Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66shc gene induces stress resistance and prolongs life span. p66shc is a splice variant of p52shc/p46shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras. We show that: (1) p66shc is serine phosphorylated upon treatment with hydrogen peroxide (H2O2) or irradiation with ultraviolet light; (2) ablation of p66shc enhances cellular resistance to apoptosis induced by H2O2 or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66shc cannot restore the normal stress response in p66shc-/- cells; (4) the p53 and p21 stress response is impaired in p66shc-/- cells; (5) p66shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.

The p66shc adaptor protein controls oxidative stress response and life span in mammals

Extrachromosomal rDNA circles--a cause of aging in yeast.

Ceramide in apoptosis: an overview and current perspectives.

Evolutionary theory predicts substantial interspecific and intraspecific differences in the proximal mechanisms of ageing. Our goal here is to seek evidence for common (‘public’) mechanisms among diverse organisms amenable to genetic analysis. Oxidative damage is a candidate for such a public mechanism of ageing. Long-lived strains are relatively resistant to different environmental stresses. The extent to which these stresses produce oxidative damage remains to be established.

Genetic analysis of ageing: Role of oxidative damage and environmental stresses

Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus under normal and pathophysiological conditions. The best understood of such pathways is retrograde signaling in the budding yeast Saccharomyces cerevisiae. It involves multiple factors that sense and transmit mitochondrial signals to effect changes in nuclear gene expression; these changes lead to a reconfiguration of metabolism to accommodate cells to defects in mitochondria. Analysis of regulatory factors has provided us with a mechanistic view of regulation of retrograde signaling. Here we review advances in the yeast retrograde signaling pathway and highlight its regulatory factors and regulatory mechanisms, its physiological functions, and its connection to nutrient sensing, TOR signaling, and aging.

Mitochondrial Retrograde Signaling

Cloning and characterization of LAG1, a longevity-assurance gene in yeast.

Divergent roles of RAS1 and RAS2 in yeast longevity.

Saccharomyces cerevisiae has a limited life span, measured by the reproductive capacity of the individual cell. Several genes that are differentially expressed during the yeast life span have been isolated. One of these genes, LAG2, has been characterized for its role in longevity. LAG2 is preferentially expressed in young cells. It encodes a predicted 680 amino acid protein with a putative transmembrane helix. The sequence does not show significant similarity to any other DNA or protein sequences in the databases. Deletion of LAG2 in a haploid strain did not affect growth, but it resulted in a 50% decrease in the mean and maximum life span. When LAG2 was overexpressed, the mean and maximum life span of the yeasts was extended by about 36% and 54%, respectively. These results indicate that this is a longevity-assurance gene in yeast.

A. M. Childress

Papers

Cloning and characterization of LAG1, a longevity-assurance gene in yeast.

Divergent roles of RAS1 and RAS2 in yeast longevity.

LAG2, a gene that determines yeast longevity