SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

Abstract

Mitochondrial NAD+‐dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)‐dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR‐mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole‐body aerobic capacity but is dispensable for CR‐dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3−/−) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3−/−CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.

Vascular Ageing: Mechanisms, Risk Factors, and Treatment Strategies

“…A guided reduction in food intake or calorie restriction constitutes another lifestyle modification-mediated anti-ageing intervention. By diminishing both the age-related decline in physiological fitness and the risk of ARD development, calorie restriction extends the healthy lifespan [176,177] in that increases in telomerase activity and SIRT1 and SIRT6 expressions appear to play critical roles [178,179]. Results of a two-year clinical trial conducted with healthy and non-obese individuals show that calorie restriction may also improve overall health and wellbeing by significantly attenuating oxidative stress [180].…”

Challenges in anti‐aging medicine–trends in biomarker discovery and therapeutic interventions for a healthy lifespan

“…This is raising the question of whether a therapeutic intervention on one mechanism would not negatively impact another one within the aging network. Experiments in worms and mice often demonstrated that one can make organisms live longer (by caloric restriction, for instance) but at the expense of some inherited dysfunctions or unhealthy lifespans 59,60 . In humans, centenarians and super‐centenarians may offer clues about the conditions necessary for slowing down the aging pace and living a long and healthy life.…”

“…Experiments in worms and mice often demonstrated that one can make organisms live longer (by caloric restriction, for instance) but at the expense of some inherited dysfunctions or unhealthy lifespans. 59 , 60 In humans, centenarians and super‐centenarians may offer clues about the conditions necessary for slowing down the aging pace and living a long and healthy life. For instance, compared to old non‐centenarians, centenarians seem to display a unique, adapted peripheral immune profile (‘ immune resilience ’) that enables them to better recover from infections during their lives.…”