Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue

Abstract

Considerable evidence implicates cellular senescence in the biology of aging and chronic disease. Diet and exercise are determinants of healthy aging; however, the extent to which they affect the behavior and accretion of senescent cells within distinct tissues is not clear. Here we tested the hypothesis that exercise prevents premature senescent cell accumulation and systemic metabolic dysfunction induced by a fast-food diet (FFD). Using transgenic mice that express EGFP in response to activation of the senescence-associated p16INK4a promoter, we demonstrate that FFD consumption causes deleterious changes in body weight and composition as well as in measures of physical, cardiac, and metabolic health. The harmful effects of the FFD were associated with dramatic increases in several markers of senescence, including p16, EGFP, senescenceassociated b-galactosidase, and the senescenceassociated secretory phenotype (SASP) specifically in visceral adipose tissue. We show that exercise prevents the accumulation of senescent cells and the expression of the SASP while nullifying the damaging effects of the FFD on parameters of health. We also demonstrate that exercise initiated after long-term FFD feeding reduces senescent phenotype markers in visceral adipose tissue while attenuating physical impairments, suggesting that exercise may provide restorative benefit by mitigating accrued senescent burden. These findings highlight a novel mechanism by which exercise mediates its beneficial effects and reinforces the effect of modifiable lifestyle choices on health span.

Cellular senescence: Implications for metabolic disease

“…Chronic reductions in TAF + senescent cells are associated with attenuated endothelial dysfunction in aged mice, improved vascular smooth muscle sensitivity to nitric oxide donors in hypercholesterolemic mice, and reduced vascular calcification in hypercholesterolemic mice (Roos et al, 2016). Critically, our group also found that the beneficial cardiovascular effects of chronic exercise training are closely associated with reductions in visceral adipose tissue senescence, suggesting that reducing senescent cell burden at non-cardiovascular sites may have significant benefits through systemic or paracrine factors (Schafer et al, 2016). Collectively, conflicting reports highlight the need for additional studies to understand the mechanistic contribution of senescent cells in individual pathogenic contexts; however, our recent findings demonstrate that targeting senescent cells is a viable strategy to improve age- and obesity-related cardiovascular phenotypes.…”

“…Senescence effector activation was associated with increased SA-β-gal activity, with 12% of adipose cells staining positively, presentation of the SASP, and systemic metabolic disease. Exercise initiated at the same time as the high calorie diet or after accumulation of senescent burden ameliorated these effects (Schafer et al, 2016). In the absence of obesity, age-related adipose tissue atrophy is prevented by transgenic clearance of senescent cells (Xu et al, 2015a).…”

“…p53 expression increases in the liver of obese mice (Minamino et al, 2009). Likewise, high calorie consumption in mice increases hepatic p21 expression, liver weight, triglycerides, ceramides, and ectopic fat accumulation, and exercise ameliorates these outcomes (Schafer et al, 2016). Hepatic senescence may also drive malignancy through a high fat diet and microbiota-driven mechanism (Yoshimoto et al, 2013), a phenomena described in a subsequent section.…”

“…Voluntary running wheel exercise prevents and mitigates visceral adipose senescence and SASP resulting from high calorie feeding (Schafer et al, 2016) and, similarly, reduces aortic senescence markers (Werner et al, 2009). Calorie restriction (CR), which extends health- and life-span, decreases p16-and SA-β-gal-positive senescent cell burden in the kidney of aged rats, coincident with altered glomerular volume and fibrosis (Ning et al, 2013).…”

The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon

“…This study re‐enforces the importance of dietary interventions for senescence induction or prevention. Indeed, CR was previously shown to reduce senescence in the mouse liver and intestine (Wang et al., 2010), and high‐fat diet was recently implicated in promoting accelerated senescence with detrimental effects in mice (Schafer et al., 2016). Of course, more studies are warranted to understand how lowering calorie intake reduces senescence burden, and whether the reduction in senescence is sufficient to directly lower the levels of various tissue‐remodeling factors and interleukins, which could be affected by several other variables independently perturbed by the presence of senescent cells.…”