Dietary or caloric restriction (DR or CR), typically a 30-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend lifespan and healthspan in diverse organisms, including mammals. Although the lifespan benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers healthspan benefits.
A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related lifespan-enhancing protocols. Increased expression of FGF21, a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends lifespan to a similar extent as DR in a recent study.
FGF21 may achieve these effects by attenuating GH/IGF1 signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents which is a critical component of alternate day fasting, a DR-like protocol that also increases lifespan and healthspan in mammals. Various drugs have been reported to induce FGF21 [but] of these, only metformin has been reported to extend lifespan in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression.
Perhaps the most parsimonious explanation is that high, possibly unphysiological, levels of FGF21 are needed to achieve maximum life- and healthspan benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and healthspan are warranted.