NNIW83 - Frailty Pathophysiology, Phenotype, and Patient Care

Editor(s): R.A. Fielding, C. Sieber, B. Vellas. Clinical Nutrition Series 83

Worldwide, the population aged 65 years and more is expected to grow from near 500 million people in 2004 to an estimated 2 billion people by 2050. The geriatric syndrome of frailty is likely to affect a large number of elderly living in the community, as approximately 14% of those are frail and 43% are prefrail based on findings of the Survey of Health, Aging and Retirement in Europe (SHARE) conducted in 10 major European countries.In a frail state, older adults are at greater risk for adverse outcomes, including falls and admissions to hospitals and nursing homes. Early action is warranted in vulnerable individuals because frailty is a predisabled condition, disability is costly, and initiating intervention may modify the frailty trajectory. Yet, today it is more common for older adults to progress to a worsened level of frailty than to transition to an improvement. The development and application of evolving science is important for better patient-centric health care.


Cellular Senescence and the Biology of Aging, Disease, and Frailty

Author(s): N.K. LeBrasseur, T. Tchkonia, J.L. Kirkland

Population aging simultaneously highlights the remarkable advances in science, medicine, and public policy, and the formidable challenges facing society. Indeed, aging is the primary risk factor for many of the most common chronic diseases and frailty, which result in profound social and economic costs. Population aging also reveals an opportunity, i.e. interventions to disrupt the fundamental biology of aging could significantly delay the onset of age-related conditions as a group, and, as a result, extend the healthy life span, or health span .There is now considerable evidence that cellular senescence is an underlying mechanism of aging and age-related conditions. Cellular senescence is a process in which cells lose the ability to pide and damage neighboring cells by the factors they secrete, collectively referred to as the senescence-associated secretory phenotype (SASP). Herein, we discuss the concept of cellular senescence, review the evidence that implicates cellular senescence and SASP in age-related deterioration, hyperproliferation, and inflammation, and propose that this underlying mechanism of aging may play a fundamental role in the biology of frailty.

The Role of Genome Instability in Frailty: Mitochondria versus Nucleus

Author(s): A.Y. Seo, C.Leeuwenburgh

Late-life aging in humans is often associated with severe frailty. This suggests catastrophic events reaching an undeniable biological threshold in cellular stability and a rapidly diminished homeostasis. The driving force of the syndrome is likely ‘genetic instability’ or ‘genomic instability’, a high frequency of mutations and deletions within the genome (both nuclear and mitochondrial DNA) of bodily somatic cells caused by DNA damage and inefficient repair. Reactive oxygen species, calcium deregulation, and iron dyshomeostasis are potential chemical triggers of nucleic acid sequence alterations and chromosomal rearrangements.These include mutations, deletions, translocations, chromosomal inversions, and single- and double-strand DNA breaks. Nuclear damage, such as telomere shortening, also appears to cause an abnormal expression of several proteins, including p53, which leads to impaired mitochondrial biogenesis, mitochondrial permeability transition pore opening, apoptosis, and other biological events. Moreover, mitochondrial DNA damage could produce inaccurate translation and synthesis of proteins important for energy production in the inner mitochondrial membrane. Another cause of genomic instability may be a reduced expression and function of DNA repair genes, especially when stressful events trigger slow responses. With late-life frailty, overall endogenous damage occurs much more frequently and repair is much less efficient, which further accelerates genomic instability.

Determinants of Frailty and Longevity: Are They the Same Ones?

Author(s): L. R. Manas

Older people are at risk of developing frailty with advancing age. The prevalence of frailty increases from 2.5–3% in adults aged 65 years to 30–35% in those older than 85 years. These results suggest that an association exists between longevity and frailty. However, at the same time, even at advanced age, the majority of older adults are free of frailty, suggesting that factors different from those contributing to or produced by the life length are involved in producing frailty.Genetic and epigenetic factors, nutrient-sensing systems, mainly the so-called insulin/insulin-like growth factor-1 signaling pathway, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, inflammation, and some hormonal systems are involved in longevity. However, factors involved in frailty are mainly inflammation and hormones, with an anecdotal role for genetic and other potential factors, but even these two common factors seem to regulate longevity and frailty in different ways. Moreover, their effect on frailty seems to change when they are acting in combination.

Psychological Frailty in the Aging Patient

Author(s): L.J. Fitten

There is little written in the geriatric literature about the concept of psychological frailty which encompasses cognitive, mood, and motivational components. The concept is intended to consider brain changes that are beyond normal aging, but not necessarily inclusive of disease, that result in decreased cognitive or mood resilience in the presence of modest stressors, and may eventually lead to negative health outcomes in a manner parallel to physical frailty, an entity well known to clinicians.Most work exploring the interface between cognition, mood, and physical frailty has demonstrated a bidirectional association between the two domains. Psychological symptoms or deficits have been described as either worsening the degree of physical frailty, or physical frailty has been viewed as a risk to a worsening cognition or depression. However, psychological frailty, a consequence of age-altered brain function, has not been studied for itself.By what possible mechanism does the brain reveal its loss of resiliency under modest stress and how can this be visualized? Are there markers that predate a psychological decline that might permit a preventive intervention which could delay the appearance of negative health outcomes such as reduced functional capacity or increased dependency? The present review will explore these concepts and possibilities.

Frailty Clinical Phenotype: A Physical and Cognitive Point of View

Author(s): M. Cesari, B. Vellas

Frailty is recognized as a clinical geriatric syndrome used to describe the weakest or most vulnerable older adults. Although the term frailty is commonly used in clinical practice, and the theoretical phenomenon is well accepted, it remains an evolving concept that lacks a universally accepted definition and specific diagnostic criteria. Different perspectives on frailty have led to two distinct viewpoints of this phenomenon in the literature. The first describes the phenomenon based solely on physical attributes and capabilities.In contrast, more recent perspectives describe the phenomenon in broader, multidimensional terms by incorporating the concept of cognitive frailty. In support of this view, there is increasing evidence that consideration of both cognitive and physical factors can better improve the ability to predict adverse health outcomes among frail older adults over physical factors alone. The recent recognition of the importance of cognitive factors has increased the complexity of this phenomenon and difficulty in developing a consensus definition. To add to this challenge, frailty can present in different stages of severity (from mild to severe), and there appears to be a dynamic relationship between these stages. Despite these challenges, a consensus on an international definition of frailty including physical and cognitive criteria is essential in order to advance research and treatment of this condition

Overlaps between Frailty and Sarcopenia Definitions

Author(s): T. Cederholm

Aging is characterized by the catabolism of muscles leading to sarcopenia and frailty. These are two geriatric syndromes with partly overlapping phenotypes. Primary sarcopenia, i.e. loss of muscle mass and function related to aging alone, usually precedes frailty. Thus, robustness passes from sarcopenia over frailty to disability leading eventually to a mortal outcome.Frailty (defined according to the phenotype model) encompasses states as exhaustion, weakness, and slowness, whereas sarcopenia, combining mass and function, is more strictly focused on muscles. Frailty is age related, whereas sarcopenia is also related to disease, starvation, and disuse.In general, the criteria for the two conditions overlap, but frailty requires weight loss, whereas sarcopenia requires muscle loss. Both gait speed and hand grip strength are suggested to be used as diagnostic measures for the two conditions since muscle function is crucial for any of the two syndromes. It is suggested that frailty screening should be part of the geriatric comprehensive assessment starting with measuring walking capacity and complemented by taking a history of fatigue and low activity. For younger adults (i.e. provide adequate protein and vitamin D supplementation, and encourage resistance exercise.

Physical Exercise as Therapy for Frailty

Author(s): L.E. Aquirre, D.T. Villareal

Longitudinal studies demonstrate that regular physical exercise extends longevity and reduces the risk of physical disability. Decline in physical activity with aging is associated with a decrease in exercise capacity that predisposes to frailty. The frailty syndrome includes a lowered activity level, poor exercise tolerance, and loss of lean body and muscle mass.Poor exercise tolerance is related to aerobic endurance. Aerobic endurance training can significantly improve peak oxygen consumption by ∼ 10–15%. Resistance training is the best way to increase muscle strength and mass. Although the increase in muscle mass in response to resistance training may be attenuated in frail older adults, resistance training can significantly improve muscle strength, particularly in institutionalized patients, by ∼ 110%. Because both aerobic and resistance training target specific components of frailty, studies combining aerobic and resistance training provide the most promising evidence with respect to successfully treating frailty.At the molecular level, exercise reduces frailty by decreasing muscle inflammation, increasing anabolism, and increasing muscle protein synthesis. More studies are needed to determine which exercises are best suited, most effective, and safe for this population. Based on the available studies, an inpidualized multicomponent exercise program that includes aerobic activity, strength exercises, and flexibility is recommended to treat frailty.

Integrating Frailty into Clinical Practice to Prevent the Risk of Dependency in the Elderly

Author(s): B. Vellas

Geriatric medicine started to be developed approximately 40 years ago when the increasing number of older adults with disability and dementia admitted to hospital emergency units threatened the sustainability of the healthcare organizations. Today, almost 90% of the geriatric medicine forces are devoted to the care of age-related disabilities.The epidemiological scenario and the high healthcare costs required for the management of dependent individuals require the adoption of strategies aimed at preventing the loss of physical function and anticipate the take in charge of older persons at risk of negative outcomes. Major medical specialties (e.g., oncology, cardiology, neurology…) have already moved to an early stage of the diseases to be more effective. Geriatric medicine must do the same, moving to frailty an early stage of disability where interventions are more likely to be effective.

Connecting Age-Related Biological Decline to Frailty and Late-Life Vulnerability

Author(s): J. D. Walston

Frailty is an important construct in aging which allows for the identification of the most vulnerable subset of older adults. At least two conceptual models of frailty have been developed that have in turn facilitated the development of multiple frailty screening tools. This has enabled the study of populations of frail and nonfrail older adults, and facilitated the risk assessment for adverse health outcomes.In addition, using the syndromic approach to frailty, numerous biological hypotheses have been tested, which have identified chronic inflammatory pathway activation, hypothalamic-pituitary-adrenal axis activation, and sympathetic nervous system activity as important in the development of frailty. In addition, age-related molecular changes related to autophagy, mitochondrial decline, apoptosis, senescent cell development, and necroptosis likely contribute to the heterogeneous phenotype of frailty.The recent development of a frail mouse model with chronic inflammatory pathway activation has helped to facilitate further whole organism biological discoveries. The following article attempts to create an understanding of the connections between these age-related biological changes and frailty.

A Summary of the Biological Basis of Frailty

Author(s): R. A. Fielding

Frailty has been defined as a geriatric syndrome that is characterized by a reduction in the physiological reserve required for an inpidual to respond to endogenous and exogenous stressors. Using a discrete definition of frailty that includes sedentariness, involuntary weight loss, fatigue, poor muscle strength, and slow gait speed, ‘frailty’ has been associated with increased disability, postsurgical complications, and increased mortality.Despite the strong associations between frailty and subsequent poor outcomes, limited attention to this common geriatric condition has been paid in clinical settings. A more fundamental basic understanding of the biological factors that contribute to the frailty phenotype has begun to emerge.Multiple underlying biological factors such as dysregulation of inflammatory processes, genomic instability, oxidative stress, mitochondrial dysfunction, and cellular senescence appear to contribute to the clinical presentation of frailty. This chapter summarizes the papers presented on the biological basis of frailty from the 83rd Nestlé Nutrition Institute Workshop on ‘Frailty, Pathophysiology, Phenotype and Patient Care’ held in Barcelona, Spain, in March 2014.

Recovery after Hip Fracture: Interventions and Their Timing to Address Deficits and Desired Outcomes – Evidence from the Baltimore Hip Studies

Author(s): J. Magaziner, N. Chiles, D. Orwig

Hip fracture is a significant public health problem affecting an estimated 1.6 million persons annually. The consequences of hip fracture are also significant, with more than half of those who sustain a fracture either dying or not returning to functional abilities present before fracture required to function independently. The Baltimore Hip Studies (BHS) is a program of research that for more than 30 years has been doing investigations to identify, develop, and evaluate strategies to optimize recovery from hip fracture.This paper provides an overview of known outcomes and recovery patterns following a hip fracture, which are derived primarily from the BHS. Target areas and timing for interventions based on this recovery sequence are suggested. The paper concludes with a discussion of some of the areas that the next generation of studies needs to concentrate on in order to advance knowledge about the care of hip fracture patients to maximize their recovery.

Frailty in Clinical Practice

Author(s): M. Cesari, B. Vellas

Frailty is a geriatric syndrome characterized by reduced homeostatic reserves, exposing the organism to extreme vulnerability to endogenous and exogenous stressors. Since disability is considered as an almost irreversible condition at advanced age, frailty has been indicated as a promising target for specific interventions in order to prevent disability. From a theoretical viewpoint, the concept of frailty has been well established, but its operationalization is still subject to controversy.This impediment leads to the postponement of the integration of frailty in the clinical setting. In the present article, we discuss the main issues regarding the frailty syndrome in the clinical setting, describe possible solutions (especially on the basis of our experience derived from the frailty clinic we have set up in Toulouse, France), and present the most relevant research perspectives in the field.