Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Aging Cell. 2022 Dec;21(12):e13721. doi: 10.1111/acel.13721. Epub 2022 Oct 5.
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.
线粒体 NAD 依赖性蛋白去乙酰化酶 Sirtuin3（SIRT3）被认为介导热量限制（CR）依赖性代谢调节和寿命延长。在这里，我们研究了 SIRT3 在 CR 介导的长寿、线粒体功能和有氧适应能力中的作用。我们报告称，SIRT3 是全身有氧能力所必需的，但对于 CR 依赖性寿命延长是可有可无的。在 CR 下，与 Sirt3 小鼠相比，SIRT3（Sirt3）缺失导致整体和最大寿命延长。这种出乎意料的寿命延长与氧化代谢途径中改变的线粒体蛋白乙酰化、减少的线粒体呼吸和减少的有氧运动能力有关。此外，Sirt3 CR 小鼠在餐后期间表现出较低的自发活动和有利于脂肪酸氧化的趋势。这项研究表明寿命和健康寿命参数（有氧适应能力和自发活动）的解耦，并为 SIRT3 在 CR 适应、燃料利用和衰老中的功能提供了新的见解。
