Abstract
Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose threefold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet-restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet-restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects.
Highlights
An inhibitor of mTOR kinase, increases lifespan of genetically heterogeneous University of Michigan (UM)-HET3 mice when given at a dose of 14.7 mg kgÀ1 in food from either 9 or 20 months of age (Harrison et al, 2009; Miller et al, 2011)
Enteric-released rapamycin-treated UM-HET3 mice, show decelerated rates of change in a wide range of age-related physiological and pathological endpoints (Wilkinson et al, 2012), suggesting that the drug may be inhibiting at least some aspects of the aging process in addition to any direct effects it may have on cancer cells
We explored the idea (Kaeberlein & Kennedy, 2009) that the lifespan extension caused by lifelong dietary restriction (DR) might be due largely to inhibition of mTOR function, by comparing features of DR mice to those of rapamycin-treated mice
Summary
An inhibitor of mTOR kinase, increases lifespan of genetically heterogeneous UM-HET3 mice when given at a dose of 14.7 mg kgÀ1 in food from either 9 or 20 months of age (Harrison et al, 2009; Miller et al, 2011). Genetic knockout of S6 kinase 1, one of the mediators of mTORC1 action, has been shown to increase lifespan of female (but not of male) C57BL/6 mice (Selman et al, 2009), consistent with the rapamycin studies. Rapamycin can block function of both mTOR complexes, differential inactivation of mTORC1 via hemizygous deletion of both mTOR and mLST8 extends lifespan of female (but not of male) mice on a background containing a mixture of C57BL/6 and 129S5 genes (Lamming et al, 2012), suggesting that effects on TORC1 may be germane to control of aging and/or late-life lethal disease. An antiaging effect is the most likely pathway for lifespan extension in worms and flies, in which neoplastic disease is uncommon as a cause of death
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