262 BioScience Trends. 2023; 17(4):262-270.

Review DOI: 10.5582/bst.2023.01184

Geriatric syndromes, chronic inflammation, and advances in the

management of frailty: A review with new insights
Niuniu Li1, , Gaolin Liu2, , Hong Gao1, ,*, Qiang Wu1, Juan Meng1, Fei Wang1, Siwei Jiang1,
§ § §

Meixia Chen1, Wenhui Xu1, Yifan Zhang1, Yanjun Wang1, Yingqian Feng1, Juncai Liu1,
Cheng Xu1, Hongzhou Lu3,*
1
Department of Geriatric Medicine, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen,
Guangdong, China;
2
Washington University in St. Louis, St. Louis, United States;
3
Department of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the Third People's Hospital of Shenzhen, Shenzhen,
Guangdong, China.

SUMMARY As people age, geriatric syndromes characterized by frailty significantly impact both clinical
practice and public health. Aging weakens people's immune functions, leading to chronic low-
grade inflammation that ultimately contributes to the development of frailty. Effectively managing
geriatric syndromes and frailty can help alleviate the economic burden of an aging population. This
review delves into the intricate relationship among aging, infection-induced inflammation, chronic
inflammation, and frailty. In addition, it analyzes various approaches and interventions to address
frailty, such as smart rehabilitation programs and stem-cell treatments, offering promising solutions
in this new era. Given the importance of this topic, further research into the mechanisms of frailty is
crucial. Equally essential is the devising of relevant measures to delay its onset and the formulation
of comprehensive clinical, research, and public health strategies to enhance the quality of life for
elderly individuals.

Keywords HIV infection, community, multi-dimensional intervention, smart rehabilitation, stem cell treatments

1. Introduction multiple diseases or multiple factors (including clinical,

psychosocial, and environmental vulnerability). Based
1.1. Aging and geriatric syndromes on a literature review, four shared risk factors ‒ older
age, baseline cognitive impairment, baseline functional
With the improvement of the medical and health care impairment, and impaired mobility ‒ were identified
system, human life expectancy has gradually been across five common geriatric syndromes (pressure
extended, and life expectancy is increasing worldwide; ulcers, incontinence, falls, functional decline, and
by 2040, it is expected to further improve and exceed 80 delirium) (4). Frailty, an important clinical feature of
years in most countries (1). As of 2019, 88 out of 188 GS, is a prominent problem in aging of the population.
countries have been defined as aging societies, with the At present, the definition of frailty has not been
proportion of the population aged 65 or older exceeding completely standardized. Fried et al. proposed that
7% (2). The proportion of the population age 65 ≥ is frailty is a clinical syndrome based on studies related
estimated to increase from 9% in 2019 to 16% by 2050 to cardiovascular health, in which the reserve and
(3). Statistics indicate that the prevalence of aging-related function of several physiological systems are reduced.
diseases will increase as well. Geriatric diseases such as Those physiological systems are highly correlated
multiple comorbidities, functional impairment, cognitive with age, resulting in increased physical vulnerability
impairment, and malnutrition have garnered greater and an increased risk of falls, hospitalization, death,
attention. Geriatric medicine has emerged and developed and other adverse consequences. Frailty is believed to
over the years. be present if the patient experiences three or more of
Geriatric syndromes (GS) are a concept commonly the following: unintentional weight loss, self-reported
used in geriatric medicine that refers to syndromes exhaustion, weakness, a slow walking speed, and
with the same clinical manifestations caused by little physical activity (5). In 2013, a consensus group

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consisting of delegates from 6 major international nascent T cells is entirely dependent on the thymus.
societies conceptualized frailty as "a medical syndrome As aging occurs, one of the major changes in adaptive
with multiple causes and contributors, which is immunity is thymus degeneration, which leads to
characterized by diminished strength, endurance, and changes in the number of initial T cells. CD4 T cells can
reduced physiologic functions that increase individual's maintain their number through homeostatic proliferation,
vulnerability and dependency, and/or death" (6). while CD8 T cells significantly decrease (14). In innate
immunity, the proportion of macrophages, chemotaxis,
1.2. Frailty, geriatric syndromes, and beyond antigen-presenting capacity, and phagocytosis capacity
all decrease with age (3).
Although frailty is a main feature of GS, it is not limited
to the elderly. Studies have indicated that about 7-20% of 2.1. Low-grade chronic inflammation and frailty
the elderly are identified as frail, though it has a similar
prevalence among the middle-aged (5,7), Due to different However, some signaling pathways are abnormally
concepts, standardization, and study populations, the activated and some cytokine levels (such as IL-6, tumor
prevalence of frailty fluctuates widely (between 4-59%) necrosis factor-alpha (TNF-α), C-reactive protein (CRP),
(8). Women ages 45-79 have, on average, a higher frailty and clotting factor) abnormally increase (15). Therefore,
index and higher prevalence of frailty than men. For changes in the innate immune system are paradoxical.
every 0.1-increment in the frailty index, adjusted for On the one hand, as immune function declines, the body
established and potential risk factors for death, the risk continues to produce inflammatory factors in response to
of all-cause death increases (hazard ratio (HR): 1.68, intruders. On the other hand, most senescent cells secrete
95% confidence interval (CI): 1.66-1.71). Moreover, this a suite of cytokines, growth factors, and proteases, known
association was stronger in younger people than in older as the senescence-associated secretory phenotype (SASP)
people (7). At present, studies have also increasingly (3). The SASP is a bioactive secretome that promotes
indicated that the actual age of the elderly is not the recruitment and activation of immune cells that
sufficient to predict disease prognosis or death, which clear senescent cells when clearance fails. The process
indicates that the concept of frailty may provide a more results in the accumulation of senescent cells and SASP
objective description of chronic health problems in the factors, which eventually contributes to diminished tissue
elderly and explain the differences in disease prognosis, function and steadily elevated proinflammatory tone (16).
outcome, and quality of life (9). Frailty is an emerging In young healthy tissues, SASP is usually transient and
global health burden with significant implications for tends to contribute to the preservation or restoration of
clinical practice and public health. Frailty is dynamic but tissue homeostasis, but inflammatory factors gradually
also preventable. Strategies to prevent its pathogenesis or accumulate during aging. SASP is thought to be a driving
slow its progression are of great importance (8). The risk force behind the low-level, chronic inflammation that
factors for developing frailty involve sociodemographic, causes or exacerbates age-related pathologies (17). This
clinical, lifestyle, psychological, and biological factors particular low-grade chronic inflammatory state is called
(8,10). The relationship between chronic inflammation "inflammation" and is non-infectious inflammation (15).
and aging has become the focus of attention. At present, many studies have suggested that chronic
low-grade inflammation may be part of the underlying
2. Human immune system and frailty cause of age-related frailty (18-20). There are many
factors associated with frailty in low-grade chronic
The human immune system includes innate immunity inflammation, including IL-6, CRP, TNFα, IL-10, IL-
and adaptive immunity. With age, thymus atrophy, a 8, IL-9, and MCP-1 (21). Research has focused more on
decrease in naive lymphocytes, and decline of adaptive IL-6, TNFα, and CRP (22,23), and the conclusions are
immune function mainly manifest as follows: impaired not entirely consistent. A meta-analysis of 4,263 patients
antigen presentation, naïve T-cell priming, diminished from 45 studies by Xu et al. suggested that peripheral
cluster of differentiation (CD) 8 + T cell cytotoxic inflammatory biomarkers, i.e., lymphocytes, IL-6, CRP,
function, shrinkage of naïve B-cell and T-cell repertoires, and TNF-α, are related to frailty status (24). A meta-
and the production of lower amounts of highly acidity analysis of more than 20,000 older adults highlighted
antibodies (11). The change in innate immunity differs, that frailty and prefrailty status were directly related to
and findings have suggested that innate immunity is inflammatory markers, and especially CRP and IL-6
weakened (3). Bleve et al. demonstrated that the innate levels (25), which was consistent with Marcos-Perez
immune cells continue to function relatively well in the et al. (26). A longitudinal study of 981 community-
elderly (12). Innate immunity undergoes more subtle dwelling elderly men found that IL-6 was associated with
changes that could result in mild hyperactivity (13). frailty events, but there was no statistically significant
In adaptive immunity, adult T cell replenishment difference between CRP and frailty (27). A study of 347
relies less on thymic activity and more on homeostatic community-dwelling elderly patients found that the level
self-renewal of initial T cells, while the production of of IL-6 in pre-frail patients was significantly higher than

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that in non-frail subjects (28). Frai elderly people living indicate that the proportion of patients age 60 and older
in the community have higher levels of TNFα compared who were newly diagnosed with HIV in China increased
to healthy elderly people (29). However, Marcos-Perez from 12% to 25% from 2011 to 2019 (39, 40). In patients
et al. contend that there may be a correlation between with HIV, and especially geriatric HIV patients, frailty is
TNF-α and frailty that is significantly weaker than the the main cause threatening their life. Like in older adults
correlation between CRP and IL6 (26). In addition, the without HIV, these HIV cohort studies have indicated an
relationship between inflammatory factors and frailty increased frailty burden with age, among women, and
also differs in elderly patients of different ages. An with increased chronic comorbidities (41-43).
analysis of 80 studies (58 on frailty and 22 on sarcopenia) The higher prevalence of frailty may have multiple
by Picca et al. found that IL6 was only related to frailty factors, including direct HIV infection, suboptimal
in people < 75 years (29). medication after infection, early control of infection,
A meta-analysis by Byrne et al. suggested that or comorbidities (either infectious or non-infectious)
intervention trials in frail and sarcopenic older adults (44-46). HIV infection is a type of systemic disease.
could also reduce CRP, IL-6, and TNF-α, but there was Sustained activation of the immune system and the
a lack of literature consistency (30). The pan-immune chronic inflammatory reaction after its attack are
inflammation value (PIV) has also received attention. important factors for the early onset of frailty (47, 48).
By calculating the PIV ((neutrophils × monocytes × Compared to HIV+ non-frail men, HIV+ frail men
platelets)/lymphocytes) in 405 elderly patients, Okyar had higher levels of the serum inflammatory markers
Bas et al. concluded that both PIV and PIV-high (> 372) sCD14, sIL2Rα, sTNF-R2, IL-6, TNF-α, and CRP (after
were significantly associated with frailty independently adjusting for multiple comparisons, age, race, study site,
of confounders (31). In conclusion, CRP, IL-6, and and education) (49).
TNF-α can be used as indicators to evaluate effectiveness In conclusion, the number of elderly patients and
in the process of frailty assessment, prediction, and geriatric HIV patients will continue to rapidly increase,
intervention, and IL-6 may be of greater significance. and the relationship between chronic inflammation and
frailty warrants more attention.
2.2. HIV infection and frailty
3. Assessment and management of frailty
External infection is one of the factors for frailty.
Human immunodeficiency virus (HIV) infection Frailty is a multidimensional and dynamic spectrum
accelerates aging and can induce frailty. Illnesses that syndrome. Here, a series of specific tools targeting
are attributes of the elderly are highly frequent among frailty triggered by chronic inflammation in the elderly
people infected with HIV. However, they develop at a are proposed and discussed. Elderly who become frailty
much earlier age (10-15 years earlier), and even more are vulnerable to many medical conditions, including
so in patients treated with highly active antiretroviral cardiovascular diseases and dementia. There are
therapy (HAART) patients (32,33). Geriatric HIV is generally three stages (physical outcomes) of frailty:
defined as people 50 years of age or older who are falls, hospitalizations, and death (50). However, frailty
infected (34,35). Frailty studies in patients with acquired may be dynamic, which means there are often transitions
immune deficiency syndrome (AIDS) caused by HIV between stages including not frail, pre-fail, and frail (50).
infection suggested that patients with HIV/ARDS This variation should be considered when considering
are more likely to suffer from frailty (36). The Multi- backup management plans to avoid potential risks if
center AIDS Cohort Study (MACS) indicated that HIV frailty worsens.
infection increases the likelihood and timing of a frailty-
related phenotype compared to HIV-uninfected controls 3.1. Frailty screening and post-screening assessments
(37). Immune damage caused by HIV is characterized by
the destruction of CD4 +T cells. As the number of CD4 The screening process is the first step in considering
+T cells in patients' peripheral blood decreases, HIV- management options in most cases with a massive
related complications and mortality also increase (38). population. Popular validated screening instruments
Therefore, abnormal immune function after infections is include the Clinical Frailty Scale, FRAIL Scale,
considered to be one of the causes of frailty, which has Cardiovascular Health Study Measure, and K-FRAIL
led to an exploration of the relationship between immune scale (6). These scales are simple and can be used
aging and frailty in the non-HIV/ARDS population. under most conditions. They mostly focus on clinical
According to one study, out of a total of 566 older judgments of physical condition and rely on self-reported
patients from eastern China age 50 or older, viral questionnaires. Early screening of at-risk populations
suppression was observed in 446 (78.8%), treatment was for frailty is recommended. After preliminary screening,
immunologically effective in 410 (72.4%), and treatment professionals should determine whether a "pipeline" for
was effective in 324 (57.2%) (39). As reported, geriatric CGA and related tools is appropriate for implementation
HIV rapidly increases after HAART treatment. Data for the people being tested. The frailty assessment

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 BioScience Trends. 2023; 17(4):262-270. 265

Figure 1. A flow diagram of the frailty assessment process.

process is shown in Figure 1. implementing and periodically reviewing the treatment

There are two well-validated post-screening methods plan is recommended.
of assessing frailty: 1) the phenotypic definition of frailty Management is not only to ameliorate the patient's
and 2) the accumulation of deficits definition of frailty. health but should also focus on formulating and
The phenotype definition sticks with biological concepts, implementing health care plans. The Palliative and
considering frailty to be losing physiological reserve Therapeutic Harmonization (PATH) model is a system
(5). Frailty is considered if the patient meets 3 out of that can be applied to this process (53). It constructs
the 5 indicators among 1) weakness (grip strength), 2) a decision-making system based on the frailty score
slowness (gait speed deviation), 3) exhaustion (self- and dementia stage of the dataset's comprehensive
reported fatigue questionnaire), 4) activity decline (energy medical history and incorporates medical or surgical
expenditure from questionnaire-based calculations), and interventions. As the frailty level increases, less
5) unintentional weight loss. The accumulation of deficits aggressive treatments will be chosen, which largely
definition relies on index numbers mapped by healthcare adhere to the patients' potential well-being.
data and self-reported items (51). At most, at least 30-
40 measurements have to be taken, so this assessment 3.2. Interventions and training strategies
is comparatively time-consuming. Although there is
no gold standard for frailty assessment, FI is more Frailty is noted to be prevalent in community-dwelling
feasible for proposing follow-up management because it elderly at present (54). Infectious diseases are among
interprets frailty as a spectrum of aging, which is closer the leading critical factors for chronic inflammation and
to its dynamic nature. Therefore, this model will be frailty (55). Accordingly, different training interventions
more feasible for the identification of highly vulnerable have been proposed to reduce the development of
patients while figuring out the physiological risk frailty. The physical activity prescription by the
domains. Its quantitative nature is more systematically American College of Sports Medicine guidelines for
beneficial for assessing frailty causally linked to chronic older adults emphasizes strength and balance (56).
inflammation. There are four ongoing treatments to manage frailty:
By now, the medical community has reached a exercise, caloric and protein support, vitamin D,
consensus in consulting the guidelines published and reduction of polypharmacy (which is likely to
by the task force of the International Conference on cause adverse reactions that induce pathogenesis).
Frailty and Sarcopenia Research in 2019 (52). Strong The consensus recommendation that vitamin D is
recommendations proposed include 1) a multicomponent not universally needed should be reviewed, but the
physical activity program, 2) a progressive resistance three other components can be applied appropriately
training component, 3) a care plan addressing in different combinations. Patients' diets and quality
polypharmacy, management of sarcopenia, weight loss, may contribute to inflammatory factors and lead to
and causes of fatigue, and 4) a proper plan of social frailty. Supply of antioxidant nutrients is feasible. Oral
support (52). Several consensus-based recommendations health, gut microbiome health, and metabolome may
should also be emphasized: 1) Cognitive therapy be future research targets to explore better nutrient
is not systematically recommended, 2) Vitamin D management plans (57). Studies have indicated that
supplementation should be assigned only if it is deficient, frailty was successfully ameliorated after a combination
and 3) Hormone therapy is not recommended (52). of nutritional education and a systematic physical
These clinical suggestions are vital in an emergency training plan (58-60). Such a multi-component program
or if the patient is in severely poor health. Routinely is promising and remains the best treatment option.

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266 BioScience Trends. 2023; 17(4):262-270.

Figure 2. Elements of strength training, balance training, and nutrition support.

Specific prescription plans are outlined in Figure 2

(61,62).
However, more research and clinical controlled
trials need to be conducted to verify its efficacy and
consistency in treating frailty. An optimal set of strategies
should be formulated as soon as possible (63).

3.3. Smart rehabilitation strategies

With breakthroughs in artificial intelligence, virtual

reality, and various computer-programmed systems,
smart rehabilitation is an area that should be emphasized.
An immersive motor protocol integrated with innovative Figure 3. A conceptual graph of virtual training.
virtual reality programs was proposed by Pedroli et al.
in 2019 (64). The training program is conducted inside
a special room-sized environment named the Cave world. Devices such as balance pads, proprioceptive
Automatic Virtual Environment (CAVE). The functional footboards, and rocking footboards can also be used to
system integrates 3D full-view projectors in combination, promote the efficacy of balance training. A tablet-based
a cyclo ergometer, CAVE goggles, stationary bike, system has been found to be safer than head-mounted
and software development tool kit (SDK) inside a PC. displays and will exploit the potential of 360◦videos at
Completely virtual training and virtual reality training home. In short, high-end settings, low-end technology
are two methods of smart rehabilitation (Figure 3). (higher cost performance), fewer injuries, and portability
The exercise designed by Pedroli et al. has two main are the areas for improvement in the future.
components serving as balance training tasks: "stationary
bike riding" and "avoiding the rocks," where a virtual 3.4. Stem cell treatments
map with obstacles is simulated for patients to exercise.
The virtual model models the path of the patient to Chronic inflammation is an important mechanism
detect collisions and track his performance. Optimally, of frailty. Physiological evidence supports this claim
this training program can be applied in a lot of different and provides new insights into potential treatments.
settings, including rehabilitation centers, hospitals, and Mesenchymal stem cells (MSCs) were originally isolated
homes. The virtual environment ensures a safer location from bone marrow in 1968 (65). MSCs are plastic-
for exercise, and many more circumstances can be adherent and can differentiate into multiple lineages
simulated than a single space of limited size in the real according to in vitro experiments (66). MSCs can be

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obtained from tissue such as cord blood, adipose tissue, and management still need to be addressed. Infection
marrow, and bone marrow spaces of long bone, muscles, and non-infection inflammation can both induce the
and peripheral blood (67-72). MSCs can exhibit both pathogenesis of frailty syndromes, and they are more
immunomodulatory and immunosuppressive activity. prevalent in vulnerable elderly. Atypical presentations
By interacting with cells from the adaptive and innate of infections and under-diagnosis or over-diagnosis
immune systems, they can suppress the release of pro- of different types of infections are common in older
inflammatory cytokines. They also secrete a variety of adults, requiring multi-component interventions in a
trophic factors including growth factors, morphogens, multidisciplinary approach for treatment. Systematic
chemokines, cytokines, and extracellular vesicles that and sensitive screening and assessment are important for
facilitate an anti-inflammatory response and promote individuals with infections like HIV.
tissue repair (73-75). Therefore, this characteristic of CGA is considered to be a useful diagnostic process
MSCs means that they are a type of biological treatment with which to comprehensively assess frailty status and
that ameliorates or reverses frailty (76, 77). various GS. CGA-based interventions, multicomponent
Clinical trials have revealed that frail patients treated physical training, and multidimensional interventions
with MSCs had marked improvement in physical including stem cell treatments and nutritional support,
performance measures and inflammatory biomarkers, along with improved communication and collaboration
providing new treatment ideas for frailty. In the between healthcare sectors, have been found to be
CRATUS trial, a Phase I study revealed that intravenous, effective in hospital, community, and primary care
allogeneic, bone marrow-derived mesenchymal stem cell settings. However, caution must be exercised when
(allo-hMSC)-based therapy is safe and immunologically assessing frailty in general clinical settings. Continuous
tolerated in patients with aging frailty (n = 15 mean age management systems beyond a simple one-time
78.4 ± 4.7). The TNF-α level was found to decrease evaluation should be created.
with allo-hMSC treatment, and no significant changes At the individual level, the management of frailty
were seen in IL-6 or CRP (78). In the Phase II study, is a complex issue that requires tailored interventions
(randomized, double-blinded, and dose-finding), 30 to preserve the physical function, independence, and
patients (mean age 75.5 ± 7.3) diagnosed with frailty cognition of the elderly. At present, there is a lack of
received intravenous allo-hMSCs (100 or 200-million quality cutting-edge evidence regarding "how best to
[M]) or a placebo. Results indicated that results on the identify and treat people with frailty" and "what are the
6-minute walk test, short physical performance exam, most cost-effective interventions." The challenges of
forced expiratory volume (in 1 second), and responses managing frailty, such as the complexity of combined
on the female sexual quality of life questionnaire all interventions, limited cost-effectiveness, and the need for
improved, while the serum TNF-α level decreased in the a simple, low-cost strategy still need to be solved.
100 M group compared to that in the 200 M and placebo
groups (77). These clinical trials suggest that MSC Funding: This work was supported by a grant for a
treatment is safe and immunologically tolerated. No trial- project (JCYJ20190809143609762) under the City of
related adverse events in participants were identified Shenzhen's Science and Technology Plan.
for 12 months after infusion, (77, 78). However, the
CRATUS trial was limited due to its small sample size. Conflict of Interest: The authors have no conflicts of
Another clinical trial involving 150 subjects with interest to disclose.
frailty is nearing conclusion. It evaluated the efficacy
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