients with long history
of depression

Psychologie.de/newsticker/media
GLUCOCORTICOIDS & ALZHEIMER’S
DISEASE
Alzheimer patients have elevated levels of
glucocorticoids
Hippocampus primary site of neurodegeneration
in the disease
Alzheimer’s
disease alters
response of the body
brain to stress
Chronic stress
linked to
progression of AD
https://herbalpainrelief.co.nz/stress-and-alzheimers-disease/
OTHER GLUCOCORTICOID ACTIONS
Glucocorticoids –  release of gonadotropin
releasing hormone →  reproductive hormone
levels
Relationship to sexual dysfunction in aging?

Cortisol –  storage of
abdominal fat
 incidence of hypertension,
diabetes, cerebrovascular
and cardiovascular disease,
hyperlipidemia
CHRONIC USE OF GLUCOCORTICOIDS

Glucocorticoids used therapeutically

eg. inflammatory bowel disease
arthritis, organ transplant

Side-effects of prolonged use can include:

diabetes, osteoporosis, impaired wound healing,
ulcers, muscle wasting

CNS effects: less well known

Long-term use associated with

depression
Cardiovascular effects:
Long-term glucocorticoid treatment characterized by:
 blood pressure
 low density lipoprotein cholesterol, triglycerides
 risk of glucose intolerance
Could contribute to exacerbation of
cardiovascular risk factors
BUT: Glucocorticoids  inflammation (plays central role
in the pathogenesis of atherosclerosis)
 glucocorticoids may exert some anti-atherosclerotic
effects
AGING AND THE URINARY SYSTEM

Urinary System: plays important role in homeostasis

removes waste products

water/electrolyte balance
acid/base regulation
blood volume/pressure
hormones (erythropoietin, renin, vitamin D
activation)
With increasing age: direct (cellular/extracellular)
or indirect (cardiovascular, endocrine, metabolic)
changes can occur
THE KIDNEY

Renal function  with

age
- begins after age 30
- ~50 % loss by age 85
Impact on homeostasis
variable
Presence of disease
can dramatically affect
homeostasis
 THE NEPHRON

Functional unit of the kidney

Bowman’s capsule -filters up
to 180 L/day
Most water reabsorbed
Collecting duct - ~1.5 L urine excreted/day
 GLOMERULAR FILTRATION

Glomerular filtration rate

(GFR)
-depends on efficiency of
renal blood flow &
glomerular integrity

Renal blood flow  ~10 % every 10 years after age 40

Wide-spread degeneration of glomerular vessels
(greater in cortical than juxtamedullary nephrons)
Changes independent of, but aggravated by
hypertension
 GLOMERULAR FILTRATION RATE

GFR determined by blood pressure, osmotic pressure

& hydrostatic pressure in glomerulus
GFR declines from 120 mL/min (age 40) to
60 to 70 mL/min (age 80)
Filtrate passes through:
Negatively charged pores (endothelial cells)
Basal lamina (glycoproteins & collagen)
Filtration slits (epithelial podocytes)
Contractile tissue in mesangial cells &
podocytes regulate local blood flow
 With  age:
-altered blood flow
(atherosclerosis)
-reduced integrity of
endothelial cells & basement
membrane (BM)
-change in epithelial cell
shape and #
-  mesangial cell #
- # glomeruli (renal mass)*
www.courses.stu.qmul.ac.uk
- proteinuria (also associated
with hypertension & diabetes)
*main effect observed in aging
 RENAL FUNCTION TESTS

Urine volume (output per 24 h)

Urinalysis
GFR – can be assessed using chemical that is
stable in plasma and is neither reabsorbed nor
secreted after glomerular filtration
GFR = urine concentration X flow
plasma concentration
eg. inulin
In clinical practice: creatinine clearance assessed
 CREATININE CLEARANCE

Creatinine = break down product of creatinine

phosphate in muscle that is filtered by
glomerulus – can be measured in urine over
time or in serum to estimate GFR

Should be calculated based on age, lean body

mass (LBM), serum creatinine (Cr) and gender
Cr clearance = (140-age) x LBM (X 0.85 if female)
72 x serum Cr
In women clearance is  85 % that of men of the
same age
National Kidney Foundation
PROXIMAL TUBULE

Active transport of sodium,

glucose, other molecules
Passive transport of urea
Ability to concentrate/ dilute
urine  with age
Normally – most glucose in
urine reabsorbed
High glucose levels – carriers
become saturated & glucose
is excreted in urine
 ASCENDING LIMB & COLLECTING
TUBULE

Reduced Na+ reabsorption

 responsiveness to
antidiuretic hormone
(ADH)
 COLLECTING DUCT

Aldosterone: decreased
responsiveness in aging
kidney
Linked to alterations in H+
(acid/base balance) and K+
secretion

With age:
-tubules become thicker, shorter & more irregular
-reduced capacity for reabsorption & secretion
-ability to rapidly concentrate or dilute urine reduced
AGE-RELATED RENAL PROBLEMS

Impaired drug excretion

Alterations in electrolyte/urine concentration –
associated with  night-time urination
Urinary tract infections
Nephritis
Renal failure (acute & chronic)
- acute more common
-results in ion, water & waste product
retention

Related: hypertension, heart failure, diabetes

 ACUTE RENAL FAILURE
Rapid loss of kidney function
Causes:

Treatment: supportive until kidney function returns

greater risk for subsequent renal failure

 CHONIC RENAL FAILURE
Slow & progressive loss of kidney function
Causes/contributing factors:

Treatment: symptomatic &

aimed at reducing
further damage
SYMPTOMS OF RENAL FAILURE

Variable – can be asymptomatic initially

Elevated blood urea: nausea, vomiting, weight
loss, altered urine output
Increased phosphates: muscle cramps, bone
damage, itching
Hyperkalemia: arrhythmias
Water retention: edema
Decreased erythropoietin - anemia
 THE BLADDER

www.thewomens.org.au

Collects urine from the kidneys

 BLADDER CONTROL
Micturition = urination
Spinobulbospinal reflex inhibited & facilitated
by higher brain regions
Autonomic and somatic control
Full bladder → signal via spinal cord to CNS =
urinary urge
Urination is consciously initiated
Incontinence = involuntary loss of urine
affects 10 to 30 % of elderly population
40 to 60 % of those in long-term care
 THE AGING BLADDER
Increased risk of infection
Increased fibrous material in walls (less elastic)
-reduced ability to stretch &
store urine
-weakening of bladder muscle
Blader collagen fiber deposition
Wolf-Johnston et al 2019 ICS
Weakened pelvic floor
Contribute to incomplete emptying, more frequent
urination, leaking & could contribute to incontinence
Many other factors predispose elderly to
incontinence
PREDISPOSITION TO INCONTINENCE
In Males:
increased prostate size (impaired urine flow,
urinary retention, detrusor instability)
In Females:
pregnancy, childbirth, estrogen deficiency
(weak pelvic floor, decreased urethral muscle
tone, weakening of external sphincter)
Other:
cognitive impairment, spinal injury, drugs,
infections, obesity, stroke, muscle/nerve damage
Incontinence is not inevitable, usually results from
larger, underlying issue
TYPES OF PERSISTENT INCONTINENCE

Stress: weakness of pelvic floor muscle – urine

loss associated with laughing, sneezing etc.
Urge: involuntary detrusor muscle contraction -
inability to delay voiding when bladder is full
Functional: unable to get to washroom in time –
physical (mobility, eyes sight), psychological
(dementia, anxiety, depression)
Overflow: weak bladder muscles (neuropathy)
or blocked urethra (cancer, stones) – bladder is
always full and leaks urine
Treatment for incontinence:
absorbent products
weight loss
exercise
behavioural modification
urethral inserts
medication

SUMMARY:
Main effect of aging = loss of glomeruli
In the absence of disease, overall resting
renal function maintained
Ability to maintain homeostatic equilibrium
under conditions of renal stress reduced
 BIOM*4050
Biomedical Aspects of Aging

Reproductive Function

Dr. Pawel M. Bartlewski

U of G Biomed 1
 Reproductive Function

Lucas Cranach the Elder “The fountain of youth”

U of G Biomed 2
 Reproductive Function

Lucas Cranach the Elder “The fountain of youth”

U of G Biomed 3
 Reproductive Function

Female Reproductive System

Fertilization site
102
103
Hormone
production

Ovary Uterus Incubator

105
Transporter
Cervix
Vagina from: Human Physiology,
107 S.I. Fox
Copulatory
organ

U of G Biomed 4
 Reproductive Function

The Menstrual Cycle

Pathways to pregnancy and parturition by P. L. Senger

U of G Biomed 5
 Reproductive Function

Antral Follicle Turnover in Women

1 wave - 56.7%
2 waves - 23.3%
20 3 waves - 16.7%
24
001

18 5 waves - 3.3%

Follicle diameter (mm)

>9mm

22 Ovulatory
20 Wave #3 16
Ov #1 14
18 Anovulatory
16 Wave #2 12
14

12 10
10
Anovulatory 8
8
Wave #1 6
6

4
menses 4
-32 -30 -28 -26 -24 -22 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0
2 menses
-28 -26 -24 -22 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0
* In all cases of multiple waves, only the final wave resulted in ovulation.
Luteal Phase Follicular Phase
Cycle day (day 0=OV)

Hess and Pierson, 2003 Fertility & Sterility

U of G Biomed 6
 Reproductive Function

Menopause

• Obvious signs of female aging

• Decline in fertility (expiry of ovarian reserve)
• Cessation of menses and ovulations
• Changes in hormone levels and sensitivity
• Physical and psychological changes

U of G Biomed 7
 Ovarian Function

Ovarian Reserve
• At 18-22 weeks post-conception, the female ovary
contains a peak number of eggs, about 300,000 in
the average case, but individual peak populations
range from 35,000 to 2.5 million.
• The size of the initial ovarian reserve is strongly
influenced by genetics, but elevated androgen levels
during prenatal development may have an adverse
effect on the early establishment of the ovarian
reserve.
• Each menstrual cycle one egg cell is released by
ovulation. In addition, the remaining follicles that
were recruited towards maturation are lost by atresia
(majority).
• Few if any egg cells are replenished during the
reproductive years.
U of G Biomed 8
 Ovarian Function

Natural Process or Deficiency Disease

1400

U of G Biomed 9
 Ovarian Function

Ovarian Reserve

• According to a recent Scottish study analyzing

the female egg supply from conception to
menopause in 350 women of various ages, in
Europe and the USA, women lose 88% of their
eggs by the age of 30, and by the age of 40 only
3% of their reserve of oocytes remain.
• Premature ovarian failure is the loss of cyclic
ovarian function before the age of 40; it affects
1% of the population.

U of G Biomed 10
 Ovarian Function

Declining Fertility

• Oocyte depletion
• Implantation rates 
• Risk of spontaneous abortion 
• Developmental abnormalities 
• Older oocytes: altered placement of
microtubules and chromosome at the second
metaphase of meiosis (oocyte competence)

U of G Biomed 11
 Points to Ponder

World’s Oldest Mothers (I)

• A British woman who gave birth at the age
of 59 is believed to be the world's oldest
natural mother.
• Dawn Brooke gave birth in 2007 without the
aid of fertility treatment, breaking the
previous world record for a natural
pregnancy by two years.
• Mrs. Brooke and her husband Raymond
avoided publicity at the time of their son's
birth 10 years ago and details have only now
emerged after some of the family spoke out.

Unit 10 U of G Biomed 12
 Points to Ponder

World’s Oldest Mothers (II)

• The 65-year-old Berlin woman, who already had 13 children

and seven grandchildren, gave birth in the summer of 2017
(quadruplets, IVF).

Unit 10 U of G Biomed 13
 Reproductive Biotechnology

World's First Child Born after Uterus

Transplantation

Mats Brännström, Professor of Obstetrics and Gynaecology at the University of

Gothenburg
Seven Swedish women have had embryos reintroduced after receiving wombs
from living donors. Now the first transplanted woman has delivered a baby –
a healthy and normally developed boy.
http://www.sciencedaily.com/releases/2014/10/141007092110.htm

U of G Biomed 14
 Reproductive Biotechnology

An Artificial Womb Successfully Grew

Baby Sheep and Humans Could Be Next

The lambs spent four weeks in the external wombs and seemed to grow
normally

https://www.theverge.com/2017/4/25/15421734/artificial-womb-fetus-biobag-uterus-lamb-sheep-birth-premie-preterm-infant

U of G Biomed 15
 Menopause

Ovarian and Endocrine Function

• Ovaries become less
responsive to stimulation
by follicle-stimulating
hormone (FSH) and
luteinizing hormone (LH)
• Body compensates by
producing more FSH and
LH
• Decrease in negative
feedback
• Estrogen (estradiol),
progesterone and other
follicular products 
• Eventually, FSH and LH 

U of G Biomed 16
 Menopause

Ovarian and Endocrine Function

• Ovaries become less
responsive to stimulation
by follicle-stimulating
hormone (FSH) and
luteinizing hormone (LH)
• Body compensates by
producing more FSH and
LH
• Decrease in negative
feedback
• Estrogen (estradiol),
progesterone and other
follicular products 
• Eventually, FSH and LH 

U of G Biomed 17
 Changes Related to Menopause

Morphological Changes

• Because hormone levels drop, changes

occur in all areas of the reproductive
system (vagina, cervix, uterus, ovaries)
• Changes are closely related to changes in
urinary system
• Estrogen receptors found throughout the
body; therefore, changes occur in other
systems as well (CNS, cardiovascular,
skeletal, etc.)

U of G Biomed 18
 Changes Related to Menopause

Tubular Genitalia
Vagina
• epithelial atrophy ( secretions and vulnerable
to mechanical injury with dryness)
• increased vaginal pH
( glycogen →  lactobacilli →  lactic acid)
• associated with increased bacterial/fungal
infections
Cervix
• epithelial atrophy and loss of fibro-muscular
stroma
• decreased mucosal secretions/sperm
transport
U of G Biomed 19
 Changes Related to Menopause

Uterus and Ovaries

Uterus
• decreased size ( 30 to 50%)
• endometrial atrophy
• glandular hyperplasia (premenopausal period)
Ovary
• decreased size, more fibrous
• hyperplasia of ovarian stroma
• accumulation of “scar tissue” (post-atrophy)

U of G Biomed 20
 Bones/Osteoporosis

Changes Related to Menopause

Skeletal system (4 to 5 years post-menopause)
• bone resorption > bone formation
• increased fragility

U of G Biomed 21
 Blood Flow/Vessels

Cardiovascular Effects
• Estradiol (E2) and progesterone (P4) have
profound effects on peripheral blood flow; E2
has vasodilator effects on the endothelium
via increased nitric oxide (NO) production.
• E2 increases circulating HDL cholesterol and
decreases LDL cholesterol, while inhibiting
LDL cholesterol oxidation – all effects
associated with reduced atherogenesis.
• However, HRT also enhances coagulation
factor synthesis; therefore, +ve effect of HRT
on overall cardiovascular disease incidence
remains unproven.
U of G Biomed 22
 General/Cardiovascular Symptoms

Hot Flushes

• Most common complaint associated with

perimenopause and menopause
• Often begin prior to menstrual cessation
• Vary in intensity and associated with:
°fatigue/disturbed sleep
°irritability
°dizziness
°headaches
°numbness of extremities
°itchiness

U of G Biomed 23
 Therapy?

Hormone Replacement Therapy

• Estrogen/progestin pills effective at treating many
symptoms of menopause BUT
• Side-effects: breast tenderness, fibroids, irritability,
weight gain, acne, fluid retention, constipation, depression
• Risks: endometrial cancer (estrogen), breast cancer, gall
bladder disease, blood clots, can aggravate seizures,
diabetes, migraines, asthma, liver disease

U of G Biomed 24
 Therapy?

Hormone Replacement Therapy

• Highly controversial
• Field complicated by the fact that many “hormone
replacement” trials were not in fact hormone replacement –
they used synthetic hormones with different properties
than the natural hormones
• Many people argue that reproductive ageing is natural
• To try to return hormone levels to what is found in young
people is unnatural and dangerous

U of G Biomed 25
 Reproductive Function

Male Reproductive System

Ampulla

Ureter Testes and accessory

sex glands:
• Ampullae of ductus
deferens
Ductus
Seminal deferens

• Seminal vesicles
vesicle

• Prostate
Seminal
vesicle duct
Excretory duct • Bulbourethral glands
Ejaculatory sinus
• Not all species have
all sex glands
Ejaculatory duct • Form a mixture of
Bulbourethral glands
fluids known as
seminal fluid

Urethra
Modified from Trainer (2007), Histology for Pathologists.

U of G Biomed 26
 Semen and Spermatogenesis

Spermatogenic Efficiency
Mitosis (proliferation)
Spermatogonia

Meiosis
Spermatocytes

Spermatids to
spermatozoa

Spermiogenesis
of haploid cells

• Estimated that 75% of spermatogonia do not survive to

become mature sperm
U of G Biomed 27
 Semen and Spermatogenesis

The Decline in Male Fertility

• Testes produce 200 to 300 million sperm daily

U of G Biomed 28
 Reproductive Function

Aging and Male Reproductive

Function
• Testes – 2 functions:
testosterone and sperm
production
• Age-related changes:
− hormone levels
− spermatogenesis
− prostate size
− sexual dysfunction
• Male menopause =
Andropause (mid-life
crisis)
− associated with 
free testosterone

U of G Biomed 29
 Reproductive Function

Male Reproductive System

•  number and
responsiveness of
Leydig cells
•  FSH (impaired
feedback)
• Both  and  LH
reported (altered
stimulation of T
secretion)
urethr
a

U of G Biomed 30
 Male Reproductive Function

Reproductive Aging in Men

Chronological Changes with Age:

• Loss of Sertoli cells
• Atrophy of seminiferous tubules
•  number seminiferous tubules containing
sperm (20-year-old ~90%; 80-year-old ~10%)
• Little morphological difference in semen
from young and old males, but
biochemical deterioration

U of G Biomed 31
 Male Reproductive Function

Erectile Dysfunction
• Incidence: age 25 – 0.4 %; age 75 – 55%
• Causes:
• Psychological
• Vascular (atherosclerosis, hardening of
veins or arteries, venous leakage)
• Neurological (toxin, trauma, diabetes
mellitus, multiple sclerosis)
• Endocrine (very low T levels)
• Treatments: depend on cause –
counseling, hormone replacement,
transplantology, implants, medication

U of G Biomed 32
 Male Reproductive Function

Penis Transplant vs. Implant

U of G Biomed 33
 Male Reproductive Function

Enlarged Prostate
• Also called benign prostate hyperplasia
(BPH)
• Most common prostate problem for men
over age 50
• >50% by age 60, 90% over age 85;
caused by changes in hormone balance
and cell growth
• Urinary symptoms: difficulty starting,
stopping urine stream; weak urine stream;
incomplete bladder emptying; frequent
urge to urinate (night-time urinating)

U of G Biomed 34
 Reproductive Function

Don't worry about avoiding

temptation... as you grow
older, it will avoid you.
Winston Churchill (1874-1965)

U of G Biomed 35
In studying for the final exam, I would like you to focus on the following aspects
of reproductive aging:

i. What are the 'rates' of declining fertility estimated using ovarian follicular
reserve/age at menopause in females and semen viability/libido in males?

ii. Briefly describe contemporary medical approaches (at east two in females
and two in males) to alleviate the consequences of reproductive aging and/or
extend the period of fertility?

iii. Describe the most apparent differences in the onset of 'reproductive

senescence' (e.g., cessation of fertility) between men and women.

Good luck!

U of G Biomed 36
 GENETICS AND AGING

True or false?
Someone who has long-lived parents has a
greater chance of living a long life themselves.
Our genes determine many of our traits –
including our health & lifespan
Longevity is related to the X or Y chromosome
Susceptibility to or protection against fatal
diseases is inherited
 EARLY GENEALOGICAL STUDIES
Alexander Graham Bell
(published in 1918)
Analysis of longevity among
descendants of Connecticut
family
Excellent correlation between
life span of parents and
offspring but offspring always
had shorter life span
Influence of the father seemed
to be greater than that of the
mother
I.C. Yuan (published in 1932)
Followed life span of southern Chinese family
Sons of long-lived parents had greater life expectancy
than those of short-lived parents
Larger proportion of women lived into their 90s

Later studies (1950s to 1990s)

Effect of maternal longevity > than paternal longevity
Longevity is heritable and environmental
 MORE RECENT RESEARCH
Genetic factors account for 25 % of the variation in
human longevity (Passarino et al 2016; Caruso et al 2022)
Greater correlation for life span between identical
twins compared to fraternal twins or other siblings
(Steves et al 2012)

Nonagenarian study: siblings & spouses - genetic

factors have higher impact in males (Montesanto et al 2011)
Children with older fathers had longer telomeres but
were more likely to have certain disease (Kuzawa et al
2012)

Overall conclusions: genetics has some effect on

length of life
SEX DIFFERENCES AND LONGEVITY
Estimates – male:female
At conception - 170:100; at birth – 106:100; at
adolescence – 100:100; at age 75 – 60:100
Consistent survival advantage of women
compared with men in all life stages: early, late,
and in total life.
Seen in every country in every year for which
reliable birth and death records exist.
Faulty gene on X chromosome:
females have a healthy ‘backup’
copy; could put males at a
greater risk of disease.
 Life-style factors:
Risky behaviours
Stress
Smoking, drinking etc.

Females generally have more illnesses, but they are

less likely to be fatal; immune response: women > men
Animal studies: treating females with male hormones 
immune response
Estrogen: antioxidant; Testosterone: bodies stronger in
the short-term, but more vulnerable later in life.
 GENE EXPRESSION AND AGING
Gene expression altered in many regions in old vs.
young humans and non-human animals (many studies)
With increasing age:
 Stress-response genes (muscle, bone, brain)
 Structural proteins (matrix proteins, collagen
deposition in cardiovascular system)
 Protein synthesis/turnover (brain, heart)
 Energy metabolism (muscle, heart)
Aging & longevity likely result from modifications of
several genes, but isolated genetic variations/
mutations have been identified that affect life span
 CALORIC RESTRICTION & AGING
Gene expression studies in mice:
CRON or CRAN (caloric restriction with
optimal/adequate nutrition) – associated with enhanced
longevity
Genes altered during aging (ie. stress response genes,
protein turnover, energy metabolism) partly or
completely suppressed by CRAN in many organ
systems, including brain, skeletal muscle & heart in
some strains of mice
Gene expression profiling could be important in
understanding aging processes and effects of CR
Manzanero et al 2011
Marcus and Morris 2008
 BARKER HYPOTHESIS
Under nutrition during pregnancy and in infancy
leads to increased risk of:
Cardiovascular
disease
Hypertension
Diabetes
mellitus
Elevated
cholesterol
Abnormal
coagulation
www.diapedia.org
 FRAMINGHAM STUDY

Studied genetic & non-genetic factors in biological

aging from participants originally part of Framingham
Heart Study and their offspring
X-ray analysis of bone: joint deformity, bone density,
bone proliferations (spurs), sclerosis
Osseographic scoring system (OSS): prevalence,
severity & location
Other information collected: sex, height, weight, BMI,
type and frequency of alcohol consumption, cigarette
consumption, type and frequency of physical activity,
hormone status
 Original cohort Offspring

Contribution of modifiable factors: minimal between

individuals of same cohort and identical chronological
age, substantial to difference between cohorts
Linkage analysis: Loci identified that are likely to be
inherited together and contain possible candidate
genes that contribute to bone aging
Conclusion: Biological bone age = combination of
genetic & environmental factors
 SINGLE-GENE TRAITS & AGING

Many genetic alterations identified that cause

segmental aspects of aging
Segmental = pathology in one or a few organ
systems
Genetic component of many diseases (diabetes,
arthritis, Alzheimer’s disease etc.)
Premature aging syndromes – at least 10 types (ie.
Down’s, Werner, Progeria): effect on aging process
fundamentally important
MUTATIONS & ALZHEIMER’S DISEASE
Confirmed if neurofibrillary tangles and amyloid
plaques present in hippocampus and cortex

Tangles = intracellular
accumulation of twisted
fibers of phosphorylated
tau protein
Plaques = extracellular
deposits of beta- amyloid
protein

Causative mutations identified

Aβ – main constituent of plaques, toxic to neurons &  tau
phosphorylation
Alzheimer’s disease – all causative mutations → Aβ

APP (Chromosome 21)

27 mutations: clustered around A
sequence to enhance cleavage or favour
A production
PS1 (Chromosome 14)
157 mutations: enhance  secretase activity or
increase PS1 stability
PS2 (Chromosome 1)
10 mutations: similar to PS1
Presenilins also involved in cell signaling, apoptosis,
calcium regulation and tau phosphorylation
APP mutations in or near secretase cleavage sites

PS form part of a complex that regulates APP cleavage

Mutations in PS alter cleavage activities of this complex
 DOWN’S SYNDROME

Aka- trisomy 21 = 3
copies of chromosome 21
Characterized by:
-delayed
development
-incomplete
development
-rapid onset of
aging in many
organ systems
Life expectancy - 1980: 25 years; today: 60 years
Those that survive into their 40 and 50s will develop
Alzheimer’s disease

Amyloid precursor protein (APP)

-found on
chromosome 21
-increased level of
APP → A
-plaques & tangles
develop (beginning at
age 12)
 HUTCHINSON-GILFORD PROGERIA
Children appear normal at
birth
Lose hair & subcutaneous fat
in year 1
Growth slows, skin thins, age
spots develop, bone
resorption increases,
connective tissue
abnormalities
Few survive beyond age 13 –
death due to complications
from atherosclerosis
Caused by point mutation in LMNA gene – encodes
Lamin A protein; scaffold component of
nuclear envelope
Mutations in Lamin A = unstable nuclear
structure & premature cell death

Ashapkin et al 2019 Front. Genet.

 WERNER SYNDROME

Accelerated aging
evident only after
puberty

Lack of adolescent
growth spurt

Hair turns gray & thins, voice weakens, age spots

develop, osteoporosis, diabetes, heart disease,
cataracts, predisposition to cancer
Median age of death = 47; caused by malignancy or
cardiovascular complications
Autosomal recessive: mutation in WRN gene –
encodes protein with exonuclease and helicase
activity
WRN – important in
DNA maintenance,
repair & replication,
telomere length
Mutated WRN
reduced activity
GENETIC POLYMORPHISMS & AGING
Eg. Apolipoprotein E (ApoE) & Alzheimer disease

ApoE (Chromosome 19):

Three isoforms (ApoE2, ApoE3, ApoE4) ApoE4
associated with  risk of developing Alzheimer
disease
Alzheimer patients with ApoE4 allele have:
greater cholinergic neuron loss, enhanced
plaque and tangle formation and earlier age of
onset than Alzheimer patients without ApoE4
allele
ApoE2 allele: neuroprotective
 GENETICS & AGING
Aging, health-span and longevity are modifiable &
intrinsically programmed processes
Siblings/children of long-lived individuals are more
likely to remain healthy longer & live to an older age
Appearance of age-associated diseases can differ by
many years in identical twins (or be absent in one)
Mutations & polymorphisms can alter aging processes
and development of age-related diseases
Detailed analysis of gene expression will likely reveal
both tissue specific & general patterns of change that
are associated with aging
Nature versus nurture?
PHARMACOLOGY AND AGING
 PHARMACOLOGY AND AGING
Seniors make up ~18 % of Canadian population
BUT consume > 30 % of prescription medications and
> 50 % of over-the-counter medications Health Canada

Age related physiological changes and  use of

medications (including polypharmacy) →  risk of
adverse effects and drug interactions
Elderly 2 to 3 times more likely to experience adverse
effect as compared to younger adults
Up to one third of hospital admissions of elderly
patients are medication related
 PHARMACOKINETICS

How a drug is handled within the body

ABSORPTION
DISTRIBUTION
METABOLISM
ELIMINATION
 ABSORPTION
Common routes of drug administration
Intravenous (IV)
Dermal
Oral
Intramuscular (IM)

Age-related changes in skin

 hydration and lipid content
 keratinization
 peripheral blood flow

 Transdermal absorption of drugs

Age-related changes in GI tract (rarely clinically
significant)
1.  gastric emptying time -Delays absorption
2.  intestinal motility -Enhances absorption
3.  blood flow to GI tract (common in congestive
heart failure) -Decreases absorption

Age-related changes in muscular system

1.  peripheral blood flow
2.  connective tissue
3.  muscle mass
 Absorption of drugs administered IM
 DISTRIBUTION

Distribution depends on water or lipid solubility of a drug

Volume of distribution= _amount of drug in the body_
amount of drug in the blood
 age →  fat content  lean body mass/ water content
Increased volume of distribution of fat-soluble drugs
Decreased cardiac output & altered regional blood flow
can affect distribution and  effectiveness of some
medications
Tissue barriers altered with age (ie blood brain barrier)
can affect drug response or risk of adverse effects
 METABOLISM
Liver is the main site of drug metabolism

Orally administered
drugs pass through
the liver before
reaching the blood
stream

= first-pass
metabolism

researchgate
Phase I Reactions
Drug converted to more easily
excreted metabolite
(rate  with  age)
Phase II Reactions
Drug or phase I metabolite combined with an
endogenous substrate to more easily excreted
metabolite (little change in aging but affected by
polypharmacy)
Liver damage/ disease or medications that  or 
expression of enzymes that metabolize other drugs
 ELIMINATION

Most drugs excreted by the kidney

Changes in renal elimination considered most
significant pharmacokinetic change in the elderly

After the age of 40

1.  renal mass
2.  renal blood flow
3.  glomerular filtration
4.  creatinine clearance
Lungs are important for elimination of volatile drugs

Eg. inhalation anesthesia

Elderly can have 
respiratory capacity
and  incidence of
pulmonary disease

 Injectable
anesthetics more
commonly used in older
patients
Harmful medication prescribing to Canadian
seniors costs $419M a year
CBC News

More than one in three Canadian seniors fills a prescription

for a risky medication that should be avoided in older
patients, say researchers who estimate $419 million a year is
spent on such drugs.
Many medications are appropriate to take before age 65, but
as a person's metabolism changes, the same drugs can
become riskier compared with other available treatments,
geriatricians say. Inappropriate prescribing among seniors
can result in hospital admissions and increased risk of death.
The 1991 release of the Beers list — an index of
potentially dangerous drugs for seniors — prompted many
patients to search their medicine chests and double-check
their prescription pill bottles for possible health hazards.
The list, compiled by a U.S. team of 12 health experts led
by Dr. Mark Beers, was initially created to determine
which drugs should be used in ambulatory and nursing
homes, given that seniors were particularly at risk from
suffering adverse side-effects, including falls, depression
and, in extreme cases, death.
 PHARMACODYNAMICS

Effect and mechanisms of action of a drug

 SENSITIVITY
 EFFECTIVENESS
 SUSCEPTIBILITY TO ADVERSE
REACTIONS

to some drugs during aging

Some evidence for age-related changes in the

responsiveness or number of receptors
PHARMACODYNAMICS IN THE AGING
NERVOUS SYSTEM
PNS:  β1 receptor activation in the heart
β-blockers used to  blood pressure may not be as
effective & can be hazardous for individuals with
respiratory disease (block of β2 receptors
→bronchoconstriction)

CNS: More sensitive to drugs that  or  CNS activity

Older patients require lower dose and serum
concentrations for same level of CNS action
Could be due to neuron loss or impaired blood-brain
barrier integrity
MAJOR GROUPS OF DRUGS USED BY
OLDER INDIVIDUALS
•Sedative-Hypnotics
•Analgesics
•Antipsychotics and antidepressants
•Antihypertensive drugs
•Lipid lowering drugs
•Antiarrythmic agents
•Antimicrobial drugs
•Anti-inflammatory drugs
 SEDATIVES AND ANALGESICS
Sedative hypnotics (ie. valium)
Analgesics (ie. opioids)
 Liver and/or kidney function
 Volume of distribution (fat soluble)
→ concentration and duration of exposure
 Blood brain barrier integrity &  drug sensitivity
→ sedation →  psychomotor control
Could affect respiratory areas in CNS – particularly if
combined with other CNS depressants (eg. alcohol)
Antipsychotic Drugs in Nursing Homes
Story by Elaine K. Howley; November 15, 2024

Alzheimer's disease and other forms of dementia, steals one’s

ability to communicate their needs and preferences. Just like for
anyone else, people with these progressive cognitive disorders
may express frustration with anger, aggression or agitation.
Those strong and difficult-to-manage emotions, however, can
sometimes become overwhelming for their caregivers.

Unfortunately, it's not uncommon for nursing homes to use

antipsychotic drugs. Antipsychotics can pose significant health
risks for older adults. For instance, haloperidol (Haldol) is a
sedative antipsychotic medication that carries an FDA warning.
When used in elderly patients with dementia-related psychosis,
Haldol significantly increases the risk of death from heart
problems, falls and infections.
Seniors in care drugged with antipsychotics to much
higher degree in B.C. than in Alberta and Ontario
by Charlie Smith on February 17th, 2022

Grace Hann has a long list of concerns about the challenges

facing seniors in B.C., ranging from their housing needs to
addressing their chronic loneliness. Also at the top of her
worries is the overprescribing of antipsychotic medications
to seniors in residential care.
A November 2020 report called Staying Apart to Stay Safe,
revealed that there was a 7 % increase in the proportion of
B.C. long-term–care residents who were dispensed
antipsychotic medicines from March 2020, when the
pandemic began, to the end of September 2020.
ANTIPSYCHOTICS & ANTIDEPRESSANTS
Antipsychotics
Overprescribed:
Used in the treatment of schizophrenia,
delirium, dementia, agitation, combativeness
and paranoid syndrome

Antidepressants
Some studies suggest they are underused:
Suicide rate in individuals over age 65 is 2 X
the national average
Symptoms often mistaken for dementia
Age-related changes
 Liver function and/or kidney function
 Sensitivity
 dosage should be started at fraction of what is used
in younger adults

Increased incidence of adverse effects

Antipsychotics inhibit dopamine pathways
Parkinson-like
side-effects
common
CDC Healthy Aging: Depression and Aging
•KEY POINTS
•Older adults often face health challenges and life
changes that may put them at greater risk for
depression.

•Depression is not a normal part of aging. It is a

treatable condition that requires medical attention.

•With the right treatment, older adults can get relief

from the symptoms of depression.
September 3, 2024
 ANTIHYPERTENSIVES
Blood pressure (particularly in western world)
increases with age
Left untreated:  incidence of stroke, congestive
heart failure and renal failure
Common treatments: angiotensin inhibitors,  or 
blockers, diuretics, calcium channel blocker
Beta-blockers may not be as effective and could
be dangerous (respiratory problems)
Diuretics problematic for patients with kidney
dysfunction
 ANTIMICROBIAL DRUGS

Age-related changes in
Host defenses
Organ system function
Exposure to microorganisms
(eg. hospitalization)
 incidence of infections in elderly
as compared to younger adults
Antimicrobials likely contribute more to prolonging
life than any other drug group
 For most antimicrobials, therapy is not different
for elderly patients

Aminoglycosides:
Drug and metabolites
toxic to kidneys  ↓ dose
or alternate drug should
be used for patients with
renal dysfunction
additional side-effects:
ototoxicity; damages
cranial nerve VIII – can
→ permanent deafness
and / or vertigo
 ANTI-INFLAMMATORY DRUGS

Arthritis common in elderly population

NSAIDs
(non-steroidal anti-inflammatory drugs)
→ incidence of GI irritation and bleeding
cleared by the kidney, can accumulate in patients
with renal dysfunction causing more kidney
damage (newer NSAIDs can cause permanent
kidney damage)
Corticosteroids →  bone & muscle mass,
immunosuppression, cognitive changes
 DRUG INTERACTIONS
Many drug interactions – physicians need to know
about all medications (including non-prescription)
Food:drug interactions
Grapefruit juice – inhibits specific P450 enzyme
responsible for metabolizing some drugs (at least 85 -
calcium channel blockers, sildenafil (Viagra),
benzodiazepines (eg. valium), antiarrhythmics)

St. John’s wort – combined with some anti-depressants

(SSRIs) → incoherence, confusion, weakness, nausea
ADVERSE DRUG REACTIONS (ADRs) IN
OLDER INDIVIDUALS
Potent &/or multiple medications
Positive correlation between number of medications
and incidence of adverse reactions; risk of adverse
effects ↑ approximately 10% with each additional drug
Most seniors (over 65 years of age) take 5 or more
prescription drugs
Those taking 10 or more drugs:
25 % age 65 and older
40% age 85 and older
65 % age 65 and older in long-term care facilities
(Canadian Institute for Health Information)
Prescription errors
Inappropriate dosage or medication
Physician does not appreciate the importance
of pharmacokinetic changes associated with
age or age-related diseases
Physician unaware of medications prescribed
by other physicians, non-prescription
medication or is unfamiliar with specific drug-
drug interactions
Non-compliance
Incorrect taking of medication
Can be deliberate (negative
experience with drug
previously, expensive)
Result from
miscommunication
(between patient and
caregiver)
Due to psychological or
physical changes
 PRACTICAL ASPECTS
Combating unhealthy lifestyles, such as smoking,
poor diet, and being sedentary (with all their
possible consequences) and prevention of risky
behavior effective in the “long run”.
Use non-pharmacological methods when possible
Take a careful patient and drug history – have
patient bring/list all other medications
(prescription/over-the- counter), herbal remedies
Enquire about allergies, tobacco, caffeine, alcohol
and recreational drug use
Be sure similar medications are not being
prescribed by more than one physician
Treatments should be prescribed with clear goals in
mind – benefits should outweigh the risks of
treatment
Dosages should be adjusted to account for altered
physiology
Keep the number of prescribed drugs to a minimum
Drug regimen should be as simple as possible
Start low and go slow
New drugs should be used with caution
Be aware of prescription costs and cheaper
alternative therapies
After treatment has begun, inquire about specific
adverse effects
Patients and caregivers should be encouraged to
report any unusual occurrences while on any
medication
Laboratory monitoring of drug levels/ therapeutic
benefit used when possible
Medications (prescription and over the counter)
should be monitored and re-evaluated regularly for
effectiveness and need
Warn of hazards of using expired medication
Wound healing, regeneration,
and aging

Matt Vickaryous, Biomedical Sciences

 “hardly a skin is without scars’
Darwin, 1883

Keywords

physiological regeneration re-epithelialization

reparative regeneration axolotl
epidermis paedomorphic
dermis metamorphic
normal (intrinsic) aging fidelity of regeneration
environmental (extrinsic) aging
dermo-epidermal junction
scar
hemostasis
inflammation
regeneration

physiological regeneration –
natural episodic loss and
replacement (e.g., hair, epithelial
cells)

Simkinet al. (2011) Current Problems in Surgery, Volume 48, 148-212

 regeneration

physiological regeneration –
natural episodic loss and
replacement (e.g., hair, epithelial
cells)

• cellular turnover is 330 billion cells/day (4 million/second)*

• new intestinal epithelial cells every 2-4 days
• new epidermis every ~four weeks

*Sender and Milo 2021 Nature Medicine 27: 45-48

 regeneration

physiological regeneration –
natural episodic loss and
replacement (e.g., hair, epithelial
cells)

But some cell types are essentially non-renewable

• annual renewal rate of cardiomyocytes = 0.5%

• essentially no renewal (oocytes, lens cells, neurons?)
regeneration

• annually replaced
• daily growth rate = 2.75cm!!

Stem cells drive antler regeneration, Volume: 379, Issue: 6634, Pages: 757-758, DOI: (10.1126/science.adg9968)
regeneration
liver regeneration
physiological regeneration –
natural episodic loss and
replacement (e.g., hair, epithelial
70% partial
cells) hepatectomy
(PHx)

reparative regeneration –
injury-induced replacement original liver
weight is
restored in
~14 days
 reparative regeneration:

zebrafish (Danio rerio)

before 1 dpa* 3 dpa 6 dpa 12 dpa 20 dpa

Regeneration
*dpa = days post-amputation
Volume 2, Issue 2, pages 72-83, 19 MAY 2015 DOI: 10.1002/reg2.33
http://onlinelibrary.wiley.com/doi/10.1002/reg2.33/full#reg233-fig-0003
• skin: structure, age-related changes, and healing

• comparative models of regeneration

➢ wound healing deteriorates with aging

agingtheafricanlion.org
• fewer progenitor cells
• reduced cell proliferation
• reduced inflammatory response

agingtheafricanlion.org
 Injury!

wound healing non-healing

(e.g., ulcer)

scar-free wound healing formation scar formation

non-specific healing
regeneration (often involving fibrosis)

specific substitution of tissues

skin has multiple barrier functions:
• mechanical
• radiation
• pathogens
• water loss

most frequently injured

organ of the body

injuries must be rapidly

addressed
skin - epidermis + dermis (+ hypodermis)

epidermis
• barrier
• keratinocytes

dermis
• fibrous reinforcement
• fibroblasts
• blood vessels
• nerves
• glands/hair

hypodermis
• adipose tissue
• connective tissue
Kawasumi et al. (2013) Current Topics in Microbiology and Immunology, Volume 367, 33 -49
 fibrillar elastic
proteoglycans
collagens fibres

epidermis

dermis

tensile resilience
hydration
strength (recoil)

Naylor et al. (2011) Maturitas, 69, 249-256

 75 years old
(buttock)

23 years old
(inner forearm)

normal
fibrillar
aging elastic fibres proteoglycans
collagen
reduction of:

Naylor et al. (2011) Maturitas, 69, 249-256

 75 years old
(buttock)

environmental
fibrillar
aging elastic fibres proteoglycans
collagen
23increases
years old
reduction
(inner of:
forearm)

75 years old
(forearm)

Naylor et al. (2011) Maturitas, 69, 249-256

unilateral dermatoheliosis

• 28 years of sun exposure

through a (vehicle) window

• thickening, loss of elastin

• result of UVA exposure

New England J Med. 2012 366:e25 DOI: 10.1056/NEJMicm1104059

• young skin has a convoluted dermo-epidermal junction
• this junction flattens with age
• the result is an increased susceptibility to trauma

Thomason & Hardman (2009) Rev. Clin. Gentol., 19, 171-181

dysfunctional repair: scars
dense
organization
of collagen

hemostasis inflammation formation + remodelling

(& clot formation) (white blood proliferation (scar
cells) (fibroblasts & formation)
blood vessels)
Kawasumi et al. (2013) Current Topics in Microbiology and Immunology, Volume 367, 33 -49
wound healing
• biological process that restores tissue integrity and homeostasis

• conserved overlapping series of events

tissue
formation tissue
inflammation remodelling

Injury

immediate to a
week 2 days to weeks
weeks to months (year)
wound healing – scar formation
tissue
formation tissue
inflammation remodelling

Injury

inflammation with aging

• large inflammatory • reduced inflammatory
response response
• lengthy period of re- • keratinocyte proliferation
epithelialization reduced, re-epithelialization
delayed
wound healing – scar formation
tissue
formation tissue
inflammation remodelling

Injury

tissue formation with aging

• abundant fibroblast • reduced fibroblast
proliferation proliferation, less fibrous
• abundant blood vessel tissue
formation • reduced blood vessel
formation
wound healing – scar formation
tissue
formation tissue
inflammation remodelling

Injury

tissue remodeling with aging

• collagen arrange in • improve collagen
parallel, diminished arrangement, but tensile
tensile strength strength remains poor
 Injury!

wound healing non-healing

(e.g., ulcer)

scar-free wound healing formation scar formation

non-specific healing
regeneration (often involving fibrosis)

specific substitution of tissues

reparative regeneration:
leopard geckos (Eublepharis macularius)

3mm full thickness biopsies

day 0 day 45
wound healing – scar vs scar-free
scar

scar-free

during scar-free: inflammation

• limited inflammation
• short period of re-epithelialization
wound healing – scar vs scar-free
scar

scar-free

during scar-free: tissue formation

• modest blood vessel growth
• fibrous tissue deposition delayed/eliminated
wound healing – scar vs scar-free
scar

scar-free

during scar-free: tissue remodeling

• original blood vessel and collagen arrangement restored
regeneration

axolotl (Ambystoma mexicanum)

reparative regeneration – injury-induced replacement

Regeneration
Volume 2, Issue 2, pages 54-71, 11 MAY 2015 DOI: 10.1002/reg2.32
http://onlinelibrary.wiley.com/doi/10.1002/reg2.32/full#reg232-fig-0001
McCusker et al., 2015 Regeneration 2(2):54-71
aging and regeneration: the axolotl

• axolotls are paedomorphic: juvenile appearance as adults

• induce metamorphosis – how well do they regenerate?

Monaghan et al., 2014 Regeneration 1(1):2-14

aging and regeneration: the axolotl

• metamorphs: regenerate slower (take twice as long)

Monaghan et al., 2014 Regeneration 1(1):2-14

 paedomorph metamorph
uninjured regenerate
regenerate

7% 100%

• metamorphs: 100% show skeletal defects

Monaghan et al., 2014 Regeneration 1(1):2-14
aging and regeneration: newts and axolotls

‘perfect’

• widespread but the

fidelity of some organs
varies with age

none

Seifert & Voss, 2013 BMC Biology 11:2

aging and regeneration: mammals

‘perfect’

• tadpoles regenerate
better than frogs

none

• early life stages regenerate better

than later life stages
Seifert & Voss, 2013 BMC Biology 11:2
aging and regeneration: mammals

• limited and largely

‘perfect’
disappears before
puberty
digit tip

portions of
the heart

none

Seifert & Voss, 2013 BMC Biology 11:2

Wound healing, regeneration, and aging

progenitor cells

cell proliferation

inflammation