Aging, which affects all organ systems, is one of the most complex phenotypes. Recent discoveries in long-lived mutant mice have revealed molecular mechanisms of longevity in mammals which may contribute to our understanding of why humans age. These mutations include naturally occurring spontaneous mutations, and those of mice genetically modified by modern genomic technologies. It is generally believed that the most fundamental mechanisms of aging are evolutionarily conserved across species. The following types of longevity mechanisms have been intensively studied: suppression of the somatotropic (growth hormone/insulin-like growth factor 1) axis, decreased metabolism and increased resistance of oxidative stress, reduced insulin secretion and increased insulin sensitivity, and delayed reproductive maturation and reduced fertility. In addition, many of the mutations have a sex-dependent effect on lifespan, and when present in different genetic backgrounds, the effects of the same gene mutation can vary considerably. The present review discusses these phenotypic variations as well as describing the known longevity genes in long-lived mutant mice and the molecular mechanisms specifying longevity. We anticipate that these mouse studies will ultimately provide clues about how to delay the aging and prolong lifespan, and help to develop therapies for healthier human aging.
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