Genome-Environment Interactions That Modulate Aging: Powerful Targets for Drug Discovery

Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
Pharmacological reviews (Impact Factor: 17.1). 11/2011; 64(1):88-101. DOI: 10.1124/pr.110.004499
Source: PubMed


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.

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    • "inhibitors of mTOR and inducers of autophagy (Fig. 1; Ferrari et al., 2011; Zhang et al., 2011; Zhou et al., 2010). These compounds are termed rapologues because they mimic the mTOR inhibitor rapamycin ; and considerable interest in mTOR inhibitors is being exhibited by the pharmaceutical industry in the quest for caloricrestriction (CR) mimetic drugs (Davinelli et al., 2012; de Magalhães et al., 2011). It is highly probable that modulation of cell signalling (if confirmed ) of the type described above is only one of a number of potentially interactive factors involved in the observed health benefits, including psychological effects, execise, more effective immunoregulation, vitamin D and exposure to sunlight, as well as dietary uptake of bioactive phytochemicals (Allen et al., 2013; Cox et al., 2014; Del Rio et al., 2013; Depledge et al., 2013; Lisse and Hewison, 2011; Maas et al., 2006; Pandey and Rizvi, 2009; Pearce and Cheetham, 2010; Rook, 2013; Seedorf et al., 2014; Smillie et al., 2011; Wheeler et al., 2012; White et al., 2010, 2013; Wu and Sun, 2011). "
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    • "Unfortunately, rapamycin has a number of adverse side effects (Johnson et al., 2013a; Testa et al., 2014), but some of these may be mitigated by the co-administration of other compounds. Biological signaling is intrinsically complex, typically involving nonlinear pathways, feedback loops, and compensatory mechanisms (de Magalhaes et al., 2012). Consequently, employing combinations of compounds to target multiple pathways is likely to be a more productive approach to improve efficacy and minimize toxicity (Hopkins, 2008). "
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    ABSTRACT: Diet has profound effects on animal longevity and manipulation of nutrient sensing pathways is one of the primary interventions capable of lifespan extension. This often is done through caloric restriction (CR) and a variety of CR mimics have been identified that produce life extending effects without adhering to the rigorous CR dietary regimen. Glycerol is a dietary supplement capable mimicking CR by shifting metabolism away from glycolysis and towards oxidative phosphorylation. Glycerol supplementation has a number of beneficial effects, including lifespan extension, improved stress resistance, and enhanced locomotory and mitochondria activity in older age classes. Using rotifers as a model, we show that supplements of 150–300 mM glycerol produced 40–50% extension of mean lifespan. This effect was produced by raising glycerol concentration only three times higher than its baseline concentration in rotifer tissues. Glycerol supplementation decreased rotifer reliance on glycolysis and reduced the pro-aging effects of glucose. Glycerol also acted as a chemical chaperone, mitigating damage by protein aggregation. Glycerol treatment improved rotifer swimming performance in older age classes and maintained more mitochondrial activity. Glycerol treatment provided increased resistance to starvation, heat, oxidation, and osmotic stress, but not UV stress. When glycerol was co-administered with the hexokinase inhibitor 2-deoxyglucose, the lifespan extending effect of glycerol was enhanced. Co-administration of glycerol with inhibitors like 2-deoxyglucose can lower their efficacious doses, thereby reducing their toxic side effects.
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    • "Interestingly, intricate interactions between Akt and FoxO have been recently reported in the context of the mechanisms of cellular regulation. For example, in yeast, a mutation of Sch 9, which is homologous to Akt, extended lifespan (Fabrizio et al. 2001), and an insulin receptor mutation that decreased the activity of the insulin/IGF-1-like pathway has been reported to increase longevity in fruit flies (Tatar et al. 2001), mice (Bluher et al. 2003), and human (de Magalhães et al. 2012). "
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