Single-gene mutations and healthy ageing in mammals

Abstract

Studies of the effects of single-gene mutations on longevity in Caenorhabditis elegans, Drosophila melanogaster and Mus musculus identified homologous, highly conserved signalling pathways that influence ageing. In each of these very distantly related species, single mutations which lead—directly or indirectly—to reduced insulin, insulin-like growth factor (IGF) or insulin/IGF-like signalling (IIS) can produce significant increases in both average and maximal lifespan. In mice, most of the life-extending mutations described to date reduce somatotropic (growth hormone (GH) and IGF-1) signalling. The reported extensions of longevity are most robust in GH-deficient and GH-resistant mice, while suppression of somatotropic signalling ‘downstream’ of the GH receptor produces effects that are generally smaller and often limited to female animals. This could be due to GH influencing ageing by both IGF-1-mediated and IGF-1-independent mechanisms. In mutants that have been examined in some detail, increased longevity is associated with various indices of delayed ageing and extended ‘healthspan’. The mechanisms that probably underlie the extension of both lifespan and healthspan of these animals include increased stress resistance, improved antioxidant defences, alterations in insulin signalling (e.g. hypoinsulinaemia combined with improved insulin sensitivity in some mutants and insulin resistance in others), a shift from pro- to anti-inflammatory profile of circulating adipokines, reduced mammalian target of rapamycin-mediated translation and altered mitochondrial function including greater utilization of lipids when compared with carbohydrates.

Comparative and meta‐analytic insights into life extension via dietary restriction

“…This laboratory convergence explanation, however, runs counter to recent findings that the same or homologous nutrient-signalling pathways (e.g. TOR, IIS) are involved in prolonging lifespan among these distantly related model species (Fontana et al, 2010;Partridge, 2010;Bartke, 2011;Kenyon, 2011;McCormick et al, 2011). It is more parsimonious to think that such pathways are evolutionarily conserved and the life extension by DR is an ancestral response incurred by the nutrient-signalling pathways shared by contemporary animals.…”

“…Studies of single-gene mutations in the model species are now elucidating some of the molecular pathways of DR effects (Bartke, 2011). Mutations that prolong lifespan are usually involved in slowing down nutrientsignalling pathways.…”

Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage

“…In contrast, significant reduction in protein carbonyl content were reported in brain and liver of Ames and Snell dwarf mice compared to WT controls (Brown-Borg et al 2001;Brooks et al 2007). Discrepancies between Irs1 −/− and GH deficient mice may be due to differences in GH signalling, genetic background and/or insulin sensitivity Bartke 2011). In contrast, the GSH/GSSG ratio was significantly lower in livers of Irs1 −/− relative to WT mice, suggesting an oxidized hepatic environment.…”

“…In addition, this lifespan extension has been shown to be associated, in some models , with a greater period of adult life free from disease (see . Attenuated IIS may also underlie the longevity of growth hormone (GH)/GH receptor-deficient dwarf mice, i.e., Ames (Prop1 df/df ), Snell (Pit1 dw/dw ), Little (Ghrhr lit/lit ), growth hormone receptor knockout (GHRKO) mice (Masternak et al 2009;Bartke 2011). Polymorphisms of several IIS genes are also correlated with longevity in humans (Bonafe et al 2003;Pawlikowska et al 2009).…”

Growth hormone modulates hypothalamic inflammation in long‐lived pituitary dwarf mice

“…Disruption of IGF‐1 gene expression during early life causes growth retardation and defects in the development of metabolic organs that can alter energy homeostasis throughout adult life (Woods et al ., 1996). GHR −/− mice have increased expression of hypothalamic IGF‐1 and IGF1R (Nyberg, 2000; Bartke, 2011), despite lower levels of plasma IGF‐1. Enhanced hypothalamic IGF‐1 expression in the mice with global disruption of GHR raises the possibility that compensatory increases in the local production and paracrine/autocrine actions of IGF‐1 could account for some characteristics of GH‐deficient mouse strains, because both GH and IGF‐1 exert neuroprotective effects (Sonntag et al ., 2005).…”