It has long been understood that many of the same manipulations that increase longevity in Caenorhabditis elegans also increase resistance to various acute stressors, and vice-versa; moreover these findings hold in more complex organisms as well. Nevertheless, the mechanistic relationship between these phenotypes remains unclear, and in many cases the overlap between stress resistance and longevity is inexact. Here we review the known connections between stress resistance and longevity, discuss instances in which these connections are absent, and summarize the theoretical explanations that have been posited for these phenomena. deletions in Caenorhabditis elegans alter the localization of intracellular reactive oxygen species and show molecular compensation. J Gerontol A Biol Sci Med Sci. 2009; 64:530-539. 30. McCord JM, Fridovich I. Superoxide dismutase. an enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969; 244:6049-6055. 31. Walker TK, Tosic J. The ;catalase test', with special reference to acetobacter species. Biochem J. 1943; 37:10-12. 32. Mills GC. The purification and properties of glutathione peroxidase of erythrocytes. J Biol Chem. 1959; 234:502-506. 33. Brenot A, King KY, Janowiak B, Griffith O, Caparon MG. Contribution of glutathione peroxidase to the virulence of streptococcus pyogenes. Infect Immun. 2004; 72:408-413. 34. Larsen PL. Aging and resistance to oxidative damage in. A redox-sensitive peroxiredoxin that is important for longevity has tissue-and stress-specific roles in stress resistance.

A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells.

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.

Many plant molecules interact with and modulate key regulators of mammalian physiology in ways that are beneficial to health, but why? We propose that heterotrophs (animals and fungi) are able to sense chemical cues synthesized by plants and other autotrophs in response to stress. These cues provide advance warning about deteriorating environmental conditions, allowing the heterotrophs to prepare for adversity while conditions are still favorable.