Dietary restriction involves NAD+‐dependent mechanisms and a shift toward oxidative metabolism

Aging Cell

Natalie Moroz²  Juan J. Carmona³  Edward Anderson⁴  Anne C. Hart⁴  David A. Sinclair¹ 

[1] Department of Genetics and Paul F. Glenn Labs for the Biological Mechanism of Aging, Harvard Medical School, Boston, MA, USA;Department of Genetics and Complex Diseases, Division of Biological Sciences, Harvard School of Public Health, Boston, MA, USA;Laboratory of Environmental Epigenetics and Program in Quantitative Genomics, Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA;Department of Neuroscience, Brown University, Providence, RI, USA

关键词: aging;    dietary restriction;    C. elegans;    stress response;    sirtuins;    NAD+;   

DOI  :  10.1111/acel.12273

来源: Wiley

【 摘 要 】

Summary

Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD⁺-dependent deacylases known as sirtuins, and increases in NAD⁺ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol. DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD⁺ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption. We conclude that stress response and NAD⁺-dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD⁺ salvage. Under DR conditions, NAD⁺-dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.

【 授权许可】

CC BY   
© 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.