The role of insulin-like signalling in the regulation of ageing
The role of insulin-like signalling in the regulation of ageing
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DOI：
10.1159/000080765
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Holzenberger, M
中科院分区：
文献类型：
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作者：
Holzenberger, M
胰岛素样生长因子I(IGF-I)信号通路的失活已被证明可以延长各种低等物种的寿命，包括线虫秀丽线虫。为了在哺乳动物物种中研究这种关系，用IGF-I受体基因杂合子突变的小鼠模型进行了一系列实验。这些杂合子小鼠只有轻微的出生后生长迟缓，但寿命比正常延长了26%。他们的生育力和饮食摄入量没有受到影响。这些突变小鼠寿命延长的机制似乎是增强了对氧化应激的抵抗力：在体内产生严重的氧化应激后，杂合子小鼠的存活率高于野生型小鼠，而来自杂合子动物的细胞在体外对过氧化氢的抵抗力强于野生型动物的细胞。这些突变动物对氧化应激的抵抗力可能是由于IGF-I信号通路中IGF-I受体下游分子的磷酸化减少所致，其中之一被认为是p66shc。IGF-I信号减少和寿命之间的这种联系在包括人类在内的其他哺乳动物物种中是否保守，目前尚不清楚。如果是这样的话，它可能会对生长激素治疗产生影响，生长激素治疗会提高血清IGF-I水平。版权所有(C)2004 S.Karger AG，巴塞尔。
Inactivation of insulin-like growth factor I (IGF-I) signalling pathways have been shown to extend lifespans in various lower species, including the nematode Caenorhabditis elegans. In order to investigate this relationship in a mammalian species, a series of experiments were carried out with a mouse model heterozygous for a mutation in the IGF-I receptor gene. These heterozygous mice only had slight post-natal growth retardation, but had a lifespan 26% longer than normal. Their fertility and dietary intake were unaffected. The mechanism for increased lifespan in these mutant mice appears to be enhanced resistance to oxidative stress: heterozygous mice had a greater survival rate subsequent to severe oxidative stress generated in vivo than wild-type mice, and cells from heterozygous animals had a better resistance to hydrogen peroxide in vitro than cells from wildtype animals. Resistance to oxidative stress in these mutant animals could be caused by decreased phosphorylation of molecules downstream of the IGF-I receptor in the IGF-I signalling pathway, one of which is thought to be p66shc. Whether this link between reduced IGF-I signalling and longevity is conserved in other mammalian species, including humans, is presently not known. If it was, it could have implications for growth hormone therapy, which increases serum IGF-I levels. Copyright (C) 2004 S. Karger AG, Basel.