All studies in primates including those in mouse lemurs, macaques, or humans seem nevertheless to lead to the same conclusion: eating too much is deleterious for health and longevity. However, it remains difficult to determine what is the optimal level of calories for a given species, at a given age. In the Restrikal project, even if reducing the number of calories was strongly efficient to promote health and longevity, it was accompanied by a deleterious effect on brain gray matter integrity. This suggests that, as for most therapies an optimal balance between positive and negative effects should be further studied and biological mechanisms leading to positive and negative effects should be explored. With regards to our data, it seems critical to evaluate the impact of calorie restriction on brain health. Such analyses are merely described in the literature and should be the object of further dedicated studies. The tissues and longitudinal data stored over the course of our 10-year study (see ref. 1 for the full description of the project and list of analyses performed) present a unique resource to identify the pathways involved in CR effects in primates in order to optimize the development of nutrition-based clinical interventions to offset age-related morbidity. In addition, the strength to work in lemurs is that, due to the small size of the animals and their relatively short lifespan, it is possible to perform studies involving large cohorts leading to robust results.

One perspective to the Restrikal study would be to develop combined strategies to counterbalance the adverse effects of chronic-moderate CR. One option could be the combination of CR with therapeutic intervention. For example, although still debated10,11, resveratrol, which has long been considered as a CR mimetic compound12,13, seems to have beneficial effects on health parameters and potentially lifespan, with positive effects on the development of neurodegenerative diseases14. Since long-term CR is very difficult to implement in humans because of social and practical constraints, it is of major interest to find compounds that could contribute to slow down the aging process and delay the onset of age-related diseases without modifying, or only slightly modifying, feeding habits. Therefore, it would be very interesting to verify whether resveratrol supplementation induces beneficial effects in mouse lemurs, and whether combined with very moderate (~15%) CR, this treatment could decelerate the brain gray matter atrophy. One additional option would be the improvement of behavioral habits, for example physical activity. Indeed, moderate chronic physical activity is known to enhance cognitive functions and favor neurogenesis15,16. Thus, efforts should be put in the future into the investigation of combining very moderate (~15%) CR with daily physical activity (~800 m of walking per animal per day, corresponding at 0.2 m s−1).

The question of whether there is a limit for the maximum of human lifespan was recently asked and is strongly debated17,18,19. Nevertheless, the aim of nutrition-based clinical interventions is not necessarily to extend human lifespan, but rather to delay the onset of age-related diseases that are part of the aging process. In this perspective, the most promising option is probably to combine strategies to aim for an optimum of synergic effects between nutritional, behavioral and therapeutic interventions.