Aging is believed to be a nonadaptive process that escapes the force of natural selection. Here, we challenge this dogma by showing that yeast laboratory strains and strains isolated from grapes undergo an age- and pH-dependent death with features of mammalian programmed cell death (apoptosis). After 90–99% of the population dies, a small mutant subpopulation uses the nutrients released by dead cells to grow. This adaptive regrowth is inversely correlated with protection against superoxide toxicity and life span and is associated with elevated age-dependent release of nutrients and increased mutation frequency. Computational simulations confirm that premature aging together with a relatively high mutation frequency can result in a major advantage in adaptation to changing environments. These results suggest that under conditions that model natural environments, yeast organisms undergo an altruistic and premature aging and death program, mediated in part by superoxide. The role of similar pathways in the regulation of longevity in organisms ranging from yeast to mice raises the possibility that mammals may also undergo programmed aging.

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Among the phenotypes of Saccharomyces cerevisiae mutants lacking CuZn-superoxide dismutase (Sod1p) is an aerobic lysine auxotrophy; in the current work we show an additional leaky auxotrophy for leucine. The lysine and leucine biosynthetic pathways each contain a 4Fe-4S cluster enzyme homologous to aconitase and likely to be superoxide-sensitive, homoaconitase (Lys4p) and isopropylmalate dehydratase (Leu1p), respectively. We present evidence that direct aerobic inactivation of these enzymes in sod1⌬ yeast results in the auxotrophies. Located in the cytosol and intermembrane space of the mitochondria, Sod1p likely provides direct protection of the cytosolic enzyme Leu1p. Surprisingly, Lys4p does not share a compartment with Sod1p but is located in the mitochondrial matrix. The activity of a second matrix protein, the tricarboxylic acid cycle enzyme aconitase, was similarly lowered in sod1⌬ mutants. We measured only slight changes in total mitochondrial iron and found no detectable difference in mitochondrial "free" (EPRdetectable) iron making it unlikely that a gross defect in mitochondrial iron metabolism is the cause of the decreased enzyme activities. Thus, we conclude that when Sod1p is absent a lysine auxotrophy is induced because Lys4p is inactivated in the matrix by superoxide that originates in the intermembrane space and diffuses across the inner membrane.The antioxidant enzyme copper/zinc-superoxide dismutase 1 plays an integral role in the protection of many organisms from the oxidative aerobic environment.CuZn-SOD is localized to the cytosol, nucleus, and the intermembrane space (IMS) of the mitochondria, suggesting that it exerts its protective effect in multiple compartments (1). Another SOD that contains manganese (Mn-SOD or Sod2p) is located in the matrix of mitochondria. Saccharomyces cerevisiae lacking CuZn-SOD (sod1⌬) have distinct and well established aerobic phenotypes including diminished growth, auxotrophies for lysine and either methionine or cysteine, decreased ability to grow on nonfermentable carbon sources (2, 3), increased "free" (EPR-detectable) iron (4), hypersensitivity to millimolar concentrations of zinc (5), and exquisite sensitivity to redox-cycling drugs such as the herbicide paraquat (6, 7). All of these phenotypes (except zinc sensitivity) are also observed in mutants lacking the copper chaperone for CuZn-SOD 2 (lys7⌬ or ccs1⌬) and thus contain a form of the Sod1p polypeptide that is inactive because of a lack of copper in the active site (5, 8). Mutants lacking Sod2p have a less dramatic phenotype; they are sensitive to redox cycling drugs and grow poorly on nonfermentable carbon sources but show no aerobic auxotrophies (2).Many cellular components are susceptible to oxidative damage, including proteins, lipids, and DNA (9, 10). However, targets of superoxide-specific damage are much more limited. A particular type of protein prosthetic group, solvent-exposed 4Fe-4S clusters occurring in nonelectron transfer proteins, have been shown to be specifically damaged by superoxid...

Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Δ mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods—mitochondrial Sod2 and cytosolic CuZnSod (Sod1)—delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension.