Articless43587 021 00099 3 PDF

REVIEW ARTICLE
https://doi.org/10.1038/s43587-021-00099-3
The degree of frailty as a translational measure of

health in aging
Susan E. Howlett! !1,2, Andrew D. Rutenberg3 and Kenneth Rockwood! !1 ✉
Frailty is a multiply determined, age-related state of increased risk for adverse health outcomes. We review how the degree of
frailty conditions the development of late-life diseases and modifies their expression. The risks for frailty range from subcel-
lular damage to social determinants. These risks are often synergistic—circumstances that favor damage also make repair
less likely. We explore how age-related damage and decline in repair result in cellular and molecular deficits that scale up to
tissue, organ and system levels, where they are jointly expressed as frailty. The degree of frailty can help to explain the distinc-
tion between carrying damage and expressing its usual clinical manifestations. Studying people—and animals—who live with
frailty, including them in clinical trials and measuring the impact of the degree of frailty are ways to better understand the dis-
eases of old age and to establish best practices for the care of older adults.
I
n 2014, an influential commentary decried conventional, one- are much more susceptible to adverse outcomes than those with
disease-at-a-time approaches to age-related illnesses1. This gero- lower frailty scores21. Severe frailty typically occurs more often in
science view steers away from the ‘whack-a-mole’ approach2 of women25, is observed in 12–24% of older adults and is age related26.
treating specific diseases individually—a process that often yields Increasingly, frailty is seen as modifiable, even potentially prevent-
further problems including polypharmacy3 and hospital-induced able, thereby making it a target of treatment27–31. Trials of nutrition
functional decline4,5. Instead, the geroscience agenda envisages and physical exercise face challenges in relation to blinding, types
moving toward a systems-level approach that slows the aging proof controls and measurement of dosing that can be more chal-
cess2,6. Progress has been made, for example, with human clinical lenging than pharmaceutical studies, especially for well-tolerated
trials of senolytic drugs that target senescent cells7,8. Even so, aging compounds27. These challenges must be faced in sufficiently large,
is multiply determined and has many manifestations9,10 meaning locally adapted, randomized controlled trials if the prospect of pre-
that despite any one advance, gaps will remain between the diseases vention or even mitigation is to be more than aspirational. For this,
of aging and optimal health in old age11. multicomponent programs will be important, including taking the
These gaps between healthy aging and the diseases of old age social context into account29, something not always done31. Even so,
reflect important conceptual and operational challenges in con- caution is required: one indication that the path to success may be
tinuing to address age-related impairments in health. Major non- quite long is signaled by a multicomponent trial of metformin and
communicable age-related diseases such as cancer, coronary heart exercise—instead of increasing, metformin attenuated some of the
disease, dementia, diabetes mellitus and stroke share common risk benefit associated with exercise32.
factors12,13. Their prevention, and improving poor health in old age In reviewing how frailty relates to disease in old age, we explore
more generally, requires developing new systemic interventions. how age-related damage and decline in repair in various guises are
Some such systemic interventions already exist, such as tackling the detectable. We examine frailty and its antecedents from cellular and
shared and modifiable risks of physical inactivity and poor diet12,14. molecular damage33–36 to social determinants of health such as edu-
Less appreciated has been the opportunity to ‘treat aging’1, which cation, social position, race and financial stability13,14,23. We consider
can be operationally framed as an opportunity to ‘treat frailty’11, a frailty as a means of understanding variability in aging, in translat-
proposition that can be indifferent to exactly which aging mecha- ing interventions from preclinical to clinical studies, and as an aid
nism is being targeted15. That opportunity arises because detecting to clinical decision-making. Finally, we call for the development of
widespread effects of existing and future interventions requires inte- new intervention strategies, investigation of frailty mechanisms and
grative measures of age-related health. The degree of frailty, that is, use of frailty as an outcome measure in clinical trials and in improv-
variability in risk, is a widely used, theoretically grounded means of ing hospital best practices.
quantifying health in old age. Other candidate integrative measures
of health include ‘biological age’ such as provided by ‘physiological Operationalizing frailty in humans and other animals
dysregulation’16, DNA methylation clocks17,18, telomere length and No one who has attended a thirtieth high school reunion doubts
other aging biomarkers19,20. Frailty is a coarsely grained, system- that people age at different rates. In 1979, variability in rates of aging
level measure that can be used across levels from molecular and cel- was invoked to explain the apparent decline in the mortality rate
lular measures to tissues to organs to whole organisms21—and can at extreme old ages37, positing that eventually only slow agers are
also be applied to animals22. left after the frailer rapid agers die. While late-life deceleration of
Measuring frailty offers insights into clinical medicine and pop- mortality is still debated38,39, the notion of frailty as variability in the
ulation health14,23,24. At any age, individuals with high levels of frailty risk of death in people of the same age—generalized as variability
Geriatric Medicine Research Unit, Department of Medicine, Dalhousie University & Nova Scotia Health, Halifax, Nova Scotia, Canada. 2Department of
1
Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada. 3Department of Physics and Atmospheric Science, Dalhousie University, Halifax,
Nova Scotia, Canada. ✉e-mail: kenneth.rockwood@dal.ca
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REVIEW ARTICLE NATURE AGING
in the risk of an adverse outcome to people with the same degree antecedents of differential aging. Some antecedents will be risk fac-
of exposure—is an established concept. Describing people as being tors for differential aging (such as genetic influences or social vul-
frail when they appear to be substantially ‘older than their stated nerability), while others will be features of aging, such as multiply
age’ is now part of the clinical lexicon40. determined loss of the ability to withstand stress (the idea of robust-
In 2001, several papers proposed new operational approaches to ness64) or to remove or repair damage when it arises (the idea of
frailty41–43. Since then, although many frailty tools have been devel- resilience64). The loss of either robustness or resilience is seen as
oped, two approaches have predominated (Table 1)44–46. One sees arising from the diminution in ‘physiological reserve’. A common
frailty as conforming to a phenotype or syndrome that underscores unifying definition of frailty includes both robustness and resil-
physical decline: low levels of grip strength, slow walking speed, loss ience. Frailty is an age-related, multiply determined loss of ability to
of weight, reduction in usual activities and feeling exhausted; any respond to common stressors.
three of these five features define a person as frail41. With the frailty Preclinical frailty models have been developed from both the
syndrome, the degree of frailty can be expressed as the number of phenotypic and accumulation-of-deficits approaches;22 so far, the
the five attributes that are present, which allows a six-point scale. best studied are murine models. Some items correspond to integra-
The other approach, developed by our group, sees frailty not as tive attributes (such as gait speed, usual activities41, health attitude,
a specific syndrome but as a more general age-related state of poor role function, instrumental activities of daily living and mobility in
health that is proportional to how many age-related health defi- people42,43,45,65; and gait speed, grooming, body temperature, body
cits an individual has accumulated42. Deficits can be drawn from condition score and menace reflex in mice66–68), although more
a variety of attributes or functions, the relevance of which can vary focused attributes are also available (such as hip flexor strength, cat-
depending on the context (for example, deficits related to exposure aracts, hearing loss and specific comorbidities in people; and hear-
to malaria, frostbite or prolonged mechanical ventilation). The ing loss, kyphosis, cataracts and tumors in mice67; Table 1). Frailty
degree of frailty for any individual can be expressed as the frac- tools have also been developed for use in dogs69,70 and nonhuman
tion of deficits that are present in an individual to the number that primates71. Quantifying frailty with similar approaches in both clin-
were considered in a standard clinical or epidemiological study. If ical and preclinical studies will facilitate translational research.
at least 30 age-related and adverse-outcome-associated items are
considered, the degree of frailty, for the most part, does not depend The degree of frailty contextualizes changes during aging
strongly on which items are counted21,47,48. While frailty inspires investigators, this enthusiasm is not uni-
The operationalization of each approach can vary considerably versal. Some are quoted as seeing in frailty "a pejorative concept
(Table 1), but the results remain robust. Not all five items in the that validates and reinforces the disadvantage and vulnerability
frailty phenotype are present in every database or clinic record, so of aging adults"72. Frail patients have multiple, interacting, medi-
that sometimes only four are used49. Sometimes self-reported data cal and social problems that confound the single-problem treat-
or different questions than those originally proposed are used49. ments for which much of contemporary health care is organized73.
The FRAIL scale, a self-report version, to which an item about the They can be characterized by a physician as ‘unsuitable’ for care74.
number of comorbidities has been added, is a popular variant50. Nevertheless, growing evidence suggests that the degree of frailty
The original frailty phenotype is sometimes referred to as ‘physi- helps us to understand not just risk, but the expression of chronic
cal frailty’, to distinguish it from similarly constructed frailty syn- and acquired diseases in older people.
dromes for cognitive frailty51, social frailty52 and organ-specific Indeed, a higher degree of frailty has been linked to a greater risk
frailties53. All of these are constructed with specific health deficits of disability in activities of daily living and falls75,76, delirium77–79, as
that typically increase with age and individually are associated with well as more hospital admissions, with longer lengths of stay75,80, and
adverse health outcomes. more primary care visits—all leading to greater health care costs73,81.
The frailty index is also subject to variable operationalization. Work on the degree of frailty and risk extends to a variety of clinical
Although a frailty index can be derived from any combination of settings, including critical care5, during invasive interventions46 and
symptoms, signs, laboratory values or other measures42, work with in nursing homes82.
a frailty index developed from laboratory data54 or biomarkers55
suggests quantitative differences in the distributions of the data, Frailty and COVID-19. Recent experience with coronavirus dis-
and slopes and intercepts in relation to age (Table 1). Other varia- ease 2019 (COVID-19) illustrates how frailty can integrate risk.
tions include the Clinical Frailty Scale, which proposes ordered Mortality in COVID-19 is related to the degree of frailty83–87, how-
combinations of high-information deficits to grade the degree of ever operationalized88. The mortality data from COVID-19 reflect
frailty56. The ‘modified frailty index’, especially in the American the known dose–response relationship between the degree of frailty
surgical literature, includes measures, mostly comorbidities, using and the risk of death58. Similarly, frailty is related to the risk of
a smaller number of deficits, such as a modified frailty index with COVID-19 being severe89 and to important complications, includ-
11 items (Table 1). However, such shorter versions have been criti- ing incomplete recovery90 and prolonged hospital stay85,86. Frailty
cized as being too brief to constitute a frailty index based on deficit can also be more common in people with COVID-19 who develop
accumulation5,57. delirium; mortality is especially high in this setting84,91. Indeed,
The differences between frailty as a syndrome and frailty as a new onset delirium may be a presenting symptom of COVID-19
state of deficit accumulation, although real, are easily exaggerated. (ref. 92). That delirium is associated with frailty93,94 illustrates why
Each has been used in a variety of applications, including at the patients who live with frailty can be perceived as unsuitable. By not
population level58–61. Both approaches are informative: at the group being able to describe what is wrong with them, frail patients who
level, they consistently classify people who are at an increased risk of are delirious fail to engage providers at the typical point of encoun-
death and do so in ways that tend to reduce the explanatory power of ter in health care95. As a result, delirium is underdiagnosed95.
age62. They appear to share genetic determinants63. Fundamentally, Among the patients with delirium, 37 (16%) had delirium as a
what the two main approaches have in common is that each sees primary symptom, and 84 (37%) had no typical COVID-19 symp-
frailty as rooted in aging. Each captures that not all people age at toms or signs, such as fever or shortness of breath96. Despite the
the same rates and that not everyone of the same age has the same toll taken by COVID-19, the increased risk of adverse outcomes
risk of death. Rather than searching for a single aging biomarker, noted above and the potentially negative impact of frailty on the
each approach uses more than one feature to define frailty. For response to vaccination97, frail older adults are underrepresented
each, once frailty is characterized, effort can be made to explore the in vaccine trials98,99.
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NATURE AGING REVIEW ARTICLE
Table 1 | Translational potential of frailty assessment tools in humans and mouse models
Frailty instrument Selected health deficits Strengths and weaknesses Refs.
Humans Mouse models
Frailty phenotype 1. Unintended weight loss 1. Weight loss, gain or not used Strengths: 41,68,173–
2. Weakness 2. Grip test/wire hang time 1. Simple five-point scoring system 175,187
3. Low physical activity 3. Tightrope, wheel running or open 2. Comparable measures in humans and
field test animals
4. Slow walking speed 4. Rotorod, walking speed or treadmill Weaknesses:
running speed
5. Exhaustion/endurance 5. Hang time plus rotorod or treadmill 1. Focuses only on physical frailty
running time, or inclined screen test
6. Tightrope test for gait and balance 2. Measures used in animal models are not
standardized
3. No consensus on use of weight in animal
models
Frailty index, examples 1. Gait disorders 1. Gait disorders Strengths: 42,67
of clinical signs 2. Vision loss 2. Vision loss 1. Frailty can be scored with a noninvasive
clinical exam in humans and animals
3. Resting tremor 3. Tremor 2. Many similar items can be used in
humans and animal models
4. History of malignancy 4. Tumors 3. Flexible, can use different measurements
and varying numbers of items (generally
>30 deficits)
5. Difficulties hearing 5. Hearing loss Weaknesses:
6. Skin abnormalities 6. Skin lesions, dermatitis 1. Animal models do not consider cognitive
aspects of frailty or activities of daily living
7. Abdominal abnormalities 7. Distended abdomen 2. Ideally at least 30 measures required
8. Respiratory complaints 8. Breathing disorders
9. Incontinence of stool 9. Diarrhea
10. Rectal abnormalities 10. Rectal prolapse
11. Difficulty with grooming 11. Coat condition
12. Vibration sense disorders 12. Vestibular disturbance
13. Feeling sad or depressed 13. Piloerection
14. Difficulty with memory 14. Kyphosis
15. History of stroke 15. Menace reflex
Frailty index, examples 1. Sodium 1. Sodium Strengths: 54,183
of laboratory measures 2. Potassium 2. Potassium 1. Frailty can be easily scored based on
readily available laboratory measures
3. Calcium 3. Calcium 2. Many similar items can be used in
humans and animal models
4 Glucose 4. Glucose 3. Can be created from existing datasets
5. Hemoglobin 5. Hemoglobin 4. Flexible, can use different measurements
and varying numbers of items (generally
>30 deficits)
6. Creatinine 6. Creatinine Weaknesses:
7. Systolic BP 7. Systolic BP 1. Physical, psychological, and social
components of frailty are not considered
8. Diastolic BP 8. Diastolic BP 2. Ideally at least 30 measures required
9. Urea 9. Blood urea nitrogen
10. Albumin 10. Chloride
11. AST 11. Anion gap
12. Folate 12. Carbon dioxide
13. Phosphatase 13. Heart rate
14. Protein 14. Pulse pressure
15. TSH 15. Ejection fraction
Continued

Table 1 | Translational potential of frailty assessment tools in humans and mouse models (Continued)
Frailty instrument Selected health deficits Strengths and weaknesses Refs.
Humans Mouse models
Clinical frailty scale 1. Very fit No preclinical model Strengths: 56
2. Fit 1. Simple nine-point pictorial scale that
stratifies health from fit to frail
3. Managing well 2. Useful for frailty screening
4. Very mild frailty Weaknesses:
5. Mild frailty 1. No preclinical model available
6. Moderate frailty
7. Severe frailty
8. Very severe frailty
9. Terminally ill
Tilburg Frailty Indicator Part A: determinants of frailty No preclinical model Strengths: 45
(for example, sex, age, education,
income and diseases).
Part B: score three frailty domains 1. Simple questionnaire with checkboxes
(15 items): to quantify frailty out of 15 items in three
domains as in part B
1. Physical Weaknesses:
2. Psychological 1. Determinants in part A are not scored
3. Social 2. No preclinical model available
Groningen Frailty Score four frailty domains (15 No preclinical model Strengths: 43
Indicator items):
1. Physical Simple questionnaire with checkboxes to
quantify frailty out of 15 items in four frailty
domains
2. Psychological Weaknesses:
3. Cognitive No preclinical model available
4. Social
Edmonton Frail Scale Score nine frailty domains: No preclinical model Strengths: 65
1. Cognition Simple questionnaire that quantifies frailty
based on nine domains; uses standardized
tests including the Timed Up and Go and
clock-drawing tests
2. General health status Weaknesses:
3. Functional independence No preclinical model available
4. Social support
5. Medication use
6. Nutrition
7. Mood
8. Continence
9. Self-reported performance
FRAIL scale Score five frailty components: No preclinical model Strengths: 50
1. Fatigue Simple questionnaire that quantifies frailty
based on five frailty components
2. Resistance Weaknesses:
3. Ambulation No preclinical model available
4. Illness
5. Loss of weight
This table illustrates various instruments that are used to measure frailty in human studies. The frailty phenotype and frailty index instruments, including a frailty index based solely on laboratory data, have
been translated for use in animal models. AST, aspartate aminotransferase; BP, blood pressure; TSH, thyroid stimulating hormone.
Frailty and the risk of dementia in Alzheimer disease. Alzheimer between aging and important diseases of old age. By 2011, it was
disease and late-life dementia illustrate how measuring the degree evident that clinical trials designed to prevent the accumulation of
of frailty can allow a deeper understanding of the relationship the form of the beta-amyloid protein most associated with dementia

Healthy for both cardiovascular and non-cardiovascular mortality. Frailty
was associated with a greater risk of both cardiovascular events and
mortality, independently of traditional cardiovascular risk factors.
✓
Lowest
+ = dementia A meta-analysis of older adults with atrial fibrillation revealed
risk that fewer fitter patients living with severe frailty were given oral
anticoagulants for stroke prevention than were fitter people with
atrial fibrillation120. A study using a records-based electronic frailty
Atrophic, pathological index121 confirmed that the risk of atrial fibrillation, death and gas-
trointestinal bleeding (and among women, stroke) all increased with
✓
Low the degree of frailty122. Prescription of oral anticoagulants increased
Plaques + = dementia
risk with the degree of frailty except in those with severe frailty so that
fitter people had lower rates of oral anticoagulant prescription than
Lewy bodies
did their frailer peers122. In a post hoc analysis of a clinical trial of
a direct oral anticoagulant medication (edoxaban) in patients with
High
+ = dementia
atrial fibrillation, each 0.1 increment in the frailty index was associ-
Tangles
risk ated with a greater risk of stroke or spontaneous embolism, and of
major bleeding123. Patients receiving edoxaban had a similar benefit
from oral anticoagulation as did those receiving the more traditional
Fig. 1 | Frailty is not a disease, but it profoundly influences disease
drug warfarin, but a lower risk of bleeding, save in people living
expression. The pathological changes in the brain that are thought to
with severe frailty. Thus, the degree of frailty influences responses to
increase dementia risk include plaques, tangles, Lewy bodies and ischemic
cardiovascular medications, including those frail older individuals
changes. Individuals with marked Alzheimer disease pathology may not
who are the most likely to take these drugs.
meet criteria for dementia if they are fit, with low levels of frailty, while
those with a modest neuropathological burden are at increased risk for
Frailty and outcomes of hypertension. A similar body of work
dementia if they have a high degree of frailty. This figure was modeled on
exists relating the degree of frailty with hypertension. Frailty indices
data in refs. 14,110,112,113,114,157.
have been calculated both retrospectively124 and prospectively125 in
clinical trials of antihypertensive medications. Using frailty to iden-
tify and control for heterogeneous populations of older adults125
pathologically were not working. A move was made to distinguish led to recommendations for aggressive blood pressure control
between Alzheimer disease as a biomarker-defined entity, and even in frail older adults. Even so, those same guidelines have been
Alzheimer dementia as a clinical syndrome100. Not everyone with criticized on the grounds that they do not generalize to the general
phenotypical Alzheimer disease demonstrated that they carried the population, given how restrictive typical clinical trial enrollment
toxic form of amyloid101—the resulting ‘lack of target organ engage- criteria are, even when frailty may have been measured126–128. For
ment’ was understood as the reason for much of the failure rate of this reason, guidelines have been proposed to move with great cau-
anti-amyloid therapy102,103. Drugs could result in amyloid plaques tion in people living with severe frailty or dementia127,128.
being cleared from the brain, without any detectable impact on cog-
nition103,104. Indeed, pure Alzheimer disease is uncommon; instead, The paradox of excluding those most at risk from clinical prac-
most older adults with dementia have multiple neuropathological tice guidelines. In addition to brain and cardiovascular disease, and
markers105–108. Community-based neuropathological studies show COVID-19, frailty and disease-specific risk factors overlap in dis-
that not everyone who meets clinical criteria for Alzheimer disease ease progression in a variety of illnesses, including osteoporosis129,
has dementia, and not everyone who meets dementia criteria meets HIV/AIDS130 and systemic lupus erythematosus131. Despite this,
the neuropathological criteria109,110. Instead, a host of other features, excluding patients who live with higher degrees of frailty from clini-
including age, atrophy and social position come into play. cal trials is a common, if derided, practice98,99,132–134. Nevertheless,
Age-associated health deficits that do not include known people living with mild to moderate frailty find their way into trials
dementia risk factors (for example, stroke, slow motor speed and and bring with them a higher risk of adverse outcomes135. In conse-
functional impairment) nevertheless increase the risk of late-life quence, it has been recommended that people who live with frailty
cognitive impairment111 and dementia112. Even people with a high merit closer monitoring135, and that trials in chronic diseases in
burden of Alzheimer disease pathology are at less risk of meeting which frailty is common should determine which treatments frailer
criteria for dementia if they have low frailty scores110 (Fig. 1). In late- patients might tolerate best136. Indeed, in many subgroups, includ-
life dementia, it is now appreciated that neuropathological markers ing younger people, patients with higher degrees of frailty appear to
denote risk but do not permit a definitive diagnosis of cognition be more likely to benefit from treatment.
before death. Risks of all-cause dementia are additive when con- Context matters, and especially in relation to excluding older
sidering neuropathological markers of dementing illnesses113 and adults who live with frailty; informative context also extends to social
known risk factors act even more potently in the face of frailty114. and economic settings137,138, race13,86,139 the clinical setting5,46,82,86,140,
Risks for frailty and dementia overlap—especially in relation to childhood influences141, and cohort and period effects13,142–146.
social position, education and physical activity14,115.
Frailty and age-related deficit accumulation
Frailty and clinical cardiovascular disease. Clinical studies show Deficit accumulation leading to increased frailty occurs across the
that the degree of frailty is related to the risk of various outcomes human life course. Early life influences are reflected in birth cohort
of cardiovascular disease, such as myocardial infarction, stroke, studies147,148 and cross-sectional population studies from ages 20 and
heart failure or atrial fibrillation 116–119. For example, using clinical younger149,150. Country-of-origin studies151–153 also reveal important
and test data, a 34-item frailty index was constructed from which effects. Those using data on related childhood socioeconomic con-
were excluded deficits that were traditional risk factors for cardio- ditions141,154,155 also highlight the importance of what happens in
vascular disease. The resulting 26-item frailty index was compared childhood. Genetic and proteomic studies have been done in spe-
with traditional risk as assayed using the Framingham risk score118. cial populations, such as in twin studies156–158 including adopted
Each 0.1 increment in the frailty index increased the hazard ratios twins raised apart19, or in comparing offspring of people who come

methylation changes18,19,162. Deficits arising from disruptions in cel-

lular and molecular processes then affect tissues, promote organ
dysfunction and lead to clinical manifestations and frailty21,162.
Evidence that the accumulation of subcellular deficits heralds the
development of clinical frailty includes studies with a frailty index
(FI-Lab) created from routine laboratory tests and blood tests54,150,165
or from biomarkers55. Higher FI-Lab scores are also seen in people
Balanced diet High-fat diet who live in more stressed circumstances166.
Calorie restriction Radiation therapy Deficits accumulate at a constant rate, doubling roughly every
Education Poor maternal health
Geroprotectors Low personal wealth 12–15 years167,168. The resulting pattern of accumulation shows
Exercise Polypharmacy acceleration in the number of deficits in later life, suggesting that
Social engagement Low childhood education
High personal wealth Stressful environment deficits do not accumulate independently: people who enter old age
Safe neighborhood Low social position with fewer deficits will accumulate fewer, and those who enter with
many deficits will accumulate more, as longitudinal studies show169.
In consequence, even small differences in early life can have increas-
ingly larger impacts across the life course, even into late old age.
Further, within-person acceleration in the frailty index score can
Fit Frail appear as a preterminal event170. Factors that affect deficit accumula-
tion include sex/gender, education, maternal health, social position,
race, financial stability, childhoodfrailty states, early signs of chronic
inflammation and a host of specific disease states, together with the
complex relationships between factors13,86,137–139,148,170,171. Different
studies report differing mean frailty scores. Secular effects on the
Fig. 2 | Medical interventions, lifestyle factors and social factors have a lethality of frailty appear to be important. Most studies13,143,144 but
strong impact on the prevalence of frailty. The degree of fitness or frailty not all146 report decreasing lethality in relation to frailty. In general,
in an individual is profoundly affected by lifestyle factors, social factors even with secular improvements in the mean degree of frailty13, dis-
and medical interventions. Dietary modifications (for example, calorie advantaged groups do less well than advantaged ones. Disadvantage
restriction), exercise, social engagement, education and drug therapies is related to race, as well as to social disparities13,41,139,151–153,166. Some
(for example, geroprotectors, senolytic drugs and repurposed drugs) have of the greater lethality of frailty in disadvantaged groups can be
been shown to attenuate frailty in preclinical and/or clinical studies. Other linked to a higher pathogen burden (for example, cytomegalovi-
lifestyle factors (for example, stressful environment and high-fat diet) rus, human immunodeficiency virus and human papilloma virus)
and interventions including medical treatments (for example, radiation through a variety of mechanisms that consist of either greater expo-
therapy and polypharmacy) can make frailty worse. Factors such as low sure or less ability to mitigate the burden172.
social position, limited personal wealth, poor maternal health, low levels of
childhood education, low per-capita gross domestic product and a host of Frailty from molecular to organismal scales
specific disease states increase the prevalence and consequences of frailty Heterogeneity in effects of aging is detectable in cellular and
in affected populations. molecular processes. The degree of frailty affects the risk of adverse
outcomes and treatment responses in a variety of cardiovascular
diseases. Consistent with the geroscience hypothesis, frailty may set
from long-lived families with those whose parents had usual sur- the stage for such diseases before they present themselves clinically.
vival patterns159. Briefly, as summarized in a detailed 2020 review63, For these inquiries, animal models are well suited (see below), given
the heritability ranges from 25–30% (using phenotypic and deficit that frailty increases with age and is associated with adverse events
accumulation measures)160 to about 45%156. including increased mortality in mice, rats and dogs66,67,69,70,173–177.
Together, these studies suggest that genetic, environmental and In the cardiovascular system, links between chronological age,
social effects operate broadly and affect frailty (Fig. 2). Note that frailty and maladaptive changes in heart function have been inves-
we do not have a cohort study in which individuals have been fol- tigated in mice of different ages. On average, the ability of the heart
lowed from birth to complete mortality, so some inferences from to contract deteriorates with age35,36. Unsurprisingly, there is also
what data we do have are needed. considerable interindividual variability—not all older mice exhibit
Note too that, just as with the genetics, no single influence age-associated deterioration in function35,36. When measures of
amounts to destiny. For example, although immigrating from a cardiac contraction are plotted as function of an animal’s frailty
lower-middle-income country to a high-income Northern European index score rather than age, a linear relationship is revealed where
country showed a deficit never entirely caught up, people moving the frailest mice exhibit the most profound dysfunction35,36. This
to Southern/Eastern Europe and people from lower- and middle- may underlie why frail older individuals develop exercise intol-
income countries were no worse off151. Somewhat more optimisti- erance and heart failure, as seen clinically178. Similarly, the speed
cally, and also from the Survey of Health, Ageing and Retirement with which electrical impulses are conducted across the atria
in Europe, the impact of childhood socioeconomic conditions on declines with age, an effect clearly evident in mice with high lev-
frailty at old age could be mitigated by better conditions in adult- els of frailty33,34. Slowed atrial conduction then provides a substrate
hood: improving socioeconomic conditions can reduce health for the development of arrhythmias, like atrial fibrillation, that are
inequalities in old age155. Unsurprisingly, many influences will vary common in frail people179. We summarize the heterogeneity of age-
across the life course148,151,155,158. associated changes in function and how these changes are graded
At the individual level, these influences give rise to deficit accu- by frailty scores in Fig. 3.
mulation through a variety of mechanisms, including intrinsic pro-
cesses that result in damage going unremoved or unrepaired15,19,161,162. The effects of frailty are seen across physiological scales. Poor
Such damage is detectable across the levels at which maladaptive overall health, quantified with a frailty index, predicts functional
aging-related changes can be observed, for example, with decline decline at the organ level in experimental models. These models
in telomere length163, mitochondrial DNA abundance164 or DNA provide the opportunity to explore how deficits might arise at the

and other hallmarks of aging9,10 to address fundamental questions
Better
about how frailty accumulates.
function Preclinical models of frailty offer advantages. When compared
with their equivalent human scales, both the frailty phenotype and
frailty index tools exhibit similarities in the items of which they
are composed (Table 1). These measures are responsive to frailty
interventions and are relatively easy to administer. Further, these
tests are noninvasive so they can be used in longitudinal studies
Worse to track the impact of interventions over time for a given indi-
function
vidual. Nevertheless, existing preclinical models have limitations.
Adult Aged Frailty Index score
For example, lifestyle, environmental and social factors that pro-
foundly influence the degree of frailty in humans have yet to be
Fig. 3 | Age-dependent deterioration is heterogeneous and is graded by investigated in preclinical models. In addition, deficits in domains
frailty index scores. Schematic illustrating the marked heterogeneity in the such as cognition and activities of daily living have not yet been
effects of age on structural and functional parameters (left). This illustrates included in preclinical tools (Table 1). Future studies should fur-
that age-associated, detrimental changes in function reflect average ther refine these instruments to better model the breadth of human
responses, but many older individuals have function equal to or better than frailty during aging.
younger adults. When these parameters are plotted as a function of frailty
index scores rather than chronological age, responses are closely graded Testing frailty interventions in preclinical models. Frailty assess-
by frailty (right). This figure was modeled on data from our previously ment in preclinical models provides a translational platform to
published work33–36. test new frailty interventions (Table 2). This can include interven-
tions that attenuate frailty as well as those that exacerbate it. It is
well established that voluntary aerobic exercise and high-intensity
cellular and subcellular levels, then scale up to adversely affect func- interval training reduce frailty in animal models (for example,
tion at the organ and system levels. This idea has been tested most in refs. 186–189). Known longevity interventions, including calorie
fully in the heart. The heart contracts less forcefully in frail mice restriction, antioxidants (for example, resveratrol) and mechanistic
because there is less calcium influx to trigger contraction in individ- target of rapamycin (mTOR) inhibitors (for example, rapamycin)
ual heart cells; this is attributable to fewer calcium channel proteins also reduce frailty in naturally aging mice181,190, as well as in geneti-
in the heart cell membrane35. There are also posttranslational modi- cally manipulated mice191,192 and nonhuman primates71. In contrast
fications in the contractile proteins themselves that are graded by to these findings, a ketogenic diet that mimics calorie restriction
the level of frailty in older mice36. Slower electrical impulses in the has little effect on the level of frailty in aging mice193. Other dietary
atria arise from connective tissue deposition, known as fibrosis, and interventions like protein restriction194 or intermittent fasting195 also
this in turn arises from increased collagen secondary to changes in reduce frailty or components of frailty, but only in male mice. This
enzymes involved in extracellular matrix remodeling33,34. These cel- indicates that the effects of frailty interventions can be sex specific,
lular and subcellular modifications are also graded by the degree of which is important as many intervention studies have used only one
frailty. Clinical studies where the degree of frailty is quantified as the sex—generally male (Table 2).
frailty phenotype have similarly shown that advanced glycation end Other approaches to mitigate the degree of frailty have been
products (AGEs) that arise in chronic kidney disease bind to recep- investigated. Hematopoietic stem cell transplantation using new
tors in skeletal muscle180. This leads to capillary rarefaction that may transplantation technology can both increase life span and reduce
contribute to sarcopenia and physical frailty180. The idea of scaling the degree of frailty196. Drugs that inhibit the renin–angiotensin
by the degree of frailty, where deficits arise at the microscopic level system (for example, the angiotensin-converting enzyme inhibitor,
and then scale up to the macroscopic level to affect function at the enalapril) reduce FI scores in aging mice182. Enalapril also reduces
organ and organism levels, is illustrated in Fig. 4. biological age and increases life expectancy, as shown by two new
‘clocks’ estimated from FI scores using machine-learning tech-
Translational potential of frailty niques197. Known longevity interventions (for example, methionine-
Animal models of frailty. The ability to quantify the degree of restricted diet) also reduce frailty, lower biological age and increase
frailty in humans and other animals can facilitate translational life expectancy197. Dietary supplements like alpha-ketoglutarate or
geroscience research. Although frailty assessment tools are used to allicin (a compound derived from garlic that inhibits inflammation)
investigate the association between frailty and age in different spe- attenuate frailty in aging mice198,199. This suggests that currently
cies, few studies have explored animal frailty across the life course. approved drugs and supplements may be repurposed to treat frailty
Estimates now suggest that frailty index scores increase in a similar in people. There is still much work to be done here as most drugs
fashion from early to late life in mice and in humans, and there is a identified as geroprotectors for use in clinical studies27 have not yet
strong link between frailty and mortality at all ages67,174. been investigated for effects on frailty. Preclinical models of frailty
Although women generally live longer than men, they are frailer can also be easily used to investigate whether combination therapies
at most ages, a phenomenon called the ‘sex–frailty paradox’25. (for example, drug treatment plus an exercise regimen) may better
Studies in older mice and dogs also report that females have higher attenuate or even reverse frailty accumulation in aging.
frailty scores than males69,181–183. While clinical studies suggest that While some interventions can attenuate frailty in preclinical
behavioral and social factors are also involved in this sex–frailty models, others can make frailty worse. For example, genetic dis-
paradox25, work in preclinical models could help identify biological ruption of mTORC2 in the brain impairs glucose homeostasis and
mechanisms. increases frailty200. In addition, when aging mice were treated with
Quantifying the degree of frailty can be used to explore funda- five commonly used medications to model polypharmacy, their
mental mechanisms involved in its development. For example, neu- frailty scores increased201. Interestingly, de-prescribing reversed
trophil dysfunction increases with age but is highest in frail older this effect on frailty, which suggests that de-prescribing may be a
people184. There is also emerging evidence that older mice with high viable strategy to combat frailty in older adults201. Other work has
levels of inflammation are frailer than mice of the same age with low shown that sublethal whole-body irradiation causes premature
inflammation183,185. Future work should investigate inflammation frailty, which has implications for the long-term health of patients

AGE accumulation
Ca2+
Microscopic
damage
RAGE receptor
Atrial fibrosis Impaired contraction
Capillary rarefaction
mitochondrial dysfunction
Macroscopic
damage
System failure, Sarcopenia

Atrial fibrillation Heart failure frailty
Fig. 4 | Age-associated deficits arise at the molecular/cellular level in frail individuals, scaling up to affect function at the organ and system levels. Left,
accumulation of subcellular damage such as collagen deposition in the atria and reduced calcium channel expression in the ventricles results in atrial
fibrosis and impaired cardiac contraction, respectively. These changes may promote chronic diseases like atrial fibrillation and congestive heart failure,
which can ultimately lead to system failure and frailty. Preclinical studies show that age-related changes in the heart are closely graded by the degree of
frailty, so that for both young adult mice (7–12 months, depending on the study) and aged mice (>22 months), those with high frailty scores have the most
subcellular damage. Right, the accumulation of AGEs in aging can reduce blood supply in skeletal muscle, leading to sarcopenia and impaired physical
performance. Clinical studies indicate that individuals with high levels of frailty exhibit more AGE accumulation and functional impairment than those with
lower frailty scores. This figure was modeled on data in refs. 33–35,180.
with cancer202. Mice fed a high-fat diet showed an increase in body differential risk, both with a view to modifying or managing it.
weight in both sexes, but frailty increased only in male animals181. How should we proceed?
This sex difference could reflect male–female differences in the abil-
ity to resist a stressor, although additional work to generalize this Frailty helps us manage risk. As a clinical construct, frailty iden-
result is needed. tifies people whose age-related health status puts them at greater
risk than their aging peers. That risk can be graded by the degree
Computational models can facilitate translational research. to which someone is frail. The degree of frailty can be practically
Aging individuals are complex, interconnected systems. This inter- operationalized both for only a few key variables (as in the frailty
connectedness implies that predicting the specific effects of multiple phenotype or the Clinical Frailty Scale) and with many variables
interventions (for example, deleterious polypharmacy, but also use- (as in the frailty index). Greater frailty correlates with worse out-
ful interventions) in the face of multiple ailments (multimorbidity) comes58,84,87,118,203,204. The degree of frailty can thereby inform clinical
for a particular aging individual will be impossible without embrac- decision-making, where prognosis is the key. This is especially true
ing the system complexity. Computational models that embrace the regarding informed consent about procedural risk or tolerability of
complexity of aging (Box 1) will help us to translate results from ani- chemotherapeutic regimens. Better informed consent follows from
mal and cellular models to human medicine, and to improve the life better risk gradation for specific interventions. For example, if an
course of individual adults at any given point in their life by appro- intervention transiently increased the degree of frailty by about 0.3,
priately choosing from a suite of treatment options. Dynamical then the chance of dying can be better quantified with respect to the
models that include interactions between cellular, laboratory and baseline frailty because mortality is high when a frailty index score
clinical scales of function over individual lifetimes will help us to approaches 0.7 (ref. 205).
understand the benefits of specific therapies. Personalized medicine Knowing that increased frailty increases risk does not mean that
for aging individuals—one that respects individual priorities and the increased risk is irreversible. The elements that are giving rise to
capacity for important lifestyle change—will also be facilitated by a frailty for that individual can be treated or managed. Especially for
deeper understanding of the complexity of aging. Optimized treat- elective interventions, undertaking pre-procedural management and
ment choices and timing to best extend or improve the health span prehabilitation may offer risk mitigation206,207. Monitoring outcomes
of individuals may then be possible. by the degree of pre-intervention frailty and the risk of the procedure
could also incentivize innovations in care. Some of that innovation
Conclusion might simply be knowing which days after an intervention are the
As we age, each of us moves closer to death—although not every- riskiest, with attention being paid to the types of adverse events that
one of the same chronological age has the same risk of death. arise in relation to the degree of frailty. As attention is increasingly
Heterogeneity in rates of aging motivated the idea of frailty. The paid to frailty treatment208, there will then be a need to understand
complexity that underlies heterogeneity in aging reflects its mul- what represents a clinically meaningful treatment effect209–211.
tiply determined nature. This complexity is belied by striking This approach to quantified risk can be extended to hospital
regularities: everyone accumulates health-related deficits with care. Any number of routine hospital practices are often accepted
age; women live longer on average than men do, although often in even though they exacerbate risk—for example, being malnour-
worse health; poor people tend not to live as long as those who are ished, lonely, in pain, unnecessarily immobilized, deprived of
very well off; and everyone dies. Understanding frailty is motivated sleep, over-sedated, otherwise over-medicated, not having per-
by two goals: to finely grade risk, and to understand the basis of sonal agency or being exposed to intermittent fear-inducing events.

Table 2 | Frailty interventions in preclinical studies
Model Age Sex Key findings Effect on Refs
frailty
C57BL/6 mice 6 and 28+ mos. M An aerobic exercise program (voluntary wheel running) improves physical performance ↓ 186
and reverses frailty, assessed with the frailty phenotype tool, in aging mice.
C57Bl/6J mice 3 to 28+ mos. M Lifelong aerobic exercise (voluntary wheel running) reduces frailty assessed with the ↓ 187
frailty phenotype. Sedentary animals become frail as they age.
C57BL/6 and 18 to 24 mos. M/F Known longevity interventions (for example, CR and resveratrol treatment) reduce FI ↓ 190
short-lived scores in C57BL/6J mice. Short-lived male mice (for example, DBA/2J) are frailer than
DBA/2J mice controls (effect not seen in females).
NIH Swiss mice 2 to 24 mos. M/F Rapamycin (an mTOR inhibitor) increases longevity in female mice but not in male ↔↓ 181
mice. Rapamycin has no effect on frailty in either sex, except that it reduces frailty in
male mice fed a high-fat diet.
NIH Swiss mice 2 to 24 mos. M/F A high-fat diet reduces life span and increases frailty in male mice but has no effect in ↑ 181
female mice.
C57BL/6 mice 2–4 mos. to 30 M A ketogenic diet, which mimics aspects of CR, reduces midlife mortality but not life ↔ 193
mos. span, improves memory, with only a modest effect of FI scores in aging mice.
Nonhuman 10–28 years M/F CR reduces frailty (assessed via frailty phenotype) and increases healthy life span in ↓ 71
primates (rhesus nonhuman primates. CR reduced frailty and mortality in both sexes. No obvious sex
monkeys) differences.
C57BL/6J 24 to 28 mos. M High-intensity interval training reduces frailty, assessed with the phenotype approach in ↓ 188
aging mice, in aged male mice.
C57BL/6J 24 to 26 mos. F High-intensity interval training reduces FI scores in aging female mice, even when ↓ 189
started late in life.
C57BL/6 mice; 4 to 24+ mos. M Rapamycin (an mTOR inhibitor) treatment extends health span and reduces FI scores in ↓ 191
NF‐κB KO mice mice with enhanced NF‐κB signaling and accelerated aging (the Nfκb1−/− mouse model).
Hypothalamic 4–6 mos. to 22+ M/F mTORC2 signaling in brain regulates metabolism in aging. Genetic ablation of mTORC2 ↑ 200
mTORC2 KO mos. in hypothalamic neurons impairs glucose homeostasis, reduces life span and increases
frailty in both sexes.
AQ-RKO mice 2–3 mos. to 40+ M/F Adipose-specific deletion of mTORC Rictor (AQ-RKO) disrupts adipose mTORC2 and ↓ 192,145
mos. blunts metabolic adaptations to CR. Despite this, CR reduces FI scores and increases
life span in AQ-RKO mice in both sexes, as it does in wild-type mice.
C57BL/6 mice 9–13 mos. and M/F Enalapril (an angiotensin-converting enzyme inhibitor) treatment reduces FI scores in ↓ 182
16–25 mos. both sexes, via reducing pro-inflammatory cytokines in females and increasing anti-
inflammatory cytokines in males. FI scores are higher in females than males.
C57BL/6 mice 5–12 mos. and 22 M Treatment of 5- to 6-month-old male mice with three sessions of sublethal irradiation ↑ 202
mos. increases FI scores at 12 mos. to levels like those seen in much older (22 mos.)
nonirradiated mice.
C57BL/6 mice 18 to 33+ mos. M/F Dietary supplementation with alpha-ketoglutarate (major metabolite in tricarboxylic ↓ 199
acid cycle) extends life span in middle-aged female mice and reduces FI scores across
the life course in both sexes. No apparent sex differences in frailty.
C57BL/6J mice 19 to 27+ mos. F Replacement of aged hematopoietic stem cells with donor cells from young mice ↓ 196
increases life span and reduces frailty in aging mice.
Fischer 344 rats 6 to 21 mos. M Allicin, a component of garlic that attenuates inflammation, attenuates osteoporosis by ↓ 198
reducing bone turnover and reduces FI scores in aging rats.
C57BL/6J mice 12 to 24+ mos. M Mice treated with a chronic polypharmacy regimen with a high drug burden index have ↑ 201
high FI scores and poor physical function. These adverse effects are attenuated by
de-prescribing.
C57BL/6 mice 21 to 39+ mos. M With machine-learning approaches, longitudinal FI scores can be used to develop the ↓ 197
FRIGHT clock (predictor of biological age) and the AFRAID clock (predictor of life
expectancy). Both clocks respond to interventions that attenuate frailty (for example,
enalapril and a methionine-restricted diet).
C57BL/6 mice 16 to 36+ mos. M/F A protein-restricted diet low in BCAAs reduces FI scores and increases life span in male ↓ 194
but not female wild-type mice. A low-BCAA diet also increases survival in two short-
lived progeroid mouse models.
C57BL/6 mice 20 to 39+ mos. M/F Intermittent fasting in late life reduces frailty components in males not females. Effects ↓ 195
of dietary restriction depend on increased renal H2S production; H2S levels were
increased by intermittent fasting and correlated with lower frailty in males only.
AQ-RKO, adipose-specific Rictor KO mice; BCAAs, branched-chain amino acids; CR, calorie restriction; F, female; FI, frailty index; H2S, hydrogen sulfide; KO, knockout; M, male; mTORC2, mTOR complex 2;
NIH, National Institutes of Health; NF‐κB, nuclear factor kappa B.

Box 1 | Mathematical modeling can embrace the complexity of aging
• Embracing complexity. Health is multidimensional and indi- • Embracing the complexity of health interventions for
vidually heterogeneous, with strong coupling between health individuals. The complexity of polypharmacy and multi-
characteristics. Complex computational models will help us to morbidity highlights the difficulty of treating aging health
embrace the complexity of aging. as a collection of independent ailments. Personal health
priorities and personal capacity to undertake, for example,
• Reconciling multiple health measures. Multiple biologi- dietary restriction and exercise, make treatment even more
cal ages are correlated with frailty, but do not coincide19. complex. Complex models of aging could help individuals
Multidimensional models can help us to both reconcile to navigate this landscape, to help people see how accessi-
and improve disparate measures. ble interventions may impact their future prognosis.
• Exploring the processes behind changing individual
health. The dynamical processes of damage and recov- • Understanding aging phenomenology. Mathematical mod-
ery underlie the net changes to individual health that are els can provide simulated aging individuals and populations.
captured by frailty. Recovery or repair can be described by Joint models of health and mortality can capture heterogeneity
‘resilience’, while resistance to damage can be described by within populations and interactions between aspects of health
‘robustness’64. Measurements of health, frailty, resilience and with mortality. Joint network models have highlighted
and robustness are interdependent, and can be included in complex interactions during aging15,223.
complex models of aging15. • Analysis of aging data. Mathematical models can help us to
• Moving between individual and population health. develop new approaches to data analysis. Interactions between
Complex models of aging are typically models of indi- different measures can be described by correlation networks224
viduals, but can also be used to study populations of indi- and can be included in complex network models of aging. Dif-
viduals. They are natural tools to see how population data ferent frailty maxima observed with systematic approaches
constrains the process of individual health trajectories, and to data dichotomization225 can be recapitulated in network
conversely how personal health interventions may affect models48. Machine-learning techniques provide appealing
population health. approaches to incorporate large amounts of aging data226.
Multicomponent interventions that target such features31, such as clinically detectable grades of frailty63,217–219. A focus on multimor-
the Hospital Elder Life Program, are effective in improving out- bidity to study the treatment of what are termed ‘aging-related
comes212, including delirium, for example, by applying cognitive rather than disease-specific outcomes’ is already under way220, as is
screening, physical and social measures for delirium prevention, a testing program of established interventions from the US National
and reducing medications likely to increase delirium risk213. Indeed, Institute of Aging in a genetically heterogenous mouse model220–222.
understanding the relationship between frailty and delirium, and The complexity of aging can be addressed in large-scale ani-
frailty and dementia, offers a pragmatic means to reduce dementia mal studies of naturally aging animals. Mouse models currently
incidence214,215. A nuanced understanding is needed to strike a judi- predominate, given their suitability for genetic manipulation.
cious balance between therapeutic adventurism and nihilism. Diversification into studies of other animals, especially rats, non-
human primates and companion animals, would help to translate
Frailty provides context for age-related changes. Measuring the interventions and clarify our understanding of how human aging is
degree of frailty helps us understanding the extent to which mech- both similar to and distinct from animal models of aging research.
anisms of aging operate. We can understand how mechanisms Quantitative models of aging can also advance our understand-
change with age. We can also understand how some changes have ing. Frailty invites consideration of how measurable aspects of health
more widespread effects than others216. This synergizes with the interact. Approaches and techniques borrowed from other disci-
geroscience agenda of treating aging mechanisms that have wide- plines, such as complex networks, information theory, queuing the-
ranging effects, following the example of exercise or diet. ory and machine learning, can be used to understand how the degree
The geroscience theory of fundamental aging processes posits of frailty is related to change in frailty states or mortality. While a
that only a few key processes underpin how age-associated dis- specific health deficit can be understood as a cumulative imbalance
eases arise: chronic ‘sterile’ immune activation; macromolecular between damage and repair, measuring these processes directly over
dysfunction (from DNA damage to protein misfolding and mito- individual life courses is not simple. Quantitative models will let us
chondrial dysfunction); stem, progenitor and immune dysfunction; separately consider sources of damage, including the social environ-
and cellular senescence10. The theory posits that treating any one ment, from factors that facilitate resisting damage such as vaccina-
mechanism should affect the rest as well216. However, to avoid dilut- tion, from factors that facilitate repair such as health care.
ing the impact of separate interventions, some way must be found
to integrate different treatment effects. The wide range of poten- The impact of aging on health. Policymakers and the scientific
tial individual effects from treating fundamental aging processes community have been exhorted to prepare for an aging population.
obliges multicomponent measures so that the benefits, not just the Often, attention is drawn to some disease becoming more common
problems, of old age can come as a package1. Frailty provides such a as the population ages, so that progress relies on studying how that
broad multicomponent measure. illness arises, and how to treat it. Seldom do we consider how dis-
Of course, many other quantifiable approaches to summarizing eases become more likely to manifest as an individual ages, beyond
the effects of aging exist. They will offer complementary informa- a cumulative exposure to risk. Even so, we must conceptualize, mea-
tion to understanding the degree of frailty or the overall biologi- sure and mitigate the impact that aging has on health. The gero-
cal age, based on tailored features that explicitly relate to putative science agenda has advanced the conceptualization and is aimed
aging mechanisms. Moving forward, cohort studies can provide at developing treatments. Frailty provides a way of measuring the
that level of detail for new aging treatments and relate them to impact of aging on health. It embraces the complexity of aging in

ways that can make its heterogeneity comprehensible. The measure 17. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and
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the assertion that with aging comes myriad changes that impact on
concluding that methylation age and frailty are complementary in
any one disease of aging. In basic science investigations of the heart, predicting mortality.
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utilizing frailty screening data. Eur. J. Surg. Oncol. 46, 321–325 (2020). friend and colleague, and one who has had an enormous influence on our field. Work
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and power training to prevent frailty in community-dwellers. Aging Clin. 162462 and 155961) and the Heart and Stroke Foundation of Canada (G-19–0026260).
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209. Guralnik, J. et al. Clinically meaningful change for physical performance: Engineering Research Council of Canada (RGPIN-2019–05888). Work in the Geriatric
perspectives of the ICFSR Task Force. J. Frailty Aging 9, 9–13 (2020). Medicine Research Unit (GMRU; K.R.) is supported by grants from the Canadian
210. Jang, I. Y. et al. Evaluation of clinically meaningful changes in measures of Institutes of Health Research (PJT 156114), Research Nova Scotia (RNS-SIG-2021–1640)
frailty. J. Gerontol. A Biol. Sci. Med. Sci. 75, 1143–1147 (2020). and the Canadian Frailty Network (CFN-CSA-2019 and NSHA-2020). The GMRU has
211. Theou, O. et al. Exploring clinically meaningful changes for the frailty index received long-term philanthropic support from the Fountain Family Innovation Fund of
in a longitudinal cohort of hospitalized older patients. J. Gerontol. A Biol. the QEII Health Sciences Foundation. The figures were created with BioRender.com.
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213. Curtis, M. S., Forman, N. A., Donovan, A. L. & Whitlock, E. L. A.D.R. provided constructive input and wrote additional sections in subsequent revisions
Postoperative delirium: why, what and how to confront it at your of the manuscript. All authors approved the final version of the article and figures.
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developing public health blueprint for action. Alzheimers Dement. 16, Competing interests
K.R. has asserted copyright of the Clinical Frailty Scale through Dalhousie University’s
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Industry, Liaison and Innovation Office. Use is free for education, research and not-for-
215. Rockwood, K. et al. CCCDTD5: reducing the risk of later-life dementia.
profit health care. Users agree not to change or commercialize the scale. In addition to
Evidence informing the Fifth Canadian Consensus Conference on the
academic and hospital appointments, K.R. is cofounder of Ardea Outcomes, which (as
Diagnosis and Treatment of Dementia (CCCDTD-5). Alzheimers Dement.
DGI Clinical) in the last 3 years has contracts with pharma and device manufacturers
6, e12083 (2020).
(Biogen, Hollister, Novartis, Nutricia, Roche and Takeda) on individualized outcome
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measurement. In 2019, K.R. was paid an honorarium for an interview with Biogen.
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In 2020, he attended an advisory board meeting with Nutricia on dementia, and
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chaired a scientific workshop and technical review panel on frailty for the Singapore
for UK Biobank participants.J. Gerontol. A Biol. Sci. Med. Sci. 74, 582–587
National Research Foundation. Otherwise, any personal fees were for invited guest
(2019).
lectures, rounds and academic symposia, received directly from event organizers, for
218. Wang, Q. et al. Genetically predicted life-long lowering of low-density
presentations on frailty. K.R. is associate director of the Canadian Consortium on
lipoprotein cholesterol is associated with decreased frailty: a Mendelian
Neurodegeneration in Aging, which is funded by the Canadian Institutes for Health
randomization study in UK biobank. EBioMedicine 45, 487–494 (2019).
Research, the Alzheimer Society of Canada and several other charities. S.E.H. has a paid
219. Mekli, K. Frailty Index associates with GRIN2B in two representative
consulting role with Ardea Outcomes. A.D.R. has no competing interests to declare.
samples from the United States and the United Kingdom. PLoS ONE 13,
e0207824 (2018).
220. Espeland, M. A. et al.; Multimorbidity Clinical Trials Consortium. Clinical
trials targeting aging and age-related multimorbidity.72, 355–361 (2017). Additional information
J. Gerontol. A Biol. Sci. Med. Sci. 72, 355–361 (2017). Correspondence should be addressed to K.R.
221. Warner, H. R. et al. Program for testing biological interventions to promote Peer review information Nature Aging thanks Simon Conroy, Luigi Ferrucci, and the
healthy aging. Mech. Ageing Dev. 115, 199–207 (2000). other, anonymous, reviewer(s) for their contribution to the peer review of this work.
222. Nadon, N. L. et al. Design of aging intervention studies: the NIA Reprints and permissions information is available at www.nature.com/reprints.
interventions testing program. Age 30, 187–199 (2008).
223. Farrell, S., Mitnitski, A., Rockwood, K. & Rutenberg, A. Generating Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
synthetic aging trajectories with a weighted network model using published maps and institutional affiliations.
cross-sectional data. Sci. Rep. 10, 19833 (2020). © Springer Nature America, Inc. 2021

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The degree of frailty as a translational measure of

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methylation changes18,19,162. Deficits arising from disruptions in cel-

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System failure, Sarcopenia

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Box 1 | Mathematical modeling can embrace the complexity of aging

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