Wong Chek Hooi MRCP(UK), MMed(Family Med), Howard Bergman MD ¹
Geriatric Medicine Unit, SGH
¹ Division of Geriatric Medicine, McGill University, Montreal, Canada

* Presented at the SGH Hospital-wide Clinical Meeting on 8 May 2004.

ABSTRACT

Frailty is an emerging, controversial and enigmatic concept. Although there may be debate on the specific meaning of this term, there is no doubt about the impact of frailty on older individuals, their families and society by its adverse outcomes. This article will give an overview of the development of frailty in an older person ¾ its historical and present perspectives. Historical perspective will examine how the term frailty had been used and its eventual evolution. Current perspectives will also be discussed along with its demographic, mathematical, ageing, genetic, biological, life course, biomedical and psychosocial models in the literature today. This provides a possible look at frailty in a clinical sense to derive meaningful outcomes in terms of clinical prevention, research and treatment.

Keywords: elderly, frail, review

Introduction

The emergence of frailty as an increasingly important concept prompts inquiry into what it is. Is it a disease? Is it just ageing? Yet some younger adults are deemed frail and some older ones are not. Gillick observed that "frailty is a syndrome in desperate need of description and analysis".¹

Yet, many papers have highlighted the importance of frailty in its relation to adverse outcomes which include dependency, disability, institutionalisation, falls, injuries, acute illness, hospitalisation, slow or blocked recovery and mortality.² This challenge was first highlighted in 1990. An American Medical Association white paper concluded that "one of the most important tasks that the medical community faces today is to prepare for the problems in caring for the elderly in the 1990s and the early 21st century".³ The report particularly emphasised the growing population of "frail, vulnerable older adults". It estimated that in the community, 10 to 25% of those above 65 years are frail and 46% of those above 85 years are frail.

In Singapore, the medical community is also faced with similar problems in caring for an ageing population. The proportion of older persons above the age of 65 was 6.8% of the population in 1995 and is projected to increase to 20% by the year 2030.⁴ The increase in life expectancy and better healthcare would introduce an emergence of the very old and frail populations. Understanding the underlying mechanisms of the frail state points to opportunities for health promotion, prevention and interventions aimed at either delaying the onset of frailty or reducing its adverse outcomes.

An important step to understanding the concept of frailty starts with the historical perspective on its use and its subsequent development and evolution. Current models in the literature will be discussed to provide insight into the understanding of frailty to derive meaningful outcomes in terms of future research, prevention and treatment.

Problems with Frailty and its Historical Perspective

"I am the cygnet to this pale faint swan,
Who chants a doleful hymn to his own death,
And from the organ-pipe of frailty sings
His soul and body to their lasting rest."

William Shakespeare, King John Act 5 Scene ⁷

In this scene, Prince Henry notes that his father (King John) is nearing death.

Like Shakespeare, most doctors feel that the meaning of frailty is intrinsic to our practice. "Doctors know them when they see them", or so they say. They call them the frail elderly. The assumption is that frailty goes along with ageing, as inevitable as white hair and wrinkles. It is the price to be paid for living to an advanced age.⁵ Frailty has long been deemed to be an inevitable consequence of ageing. While some have thought of frailty as a state of predeath.⁶ Many have used frailty synonymously with disability and co-morbidity.^7,8 There is clearly no consensus on the definition of frailty.

The history of its official use dates back to the 1970s. Monsignor Charles F Fahey and the Federal Council on Aging in the United States were credited with introducing the "frail elderly" to describe a particular segment of the population.^9,10 This happened when the heterogeneity of the older population became more accepted. The term was selected to focus attention on a group of elderly with physical debilities, emotional impairments and debilitating social and physical environments. It was used as an administrative device for triggering access to core support services for the elderly.

In the 1980s, researchers began to explain the term. Early definitions would include those aged 75 and older; a vulnerable population of seniors due to physical and mental impairment; individuals admitted to a geriatric programme; institutionalisation; and those dependent on others for activities of daily living.^11-14 Chronic disease and its sequelae were felt to be the cause of increased vulnerability and frailty.^13-15 Frailty and disability were often used interchangeably. There were a growing number of researchers who postulated that frailty was another term for disability in the elderly.¹⁶

By the 1990s, researchers felt that equating frailty with disability was inadequate. A number of difficult questions were asked. Were all older disabled patients frail? If not, why weren’t they? How did one end up frail? Was it inevitable? What were the underlying mechanisms? Was frailty preventable? Is it clinically advantageous to delineate frailty? Current research is attempting to delineate the components of frailty (how do we identify it?) and the underlying physiological and biological mechanisms important in the development of a frail state.

Models on Frailty

The contemporary models on frailty should not be viewed as mutually exclusive. The diversity in concepts also has its duplication and overlap between models. It also speaks to the isolation of researchers working on frailty.² The following are brief overviews of the main concepts in the current development of frailty.

Ageing

A simple model for frailty would be that frailty is intrinsic to ageing. Ageing has been defined as a process resulting in diminished reserves in most physiologic systems and exponentially increasing vulnerability to most diseases and death. However, while some adults are more likely to be frail with increasing age, frailty is not a state universally present in all older persons. This suggests that frailty is associated with ageing but not an inevitable consequence. Older adults vary in their overall robustness.¹⁷

Biomarkers of ageing (including frailty), that were deemed inevitable, e.g. grey hair, skin wrinkles, poor endurance, work output, are not only influenced by ageing but also various genetic and environmental factors. We now know that no two individuals age in the same way.¹⁸

Lipsitz likens the changing view of frailty to the change in the way Alzheimer’s Disease was perceived. "Thirty years age, Alzheimer’s was thought to be an inevitable consequence of aging; we called it senility… The same is true of frailty. It’s a syndrome, and there probably are some physiologic underpinnings".⁵

It has also been suggested that frailty is synonymous with accelerated or pathological ageing as opposed to successful or healthy ageing.¹⁹

Demographic

Demographers have developed models for survival to include a factor for unobservable heterogeneity or frailty.²⁰ The concept of frailty has been used to explore susceptibility to the ageing process as a whole.²¹ This susceptibility may reflect genetic predisposition or cumulative effect of environmental exposures.

Another demographic observation was that death rates decrease with age for humans as well as a host of other organisms.²² A possible explanation for this is the heterogeneity of frailty. Frail individuals are more likely to die; leaving a selected subset of robust individuals.²³ It has also been postulated that the mortality plateau occurs because of the slowing of the ageing process at the level of the individual.²⁴

Mathematical

A mathematical model can be defined as a symbolic device utilising mathematical reasoning to simulate and predict aspects of behaviour of a system. There are advantages in elucidating concepts in this model as it forces the researcher to articulate a clear understanding of the assumptions underlying their models.

Recently, researchers have tried to link mathematical models to the loss physiological complexity and adaptation. Lipsitz has used the chaos theory to explore frailty. He suggested that there is a loss of complexity in the dynamics of numerous physiological systems (heart rate variability, blood pressure, hormonal rhythms, postural sway). This loss of complexity reduces an individual’s ability to adapt to stress and leads to the syndrome of frailty. The output of these processes demonstrate complex variability that can be quantified using the concept of fractals, derived from the field of nonlinear dynamics.^25,26 Mitnitski has calculated a frailty index, a collection of 40 variables conceptualised similarly to the accumulation of biologic burden in allostatic load. In his model, he postulated that the approach emphasises the "integration" (or lack of integration) of many components in a complex system.²⁷

Genetic

Kirkwood has suggested that ageing is a process of gradual accumulation of damage in cellar tissues of the body leading eventually to frailty and an increased risk from a spectrum of age-associated diseases. Mechanisms leading to cellular damage include cumulative damage to mitochondrial and nuclear DNA.²⁸ These mutations lead to a range of bioenergetically deficient cells which characterise a main phenotype of frailty: muscle weakness and sarcopaenia.²⁹

Primary Pathways

The proposal of a primary pathway enables a clearer elucidation of a concept. However, some researchers have cautioned against an oversimplification of a state characterised by multisystem dysfunction.

Sarcopaenia

The term sarcopaenia (from the Greek word sarx for flesh and penia for loss) was first coined by Rosenberg to identify loss of muscle mass and function.³⁰ It has been suggested as the major underlying cause of frailty.^31,32 The consequences include decreased strength, metabolic rate and maximal oxygen consumption. These physiologic decrements contribute to weakness and a loss of independence.³³ A cross-sectional study found that sarcopaenia was associated with increased functional impairment and disability.³⁴ However, its underlying mechanism is not fully understood. Mechanisms proposed have included hormonal dysregulation, oxidative injury from the plasma thiol/disulfide redox state and nutrition.

Endocrine

With ageing, there is a decline in the functioning of a number of endocrine systems. This leads to the development of menopause/andropause, adrenopause and somatopause.³⁵ These hormonal deficiencies may contribute to frailty. In the late 19th century, Brown-Sequard (in his 70s), treated his declining endurance, strength and mental abilities with crude testicular extract derived from dogs and Guinea pigs.³⁶ Suppression of insulin-like peptides, insulin-like growth factor, lipophilic signalling molecules, and sterols or their receptors can delay age-related functional decline and increase stress resistance in animal models. Hormones important to the development of frailty that have been proposed include testosterone, leutinising hormone, DHEA and cortisol.

Chronic Inflammation

A low level of chronic inflammation secondary to age-related dysregulation of the immune system has been proposed.^37,38 Potential markers include C-reactive proteins, tumour necrosis factor-alpha and interleukin-6.

Concurrent Dysfunction of Multiple Biological Systems

Frailty has been proposed to be a result of concurrent impairments in multiple biologic systems. Underlying mechanisms have been suggested which include impaired strength, balance and endurance. There is an attempt to link the pathophysiology and clinical manifestation of frailty.

Hamerman postulated that frailty is related to pathophysiological effects of an altered metabolic balance, manifested by cytokine over-expression and hormonal decline.³⁹ While, Fried and Walston suggested a "cycle of frailty" with sarcopaenia, neuroendocrine dysregulation and immune dysfunction being the "physiological triad" to frailty.⁴⁰ Although a variety of physiologic underpinnings have been proposed, most researchers would agree that frailty results from a multi-system reduction in reserve capacity to the extent that a number of physiological systems are close to the threshold of symptomatic clinical failure.

Life Course

With a life course approach, long term effects of biological, behavioural and/or social pathways on risks of developing a disease, condition or state are studied during gestation, childhood, adolescence, young adulthood and later adult life.

Allostatic Load

It is the "wear and tear" or "use it and lose it" that occurs in an organism over time to maintain a steady state. It is conceptualised as the cumulative biological burden exacted on the body through attempts to adapt to life’s demands.⁴¹

Symmophosis

The other life course model was introduced by Bortz was symmophosis. He postulates that there is a quantitative match of design and function; that within a given pathway, the capacities of each step tend to be matched. Frailty is a result of lessened load that leads to linked and parallel loss in form and function.⁴² A simplification of his concept is "use it or lose it".

Allostatic load and symmophosis are not mutually exclusive concepts. It is felt that there is an optimal balance between the two. This is captured by the concept of hormesis. It is known that a number of mild stresses have been found to increase longevity in animal models.⁴³ Hormesis might result from either direct stimulation or over-compensatory response to noxious stimuli.⁴⁴ To prevent frailty then, the individual has to be exposed to a mild load or stress in order to induce the appropriate adaptive response.

Combined Biomedical/Psychosocial Models

There have been attempts to develop frailty models that incorporate a diverse number of factors operating at different levels (molecular to functional levels).

Brocklehurst offered a "model of breakdown". It is a dynamic model of frailty with assets and deficits. Assets proposed included health, functional capacity, positive attitude to life, caregiver availability and other resources. Deficits proposed included chronic disease, disability, dependency and caregiver burden which threaten independence. Frail individuals are those whose deficits outweigh assets.⁴⁵

Lebel, in his model of frailty included predisposing factors that influence the development of age-associated degenerative changes that can cause impairments. Cognition, neuro-locomotor and energy metabolism impairments were emphasised.⁴⁶

The hypothesised syndrome of frailty and its clinical implications

There is growing consensus that frailty is a syndrome that can be identified and measured clinically. It is distinct from disability and comorbidity. Frailty is a state of reduced homeostasis leading to increased vulnerability and risk of adverse outcomes. It is the result of the impact of multiple system impairment with critical changes in its reserve capacities, especially metabolic, cardiovascular, musculoskeletal, immunologic and neurologic systems. It represents a dynamic, complex interaction of biological, psychological, cognitive and social factors and a complex interplay of assets and deficits.

Fried developed the "frailty phenotype", which proposes an operational definition to the clinical syndrome of frailty. The parameters are based on self-reported and performance indicators of poor hand grip strength, slow walking speed, poor levels of physical activity, unintentional weight loss (4.5kg/year) and positive report of exhaustion/fatigue. Individuals with three or more of these characteristics are classified as "frail" while those with one or two are labeled as "prefrail". Using this definition, frailty has an independent predictive validity for mortality, disability and hospitalisation.⁴⁷

Fried also hypothesised a cycle or spiral of frailty to unify the relationship of the components in the "frailty phenotype". The key components in this "phenotypic expression of the negative cycle" are chronic undernutrition, sarcopaenia and declines in strength, power and exercise tolerance with declines in activity and total energy expenditure. Thus, it is a core cycle of negative energy balance. There are three physiologic systems that appear to be integral components to frailty. They are sarcopaenia, immune dysfunction and neuroendocrine dysregulation.⁴⁰ The proposal of a primary pathway has its advantage in a clearer elucidation of the possible pathophysiology of frailty.

While the proposal of a primary pathway is attractive and necessary, we need to continue to study the role of other potential components that contribute to frailty. Researchers and clinicians, as part of the Canadian Initiative on Frailty and Aging have proposed a working framework for studying frailty (www.frail-fragile.ca). The framework holds that biological, psychological, social and environmental factors that interact across the life course are determinants of the onset of frailty. The candidate components of frailty include those identified by Fried (decreased physical activity, weakness, decreased endurance, slowness, undernutrition) with added cognitive, psychological and perhaps social components. The pathway from frailty to its adverse outcomes too is affected by various biological, psychological, social and societal modifiers (Fig. 1).

Fig. 1. A working framework in development.

Frailty is also a dynamic and complex process with multiple interacting components. The life course approach provides an attractive framework towards understanding frailty and its determinants. It integrates biological, social, clinical, cognitive, psychological and environmental factors, which interact across a person’s life span. Studies on risk factors for frailty support this approach. Stuck identified a series of risk factors in mid to late life (including cognitive impairment, depression, disease burden, increased/decreased BMI, lower extremity function limitation, decreased social contacts, low physical activity, no compared to moderate alcohol consumption, poor perceived health, smoking and vision impairment) for functional decline. He postulated that there is evidence for an association among biological, psychological and social risk factors.⁴⁸

This framework is modelled to set the stage for possible prevention/delay of the onset of frailty and its adverse outcomes (Fig. 1). Observational studies on aging suggest associations between several lifestyle factors (exercise, nutrition, education, socioeconomic status, social/intellectual activities) and the onset of frailty. These findings provide opportunities for the development of interventions to promote healthy ageing, reduce the incidence of frailty, delay its onset and/or reduce the number of years in dependency.⁴⁹

Conclusion

The current challenge is to validate a universally accepted definition to frailty, including distinguishing its components and markers. Not to define frailty is akin to looking for the cause and cure of hypertension without a way to identify or measure it. Understanding frailty, in the end, may require a paradigm shift in the ways we once viewed the ageing process and a challenge to what was accepted as normal or inevitable.

This is especially important in Singapore as Singapore is experiencing a period of population ageing. Population statistics here have consistently shown both a fall in mortality (increasing life expectancy) rates and in birth rates. Demographically, Singapore would experience a period of accelerated rejuvenation followed by accelerated ageing. In low mortality countries, the fall in mortality immediately ages the population by directly increasing the numbers and proportion of the oldest-old.⁵⁰ It is, therefore, vitally important to research frailty and the opportunities for intervention and prevention to reduce the adverse outcomes of frailty.

Important initiatives are studying frailty in order to develop a better understanding of this condition. In 2003, the National Institutes of Health in the United States announced increased funding into research on frailty, specifically into its pathophysiology and intervention. In 2004, the American Geriatrics Society organised a conference with the objective of defining and stimulating study on the current state of understanding regarding the potential components of frailty and its underlying aetiologies, the potential application of other areas of research to frailty, and the potential for prevention and treatment.

The Canadian Initiative on Frailty and Aging (www.frail-fragile.ca) brings together investigators from Canada, Europe, Israel, the United States, Japan and Singapore using an integrative and life course approach which starts from a broad and flexible perspective, integrating physiological, psychological, cognitive and social components. Although a coherent synthesis of all the evidence seems daunting, through a systematic review, the Canadian Initiative will summarise the present state of research on frailty; develop a working framework; identify research priorities/programme; propose to clinicians recommendations on interventions which may prevent, delay or slow progression of frailty; and propose recommendations to policy makers and the population. It will hopefully ensure consistent, standard and better quality research and data.

References

1. Gillick M. Pinning down frailty. J Gerontol Med Sci 2001; 56A:134-5.
2. Hogan DB, MacKnight C, Bergman H; Steering Committee, Canadian Initiative on Frailty and Aging. Models, definitions and criteria of frailty. Aging Clin Exp Res 2003; 15(3 Suppl.):1-29.
3. American Medical Association white paper on elderly health. Report of the Council on Scientific Affairs. Arch Intern Med 1990; 150:2459-72.
4. The National Survey of Senior Citizens in Singapore, 1995. Singapore: Interministry, 1996:1.
5. Kolata G. Is frailty an inevitable part of aging? In: International Herald Tribune (online). Available at: www.iht.com/articles/77611.html. Accessed May 20, 2004.
6. Isaacs B, Gunn J, McKechan A, McMillan I, Neville Y. The concept of pre-death. Lancet 1971; 1:1115-8.
7. Pope A, Tarlov A. Disability in America: Toward a National Agenda for Prevention. Institute of Medicine (U.S.) Committee on a National Agenda for the prevention of disabilities. Washington DC: National Academy Press; 1991.
8. Hoffman C, Rice D, Sung HY. Persons with chronic conditions: their prevalence and costs. JAMA 1996; 276:1473-9.
9. Achenbaum WA, Albert DM. Profiles in gerontology: a biographical dictionary. Westport, Connecticut: Greenwood Press, 1995.
10. Maddox GL (Editor-in-chief). The encyclopedia of aging. New York: Springer Publishing Company, 1987:254-5.
11. Streib GF. The frail elderly: research dilemmas and research opporturnities. Gerontologist 1983; 23:40-4.
12. Reid IR, Gallagher DJ, Bosworth J. Prophylaxis against Vitamin D deficiency in the elderly by regular sunlight exposure. Age Ageing 1986; 15:35-40.
13. Williams FM, Wynne H, Woodhouse KW, Rawlins MD. Plasma aspirin esterase: the influence of old age and frailty. Age Ageing 1989; 18:39-42.
14. Wynne HA, Cope LH, James OF, Rawlins MD, Woodhouse KW. The effects of age and frailty upon acetanilide clearance in man. Age Ageing 1989; 18:39-42.
15. Woodhouse KW, Wynne H, Baillie S, James OF, Rawlins MD. Who are the frail elderly? Q J Med 1988; 68:505-6.
16. Stone R, Cafferata GL, Sangl J. Caregivers of the frail elderly: A national profile. Gerontologist 1987; 27:616-26.
17. Verbrugge LM. Survival curves, prevalence rates and the dark matters therein. J Aging Health 1991; 3:217-36.
18. Miller RA. The biology of aging and longevity. In: Hazzard WA, Blass JP, Halter JB, Ouslander JG, Tinetti ME, editors. Principles of Geriatric Medicine and Gerontology, 5th ed. New York: McGraw-Hill, 2003;3-15.
19. van Staveren WA, de Graaf C, De Goot LC. Regulation of appetite in frail persons. Clin Geriatr Med 2002; 18:675-84.
20. Suchindran CM, Koo HP. Demography and public health. In: Detels R, Holland W, McEwen J, Omenn GS, editors. Oxford Textbook of Public Health, 3rd ed, Vol. 2. New York: Oxford University Press, 1997;830.
21. Giard N, Lichenstein P, Yashin AI. A multistate model for the genetic analysis of the ageing process. Stat Med 2002; 21:2511-26.
22. Vaupel JW, Carey JR, Christensen K, Johnson TE, Yashin AI, Holm NV, et al. Biodemographic trajectories of longevity. Science 1998; 280:855-60.
23. Hitt R, Young-Xu Y, Silver M, Perls T. Centenarians: the older you get, the healthier you have been. Lancet 1999; 354:652.
24. Masoro EJ, Austad SN, eds. Handbook of the Biology of Aging, 5th ed. San Diego: Academic Press, 2001:10-11.
25. Lipsitz LA, Goldberger AL. Loss of ‘complexity’ and aging; potential applications of fractals and chaos theory to senescence. JAMA 1992; 267:1806-9.
26. Lipsitz LA. Physiological complexity, aging and the path to frailty. Sci Aging Knowledge Environ 2004; 16:16.
27. Mitnitski AB, Song X, Rockwood K. The estimation of relative fitness and frailty in community-dwelling older adults using self-report data. J Gerontol Med Sci 2004; 59A:627-32.
28. Kirkwood TB. Molecular gerontology. J Inherit Metab Dis 2002; 25:189-96.
29. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1989; 1:642-5.
30. Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr 1997; 127:990S-991S.
31. Pendergast DR, Fisher NM, Calkins E. Cardiovascular, neuromuscular and metabolic alterations with age leading to frailty. J Gerontol 1993; 48 Spec No:61-7.
32. Roubenoff R, Harris TB. Failure to thrive, sarcopenia and functional decline in the elderly. Clin Geriatr Med 1997; 13:613-22.
33. Dutta C. Significance of sarcopenia in the elderly. J Nutr 1997; 127:992S-993S.
34. Janssen I, Heymsfield SB, Ross R. Low relative skeletal mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 2002; 50:889-96.
35. Lamberts SW, van den Beld AW, van der Lely AJ. The endocrinology of aging. Science 1997; 278:419-24.
36. Aminoff MJ. Brown-Sequard – A visionary of science. New York: Raven Press, 1993.
37. Cohen HJ. In search of the underlying mechanisms of frailty. J Gerontol Med Sci 2000; 55A:706-8.
38. Cohen HJ, Harris T, Pieper CF. Coagulation and activation of inflammatory pathways in the development of functional decline and mortality in the elderly. Am J Med 2003; 114:180-7.
39. Hamerman D. Towards an understanding of frailty. Ann Intern Med 199; 130:945-50.
40. Fried LP, Walston J. Frailty and failure to thrive. In: Hazzard WA, Blass JP, Halter JB, Ouslander JG, Tinetti ME, editors. Principles of Geriatric Medicine and Gerontology. New York: McGraw-Hill, 2003:1487-502.
41. Seeman TE, Singer BH, Rowe JW, Horwitz RI, McEwen BS. Price of adaptation: allostatic load and its health consequences. Arch Intern Med 1997; 157:2259-68.
42. Bortz WM 2nd. A conceptual framework of frailty: a review. J Gerontol A Biol Sci Med Sci 2002; 57:283-8.
43. Parsons PA. Life span: does the limit to survival depend upon metabolic deficiency under stress? Biogerontology 2002; 3:233-41.
44. Calabrese EJ, Baldwin LA. Defining hormesis. Human Exp Toxicol 2002; 21:91-7.
45. Brocklehurst JC, ed. The day hospital. In Textbook of Geriatric Medicine and Gerontology, 3rd edition. London: Churchill, 1985.
46. Lebel P, Leduc N, Leclerc C, Contandriopoulos AP, Beland F. Un modele dynamique de la fragilite. L’Annee gerontologique 1999; 13: 84-94.
47. Fried LP, Tangen C, Waltson J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol Med Sci 2001; 56:146-56.
48. Stuck AE, Walthert JH, Nikolaus T, Bula CJ, Hohmann C, Beck JC. Risk factors for functional status decline in community-living elderly people:a systematic literature review. Soc Sci Med 1999; 48:445-69.
49. Vita AJ, Terry RB, Hubert HB, Fries JF. Aging, health risks, and cumulative disability. N Engl J Med 1998; 338:1035-41.
50. Robine JM, Michel JP. Looking forward to a general theory on population aging. J Gerontol Med Sci 2004; 59:M590-7.