减少食物摄取可延长细菌和果蝇、也许还包括人类在内的多种不同生物的寿命。现在,研究发现,红酒中所含的一种名叫白藜芦醇的化合物能延长果蝇和蠕虫的寿命。这一发现使人们想到有可能在不限制营养摄取的条件下延长寿命。通过限制营养摄取来延长寿命实际上是限制热量摄取,它与被称为Sirtuins的酶的活性有关,而白藜芦醇是一种能激活Sirtuin的化合物。摄取较少热量会导致较长寿命,但却有一个严重的副作用,如用猴子做的研究表明,摄取较少热量会造成体能减少和不育。饮用红酒也不是答案,因为红酒中所含白藜芦醇太少,在食量过度所产生的更明显的副作用表现出来之前不会有任何效果。但施用白藜芦醇的果蝇仍然保持活跃,仍然有生育能力,而且想吃多少就吃多少,却仍能活得长一些。因此,新研制的具有白藜芦醇一样性能的化合物也许正好能够延长寿命,而又没有人们所不希望的副作用。
Sirtuin activators mimic caloric restriction and delay ageing in metazoans
Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
Figure 1 Effect of polyphenolic STACs on sirtuins. a, Sir2 polypeptides from various species. The NAD+-binding pocket (grey), substrate-binding groove (black) and per cent homology to SIRT1 are shown. b, Effect of polyphenolic STACs (500 µM) on TSA-insensitive deacetylase activity in Drosophila S2 cells. c, Fold stimulation of SIR-2.1 by STACs (10 µM). d, Fold stimulation of Drosophila Sir2 by STACs (10 µM). Values are the mean of at least three determinations ( s.e.). e, f, Activation of C. elegans SIR-2.1 (e) and Drosophila Sir2 (f) by resveratrol ( s.e.). g, SIR-2.1 initial rate as a function of NAD+ concentration ( s.e.). AFU, arbitrary fluorescence units.
Figure 2 C. elegans survival on resveratrol. a, Survivorship of adult wild-type N2 C. elegans treated with resveratrol fed with heat-killed OP50 E. coli. b, Survivorship of sir-2.1 mutants treated with resveratrol fed with heat-killed OP50. Adult lifespan of sir-2.1 animals does not differ significantly from N2 controls. c, Survivorship of wild-type N2 C. elegans on 100 µM resveratrol fed with live OP50. d, Survivorship of sir-2.1 mutants on 100 µM resveratrol fed with live OP50. e, Fecundity of adult hermaphrodites on 100 µM resveratrol ( s.d.). f, Feeding rates of L4 larval and adult hermaphrodites treated with 100 µM resveratrol ( s.d.).
Figure 3 Survival of wild-type female D. melanogaster adults fed resveratrol or fisetin. a, Canton-S on 15% SY media. b, Canton-S on 5% SY media. c, yw on 3% CSY media. d, yw on 2% CSY media. e, yw on 3% CSY media. f, yw on 2% CSY media. g, Mean 5 day fecundity per female of Canton-S on 15% SY media resveratrol. h, Proportion of yw females feeding on diet resveratrol in crop-filling assay. i, Mean body mass of Canton-S flies on diet resveratrol (10 µM). Errors represent s.e.
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