Genome-environment interactions that modulate aging: powerful targets for drug discovery

Abstract

Aging is the major biomedical challenge of this century. The percentage of elderly people, and consequently the incidence of age-related diseases such as heart disease, cancer, and neurodegenerative diseases, is projected to increase considerably in the coming decades. Findings from model organisms have revealed that aging is a surprisingly plastic process that can be manipulated by both genetic and environmental factors. Here we review a broad range of findings in model organisms, from environmental to genetic manipulations of aging, with a focus on those with underlying gene-environment interactions with potential for drug discovery and development. One well-studied dietary manipulation of aging is caloric restriction, which consists of restricting the food intake of organisms without triggering malnutrition and has been shown to retard aging in model organisms. Caloric restriction is already being used as a paradigm for developing compounds that mimic its life-extension effects and might therefore have therapeutic value. The potential for further advances in this field is immense; hundreds of genes in several pathways have recently emerged as regulators of aging and caloric restriction in model organisms. Some of these genes, such as IGF1R and FOXO3, have also been associated with human longevity in genetic association studies. The parallel emergence of network approaches offers prospects to develop multitarget drugs and combinatorial therapies. Understanding how the environment modulates aging-related genes may lead to human applications and disease therapies through diet, lifestyle, or pharmacological interventions. Unlocking the capacity to manipulate human aging would result in unprecedented health benefits.

Fig. 1.

Overview of CR-associated signaling and some of its key players. CR acts on the hypothalamus, which controls the secretion of GH from the pituitary. CR also lowers glucose levels and diminishes secretion of insulin from the pancreas. GH acting on the liver causes the release to the plasma of IGF1. IGF1 binds to IGF1R or insulin receptor a (IRaα-IRaβ) and triggers its autophosphorylation, which in turn serves as an anchor for recruiting various downstream effectors. Phosphotidylinositol-3-kinase (PI3K) is either activated via direct interaction with, for example, the insulin-like substrate 1 (IRS1) or RAS. PI3K catalyzes the phosphorylation of phosphatidyl-inositols, such as the conversion of phosphatidyl inositol 4,5-bisphosphate (PIP₂) to phosphatidyl inositol 3,4,5-trisphosphate (PIP₃). PIP₃ serves as a binding site for phosphoinositide-dependent protein kinase (PDK1), which activates the serine/threonine protein kinase AKT. AKT phosphorylates tuberous sclerosis protein 1 and 2 (TSC1/2) as well as FOXO transcription factors and cAMP response element-binding (CREB). TSC1/2 phosphorylation by AKT inhibits the Ras homolog enriched in brain (RHEB). RHEB stimulates the phosphorylation of the ribosomal protein S6 kinase (S6K1) and 4E-BP1 through activation of TOR. TOR's activation of S6K1 and inhibition of 4E-BP1 enhances translation. FOXO phosphorylation prevents its nuclear translocation and activation of its stress response target genes. Various cellular forms of stress and AKT activity lead to the depletion of ATP and elevation of AMP. AMPK positively regulates TSC2 and FOXO, negatively regulates CREB, and enforces energy homeostasis. FOXO and AMPK promote autophagy, whereas TOR suppresses it. Under CR, GH levels decline and therefore, via this pathway, TOR signaling decreases (CR also suppresses TOR signaling through other mechanisms) whereas AMPK and some FOXO factors are activated, in turn decreasing translation while increasing stress responses and autophagy, which seem to be some of the mechanisms by which CR retards aging. Human homologs of genes directly linked to CR life-extending effects in model organisms are highlighted with a blue halo.

Fig. 2.

Overview and overlap of genes related to aging, human longevity, and CR. Shown are the intersections between human orthologs of genes identified via genetic manipulation experiments in model organisms (aging-associated), genes that disrupt or cancel life-extending effects of CR when mutated in model organisms (CR-essential), aging differentially expressed genes in mammals (aging-differential), CR-differentially expressed genes in mammals (CR-differential) and genes associated with human longevity in at least one epidemiological study (human longevity-associated). All data obtained from the GenAge database (http://genomics.senescence.info/genes/), except for the CR-associated genes, which come from data sets assembled by the authors from the literature, available on request.

Fig. 3.

Network of CR-related proteins from yeast. Some proteins, such as Sch9 and Sir2 (indicated by red arrows), have a high number of interacting partners (hubs), whereas others have no interactions. Such analyses could be used to identify candidate regulatory hubs as well as promising new candidate genes that interact with known CR-related proteins. Sir2 mammalian homologs are the focus of considerable research (see text), whereas Sch9's mammalian homolog AKT2 is important in insulin signaling and glucose transport. Figure created using STRING (http://string-db.org/).