期刊
EMBO MOLECULAR MEDICINE
卷 5, 期 4, 页码 563-571出版社
WILEY
DOI: 10.1002/emmm.201201953
关键词
aging; cancer; diabetes; insulin signalling; obesity
资金
- Royal Society [RG071321, RG100787]
- Cancer Research UK [C23338/A10200]
- Queen Mary
- University of London
- MRC [G0700755]
- Diabetes Research and Wellness Foundation
- Wellcome Trust [093115/Z/10/Z]
- BBSRC [BB/H020527/2, BB/I007806/1] Funding Source: UKRI
- MRC [G0700755, MC_U120097114] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I007806/1, BB/H020527/2] Funding Source: researchfish
- Cancer Research UK [15965] Funding Source: researchfish
- Medical Research Council [G0700755, MC_U120097114] Funding Source: researchfish
- Wellcome Trust [093115/Z/10/Z] Funding Source: Wellcome Trust
The insulin/insulin-like growth factor-1 signalling (IIS) pathway regulates cellular and organismal metabolism and controls the rate of aging. Gain-of-function mutations in p110, the principal mammalian IIS-responsive isoform of PI 3-kinase (PI3K), promote cancer. In contrast, loss-of-function mutations in p110 impair insulin signalling and cause insulin resistance, inducing a pre-diabetic state. It remains unknown if long-term p110 inactivation induces further metabolic deterioration over time, leading to overt unsustainable pathology. Surprisingly, we find that chronic p110 partial inactivation in mice protects from age-related reduction in insulin sensitivity, glucose tolerance and fat accumulation, and extends the lifespan of male mice. This beneficial effect of p110 inactivation derives in part from a suppressed down-regulation of insulin receptor substrate (IRS) protein levels induced by age-related hyperinsulinemia, and correlates with enhanced insulin-induced Akt signalling in aged p110-deficient mice. This temporal metabolic plasticity upon p110 inactivation indicates that prolonged PI3K inhibition, as intended in human cancer treatment, might not negatively impact on organismal metabolism.
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