Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans

Abstract

Although the underlying mechanisms of longevity are not fully understood, it is known that mutation in genes that share similarities with those in humans involved in the insulin/insulin-like growth factor I (IGF-I) signal response pathway can significantly extend life span in diverse species, including yeast, worms, fruit flies, and rodents. Intriguingly, the long-lived mutants, ranging from yeast to mice, share some important phenotypic characteristics, including reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-I plasma levels. Such genetic homologies and phenotypic similarities between insulin/IGF-I pathway mutants raise the possibility that the fundamental mechanism of aging may be evolutionarily conserved from yeast to mammals. Very recent findings also provide novel and intriguing evidence for the involvement of insulin and IGF-I in the control of aging and longevity in humans. In this study, we focus on how the insulin/IGF-I pathway controls yeast, nematode, fruit fly, and rodent life spans and how it is related to the aging process in humans to outline the prospect of a unifying mechanism in the genetics of longevity.

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

“…Genes in the insulin/IGF1 signaling pathway affect lifespan in yeast, nematodes, fruit flies, and mice (Fontana et al 2010;Barbieri et al 2003). Mutation of genes in this signaling pathway confers greater resistance to oxidative stress and phenotypic characteristics consistent with delayed and slowed aging.…”

Nutrition, sirtuins and aging

“…2). Originally identified in C. elegans (Friedman and Johnson, 1988) as closely linked to aging processes, studies in S. cerevisiae, D. melanogaster and in mice demonstrate its central role in controlling aging and this holds most likely true also for humans (Barbieri et al, 2003). In C. elegans, the effect of insulin/IGF-1 signaling is completely dependent on DAF-16, a (Lin et al, 1997;Ogg et al, 1997;Kenyon, 2005).…”

“…When central members of the insulin-/ IGF-1 pathway, such as DAF-2 or AGE-1 lose their function due to mutations, life span in C. elegans is increased two-fold as compared to wild-type animals (Kenyon et al, 1993;Araki et al, 2004). Animals with weak alleles of the age-1 and daf-2 genes can bypass dauer formation as a non-feeding, stress-resistant larval state that allows dispersal under adverse conditions, and turn into long-living adults in a daf-16 dependent manner (Kenyon et al, 1993;Barbieri et al, 2003 Recent studies show that sirtuins do interfere with the insulin/ IGF-1 signaling pathway. In mammalian cells, SIRT1 and the FOXO transcription factor FOXO3 form a complex in response to oxidative stress, which leads to deacetylation of FOXO3 (Brunet et al, 2004).…”

Advances in endocrinology of aging research, 2005–2006

“…One of the most widely studied genetic pathways, and of greatest interest to endocrinologists, has been the discovery that mutations in an insulin/IGF-like signaling pathway extend lifespan in the model organisms yeast, C. elegans (nematode) and Drosophilia (fruit fly), and more recent studies suggest that this finding may extend to mice and possibly to humans (Barbieri et al 2003).…”