title: Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction.
abstract: Reduced mechanistic target of rapamycin (mTOR) signalling extends lifespan in yeast, nematodes, fruit flies and mice, highlighting a physiological pathway that could modulate aging in evolutionarily divergent organisms. This signalling system is also hypothesized to play a central role in lifespan extension via dietary restriction. By collating data from 48 available published studies examining lifespan with reduced mTOR signalling, we show that reduced mTOR signalling provides similar increases in median lifespan across species, with genetic mTOR manipulations consistently providing greater life extension than pharmacological treatment with rapamycin. In contrast to the consistency in changes in median lifespan, however, the demographic causes for life extension are highly species specific. Reduced mTOR signalling extends lifespan in nematodes by strongly reducing the degree to which mortality rates increase with age (aging rate). By contrast, life extension in mice and yeast occurs largely by pushing back the onset of aging, but not altering the shape of the mortality curve once aging starts. Importantly, in mice, the altered pattern of mortality induced by reduced mTOR signalling is different to that induced by dietary restriction, which reduces the rate of aging. Effects of mTOR signalling were also sex dependent, but only within mice, and not within flies, thus again species specific. An alleviation of age-associated mortality is not a shared feature of reduced mTOR signalling across model organisms and does not replicate the established age-related survival benefits of dietary restriction.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Garratt
authors.affiliation: Evolution and Ecology Research Group and School of Biological, Earth and Environmental Sciences, The University of New South Wales, Sydney, NSW, 2052, Australia.|Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.
authors.forename: Shinichi
authors.identifier: http://orcid.org/0000-0002-7765-5182
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Animal and Plant Sciences, University of Sheffield, Sheffield, S10 2TN, UK.
authors.forename: Mirre J P
authors.initials: MJ
authors.lastname: Simons
mesh_terms: D000818:Animals; D031204:Caloric Restriction; D004330:Drosophila / Q000502:physiology; D005260:Female; D008136:Longevity / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction; D013045:Species Specificity; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D058570:TOR Serine-Threonine Kinases
keywords: ageing; calorie restriction; demography; evolution; mortality; rapamycin; senescence