Calorie restriction mimetics: an emerging research field

Abstract

SummaryWhen considering all possible aging interventions evaluated to date, it is clear that calorie restriction (CR) remains the most robust. Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet can increase lifespan, reduce the incidence and delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline. A current major focus of this research area is whether this nutritional intervention is relevant to human aging. Evidence emerging from studies in rhesus monkeys suggests that their response to CR parallels that observed in rodents. To assess CR effects in humans, clinical trials have been initiated. However, even if results from these studies could eventually substantiate CR as an effective pro-longevity strategy for humans, the utility of this intervention would be hampered because of the degree and length of restriction required. As an alternative strategy, new research has focused on the development of 'CR mimetics'. The objective of this strategy is to identify compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. For example, drugs that inhibit glycolysis (2-deoxyglucose), enhance insulin action (metformin), or affect stress signaling pathways (resveratrol), are being assessed as CR mimetics (CRM). Promising results have emerged from initial studies regarding physiological responses which resemble those observed in CR (e.g. reduced body temperature and plasma insulin) as well as protection against neurotoxicity (e.g. enhanced dopamine action and up-regulated neurotrophic factors). Ultimately, lifespan analyses in addition to expanded toxicity studies must be accomplished to fully assess the potential of any CRM. Nonetheless, this strategy clearly offers a very promising and expanding research endeavor.

Dietary restriction and the pursuit of effective mimetics

“…compounds that can capture the benefits of DR without the requirement for chronic food restriction. A whole host of putative DR mimetics have been reviewed in detail elsewhere (83)(84)(85)(86) , but this review will concentrate on three compounds currently enjoying much of the limelight as plausible DR mimetics; rapamycin, metformin and resveratrol.…”

Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

“…When activated, AMPK negatively regulates mTOR activation (Mihaylova and Shaw 2011). AMPK activation slows aging in C. elegans (Apfeld et al 2004;Mair et al 2011) and is being considered as a calorie restriction mimetic (Ingram et al 2006). Therefore, metformin has been used for life extension in mammals and, in some studies although not all, has demonstrated gerosuppressive effects (Smith et al 2010;Anisimov et al 2011;Berstein 2012).…”

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

“…Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents (Ingram et al 2006). In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer, and cardiovascular disorders) in mammals (Willcox et al 2007).Whether this occurs in longer-lived species is unknown, although the effect of prolonged calorie restriction in nonhuman primates is under investigation (Fontana et al 2004;Sinclair 2005).…”