title: Accelerating aging by mouse reverse genetics: a rational approach to understanding longevity.
abstract: Investigating the molecular basis of aging has been difficult, primarily owing to the pleiotropic and segmental nature of the aging phenotype. There are many often interacting symptoms of aging, some of which are obvious and appear to be common to every aged individual, whereas others affect only a subset of the elderly population. Although at first sight this would suggest multiple molecular mechanisms of aging, there now appears to be almost universal consensus that aging is ultimately the result of the accumulation of somatic damage in cellular macromolecules, with reactive oxygen species likely to be the main damage-inducing agent. What remains significant is unravelling how such damage can give rise to the large variety of aging symptoms and how these can be controlled. Although humans, with over a century of clinical observations, remain the obvious target of study, the mouse, with a relatively short lifespan, easy genetic accessibility and close relatedness to humans, is the tool par excellence to model aging-related phenotypes and test strategies of intervention. Here we present the argument that mouse models with engineered defects in genome maintenance systems are especially important because they often exhibit a premature appearance of aging symptoms. Confirming studies on human segmental progeroid syndromes, most of which are based on heritable mutations in genes involved in genome maintenance, the results thus far obtained with mouse models strongly suggest that lifespan and onset of aging are directly related to the quality of DNA metabolism. This may be in keeping with the recent discovery of a possible 'universal survival' pathway that improves antioxidant defence and genome maintenance and simultaneously extends lifespan in the mouse and several invertebrate species.
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78245, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Hasty
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
mesh_terms: D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D001284:Atrophy / Q000473:pathology; D042822:Genomic Instability; D006132:Growth Plate / Q000166:cytology; D006801:Humans; D007738:Kyphosis / Q000235:genetics; D008136:Longevity / Q000235:genetics* / Q000502:physiology; D051379:Mice / Q000235:genetics*; D023421:Models, Animal; D009369:Neoplasms / Q000235:genetics; D012867:Skin / Q000473:pathology