Elsevier

The Lancet

Volume 381, Issue 9868, 2–8 March 2013, Pages 752-762
The Lancet

Seminar
Frailty in elderly people

https://doi.org/10.1016/S0140-6736(12)62167-9Get rights and content

Summary

Frailty is the most problematic expression of population ageing. It is a state of vulnerability to poor resolution of homoeostasis after a stressor event and is a consequence of cumulative decline in many physiological systems during a lifetime. This cumulative decline depletes homoeostatic reserves until minor stressor events trigger disproportionate changes in health status. In landmark studies, investigators have developed valid models of frailty and these models have allowed epidemiological investigations that show the association between frailty and adverse health outcomes. We need to develop more efficient methods to detect frailty and measure its severity in routine clinical practice, especially methods that are useful for primary care. Such progress would greatly inform the appropriate selection of elderly people for invasive procedures or drug treatments and would be the basis for a shift in the care of frail elderly people towards more appropriate goal-directed care.

Introduction

Population ageing is accelerating rapidly worldwide, from 461 million people older than 65 years in 2004 to an estimated 2 billion people by 2050,1, 2 which has profound implications for the planning and delivery of health and social care. The most problematic expression of population ageing is the clinical condition of frailty. Frailty develops as a consequence of age-related decline in many physiological systems, which collectively results in vulnerability to sudden health status changes triggered by minor stressor events. Between a quarter and half of people older than 85 years are estimated to be frail, and these people have a substantially increased risk of falls, disability, long-term care, and death.3, 4 However, up to three-quarters of people older than 85 years might not be frail, which raises questions about how frailty develops, how it might be prevented, and how it can be detected reliably.

Section snippets

Definition and presentations

Frailty is a state of increased vulnerability to poor resolution of homoeostasis after a stressor event, which increases the risk of adverse outcomes, including falls, delirium, and disability.3, 5, 6 Frailty is a long-established clinical expression that implies concern about an elderly person's vulnerability and outlook. Figure 1 shows this state of vulnerability diagrammatically; an apparently small insult (eg, a new drug, minor infection, or minor surgery) results in a striking and

Pathophysiology

Frailty is a disorder of several inter-related physiological systems (figure 2). A gradual decrease in physiological reserve occurs with ageing but, in frailty, this decrease is accelerated and homoeostatic mechanisms start to fail.8, 9 Therefore, an important perspective for frailty is to consider how the complex mechanisms of ageing promote cumulative decline in several physiological systems, the subsequent depletion of homoeostatic reserve, and vulnerability to disproportionate changes in

Pathway

Ageing is believed to result from the lifelong accumulation of molecular and cellular damage caused by many mechanisms that are regulated by a complex maintenance and repair network.10 The precise amount of cellular damage needed to cause impaired organ physiology is uncertain, but, importantly, many organ systems show notable redundancy, which provides the physiological reserve necessary to compensate for age-related and disease-related changes.13 For example, the brain and skeletal muscle

The frail brain

Ageing is associated with characteristic structural and physiological changes in the brain. The loss of individual neurons in most cortical regions is low,23 but neurons with high metabolic demands, such as the hippocampal pyramidal neurons, could be affected disproportionally by changes in synaptic function, protein transport, and mitochondrial function.23 The hippocampus has been identified as an important mediator in the pathophysiology of cognitive decline and Alzheimer's dementia24 and is

The frail endocrine system

The brain and endocrine system are linked intrinsically through the hypothalamo-pituitary axis, which controls metabolism and energy use through the signalling action of a series of homoeostatic hormones.23 During ageing, production of three major circulating hormones decreases. First, a lessening of growth hormone synthesis by the pituitary gland causes a reduction in production of insulin-like growth factor-1 (IGF-I) by the liver and other organs. IGFs are a family of small peptides that

The frail immune system

The ageing immune system is characterised by a reduction in stem cells, changes in T-lymphocyte production, blunting of the B-cell-controlled antibody response, and reduced phagocytic activity of neutrophils, macrophages, and natural killer cells.50, 51 This senescent immune system might function adequately in the quiescent state but fails to respond appropriately to the stress of acute inflammation.50 Evidence suggests that inflammation has a major role in the pathophysiology of frailty

Frail skeletal muscle (sarcopenia)

Sarcopenia has been defined as progressive loss of skeletal muscle mass, strength, and power, and is regarded as a key component of frailty.66, 67 Loss of muscle strength and power could be more important than changes in muscle mass.68 Under normal circumstances, muscle homoeostasis is maintained in a delicate balance between new muscle cell formation, hypertrophy, and protein loss. This balance is coordinated by the brain, endocrine system, and immune system, and is affected by nutritional

Frailty models

Reliable frailty models should be assessed by their success in predicting both natural history and response to therapeutic interventions and should be underpinned by biological principles of causality.70 The two main emerging models of frailty are the phenotype model3 and the cumulative deficit model, which forms the basis of the Canadian Study of Health and Aging (CSHA) frailty index.71

Epidemiology

Evidence for the importance of frailty as a leading cause of death in elderly people comes from a 10-year prospective cohort study of community-dwelling elderly people (n=754).88 Cause of death was based on clinical home-based assessments done at 18-month intervals and on death certificates. The most common disorder leading to death was frailty (27·9%); the others were organ failure (21·4%), cancer (19·3%), dementia (13·8%), and other causes (14·9%).

Prevalence

Investigators assessed the prevalence of frailty in a recent systematic review.89 21 community-based cohort studies of 61 500 elderly people were identified. The operational definitions for frailty and the inclusion or exclusion criteria varied between the studies, which largely explained the substantial variation in reported frailty prevalence rates of 4·0–59·1%. When the reported rates were restricted to the studies that used the phenotype model, the weighted average prevalence rate was 9·9%

Outcomes

The table shows the associations between frailty and adverse outcomes reported in four large prospective cohort studies,3, 92, 93, 94 with the worst outcomes in the most frail people. Frailty is a dynamic process95 but transition to a level of worse frailty is more common than is improvement in frailty, and the development of frailty often leads to a spiral of decline of increasing frailty and higher risk of worsening disability, falls, admission to hospital, and death.3 Risk of admission to

Instrumentation

The demonstration of large between-group differences for people who are frail compared with those who are not frail4 is important because it leads clinicians away from judgments based on chronological age towards the idea of frailty. Researchers and clinicians, therefore, need simple, valid, accurate, and reliable methods to detect frailty. Monitoring outcomes of interventions in frail people also needs methods that are sensitive to change.99

Interventions

Reduction of the prevalence or severity of frailty is likely to have large benefits for individuals, their families, and society. Several approaches have been investigated in clinical trials. Frail elderly people receiving inpatient comprehensive geriatric assessment on specialist elderly care wards are more likely to return home, are less likely to have cognitive or functional decline, and have lower in-hospital mortality rates than do those who are admitted to a general medical ward setting.

Conclusions

Modern health-care systems are mostly organised around single-system illnesses.139 However, many elderly people have multiorgan problems. Frailty is a practical, unifying notion in the care of elderly patients that directs attention away from organ-specific diagnoses towards a more holistic viewpoint of the patient and their predicament. It is a state of vulnerability to poor resolution of homoeostasis after a stressor event and is strongly associated with adverse outcomes. Distinction of frail

Search strategy and selection criteria

We developed a structured search strategy with the assistance of an expert librarian at the University of Leeds, UK. We searched the Cochrane Library, CINAHL, Medline, Embase, PsycINFO, and PEDro; all searches were for 2000–12. We used the search terms “frailty”, “frail elderly”, or “sarcopenia” with the terms “aged” or “aged, 80 and over” or “ageing/genetics” or “longevity” or “centenarian” or “oldest old” or “very old” or “very elderly”. We did a further search in which the results were

References (141)

  • D Attaix et al.

    Altered responses in skeletal muscle protein turnover during aging in anabolic and catabolic periods

    Int J Biochem Cell Biol

    (2005)
  • TB Harris et al.

    Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly

    Am J Med

    (1999)
  • T Qu et al.

    Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14(+) monocytes in frail older adults

    Mech Ageing Dev

    (2009)
  • T Qu et al.

    Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty

    Cytokine

    (2009)
  • J Collerton et al.

    Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study

    Mech Ageing Dev

    (2012)
  • LA Schaap et al.

    Inflammatory markers and loss of muscle mass (sarcopenia) and strength

    Am J Med

    (2006)
  • X Yao et al.

    Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults

    Vaccine

    (2011)
  • I Ridda et al.

    Immunological responses to pneumococcal vaccine in frail older people

    Vaccine

    (2009)
  • T Jefferson et al.

    Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review

    Lancet

    (2005)
  • LP Fried et al.

    The Cardiovascular Health Study: design and rationale

    Ann Epidemiol

    (1991)
  • N Sourial et al.

    A correspondence analysis revealed frailty deficits aggregate and are multidimensional

    J Clin Epidemiol

    (2010)
  • K Rockwood et al.

    Limits to deficit accumulation in elderly people

    Mech Ageing Dev

    (2006)
  • O Theou et al.

    Disability and co-morbidity in relation to frailty: how much do they overlap?

    Arch Gerontol Geriatr

    (2012)
  • NM de Vries et al.

    Outcome instruments to measure frailty: a systematic review

    Ageing Res Rev

    (2011)
  • K Kinsella et al.
  • The world at six billion

  • LP Fried et al.

    Frailty in older adults: evidence for a phenotype

    J Gerontol A Biol Sci Med Sci

    (2001)
  • X Song et al.

    Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation

    J Am Geriatr Soc

    (2010)
  • J Walston et al.

    Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults

    J Am Geriatr Soc

    (2006)
  • EM Eeles et al.

    The impact of frailty and delirium on mortality in older inpatients

    Age Ageing

    (2012)
  • AJ Campbell et al.

    Unstable disability and the fluctuations of frailty

    Age Ageing

    (1997)
  • L Ferrucci et al.

    Biomarkers of frailty in older persons

    J Endocrinol Invest

    (2002)
  • G Taffett

    Physiology of aging

  • PO McGowan et al.

    Environmental epigenomics: understanding the effects of parental care on the epigenome

    Essays Biochem

    (2010)
  • LA Lipsitz

    Dynamics of stability: the physiologic basis of functional health and frailty

    J Gerontol A Biol Sci Med Sci

    (2002)
  • LP Fried et al.

    Nonlinear multisystem physiological dysregulation associated with frailty in older women: implications for etiology and treatment

    J Gerontol A Biol Sci Med Sci

    (2009)
  • PH Chaves et al.

    Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II

    J Gerontol A Biol Sci Med Sci

    (2005)
  • J Walston et al.

    Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study

    Arch Intern Med

    (2002)
  • AB Newman et al.

    Weight change in old age and its association with mortality

    J Am Geriatr Soc

    (2001)
  • NA Bishop et al.

    Neural mechanisms of ageing and cognitive decline

    Nature

    (2010)
  • PK Panegyres

    The contribution of the study of neurodegenerative disorders to the understanding of human memory

    QJM

    (2004)
  • XG Luo et al.

    Microglia in the aging brain: relevance to neurodegeneration

    Mol Neurodegener

    (2010)
  • C Cunningham et al.

    Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration

    J Neurosci

    (2005)
  • PA Boyle et al.

    Physical frailty is associated with incident mild cognitive impairment in community-based older persons

    J Am Geriatr Soc

    (2010)
  • AS Buchman et al.

    Frailty is associated with incident Alzheimer's disease and cognitive decline in the elderly

    Psychosom Med

    (2007)
  • X Song et al.

    Nontraditional risk factors combine to predict Alzheimer disease and dementia

    Neurology

    (2011)
  • JR Florini et al.

    Hormones, growth factors, and myogenic differentiation

    Annu Rev Physiol

    (1991)
  • SW Lamberts

    The endocrinology of aging and the brain

    Arch Neurol

    (2002)
  • SW Lamberts et al.

    The endocrinology of aging

    Science

    (1997)
  • SX Leng et al.

    Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty

    Aging Clin Exp Res

    (2004)
  • Cited by (5820)

    • Molecular hallmarks of ageing in amyotrophic lateral sclerosis

      2024, Cellular and Molecular Life Sciences
    View all citing articles on Scopus
    View full text