title: Evolution of human longevity uncoupled from caloric restriction mechanisms.
abstract: Caloric restriction (CR) and chemical agents, such as resveratrol and rapamycin that partially mimic the CR effect, can delay morbidity and mortality across a broad range of species. In humans, however, the effects of CR or other life-extending agents have not yet been investigated systematically. Human maximal lifespan is already substantially greater compared to that of closely related primate species. It is therefore possible that humans have acquired genetic mutations that mimic the CR effect. Here, we tested this notion by comparing transcriptome differences between humans and other primates, with the transcriptome changes observed in mice subjected to CR. We show that the human transcriptome state, relative to other primate transcriptomes, does not match that of the CR mice or mice treated with resveratrol, but resembles the transcriptome state of ad libitum fed mice. At the same time, the transcriptome changes induced by CR in mice are enriched among genes showing age-related changes in primates, concentrated in specific expression patterns, and can be linked with specific functional pathways, including insulin signalling, cancer, and the immune response. These findings indicate that the evolution of human longevity was likely independent of CR-induced lifespan extension mechanisms. Consequently, application of CR or CR-mimicking agents may yet offer a promising direction for the extension of healthy human lifespan.
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China ; Graduate School of Chinese Academy of Sciences, Beijing, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhao
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Song
authors.initials: S
authors.lastname: Guo
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China ; Department of Biological Sciences, Middle East Technical University, Ankara, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Somel
authors.affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China ; Max Planck Institutes for Evolutionary Anthropology, Leipzig, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Khaitovich
mesh_terms: D000328:Adult; D000375:Aging / Q000502:physiology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D031204:Caloric Restriction; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008136:Longevity / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D002679:Pan troglodytes; D000077185:Resveratrol; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases; D000077185:Resveratrol; D020123:Sirolimus