Frailty syndrome
A woman supporting herself with a walking frame.
Specialty	Geriatrics

Frailty is a common and clinically significant grouping of symptoms that occurs in aging and older adults. These symptoms can include decreased physical abilities such as walking, excessive fatigue, and weight and muscle loss leading to declined physical status. In addition, frailty encompasses a decline in both overall physical function and physiologic reserve of organ systems resulting in worse health outcomes for this population.^[1][2] This syndrome is associated with increased risk of heart disease, falls, hospitalization, and death.^[3][4] In addition, it has been shown that adults living with frailty face more anxiety and depression symptoms than those who do not.^[5] The presence of frailty varies based on the assessment technique, however it is estimated that 4-16% of the population over 65 years old is living with frailty.^[6]

Frailty can have impacts on public health due to the factors that comprise the syndrome affecting physical and mental health outcomes. There are several ways to identify, prevent, and mitigate the prevalence of frailty and the evaluation of frailty can be done through clinical assessments created to combine recognized signs and symptoms of frailty.

Frailty refers to an age-related functional decline and heightened state of vulnerability. It is a worsening of functional status compared to the normal physiological process of aging. It can refer to the combination of a decline of physical and physiological aspects of a human body. The reduced reserve capacity of organ systems, muscle, and bone create a state where the body is not capable of coping with stressors such as illness or falls. Frailty can lead to increased risk of adverse side effects, complications, and mortality.^[7]

Older age by itself is not what defines frailty, it is however a syndrome found in older adults. Many adults over 65 are not living with frailty.^[8] Frailty is not one specific disease, however is a combination of many factors. Frailty does not have a specific universal criteria on which it is diagnosed; there are a combination of signs and symptoms that can lead to a diagnosis of frailty. Evaluations can be done on physical staus, weight fluctuations, or subjective symptoms.^[9] Frailty most commonly refers to physical status and is not a syndrome of mental capacity such as dementia, which is a decline in cognitive function. Although, frailty can be a risk factor for the development of dementia.^[10]

Although no universal diagnostic criteria exist, some clinical screening tools are commonly used to identify frailty. These include the Fried Frailty Phenotype and a deficit accumulation frailty index. The Fried Frailty Phenotype assesses five domains commonly affected by frailty: exhaustion, weakness, slowness, physical inactivity, and weight loss. The presence of 1-2 findings is classified as "pre-frailty", 3 or more as frailty and the presence of all 5 indicates "end-stage frailty" and is associated with poor prognosis.^[11] The deficit accumulation characterization of frailty tallies deficits present in a variety of clinical areas (including nutritional deficiency, laboratory abnormalities, disability index, cognitive and physical impairment) to create a frailty index. A higher number of deficits is associated with a worse prognosis.^[11][12]

Decreases in skeletal muscle mass (sarcopenia) and bone density are two major contributors to developing frailty in older adults. In early to middle age, bone density and muscle mass are closely related. As adults age, skeletal muscle mass or bone density may begin to decline. This decline can lead to frailty and both have been identified as contributors to disability.^[13] The development of sarcopenia or osteoporosis alone does not establish frailty, as there are many factors that are taken into account. Studies suggest that frailty is a result of multiple body systems experiencing dysregulation, and the more body systems that are affected, the higher the risk is for developing frailty. ^[1]

Sarcopenia is the degenerative loss of skeletal muscle mass, quality, and strength associated with aging.^[14] The rate of muscle loss is dependent on exercise level, co-morbidities, nutrition and other factors. Sarcopenia can lead to reduction in functional status and cause significant disability from increased weakness. The muscle loss is related to changes in muscle synthesis signalling pathways although is incompletely understood. The cellular mechanisms are distinct from other types of muscle atrophy such as cachexia, in which muscle is degraded through cytokine-mediated degradation although both conditions may co-exist.^[15]

Osteoporosis is a disease of bone mineral density loss (usually age related) that leads to an increased risk of bone fractures, especially with falls.^[16] Frailty is associated with an increased risk of osteoporosis related bone fractures.^[17]

Muscle weakness and associated muscle atrophy (muscle wasting, also known as sarcopenia) are more common in those with frailty. The prevalence of muscle weakness was more common in those with frailty in a population based study of older adults.^[18] Aging, lower levels of DHEA, testosterone, IGF-1 and increased levels of cortisol are thought to contribute to muscle wasting in those with frailty.^[11]

Frailty is also common in those with heart failure. Both frailty and heart failure share similar methods of progressive health decline and often lead to worsened health conditions when combined. ^[19]

People who had mental disorders were found to be at increased risk of frailty.^[20]

The causes of frailty are multifactorial involving dysregulation across many physiological systems.^[21][11] Frailty may be related to a proinflammatory state. A common interleukin elevated in this state is IL-6. A pro-inflammatory cytokine, IL-6 was found to be common in older adults with frailty.^[22] IL-6 is typically up-regulated by inflammatory mediators, such as C-reactive protein, released in the presence of chronic disease. Increased levels of inflammatory mediators are often associated with chronic disease; however, they may also be elevated even in the absence of chronic disease.^[23]

Sarcopenia,^[24] anemia,^[25][26] anabolic hormone deficiencies,^[27] and excess exposure to catabolic hormones such as cortisol^[28] have been associated with an increased likelihood of frailty. Other mechanisms associated with frailty include insulin resistance,^[29] increased glucose levels,^[30] compromised immune function,^[31][32] micronutrient deficiencies, and oxidative stress.^[33]

Mitochondrial dysfunction, including mitochondrial DNA mutations, cellular respiration dysfunction, and changes in mitochondrial hemostasis is thought to contribute to reduced cellular energy, production of reactive oxygen species and inflammation. This mitochondrial dysfunction is thought to contribute to the signs of frailty.^[11]

Researchers found that individual abnormal body functions may not be the best predictor of risk of frailty. However, they did conclude that once the number of conditions reaches a certain threshold, the risk of frailty increases.^[21] This finding suggests that treatment of frailty syndrome should not be focused on a single condition, but a multitude in order to increase the likelihood of better treatment results.

Declines in physiologic reserves and resilience contribute to frailty.^[34] The risk of frailty increases with age and with the incidence of diseases. The development of frailty is also thought to involve declines in energy production, energy utilization and repair systems in the body, resulting in declines in the function of many different physiological systems. This decline in multiple systems affects the normal complex adaptive behavior that is essential to health and eventually results in frailty.^[21][35]

A comparison of peripheral blood mononuclear cells from frail older individuals to cells from healthy younger individuals showed evidence in the frail older individuals of increased oxidative stress, increased apurinic/pyrimidinic sites in DNA, increased accumulation of endogenous DNA damage and reduced ability to repair DNA double-strand breaks.^[36]

The syndrome of geriatric frailty is hypothesized to reflect impairments in the regulation of multiple physiologic systems, embodying a lack of resilience to physiologic challenges and thus elevated risk for a range of deleterious endpoints. Generally speaking, the empirical assessment of geriatric frailty in individuals seeks ultimately to capture this or related features, though distinct approaches to such assessment have been developed in the literature (see de Vries et al., 2011 for a comprehensive review).^[37]

Two most widely used approaches, different in their nature and scopes,^[38] are discussed below. Other approaches follow.

A popular approach to the assessment of geriatric frailty encompasses the assessment of five dimensions that are hypothesized to reflect systems whose impaired regulation underlies the syndrome.^[39][11] These five dimensions are:

• unintentional weight loss
• exhaustion
• muscle weakness
• slowness while walking
• low levels of activity

These five dimensions form specific criteria indicating adverse functioning, which are implemented using a combination of self-reported and performance-based measures. Those who meet at least three of the criteria are defined as "frail", while those not matching any of the five criteria are defined as "robust".

Another notable approach to the assessment of geriatric frailty in which frailty is viewed in terms of the number of health "deficits" that are manifest in the individual, leading to a continuous measure of frailty.^[40][41] This score is based the presence of deficits in may areas related to frailty, including symptoms of cognitive or physical impairment, laboratory abnormalities, nutritional deficits, or disability.^[40][11]

A model consisting of four domains of frailty was proposed in response to an article in the BMJ.^[42] This conceptualisation could be viewed as blending the phenotypic and index models. Researchers tested this model for signal in routinely collected hospital data,^[43] and then used this signal in the development of a frailty model, finding even predictive capability across 3 outcomes of care.^[44] In the care home setting, one study indicated that not all four domains of frailty were routinely assessed in residents, giving evidence to suggest that frailty may still primarily be viewed only in terms of physical health.^[45]

The SHARE-Frailty Index (SHARE-FI) assesses frailty based on five domains of the frailty phenotype:^[46]

• Fatigue
• Loss of appetite
• Grip strength
• Functional difficulties
• Physical activity

The Clinical Frailty Scale (CFS) is a scale used to assess frailty which was evolved from the Canadian Study of Health and Aging. It is a 9-point scale used to assess a persons frailty level, where a score of 1 point would mean a person is very fit and robust, to a score of 9 points meaning the person is severely frail and terminally ill.^[9]

The Edmonton Frail Scale (EFS) is another method used to screen frailty. This scale is given scores of up to 17 points.^[47] It has been assessed to screen all domains of frailty, and is said to be easy to perform by clinicians. Specific tests used in this scaling system are walking tests and clock drawing. ^[48]

The electronic Frail Scale (eFI) is a scale weighted out of 36 deficit points where the higher the number in the score will represent the more frail, or more prone to frailty. Each frailty-related deficit the person has is given a point and the more deficits the person is experiencing the more likely they are frail or will experience frailty in the future. The total number of deficits is divided by 36. Then, a frailty category is assigned. A person with a score of 0.00–0.12 is in the "Fit" category. A person with a score of 0.13–0.24 is in the "Mild" category. A person with a score of 0.25–0.36 is in the "Moderate" category. Finally, a person with the score of 0.36 or above is considered to be in the "Severe" category. ^[49]

As frailty arises as a result of reduced reserve capacity in a biological system and causes an individual to have heightened vulnerability to stress, avoiding known stressors (ie. surgeries, infections, etc.) and understanding mechanisms to reduce frailty can help older adults prevent worsening their frail status.^[50] Some signs of frailty include: unwanted weight loss, muscle weakness, low energy, and low grip strength.^[51] Currently, preventative interventions focus on minimizing muscle loss and improvement of overall well-being in older adults or individuals with chronic illnesses.

When considering prevention of frailty, it is important to understand the risk factors that contribute to frailty and identify them early on. Early identification of risk factors allows for preventative interventions, reducing risks of future complications.

A 2005 observational study found associations between frailty and a number of risk factors such as: low income, advanced age, chronic medical conditions, lack of education, and smoking.^[52]

A significant target in the prevention of frailty is physical activity. As people age, physical activity markedly drops, with the steepest declines seen in adolescence and continuing on throughout life.^[53] The lower levels of physical activity and are associated with and a key component of frailty syndrome. Therefore, exercise regimens consisting of walking, strength training, and self-directed physical activity, have been examined in a number of studies as an intervention to prevent frailty.^[54][55][56] A randomized control trial published in 2017 found significantly lower rates of frailty in older adults who were assigned an exercise regimen vs those who were in the control group.^[54] In this study, 15.3% of the control group became frail in the time frame of the study, in comparison to 4.9% of the exercise group. The exercise group also received a nutritional assessment, which is another target in frailty prevention.

Nutrition has also been a major target in the prevention of frailty. A healthy dietary pattern consisting of high consumption of healthy fats, fruits, vegetables, low-fat dairy products, and whole grains can contribute to maintaining a healthy weight and postpone frailty. A 2019 review paper examined a variety of studies and found evidence of nutritional intervention as an effective way of preventing frailty.^[57] Specifically, multiple studies showed adherence to the Mediterranean diet is associated with a decreased risk of incident frailty in the US.^[58]

Frailty management largely depends on an individual's classification (i.e. non-frail, pre-fail, and frail) and treatment needs.^[3] Currently, there is a lack of strong evidence-based treatment and management plans for frailty. Physicians must work closely with patients to develop a realistic management plan to ensure patient compliance, leading to better health outcomes. In clinical practice, guidelines developed by International Conference on Frailty and Sarcopenia Research (ICFSR) can be used to identify and manage frailty based on classification.^[3]

There are currently no pharmacological interventions available for frailty.^[59]

Exercise is one of the major targets to prevent and manage frailty in older adults to improve and maintain mobility. Individuals partaking in exercise appear to have potential in preventing frailty. In 2018, a systemic review concluded that group exercise had the benefit of delaying frailty in older adults aged 65 and older.^[60]

Individualized physical therapy programs developed by physicians can help improve frail status. For example, progressive resistance strength training for older adults can be used in clinical practice or at-home as a way to regain mobility. A systematic review conducted in 2022 across multiple countries using data from twelve randomized clinical trials found evidence that mobility training can increase mobility level and functioning in older adults living in community-dwellings, such as a nursing home.^[61] However, the review also concluded little to no difference in the risk of falls.

Activities of daily living (ADLs) include activities that are necessary to sustain life. Examples are brushing teeth, getting out of bed, dressing oneself, bathing, etc. Occupational therapy provided modest improvements in elderly adults mobility to do ADLs.^[62]

Frailty can involve changes such as weight loss. Interventions should focus on any difficulties with supplementation and diet. For those who may be undernourished and not acquiring adequate calories, oral nutritional supplements in between meals may decrease nutritional deficits.^[63]

Vitamin D, omega-3 fatty acid, sex hormone (such as testosterone) or growth hormone supplementation have not shown benefits in physical functioning, activities of daily living or frailty.^[11]

Palliative care may be helpful for individuals who are experiencing an advanced state of frailty with possible other co-morbidities. Improving quality of life by reducing pain and other harmful symptoms is the goal with palliative care. One study showed the cost reduction by focusing on palliative care rather than other treatments that may be unnecessary and unhelpful.^[64]

Frail elderly people are at significant risk of post-surgical complications and the need for extended care. Frailty more than doubles the risk of morbidity and mortality from surgery and cardiovascular conditions.^[65] Assessment of older patients before elective surgeries can accurately predict the patients' recovery trajectories.^[66] One frailty scale consists of five items:^[39]

• unintentional weight loss >4.5 kg in the past year
• self-reported exhaustion
• <20th population percentile for grip strength
• slowed walking speed, defined as lowest population quartile on 4-minute walking test
• low physical activity such that persons would only rarely undertake a short walk

A healthy person scores 0; a very frail person scores 5. Compared to non-frail elderly people, people with intermediate frailty scores (2 or 3) are twice as likely to have post-surgical complications, spend 50% more time in the hospital, and are three times as likely to be discharged to a skilled nursing facility instead of to their own homes.^[66] Frail elderly patients (score of 4 or 5) have even worse outcomes, with the risk of being discharged to a nursing home rising to twenty times the rate for non-frail elderly people.

Another tool that has been used to predict frailty outcome post-surgery is the Modifies Frailty Index, or mFI-5. This scale consists of 5 key co-morbidities:^[67]

• Congestive heart failure within 1 month of surgery
• Diabetes mellitus
• Chronic Obstruction Pulmonary Disease or pneumonia in the past
• Individuals needing additional assistance to perform everyday activities of living
• High blood pressure that is controlled with medication

An individual without one of these conditions would be given a score of 0 for the condition absent. An individual who does have one of the conditions would be given a score of 1 for each of the conditions present. In an initial study using the mFI-5 scale, individuals with a sum mFI-5 score of 2 or greater were predicted to experience post-surgery complications due to frailty, which was supported by the results of the study.^[67]

Frailty scales can be used to predict the risk of complications in patients before and after surgery. There is an association between frailty and delayed transplant function after a kidney transplant.^[68] Other studies note that frailty scales alone may be innacurate in predicting outcomes for people undergoing surgical procedures, and other factors such as co-morbid medical conditions need to be considered.^[69]

Frailty is a common geriatric syndrome. Due to the absence of international diagnostic criteria, the prevalence estimates may not be accurate. Estimates of frailty prevalence in older populations vary according to a number of factors, including the setting in which the prevalence is being estimated — e.g., nursing home (higher prevalence) vs. community (lower prevalence) — and the definition used for frailty. Using the widely used frailty phenotype framework,^[39] prevalence estimates of 7–16% have been reported in non-institutionalized, community-dwelling older adults. In a systemic review exploring the prevalence of frailty based on geographical location it was found that Africa and North and South America had the largest prevalence at 22% and 17% respectively. Europe had the lowest prevalence at 8%.^[70]

The development of frailty occurs most often in individuals with low socio-economic status, those living with obesity, female sex, a history of smoking, limited activity levels, and older age.^[71]

Epidemiologic research has also indicated that presence of multiple chronic diseases (such as cardiovascular disease, diabetes, or chronic kidney disease, anemia, atherosclerosis) depression, and cognitive impairment to be risk factors for frailty.^{[72][73][74][25][26][75]} Autonomic dysfunction, hormonal abnormalities, and obesity have also been implicated in the development of frailty.^[25][76][27] obesity,^[77] Vitamin D deficiency in men may be associated with increased risk of frailty.^[78] Environmental factors such as living space and neighborhood characteristics may also be related to frailty.^[79]

Frailty is more common in those with diabetes plus peripheral arterial disease and in those with heart failure.^[80][81]

Frailty is more common in those with mental health conditions including anxiety disorders, bipolar disorder and depression. The presence of frailty with these mental disorders was also associated with a poor prognosis and increased mortality^[82]

Research comparing case management trials to standard care for people living with frailty in high-income countries found that there was no difference in reducing cost or improving patient outcomes between the two approaches.^[83]

Meta-analyses have shown that the prevalence of frailty is higher in female older adults compared to male older adults.^[84][85] This sex difference was consistently found in pre-clinical research models as well.^[86] Studies have found that the incidence of frailty was higher in females with more medical comorbidities.^[87] In recent research where muscle-biopsies were taken from fit and weak older adults of both sexes, it was shown that there were sex-specific alterations in muscle content in association with frailty-related physical weakness.^[88]

In a population based study, Non-Hispanic Black-Americans and Hispanic-Americans had a higher incidence of frailty compared to non-Hispanic White-Americans.^[89]

As of September 2021^[update], ongoing clinical trials on frailty syndrome in the US include:

• the impact of frailty on clinical outcomes of patients treated for abdominal aortic aneurysms^[90]
• the use of "pre-habilitation," an exercise regimen used before transplant surgery, to prevent the frailty effects of kidney transplant in recipients^[91]
• defining the acute changes in frailty following sepsis in the abdomen^[92]
• the efficacy of the anti-inflammatory drug, Fisetin, in reducing frailty markers in elderly adults^[93]
• Physical Performance Testing and Frailty in Prediction of Early Postoperative Course After Cardiac Surgery (Cardiostep)^[94]

• Ageing
• Osteoporosis
• Sarcopenia

• Frailty