Development of Calorie Restriction Mimetics as a Prolongevity Strategy

Abstract

By applying calorie restriction (CR) at 30-50% below ad libitum levels, studies in numerous species have reported increased life span, reduced incidence and delayed onset of age-related diseases, improved stress resistance, and decelerated functional decline. Whether this nutritional intervention is relevant to human aging remains to be determined; however, evidence emerging from CR studies in nonhuman primates suggests that response to CR in primates parallels that observed in rodents. To evaluate CR effects in humans, clinical trials have been initiated. Even if evidence could substantiate CR as an effective antiaging strategy for humans, application of this intervention would be problematic due to the degree and length of restriction required. To meet this challenge for potential application of CR, new research to create "caloric restriction mimetics" has emerged. This strategy focuses on identifying compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. Microarray studies show that gene expression profiles of key enzymes in glucose (energy) handling pathways are modified by CR. Drugs that inhibit glycolysis (2-deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicity, enhanced dopamine action, and upregulated brain-derived neurotrophic factor. Further life span analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic, but this strategy now appears to offer a very promising and expanding research field.

The anti-aging effects of Ludwigia octovalvis on Drosophila melanogaster and SAMP8 mice

“…4 inhibitor of glycolysis (Lane et al 1998), and metformin, which stimulates AMPK (Anisimov et al 2003), are two molecules currently being explored as DR mimetics. However, long-term administration of 2-deoxyglucose or metformin may produce unwanted side effects, including heart failure and lactic acidosis, making them unlikely candidates for use as DR mimetics (Ingram et al 2004;Sinclair 2005). Flies receiving metformin also showed no beneficial effect on lifespan extension (Slack et al 2012).…”

The role of the T cell in age-related inflammation

“…This has led to the development of CR mimetic (CRM) compounds that provide some of the benefits of CR without a reduction in caloric intake (Ingram et al 2004). The best studied CRM is resveratrol, a polyphenolic compound found in grapes, red wine, peanuts and some berries owing to its ability to activate SIRT1 and extend lifespan in cell cultures and animal models (reviewed in Fig.…”

Nutrition, Brain Aging, and Neurodegeneration: Table 1.

“…This has engendered increased attention on the development of calorie restriction mimetics (CRM) (Hursting et al, 2003;Ingram et al, 2004Ingram et al, , 2006Chen and Guarente, 2007), compounds which can mimic CR by targeting metabolic and stress response pathways affected by CR, but without restricting caloric intake. One of these candidates is resveratrol (Baur and Sinclair, 2006;Knutson and Leeuwenburgh, 2008;Markus and Morris, 2008).…”