Frailty Background

Population ageing worldwide is rapidly accelerating from 461 million people aged over 65 years in 2004 to an estimated 2 billion people by 2050, which has profound implications for the planning and delivery of health and social care. More essentially the problematic expression of population ageing is the clinical condition of frailty. Eventually frailty develops as a consequence of all the age-related decline in multiple physiological systems, which collectively results in a vulnerability to sudden health status changes triggered by relatively minor stressor events.
It is estimated that a quarter to a half of people over 85 years are frail and these people have significantly increased risk of falls, disability, long-term care and death. Importantly, up to three quarters of people over 85 years might not be frail, raising the questions of how frailty develops, how it might be prevented and how it can be detected reliably. This review addresses these issues.

Frailty Definition and Presentations

Frailty can be classically defined as the state of a very increased vulnerability to poor resolution of homeostasis following a stress, which increases the risk of adverse outcomes including falls, delirium and disability. Its well established fact as it is a long established clinical expression that implies concern over an older person’s vulnerability and prognosis.
This is shown diagrammatically, in which an apparently small insult (e.g. a new drug; “minor” infection; or “minor” surgery) results in a dramatic and disproportionate change in health state: from independent to dependent; mobile to immobile; postural stability to falling; lucid to delirious. The dependency oscillations observed in frail older people has been referred to as “unstable disability” to reflect the often marked changes in functional ability that are familiar to practitioners working with older people.

The Pathway to Frailty

Ageing is considered to result from the lifelong accumulation of molecular and cellular damage caused by multiple mechanisms under the regulation of a complex maintenance and repair network. There is uncertainty regarding the precise level of cellular damage required to cause impaired organ physiology but, importantly, many organ systems exhibit considerable redundancy, which provides the physiological reserve required to compensate for age and disease-related changes.

For example, the brain contains more neurons and skeletal muscle more myocytes than are required for survival. Therefore, a key question is whether there is a critical threshold of age-related, cumulative decline in multiple physiological systems beyond which frailty becomes evident. A 2009 cross-sectional study involving 1,002 female participants investigated cumulative physiological dysfunction in six different systems (haematological, inflammatory, hormonal, adiposity, neuromuscular and micronutrients) using 12 measures and reported a non-linear relationship between the number of abnormal systems and frailty, independent of age and comorbidity.

The presence of abnormal results in three or more systems was a significant predictor of frailty. Importantly, the number of abnormal systems was more predictive than abnormalities in any particular system. This provides evidence to suggest that when physiological decline reaches an aggregate critical mass, frailty becomes evident.

Endocrine system, immune system and skeletal muscle are intrinsically inter-related and are currently the organ systems best studied in the development of this frailty. These systems will be considered in greater detail, but it is important to recognise that frailty has also been associated with loss of physiological reserve in the respiratory, cardiovascular, renal and haemopoietic and clotting systems and that nutritional status can also be a mediating factor.

The Frail Brain

Ageing is associated with characteristic structural and physiological changes in the brain. The loss of individual neurons in the majority of cortical regions is minimal, but neurons with high metabolic demands, for example the hippocampal pyramidal neurons, may be disproportionally affected by altered synaptic function, protein transport and mitochondrial function. The hippocampus has been identified as an important mediator in the pathophysiology of cognitive decline and Alzheimer’s dementia and is a key component of the stress response, sensing increased glucocorticoid levels and relaying information to the hypothalamus in a negative feedback loop.

The ageing brain is also characterised by structural and functional changes to microglial cells, which are the resident immune cell population of the central nervous system (CNS) and are the CNS equivalent of macrophages. They are activated by brain injury and local and systemic inflammation and become primed (hyper-responsive) to small stimuli with ageing, which can potentially cause damage and neuronal death. Primed microglia are postulated to play an important role in the pathophysiology of delirium.

A prospective cohort study involving 273 hospitalised older people identified that frailty is associated with both increased risk of developing delirium (odds ratio, OR, 8.5, 95% confidence interval, CI, 4.8-14.8) and subsequent reduced survival (median survival in frail older patients with delirium 88 days (95% CI 5-171 days); median survival in non-frail older patients with delirium 359 days (95% CI 118-600 days)). This indicates that the combination of delirium and frailty identifies older people at particularly high risk of adverse outcomes.

There is accumulating evidence from observational studies to support a temporal association between frailty, cognitive impairment and dementia. A prospective cohort study (n=750) of older people without cognitive impairment at baseline reported that frailty was associated with an increased risk of developing mild cognitive impairment over 12 years of follow-up (hazard ratio, HR, 1.63, CI, 1.27-2.08). Increasing degree of frailty was also associated with a faster rate of cognitive decline. An independent association between frailty and dementia has been reported in two large prospective cohort studies.

The Frail Endocrine System

The brain and endocrine system are intrinsically linked through the hypothalamo-pituitary axis, which controls metabolism and energy use via the signaling action of a series of homeostatic hormones. During ageing, there is a decline in production of three major circulating hormones. Firstly, a decline in growth hormone synthesis by the pituitary causes a reduction in insulin-like growth factor-1 (IGF-1) production by the liver and other organs. IGFs are a family of small peptides that increase anabolic activity in many cells. Promotion of neuronal plasticity and increased skeletal muscle strength are considered particularly important effects. Secondly, decreased oestradiol and testosterone cause increased release of luteinising hormone (LH) and follicle stimulating hormone (FSH). Thirdly, the adrenocortical cells that produce the major sex steroid precursor dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) decrease in activity, often mirrored by a gradual increase in cortisol release.

Changes to IGF signaling, sex hormone, DHEA/DHEAS production and cortisol secretion are considered important in frailty, although the exact relationships remain uncertain and require further investigation. One cross-sectional study reported significantly lower levels of IGF-1 in people identified as frail when compared to age-matched controls. However, if IGF-1 has a key aetiological role in frailty an association between IGF-1 and mortality might be anticipated but a series of observational studies have reported inconsistent associations. Furthermore, although the muscles of frail older people appear to retain the capability to respond to IGF-1 trials of IGF-1 supplementation in older people have failed to demonstrate benefit.

Although an association between testosterone levels and frailty has been identified this may be a sensitive marker rather than a pathological mechanism. A cross-sectional study reported an association between DHEAS and frailty but the influence of comorbid conditions could not be confidently excluded. A U-shaped association between DHEAS and mortality has been reported in disabled older women.

One cross sectional study (n=214) reported that frailty was independently associated with chronically elevated diurnal cortisol levels. A link between chronically elevated cortisol and frailty is plausible, as persistently high levels of cortisol are associated with increased catabolism, leading to loss of muscle mass, anorexia, weight loss and reduced energy expenditure - cardinal clinical features of frailty.


Modern healthcare systems are largely organized around a single system illness. Many older people, however, have multi-organ problems. Frailty is a practical, unifying concept in the care of these older people that directs attention away from organ specific diagnoses towards a more holistic viewpoint of the patient and their predicament. Dependence and the state of vulnerability to poor resolution of homeostasis following a stress and is strongly associated with adverse outcomes.

Distinguishing older people who are frail from people who are not frail should therefore form an essential aspect of assessment in any health care encounter that might result in an invasive procedure or potentially harmful medication. It allows practitioners to weigh up benefits and risks, and for patients to make properly informed choices. Failure to detect frailty potentially exposes patients to interventions from which they may not benefit and indeed may be harmed. Conversely, to exclude physiologically well (non-frail) older people simply on the basis of age is unacceptable.

The most evidence-based process to detect and severity grade frailty is the process of CGA. This is a resource intensive process and new research is urgently required to find equally reliable but more efficient and responsive methods for routine care. The necessary requirements of future frailty instruments, including the important issue of clinical sensibility, have been defined. This might be achieved by development and further validation of the currently available frailty-specific multi-dimensional questionnaires, but the utility of existing clinical data sets, particularly in primary care, is attractive.

This approach would be underpinned by the cumulative deficits frailty model and implies that frailty could be both positively identified and severity graded. Such a simple tool would facilitate essential research to gain deeper insight into the complex mechanisms of frailty and aid the development and evaluation of interventions to improve outcomes. It would also have considerable clinical merit as it would be the basis for a paradigm shift in the care of frail older people towards a more appropriate goal-directed care in which individually framed clinical outcomes that span organ systems are negotiated with patients.

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