Author's Repsonse to Commentary on "Revisiting the Role of Fat Mass in the Life Extension Induced by Caloric Restriction"

Abstract

DECENTLY, mutations in several genes in the nematode s worm (1) and in the drosphilla fly (2) resulted in a dra­ matie inerease in life span. These diseoveries support the eon­ eept that genes determine longevity. Are these diseoveries rele­ vant to humans? This year a published report showed that siblings of eentenarians live longer than siblings of the eente­ narian's eohort (3), supporting a major genetie eomponent for human longevity. On the other hand, the effeets of ealorie re­ strietion on the extension of maximallife span seem to suggest that the environment also plays an important role in mediating this effeet. Are the suggestions that longevity may be deter­ mined by genes as weIl as by the environment eontradieting eaeh other? We argue that they are not-rather the environment may eause a marked differenee in the expression of longevity related genes. Dur hypothesis article (4) may help us under­ stand the interaetion between the environment and genes, and may provide an insight into how modulation of gene expression may determine longevity. We suggest that the obvious eandi­ dates for genes that influenee longevity are those expressed in fat, or whose levels are ehanged with fat mass. As an example of the latter, insulin levels inerease with fat mass and, therefore, decrease in ealorie-restrieted animals. As reviewed (4), hyperin­ sulinemia is associated with diseases and early mortality in hu­ mans, whereas a mutation in the nematodes' insulin-signaling pathway is associated with extreme longevity. Thus, this is an example demonstrating environment modulation (ealorie re­ striction), gene mutation (in nematodes), and their relationship to longevity. Fat mass is increased by 2- to 5-fold in ad-libitum fed com­ pared with calorie-restrieted animals. If the plasma levels of certain fat-derived peptides chronically increase by that many folds, they should be considered as eandidates to affect longevity (just like insulin). Durhypothesis article focused on the example of leptin-a fat-derived hormone, whose expres­ sion is modulated by fat mass, and which has been shown to control the hypothalamic response to ealorie deprivation and energy expenditure. Moreover, while fat mass is increased by several fold, the plasma leptin levels change by -2 log scales in obese humans (5) and with nutrient access to ad libitum fed an­ imals (6). This chronic -100-fold increase in the expression of a gene product is similar to differences in expression designed by genetie manipulation. Thus, together with the known actions of