Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice

Miller, Richard A.; Harrison, David E.; Astle, Clinton M.; Baur, Joseph A.; Boyd, Angela R.; Cabo, Rafael de; Fernández, Elízabeth; Flurkey, Kevin; Javors, Martin A.; Nelson, James F.; Orihuela, Carlos J.; Pletcher, Scott D.; Sharp, Zelton Dave; Sinclair, David A.; Starnes, Joseph W.; Wilkinson, John E.; Nadon, Nancy L.; Strong, Randy

doi:10.1093/gerona/glq178

Cited by 770 publications

(776 citation statements)

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“…Although the current (C2011) cohort did not contain any mice given Rapa alone, we thought it would be of interest to compare the survival of mice receiving both Rapa and Met to survival of mice treated with the same Rapa dose in previous years, C2006 and C2009 (Miller et al ., 2011, 2014). Results are shown in Table S4 (Supporting information).…”

Section: Resultsmentioning

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%

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Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

et al. 2016

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SummaryThe National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

et al. 2016

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“…We showed that reduced neoplasia is an eRapa‐mediated longevity extension mechanism in spontaneous neoplasia models (Livi et al ., 2013; Hasty et al ., 2014) and potentially in wild‐type mice (Miller et al ., 2011). T cells and IFN‐γ mediate cancer immune surveillance (Mittal et al ., 2014).…”

Section: Resultsmentioning

confidence: 99%

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

et al. 2015

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SummaryThe mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.

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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%

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

et al. 2015

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SummaryCombating the social and economic consequences of a growing elderly population will require the identification of interventions that slow the development of age‐related diseases. Preserved cellular homeostasis and delayed aging have been previously linked to reduced cell proliferation and protein synthesis rates. To determine whether changes in these processes may contribute to or predict delayed aging in mammals, we measured cell proliferation rates and the synthesis and replacement rates (RRs) of over a hundred hepatic proteins in vivo in three different mouse models of extended maximum lifespan (maxLS): Snell Dwarf, calorie‐restricted (CR), and rapamycin (Rapa)‐treated mice. Cell proliferation rates were not consistently reduced across the models. In contrast, reduced hepatic protein RRs (longer half‐lives) were observed in all three models compared to controls. Intriguingly, the degree of mean hepatic protein RR reduction was significantly correlated with the degree of maxLS extension across the models and across different Rapa doses. Absolute rates of hepatic protein synthesis were reduced in Snell Dwarf and CR, but not Rapa‐treated mice. Hepatic chaperone levels were unchanged or reduced and glutathione S‐transferase synthesis was preserved or increased in all three models, suggesting a reduced demand for protein renewal, possibly due to reduced levels of unfolded or damaged proteins. These data demonstrate that maxLS extension in mammals is associated with improved hepatic proteome homeostasis, as reflected by a reduced demand for protein renewal, and that reduced hepatic protein RRs hold promise as an early biomarker and potential target for interventions that delay aging in mammals.

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Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice

Cited by 770 publications

References 50 publications

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

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