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

Abstract

Evolving definitions of frailty, and improved understanding of molecular and physiological declines in multiple systems that may increase vulnerability in frail, older adults has encouraged investigators from many disciplines to contribute to this emerging field of research. This article reports on the results of the 2004 American Geriatrics Society/National Institute on Aging conference on a Research Agenda on Frailty in Older Adults, which brought together a diverse group of clinical and basic scientists to encourage further investigation in this area. This conference was primarily focused on physical and physiological aspects of frailty. Although social and psychological aspects of frailty are critically important and merit future research, these topics were largely beyond the scope of this meeting. Included in this article are sections on the evolving conceptualization and definitions of frailty; physiological underpinnings of frailty, including the potential contributions of inflammatory, endocrine, skeletal muscle, and neurologic system changes; potential molecular and genetic contributors; proposed animal models; and integrative, system biology approaches that may help to facilitate future frailty research. In addition, several specific recommendations as to future directions were developed from suggestions put forth by participants, including recommendations on definition and phenotype development, methodological development to perform clinical studies of individual-system and multiple-system vulnerability to stressors, development of animal and cellular models, application of population-based studies to frailty research, and the development of large collaborative networks in which populations and resources can be shared. This meeting and subsequent article were not meant to be a comprehensive review of frailty research; instead, they were and are meant to provide a more-targeted research agenda-setting process.

Systematic review and meta-analysis of frailty as a predictor of morbidity and mortality after major abdominal surgery

“…A question raised is how to use the finding that frailty is a risk factor for poor surgical outcome. It could be used to restrict access of frail patients to major surgery, although this is somewhat constraining given the increasing proportion of older and frail patients58. It could enable more individual risk assessment, discussion and consent to take place, or indeed allow targeted preoperative optimization of patients.…”

Inflammation and mortality in a frail mouse model

“…Although the underlying mechanism for frailty is likely multisystemic, the activation of inflammatory pathways is likely to play a central role in its development and its related vulnerability to adverse health outcomes (Walston et al 2006). In this study, we confirmed and extended initial findings by demonstrating that IL-10 tm/tm mice have significantly increased levels of several inflammatory cytokines, higher levels of IGF-1 at midlife, and found that they had higher mortality rates when compared to age and sex-matched B6 control mice.…”

“…Although IL-10 and IFN-γ levels have not been extensively studied in human population studies on aging and frailty, in part because of limitations in measuring serum samples that have been stored for long periods of time, investigators have reported significant elevations in macrophages and other inflammatory cells in frail compared to non-frail humans (Leng et al 2009;Yao et al 2011). The chronic inflammatory pathway activation observed in frail, older adults is likely multifactorial and stems from chronic disease states, altered body composition, and increased production of free radicals rather than a deficit in IL-10 ( Walston et al 2006). Aging mice of any strain likely have similar age-related inflammatory stimulation, but the IL-10 tm/tm frail mouse has a genetic disposition to increased inflammatory reactivity to any stimulation.…”

“…The frailty syndrome in older adults likely results from cumulative decline in multiple physiological systems, leading to poor tolerance to stressors and increased vulnerability to adverse health outcomes (Fried et al 2001;Walston et al 2006). Multiple population-based studies have demonstrated that increased interleukin (IL)-6 and other markers of inflammation are important physiological correlates of frailty, disability, and mortality (Cesari et al 2004;Cohen et al 2003;Ferrucci et al 1999;Fried et al 2001;Harris et al 1999;Leng et al 2002;.…”

Prevalence of and factors associated with frailty and disability in older adults from China, Ghana, India, Mexico, Russia and South Africa

“…In China, for instance healthy life expectancy at age 60 years is 16.5 (LE 20.8 years) for women and 14.2 years for men (LE 18 years) [3]. However, many older adults develop chronic diseases and disability as they age, and have poor quality of life in their later years [4][5][6].…”