期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 7, 页码 1564-1569出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1720673115
关键词
aging; metabolism; sirtuins; mitochondria; Sirt4
资金
- NIH [2P40OD010949, AG51449]
- Ellison/American Federation for Aging Research (AFAR) Postdoctoral Fellowship Award
- Nathan Shock Center Pilot Grant
- NIA [AG16667, AG24353]
- Glenn/AFAR Breakthroughs in Gerontology Award
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK098722] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG024353, R01AG016667, P01AG051449, R37AG016667] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [P40OD010949] Funding Source: NIH RePORTER
Sirtuins are an evolutionarily conserved family of NAD-dependent deacylases that control metabolism, stress response, genomic stability, and longevity. Here, we show the sole mitochondrial sirtuin in Drosophila melanogaster, Sirt4, regulates energy homeostasis and longevity. Sirt4 knockout flies have a short lifespan, with increased sensitivity to starvation and decreased fertility and activity. In contrast, flies overexpressing Sirt4 either ubiquitously or specifically in the fat body are long-lived. Despite rapid starvation, Sirt4 knockout flies paradoxically maintain elevated levels of energy reserves, including lipids, glycogen, and trehalose, while fasting, suggesting an inability to properly catabolize stored energy. Metabolomic analysis indicates several specific pathways are affected in Sirt4 knockout flies, including glycolysis, branched-chain amino acid metabolism, and impaired catabolism of fatty acids with chain length C18 or greater. Together, these phenotypes point to a role for Sirt4 in mediating the organismal response to fasting, and ensuring metabolic homeostasis and longevity.
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