Calorie restriction is the most studied means to slow aging, and from this numerous lines of work have emerged, each focused on one small subset of the sweeping changes in metabolism that occur in response to a lowered intake of nutrition. Lack of nutrients puts stress on cells and organisms, and this has been the case since the emergence of life. The response to calorie restriction thus has ancient evolutionary origins, and is quite similar across all eukaryotic species investigated to date. The one big difference is that maximum life span is greatly extended in short-lived species, but not in long-lived species such as our own. Why this is the case is a matter still under investigation, and an interesting scientific puzzle, given that so many of the short-term benefits of calorie restriction are more or less the same in mice and humans.
Among the multiple alterations that have a profound impact on aging, the nutrient sensing cell pathways have recently captured much interest thanks to their potential as therapeutic targets in the prevention of age-related diseases, and the extension of the healthy life-span. The nutrient sensing pathways are mainly regrouped in the IGF (insulin-like growth factor)/insulin, the TOR (target of rapamycin), and the AMPK (AMP-Activated Protein Kinase) pathways. Data from different experimental models have largely demonstrated that the mutations that induce life-span extension are associated with an altered activity of the above-listed signaling pathways.
Interestingly, the extension of the life-span upon inhibition of the nutrient sensing signaling pathways, has also been associated to the physiological condition induced by calorie restriction (CR). Actually, CR, which consists of the reduction in the caloric intake without malnutrition, has been reported as a robust intervention to promote life-span elongation and healthy aging in rodents at the beginning of last century, and has been further suggested to have similar effects in humans. CR regimens have been shown to induce metabolic adaptations, such as reduced oxidative stress and improved inflammatory response, that ultimately result in better life- and health-spans. Studies performed on experimental models allowed to attribute the life prolongation effects to the modulation of the IGF-1, TOR, and AMPK signaling pathways, but also to other targets, such as FOXO that stimulates protein synthesis and NfkappaB, which is involved in the inflammatory response.
Nowadays, the search for the effects of long-term lifestyle interventions initiated in early adulthood and carried on throughout the entire life captures much attention, due to the evidence that in some tissues and organs, such as the skeletal muscle, the functional decline can begin in adulthood. This interest has prompted several observational studies to understand the correlation between nutrition and health-span, and the potential of CR regimens and CR mimetics in improving the health-span of aging people. At date, there is also a large number of studies aimed at directly testing CR regimens and CR-mimetics, but there are still some shadows on their efficacy, because the time and the interval of the intervention, the variability among individuals, and other factors can compromise their effectiveness.