The intersection of frailty and metabolism

Abstract

On average, aging is associated with unfavorable changes in cellular metabolism, which are the processes involved in the storage and expenditure of energy. However, metabolic dysregulation may not occur to the same extent in all older individuals as people age at different rates. Those who are aging rapidly are at increased risk of adverse health outcomes and are said to be "frail." Here, we explore the links between frailty and metabolism, including metabolic contributors and consequences of frailty. We examine how metabolic diseases may modify the degree of frailty in old age and suggest that frailty may predispose toward metabolic disease. Metabolic interventions that can mitigate the degree of frailty in people are reviewed. New treatment strategies developed in animal models that are poised for translation to humans are also considered. We suggest that maintaining a youthful metabolism into older age may be protective against frailty.

Keywords: frailty index; frailty phenotype; metabolic dysregulation; metabolic syndrome; mouse models; protein restriction.

Figure 1:. Commonly used clinical frailty assessment instruments.

A. The frailty phenotype tool scores recognizable signs of physical decline in the five deficit areas illustrated. Individuals are frail if they have three or more deficits, pre-frail if they have one or two deficits and non-frail if they have none. B. The frailty index instrument considers deficits across a wide range of body systems, although the specific deficits in the index can vary between studies. The number of deficits in an individual divided by the total number of deficits in the index produces a score between 0 and 1, where higher numbers indicate a high degree of frailty. Created with Biorender.com.

Figure 2:. Metabolic factors associated with frailty.

There are many factors that may be either metabolic contributors or consequences of frailty. These include dietary factors (both undernutrition and obesity), low muscle mass, changes in protein and amino acid metabolism, and changes in nutrient sensing pathways, glucose/insulin signalling, hormones and inflammation. The causal relationships between these factors and metabolism are not yet understood. Created with Biorender.com.

Figure 3:. Proposed positive feedback loop between metabolic syndrome and frailty.

Metabolic syndrome (MetS) and associated complications increase the risk of frailty in older individuals. Factors such as inflammation, oxidative stress, altered body composition and impaired insulin/glucose dynamics are implicated in the pathogenesis of both MetS and frailty. This may promote a positive feedback loop whereby MetS exacerbates frailty and frailty sows the seeds for MetS in older adults. Created with Biorender.com.