Caloric restriction (CR) can delay morbidity and mortality in a broad range of species, including mice and macaques. Mutations and chemical agents, such as resveratrol or rapamycin that partly mimic the CR effect, can similarly increase survival or extend lifespan. In humans, however, the effects of CR or other life-extending agents have not been investigated systematically. Humans already display lower mortality and greater maximal lifespan compared to closely related species, including chimpanzees and macaques. It is thus possible that humans, during their evolution, have acquired genetic mutations mimicking the CR effect. To address this question, we compared transcriptome differences between humans and other primates, with transcriptome changes observed in mice subjected to CR [see references below]. We show that the human transcriptome state examined in multiple tissues and across different ages resembles the transcriptome state of mice fed ad libitum, relative to CR mice or mice treated with resveratrol. Furthermore, transcriptome changes induced by CR were enriched among genes showing age-related changes among primates, concentrated in specific expression patterns, and could be linked with specific functional pathways, including insulin signalling, cancer, and 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 offer a promising direction in the extension of healthy human lifespan. References for the transcriptome changes observed in mice subjected to CR: 1) Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, et al: A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008, 3:e2264. 2) Tsuchiya T, Dhahbi JM, Cui X, Mote PL, Bartke A, Spindler SR: Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiol Genomics 2004, 17:307-315. 3) Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, et al: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444:337-342. We collected post-mortem brain, heart, and liver samples from 16 human, 16 chimpanzee and 4 rhesus macaque seperately. All these individuals are adults. RNA extracted from the dissected tissue was hybridized to Affymetrix® Human Gene 1.0 ST arrays to quantify gene expression level. We collected prefrontal cortex tissues of mice with age ranging from postnatal 2 days to 2.5 years. The strain of the mice is C57BL/6. RNA extracted from the dissected tissue was hybridized to Affymetrix® Mouse Gene 1.0 ST Arrays to quantify gene expression level.