Slade Jennifer D, Staveley Brian E
Department of Biology, Memorial University of Newfoundland, 232 Elizabeth Avenue, St. John's, NL A1B 3X9, Canada.
Genome. 2016 May;59(5):311-8. doi: 10.1139/gen-2015-0213. Epub 2016 Feb 22.
The regulation of energy homeostasis is pivotal to survive periods of inadequate nutrition. A combination of intricate pathways and proteins are responsible for maximizing longevity during such conditions. The sirtuin deacetylase Sir2 is well conserved from single-celled yeast to mammals, and it controls a number of downstream targets that are active during periods of extreme stress. Overexpression of Sir2 has been established to enhance survival of a number of model organisms undergoing calorie restriction, during which insulin receptor signalling (IRS) is reduced, a condition that itself can enhance survivorship during starvation. Increased Sir2 expression and reduced IRS result in an increase in the activity of the transcription factor foxo, an advantageous activation during stress but lethal when overly active. We have found that a lowered gene dosage of Sir2, in mutant heterozygotes, can extend normal longevity and greatly augment survivorship during amino-acid starvation in Drosophila. Additionally, these mutants, in either heterozygous or homozygous form, do not appear to have any disadvantageous effects upon development or cell growth of the organism unlike IRS mutants. These results may advance the understanding of the biological response to starvation and allow for the development of a model organism to mimic the ability of individuals to tolerate nutrient deprivation.
能量稳态的调节对于在营养不足时期生存至关重要。复杂的信号通路和蛋白质共同作用，以在这种情况下最大化寿命。沉默调节蛋白去乙酰化酶Sir2从单细胞酵母到哺乳动物都高度保守，它控制许多在极端应激时期活跃的下游靶点。已证实Sir2的过表达可提高多种经历卡路里限制的模式生物的存活率，在此期间胰岛素受体信号传导（IRS）会降低，而这种情况本身就能提高饥饿期间的存活率。Sir2表达增加和IRS降低会导致转录因子foxo的活性增加，foxo在应激期间的激活是有利的，但过度活跃时则是致命的。我们发现，在突变杂合子中降低Sir2的基因剂量，可以延长果蝇的正常寿命，并极大地提高其在氨基酸饥饿期间的存活率。此外，与IRS突变体不同，这些杂合或纯合形式的突变体似乎对生物体的发育或细胞生长没有任何不利影响。这些结果可能会促进对饥饿生物学反应的理解，并有助于开发一种模式生物来模拟个体耐受营养剥夺的能力。
