Obesity and Accelerated Aging

Abstract

The population of older adults with obesity is rapidly increasing. Through shared pathophysiologic mechanisms, obesity exacerbates the age-related decline in physical function which leads to frailty and disability. Obesity and aging are characterized by chronic low-grade inflammation, which contributes to reduced muscle quality and protein control mechanisms as well as to diminished muscle anabolic response. Obesity causes oxidative stress and inflammation, which increases telomere shortening. Calorie excess increases ROS formation, which damages nucleus, endoplasmic reticulum, and mitochondria and promotes cellular senescence. Given the persistence of DNA damage associated with altered DNA repair proteins in obesity and aging, it is thought that inability to repair DNA may be the principal molecular event that underlies accelerated aging. Calorie restriction in combination with exercise slows biological aging by protecting against the molecular and cellular damages that occur in obesity and aging. Promising approaches such as Time Restricted Eating, Mediterranean Diet, and Senolytics need further investigation.

The number of older adults with obesity is rapidly increasing due to both an increase in the total number of older persons and in the percentage of the older population who are obese (1). Via shared pathophysiologic mechanisms, obesity exacerbates the age-related decline in physical function which leads to frailty and disability (2). In fact, the positive energy balance typical of obesity worsens the excess deposition of ectopic fat with aging. In visceral adipose tissue, there is elevated infiltration of inflammatory cells associated with altered chemokine expression such as higher IL-6 and TNF-α (3). The increased adipose tissue inflammation with obesity and aging establishes the typical low-grade chronic inflammation observed in older adults (“inflammaging”) (4).

Obesity and aging have shared processes that contribute to reduced muscle quality and strength, ultimately resulting in muscle wasting, disability, and impaired function. Intermuscular adipose tissue is also closely related to local inflammation, which contributes to muscle wasting through release of inflammatory cytokines (5). Protein quality control mechanisms (autophagy and ubiquitin proteosome system) are reduced in obesity and aging (3). Muscle protein synthesis response to anabolic stimuli (amino acids and exercise) are blunted (6). Satellite cell proliferation/function is impaired and during aging exacerbated by obesity, mesenchymal cell progenitors give rise to adipocyte-like cells, contributing to ectopic lipids (7). Mitochondrial fusion/fission dynamics that allow adequate mitochondrial function are altered in obesity and aging (8). Obesity causes oxidative stress and inflammation, which can increase the rate of telomere shortening (9). Obesity induces epigenetic alteration, which can accelerate age-related dysfunction (10). Calorie excess increases formation of reactive oxygen species (ROS), which damages nucleus, endoplasmic reticulum, and mitochondria (11). DNA damage from ROS upregulates p16 and p21 (proteins involved in cell cycle arrest) resulting in chromatin reorganization, cellular senescence, and production of proinflammatory factors (senescence-associated secretory phenotypes [SASP]) (8).

In this issue of the journal, Chowdhury and colleagues (12) provide a narrative review of the influence of obesity on aging in the context of DNA metabolism. Although aging has been depicted by several interrelated hallmarks (13), their hierarchical order still needs to be clarified. Based on this review, it is proposed that accumulation of DNA damage or mutations is the major hypothesis that contributes to the progressive loss of physiologic integrity that characterizes aging. In fact, persistence of DNA damage is a common molecular event associated with both obesity and aging. It is suggested that in persons with obesity, leptin overproduction, inflammation, and ROS lead to accumulation of DNA damage in adipose tissue, which in turn causes accumulation of mutation in DNA repair genes. There is an altered expression in DNA repair proteins with inefficient ability to repair DNA, which further contributes to induction of senescence. Accordingly, obesity contributes to the DNA damage that occurs with aging thereby accelerating the aging process.

Calorie-restriction (CR) is the cornerstone of obesity management and has been shown to be safe and effective in older adults with obesity (14). CR protects against the molecular and cellular damages that are the bases of the functional decline associated with obesity and aging (15). The addition of exercise further improves physical function and attenuates CR-induced reduction of muscle and bone mass (16). Indeed, the combination of CR and exercise has been shown to improve biological age in older adults with obesity (17). Other potential options to slow aging in older adults with obesity need further investigation, e.g., Time-Restricted Eating (TRE), Mediterranean Diet (MD), and Senolytics. TRE consists of restricting the window for eating in order to sustain circadian rhythms and could confer benefits similar to CR (18). MD is a “healthy food” dietary pattern that has been shown in observational studies to be associated with a lower incidence of chronic diseases and lower physical impairment in old age (19). Senolytics have been shown to reduce senescent cell burden, which could reduce obesity- and age-related metabolic dysfunction, in an open label Phase 1 study (20).