2009
DOI: 10.1038/nature08221
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Abstract: Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruit flies1–5. However, whether inhibition of mTOR signalling can extend life in a mammalian species was unknown. We report here that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. Based on age at 90% mortality, rapamycin led to an increase of 14% for females an… Show more

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Cited by 3,121 publications
(2,930 citation statements)
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References 28 publications
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“…The degree of hepatic protein RR reduction was smallest in response to 14 ppm Rapa treatment, which is established to extend maxLS by 12%, and greatest in Snell Dwarf mice, which live 40% longer than their Het/WT counterparts, while hepatic protein RRs were reduced to an intermediate level in response to 40% CR, which extends maxLS by 18% (Fig. 4) (Blackwell et al ., 1995; Flurkey et al ., 2002; Harrison et al ., 2009; Miller et al ., 2011, 2013). These data suggest that a reduction in hepatic protein RRs may be an early BM not only qualitatively of maxLS extension but also quantitatively of the degree of maxLS extension in mice.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…The degree of hepatic protein RR reduction was smallest in response to 14 ppm Rapa treatment, which is established to extend maxLS by 12%, and greatest in Snell Dwarf mice, which live 40% longer than their Het/WT counterparts, while hepatic protein RRs were reduced to an intermediate level in response to 40% CR, which extends maxLS by 18% (Fig. 4) (Blackwell et al ., 1995; Flurkey et al ., 2002; Harrison et al ., 2009; Miller et al ., 2011, 2013). These data suggest that a reduction in hepatic protein RRs may be an early BM not only qualitatively of maxLS extension but also quantitatively of the degree of maxLS extension in mice.…”
Section: Resultsmentioning
confidence: 99%
“…Consistent with the model that alterations in protein synthesis and proteostasis play roles in LS determination, numerous models of LS extension in yeast, worms, flies, and mice are characterized by reduced signaling and/or expression of machinery involved in protein synthesis as well as enhanced expression of factors involved in somatic maintenance and stress responses (McElwee et al ., 2007; Harrison et al ., 2009; Kennedy & Kaeberlein, 2009). Conversely, impaired protein quality control results in features of premature aging and shortened LS in mice (Min et al ., 2008).…”
Section: Introductionmentioning
confidence: 99%
“…Significant effects on longevity, in one or both sexes, have been published for 6 of the tested agents: aspirin (Strong et al ., 2008), nordihydroguaiaretic acid (NDGA) (Strong et al ., 2008; Harrison et al ., 2014), rapamycin (Harrison et al ., 2009; Miller et al ., 2011, 2014), acarbose (ACA) (Harrison et al ., 2014), methylene blue (Harrison et al ., 2014), and 17‐α‐estradiol (17aE2) (Harrison et al ., 2014). Here, we report survival analyses for mice treated with additional test agents, including ursodeoxycholic acid (UDCA), Protandim (Prot) and fish oil (FO), metformin (Met), or with the combination of Met plus rapamycin (Rapa).…”
Section: Introductionmentioning
confidence: 99%
“…In lower organisms, such as Caenorhabditis elegans and Drosophila melanogaster , inactivation or reduction of mTOR activity results in life extension (Sharp et al ., 2013). In addition, reduction of mTOR activity by rapamycin (Harrison et al ., 2009) or reduction in expression of mTOR kinase by hypomorphic mTOR alleles (Selman et al ., 2009; Lamming et al ., 2012; Wu et al ., 2013) can increase mouse lifespan. mTOR is a serine/threonine kinase that forms the catalytic core of at least two complexes, mTOR complex‐1 (mTORC1) and mTOR complex‐2 (mTORC2).…”
Section: Introductionmentioning
confidence: 99%