Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae
Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae
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DOI：
10.1038/nature01578
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发表时间：
2003-05-08
期刊：
影响因子：
64.8
通讯作者：
Sinclair, DA
中科院分区：
文献类型：
--
作者：
Anderson, RM;Bitterman, KJ;Sinclair, DA
热量限制延长了从酵母到哺乳动物的广泛生物体的寿命。已经提出了许多假说来解释这种现象，包括减少氧化损伤和改变能量代谢。在酿酒酵母中，通过限制热量来延长寿命需要NAD（+）依赖性组蛋白脱乙酰酶Sir 2（参考文献1）。我们最近发现，Sir 2及其最接近的人类同源物SIRT 1，p53脱乙酰酶，强烈抑制维生素B3前体烟酰胺2。在这里，我们表明，PNC 1（吡嗪酰胺酶/烟酰胺酶1）的表达增加，它编码一种酶，脱氨烟酰胺，是必要的和足够的寿命延长热量限制和低强度的压力。我们还确定PNC 1是一种长寿基因，对延长寿命的所有刺激都有反应。我们提供的证据表明，烟酰胺消耗足以激活Sir 2，这是PNC 1调节寿命的机制。我们的结论是，酵母寿命延长热量限制是一个积极的细胞反应的结果，低强度的压力和推测，烟酰胺可能会调节重要的细胞过程中的高等生物。
Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD(+)-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide2. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms.