Caloric restriction and longevity

The societal environment is marked by overabundant accessibility to food coupled with reduced physical activity leading to the metabolic syndrome in most individuals. Ageing is considered to be either 'primary' - inevitable deterioration of cells, tissue structure and function occurring independent of disease and lifestyle, or 'secondary' -decline in tissue structure and function from external influences. The focus of my presentation will be on research involving long-term calorie restriction (CR) to prevent or delay the incidence of the metabolic syndrome and delay primary ageing. More generally, I will review the literature in rodents, monkeys and humans about the impact of CR on maximum lifespan. CR extends median and maximal lifespan in a variety of lower species. One hypothesis for the beneficial impact of CR is that metabolic rate is reduced beyond the reduction in metabolically active mass leading to reduced oxidative damage. In a 6-mo pilot study of CR, energy expenditure decreased ∼7% more than expected for the loss of metabolic mass (metabolic adaptation). Serum protein carbonyls and urinary isoprostanes were unchanged from baseline whereas DNA damage decreased in the CR group only. CR increased muscle expression of genes involved in mitochondrial biogenesis including PGC1-α, mtTFA, endothelial nitric oxide, SIRT1 and PARL. In parallel, mitochondrial content increased by 35 ± 5% in the CR group only. However, the activity of key mitochondrial enzymes of the TCA cycle, β-oxidation and electron transport chain were unchanged. This study suggests that CR in non-obese humans improves biomarkers of ageing and supports the “rate of living” theory. The increased mitochondrial content with decreased DNA damage indicates that CR improves mitochondrial function. Data on a recently completed study entitled “Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE 2)” will be presented. This study was the first ever 2-y randomised clinical trial on the impact of 25% CR on biomarkers of ageing in normal weight participants.