Aging and Genome Maintenance: Lessons from the Mouse?

Abstract

Recent progress in the science of aging is driven largely by the use of model systems, ranging from yeast and nematodes to mice. These models have revealed conservation in genetic pathways that balance energy production and its damaging by-products with pathways that preserve somatic maintenance. Maintaining genome integrity has emerged as a major factor in longevity and cell viability. Here we discuss the use of mouse models with defects in genome maintenance for understanding the molecular basis of aging in humans.

Signaling mechanisms involved in the response to genotoxic stress and regulating lifespan

“…Based on the frequency and consequences of DNA damage, it is a likely culprit in the ageing process. In support of this, inherited defects in genome maintenance mechanisms cause progeroid or accelerated ageing symptoms (Hasty et al, 2003). Furthermore, DNA damage has recently 2 Correspondence should be address to: Laura J.…”

Relationships between stem cell exhaustion, tumour suppression and ageing

“…Age-related changes include slowed wound-healing responses and haematopoietic recovery rates, osteoporosis, kyphosis, hair loss and graying, reduced fertility, muscle loss, neurodegeneration and cancer (Hasty et al, 2003;Kipling et al, 2004;Lombard et al, 2005). These phenotypes are not uniformly expressed in all individuals and are not strictly age associated in all cases (eg alopecia); however, the appearance of these phenotypes in general is strongly correlated with advancing age.…”

“…These phenotypes are not uniformly expressed in all individuals and are not strictly age associated in all cases (eg alopecia); however, the appearance of these phenotypes in general is strongly correlated with advancing age. A number of human progeroid syndromes (Werner, Cockayne, Hutchinson-Gilford, trichothyodystrophy, dyskeratosis congenita, ataxia-telangiectasia) and mutant mouse models (below) recapitulate some aspects of normal ageing and in many instances produce extreme examples of these disorders (Hasty et al, 2003;Kipling et al, 2004;Lombard et al, 2005). Predominantly, the genes mutated in these examples are required for genome maintenance, either in the form of DNA repair or in the cell cycle-regulatory response to DNA damage.…”

“…These models include Ku86 À/À , XPD R722W/R722W , BRCA1 D11/D11 p53 þ /À , XRCC4 À/À p53 S18A/S23A , LIG4 Y288C , Rad50 S/S , Terc À/À , Wrn À/À Terc À/À and those expressing putatively hypermorphic variants of p53 (Hasty et al, 2003;Lombard et al, 2005;Chao et al, 2006). Tissue regenerative failures are observed in some form or another in each of these models, and recent reports indicate that mutation of many of these same genome-maintenance regulators leads to decreased stem cell number and potential with age (Ito et al, 2004;Nijnik et al, 2007;Rossi et al, 2007).…”

“…Furthermore, both cancer and ageing have been proposed to be attributable to a similar fundamental cause: the accumulation of DNA damage (Hasty et al, 2003;Lombard et al, 2005). Although cancer and age-related diseases are well correlated, there is an exception; a statistically significant decrease in cancer is observed in human populations beyond 85 years of age ( Figure 1).…”