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

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.

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Available from: Shona Wood, Sep 26, 2015
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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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    ABSTRACT: Living and taking recreation in rural and coastal environments promote health and wellbeing, although the causal factors involved are unclear. It has been proposed that such environments provide a counter to the stresses of everyday living, leading to enhanced mental and physical health. Living in natural environments will result in airborne exposure to a wide range of biogenic chemicals through inhalation and ingestion of airborne microbiota and particles. The "biogenics" hypothesis formulated here is that regular exposure to low concentrations of mixtures of natural compounds and toxins in natural environments confers pleiotropic health benefits by inhibiting the activities of interconnected cell signalling systems, particularly PI3K/Akt/mTORC1. When overactive, Akt and mTOR (mTORC1) can lead to many pathological processes including cancers, diabetes, inflammation, immunosuppression, and neurodegenerative diseases. There is a substantial body of evidence that many natural products (i.e., from bacteria, algae, fungi and higher plants) inhibit the activities of these protein kinases. Other mTOR-related interconnected metabolic control "switches" (e.g., PTEN & NF-κB), autophagy and other cytoprotective processes are also affected by natural products. The "biogenics" hypothesis formulated here is that regular intermittent exposure to a mixture of airborne biogenic compounds in natural environments confers pleiotropic health benefits by inhibiting activities of the highly interconnected PI3K/Akt/mTORC1 system. It is proposed that future experimental exposures to biogenic aerosols in animal models coupled with epidemiology, should target the activities of the various kinases in the PI3K/Akt/mTORC1 systems and related physiological processes for selected urban, rural and coastal populations in order to test this hypothesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Environmental Research 03/2015; 140:65-75. DOI:10.1016/j.envres.2015.03.015 · 4.37 Impact Factor
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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.
    Experimental Gerontology 09/2014; 57:47–56. DOI:10.1016/j.exger.2014.05.005 · 3.49 Impact Factor
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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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    ABSTRACT: Changes in the activities of FoxOs caused by phosphorylation, acetylation, or ubiquitination induce expressional changes in the genes involved in the modulation of oxidative stress by modifying histones and chromatins and can substantially alter cellular functions during aging and age-related diseases. However, the precise role that FoxO6, a novel member of the FoxO class of transcription factors, plays in the aging kidney has not been determined. The purpose of this study was to determine the role played by FoxO6 in the maintenance of redox homeostasis in HEK293T cells and aged kidney tissues isolated from ad libitum (AL)-fed and 40 % calorie restriction (CR) rats. The results obtained from AL-fed rats showed that diminished FoxO6 activity during aging was caused by FoxO6 phosphorylation, which disabled its transcriptional activity. In contrast, CR rats were found to have significantly higher FoxO6 activities and maintained redox balance. To determine the molecular mechanism responsible for FoxO6 modification by age-related oxidative stress, we examined H2O2-treated HEK293T cells in which FoxO6 was inactivated by phosphorylation and found that H2O2-induced oxidative stress promoted FoxO6 phosphorylation via PI3K/Akt signaling. The results of this study show that the protective role of FoxO6 in the aging process may in part be related to its ability to attenuate oxidative stress by upregulating catalase expression, as shown in CR. This delineation of the role of FoxO6 expands understanding of the pathological and physiological mechanisms of aging.
    Journal of the American Aging Association 08/2014; 36(4):9679. DOI:10.1007/s11357-014-9679-3 · 3.39 Impact Factor
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