The physical frailty syndrome as a transition from homeostatic symphony to cacophony

Abstract

Frailty in aging marks a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. This Perspective synthesizes the evidence on the aging-related pathophysiology underpinning the clinical presentation of physical frailty as a phenotype of a clinical syndrome that is distinct from the cumulative-deficit-based frailty index. We focus on integrating the converging evidence on the conceptualization of physical frailty as a state, largely independent of chronic diseases, that emerges when the dysregulation of multiple interconnected physiological and biological systems crosses a threshold to critical dysfunction, severely compromising homeostasis. Our exegesis posits that the physiology underlying frailty is a critically dysregulated complex dynamical system. This conceptual framework implies that interventions such as physical activity that have multisystem effects are more promising to remedy frailty than interventions targeted at replenishing single systems. We then consider how this framework can drive future research to further understanding, prevention and treatment of frailty, which will likely preserve health and resilience in aging populations.

Fig. 1 |. A hierarchical, multiscale representation of the physiological dysregulation and likely biological drivers of physical frailty.

The schema depicts the clinical syndrome of physical frailty as an emergent property, at the highest level of the hierarchy, underlain by physiological modules (systems) at a smaller scale and cellular/molecular modules (systems) at an even smaller scale. Gold circles represent the three major physiological modules (systems) with the most evidence of interactions and the most evidence of a relationship with frailty. Orange ovals represent submodules (subsystems) within these three larger modules. Stressors from age-related biological changes at the cellular/molecular scale, represented in purple ovals, likely underlie dysregulation of the physiological modules represented above, which also interact with each other. The aggregate physiotype of dysregulation (dark orange oval) is associated with both the phenotype of physical frailty, in the top oval, and the vulnerability associated with its state. Adapted from ref. .

Fig. 2 |. Stimulus–response experiments in older adults measuring physiological response to minor stressors in community-dwelling older adults who were characterized as nonfrail, prefrail or frail.

Pilot studies in a–c were conducted in community-dwelling women 85–94 years of age in WHAS II. The study in d was of male and female volunteers ages 70 and older, including WHAS II participants. a, Glucose (left) and insulin (right) dynamics during OGTT by physical frailty status; data are shown as the mean ± standard error (s.e.; error bars) for glucose and insulin values at 0, 30, 60, 120 and 180 minutes after administration of a glucose load of 75 g by frailty status. The P values for comparisons of the area under the curve (AUC) were 0.82 (prefrail versus nonfrail) and 0.02 (frail versus nonfrail) for glucose and 0.26 (nonfrail versus prefrail) and 0.27 (nonfrail versus frail) for insulin. Panel reproduced from ref. . b, Time to 95% recovery of PCr levels after mild exercise, calculated as 3/k, where k is the rate constant of the monoexponential fit. The P values for comparisons of the group means in this pilot were 0.57 (prefrail versus nonfrail) and 0.22 (frail versus nonfrail), likely owing to the sample size of 30 (ref. ). Panel reproduced from ref. . c, DHEA response to ACTH stimulation test by frailty status. Data are shown as the mean ± s.e. (error bars) for DHEA values at 0, 30, 60 and 120 minutes after administration of 250 μg ACTH. The P value for a global test of difference in mean by frailty status was 0.86 (ref. ) in this pilot study of 51 women. Panel reproduced from ref. . d, Response to influenza vaccination in people 70 years and older; data are shown as the geometric mean HI antibody titer (GMT) ratios to H1N1, H3N2 and B strains in all study participants and by frailty status (left) and the rate of ILI and laboratory-confirmed influenza infection (right) during the post-vaccination season. The P values for the GMT ratios (0.04, 0.01 and 0.05 for H1N1, H3N2 and B strains, respectively) were obtained from linear regression for a stepwise trend of decrease from nonfrail to prefrail to physically frail individuals, adjusted for age; the corresponding P values for ILI (0.005) and influenza infection (0.03) rates were obtained from logistic regression analysis for a stepwise trend of increase from nonfrail to prefrail to frail individuals, adjusted for age. Panel reproduced from ref. . Physical frailty criteria: 0, nonfrail; 1–2, prefrail; 3–5, frail.

Fig. 3 |. Hypothesized natural history of frailty: deterioration of physiological integrity in response to repeated stressors and natural aging.

The physiological integrity of the system is defined by the capacity to maintain a healthy equilibrium in the face of stressors. The rolling ball represents stress-response dynamics. The level of physiological integrity is theorized to be a function of the reserves represented by both the depth of each bowl and the radius of the curvature, with greater depth and curvature representing greater reserve and resilience to stressors. Time to recovery after a stressor is a measure of this resilience (for example, see Fig. 2a for glucose recovery curves in the OGTT showing that frail older adults have a much slower time to recovery). Both episodic (for example, stroke, fall) and chronic (for example, chronic inflammation) insults are hypothesized to decrease the integrity of the system, thus degrading the ability to return to equilibrium and to respond to subsequent stressors. Progression of frailty consists of a series of critical transitions (denoted by asterisks) between states of equilibrium of decreasing integrity; at a particular critical transition point, the system becomes overwhelmed and can no longer harness the resources needed to maintain integrity, resulting in the clinical phenotype of physical frailty. Reproduced from ref. .

Fig. 4 |. Nonlinear increase in the prevalence of physical frailty by number of dysregulated physiological systems at baseline among women aged 70–79 years participating in the WHAS I and II studies (n = 704).

The filled dots connected by the solid line segments are prevalence estimates corresponding to the number of dysregulated systems, based on a generalized linear model with a binomial family distribution for being frail (versus nonfrail) and identity link while treating the number of dysregulated systems as dummy variables. The vertical bars represent 95% confidence intervals for the prevalence estimates. When fitting a quadratic equation to the curve, the quadratic term was statistically significant, at P = 0.027. The dashed line shows that a linear model does not fit the increase in prevalence of physical frailty. Adapted from ref. .