Progress Towards Understanding the Discrete Mechanisms of Calorie Restriction

Calorie restriction increases life span and greatly improves health in almost all species tested to date. The relative degree of life extension is much greater in short-lived species, however. Human calorie restriction is not expected to improve life expectancy by more than 5-10% at most. Still, human studies have demonstrated that the practice of calorie restriction produces health benefits such as resistance to age-related disease to a degree that cannot be obtained through any other available technique or technology at the present time - though regular exercise comes close.

Researchers have shown that at least some of the response to calorie restriction stems from sensing levels of amino acids in the diet. In mammals similar results can be obtained by restricting dietary methionine without reducing calories, for example. It is still the early days when it comes to dissecting the calorie restriction response into its component parts, however, the better to understand and replicate it with drugs. Here is an example of this sort of research, in which scientists are working with flies to link calorie restriction and dietary amino acid level alterations to various known longevity-related aspects of metabolism:

Dietary restriction (DR) is an intervention whereby a considerable reduction of food intake, just short of malnutrition, extends lifespan. This has been demonstrated to be effective in a wide range of evolutionarily diverse organisms, from yeast to invertebrates and mammals, and is considered one of the most robust environmental interventions to extend lifespan in laboratory organisms. Moreover, the longevity promoting effects of DR are accompanied by a range of health benefits. DR rodents had a delayed onset or a lesser severity of age-related diseases such as cancer, autoimmune diseases and motor dysfunction and improved memory. In C. elegans, DR was shown to reduce proteotoxicity. DR rhesus monkeys were found to have improved triglyceride, cholesterol and fasting glucose profiles, and a reduced incidence of diabetes, cancer, cardiovascular disease and brain atrophy.

Reduced signalling through the insulin/IGF-like (IIS) and Target of Rapamycin (TOR) signalling pathways also extend lifespan. In Drosophila melanogaster the lifespan benefits of DR can be reproduced by modulating only the essential amino acids in yeast based food. Here, we show that pharmacological downregulation of TOR signalling, but not reduced IIS, modulates the lifespan response to DR by amino acid alteration. Of the physiological responses flies exhibit upon DR, only increased body fat and decreased heat stress resistance phenotypes correlated with longevity via reduced TOR signalling. These data indicate that lowered dietary amino acids promote longevity via TOR, not by enhanced resistance to molecular damage, but through modified physiological conditions that favour fat accumulation.

Some long-lived TOR and IIS pathway mutants [in other species] have increased fat levels. Given that not all fat mutants are long-lived, it is likely that if fat levels are causally involved in extending life, the quality of fat accumulated is important. It would be interesting in future work to determine how lipid profiles change under different dietary conditions, to identify the specific types of lipids that are altered, and whether experimental manipulation can enhance lifespan.



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