title: Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction.
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.
authors.affiliation: Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: David E
authors.initials: DE
authors.lastname: Harrison
authors.forename: Clinton M
authors.initials: CM
authors.lastname: Astle
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fernandez
authors.forename: Kevin
authors.initials: K
authors.lastname: Flurkey
authors.forename: Melissa
authors.initials: M
authors.lastname: Han
authors.forename: Martin A
authors.initials: MA
authors.lastname: Javors
authors.forename: Xinna
authors.initials: X
authors.lastname: Li
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Nadon
authors.forename: James F
authors.initials: JF
authors.lastname: Nelson
authors.forename: Scott
authors.initials: S
authors.lastname: Pletcher
authors.forename: Adam B
authors.initials: AB
authors.lastname: Salmon
authors.forename: Zelton Dave
authors.initials: ZD
authors.lastname: Sharp
authors.forename: Sabrina
authors.initials: S
authors.lastname: Van Roekel
authors.forename: Lynn
authors.initials: L
authors.lastname: Winkleman
authors.forename: Randy
authors.initials: R
authors.lastname: Strong
mesh_terms: D000367:Age Factors; D000818:Animals; D031204:Caloric Restriction; D004305:Dose-Response Relationship, Drug; D005260:Female; D008136:Longevity / Q000187:drug effects*; D008297:Male; D051379:Mice; D012737:Sex Factors; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: IGF-1; aging; caloric restriction; glucose; insulin; longevity; mTOR; mouse; rapamycin; xenobiotic metabolism