Energetic interventions for healthspan and resiliency with aging

Abstract

Several behavioral and pharmacological strategies improve longevity, which is indicative of delayed organismal aging, with the most effective interventions extending both life- and healthspan. In free living creatures, maintaining health and function into old age requires resilience against a multitude of stressors. Conversely, in experimental settings, conventional housing of rodents limits exposure to such challenges, thereby obscuring an accurate assessment of resilience. Caloric restriction (CR) and exercise, as well as pharmacologic strategies (resveratrol, rapamycin, metformin, senolytics), are well established to improve indices of health and aging, but some paradoxical effects have been observed on resilience. For instance, CR potently retards the onset of age-related diseases, and improves lifespan to a greater extent than exercise in a variety of models. However, exercise has proven more consistently beneficial to organismal resilience against a broad array of stressors, including infections, surgery, wound healing and frailty. CR can improve cellular stress defenses and protect from frailty, but also impairs the response to infections, bed rest and healing. How an intervention will impact not only longevity, health and function, but also resiliency, is critical to better understanding translational implications. Thus, organismal robustness represents a critical, albeit understudied aspect of aging, which needs more careful attention in order to better inform on how putative age-delaying strategies will impact preservation of health and function in response to stressors with aging in humans.

Keywords: Aging; Caloric restriction; Diet; Exercise; Metformin; Rapamycin; Resiliency; Resveratrol; Robustness; Senolytics.

Figure 1. Energetic Interventions to increase resilience and extend healthspan

There is compelling evidence that caloric restriction (CR) and exercise prevent and defend against multiple forms of aging-associated molecular and cellular damage, which mediate the intrinsic and progressive functional decline with aging. In contrast, nutrient excess and physical inactivity raise disease risk and accelerate aging. Through somatic maintenance, CR and exercise improve an organism's resilience to challenges and maintain physiological function (solid blue line). In the absence of resilience, chronic disease, multimorbidity, disability, and frailty manifest and compromise healthspan and lifespan (solid red line). Paradoxically, beneficial effects of CR on resiliency do not appear to be universal, as energy restriction may impair response to infections, as well as wound and fracture healing, which could lead to an inability to completely rebound from a challenge (dashed blue line). However, short-term re-feeding may be able to negate these effects of CR, while alternative approaches, such as fasting, can be uniquely leveraged to improve resilience to chemotherapy.