Multisystem physiological perspective of human frailty and its modulation by physical activity

Abstract

"Frailty" is a term used to refer to a state characterized by enhanced vulnerability to, and impaired recovery from, stressors compared with a nonfrail state, which is increasingly viewed as a loss of resilience. With increasing life expectancy and the associated rise in years spent with physical frailty, there is a need to understand the clinical and physiological features of frailty and the factors driving it. We describe the clinical definitions of age-related frailty and their limitations in allowing us to understand the pathogenesis of this prevalent condition. Given that age-related frailty manifests in the form of functional declines such as poor balance, falls, and immobility, as an alternative we view frailty from a physiological viewpoint and describe what is known of the organ-based components of frailty, including adiposity, the brain, and neuromuscular, skeletal muscle, immune, and cardiovascular systems, as individual systems and as components in multisystem dysregulation. By doing so we aim to highlight current understanding of the physiological phenotype of frailty and reveal key knowledge gaps and potential mechanistic drivers of the trajectory to frailty. We also review the studies in humans that have intervened with exercise to reduce frailty. We conclude that more longitudinal and interventional clinical studies are required in older adults. Such observational studies should interrogate the progression from a nonfrail to a frail state, assessing individual elements of frailty to produce a deep physiological phenotype of the syndrome. The findings will identify mechanistic drivers of frailty and allow targeted interventions to diminish frailty progression.

Keywords: brain; cardiovascular system; exercise; frailty; inflammation.

Graphical abstract

FIGURE 1.

Key stages in the development of frailty. The cascade of functional decline in older adults from an independent (resilient) nonfrail state through to frailty and disability (in the absence of intervention). See glossary for abbreviations. Figure adapted from Ref. , with permission under the Creative Commons license: https://creativecommons.org/licenses/by/4.0/.

FIGURE 2.

Risk factors for the development of frailty. There are several important risk factors that increase the risk of a person developing frailty. These include sex (female), non-White ethnicity, level of education, socioeconomic status, obesity, and smoking. Protective factors include eating a Mediterranean diet and maintaining physical activity into old age. Image created with BioRender.com, with permission.

FIGURE 3.

The clinical manifestations of frailty. People with frailty have high rates of heart failure, hypertension, chronic obstructive pulmonary disease (COPD), and anemia. They are also more likely to have multimorbidity (the co-occurrence of 2 or more diseases), polypharmacy, and sarcopenia. CI, confidence interval.

FIGURE 4.

Summary of the typical physiological characteristics of a frail person based on a systems physiology approach. BMI, body mass index; CSA, cross-sectional area; IL-10, interleukin 10; IMAT, intramuscular adipose tissue; LAVI, left atrial volume index; LV, left ventricular; MU, motor unit; SkM, skeletal muscle; WMH, white matter hyperintensity. Image created with BioRender.com, with permission.

FIGURE 5.

Neuromuscular function in frailty. Schematic overview of the measurement of motor unit potential (MUP) by intramuscular electromyography. Compared to the nonfrail condition, frailty is associated with a smaller MUP thought to arise from smaller motor units. NMJ, neuromuscular junction. Image created with BioRender.com, with permission.

FIGURE 6.

Overview of magnetic resonance imaging (MRI) techniques routinely used to quantify brain architecture in frailty. DTI, diffusion tensor imaging; WMH, white matter hyperintensity. Image created with BioRender.com, with permission.

FIGURE 7.

Schematic representation of increased cardiac output and the redistribution of blood flow across organs during exercise compared with rest. Image created with BioRender.com, with permission.

FIGURE 8.

Factors contributing to the age-related increase in systemic inflammation (inflammaging). Increased systemic inflammation with age, inflammaging, is multifactorial in origin. Key contributors include an increase in senescent cells, which have a proinflammatory secretome, the senescence-associated secretory phenotype (SASP); reduced physical activity, which contributes to increased adiposity, with adipose tissue being a source of inflammatory mediators such as adipokines; and gut dysbiosis and reduced intestinal integrity, which lead to leaking of microbes into the circulation that then induces an inflammatory immune response. The degree of inflammaging is associated with increased risk of moving from a nonfrail to a frail state. See glossary for other abbreviations. Image created with BioRender.com, with permission.

FIGURE 9.

Schematic illustration of the effect of frailty on substrates and pathways involved in skeletal muscle energy turnover. When the rate of ATP demand during muscle contraction exceeds that of mitochondrial ATP production, ATP turnover is maintained from nonmitochondrial routes, namely glycolysis and phosphocreatine (PCr) hydrolysis. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; Ca²⁺, calcium; CK, creatine kinase; CPT1, carnitine palmitoyltransferase I; Cr, creatine; H⁺, hydrogen ion; H₂O, water; IMP, inosine monophosphate; NAD⁺, oxidized nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; PCr, phosphocreatine; PDC, pyruvate dehydrogenase complex; Pi, inorganic phosphate; TCA cycle, tricarboxylic acid cycle.