Dietary restriction (DR) without malnutrition extends lifespan across species from yeast to primates but is not feasible as a long-term intervention in humans. Dietary methionine restriction (MR) has emerged as a promising alternative to calorie restriction. The type III endoribonuclease DICER seems to play a role in the beneficial effects of DR. Guerra et al. show that DICER is upregulated in DR as well as MR, and that MR is both sufficient and necessary for DICER upregulation. They also provide evidence that DICER is important for several beneficial health effects of DR.
Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects
Objective: Dietary restriction (DR) improves health and prolongs lifespan in part by upregulating type III endoribonuclease DICER in adipose tissue. In this study, we aimed to specifically test which missing dietary component was responsible for DICER upregulation.
Methods: We performed a nutrient screen in mouse preadipocytes and validated the results in vivo using different kinds of dietary interventions in wild type or genetically modified mice and worms, also testing the requirement of DICER on the effects of the diets.
Results: We found that sulfur amino acid restriction (i.e., methionine or cysteine) is sufficient to increase Dicer mRNA expression in preadipocytes. Consistently, while DR increases DICER expression in adipose tissue of mice, this effect is blunted by supplementation of the diet with methionine, cysteine, or casein, but not with a lipid or carbohydrate source. Accordingly, dietary methionine or protein restriction mirrors the effects of DR. These changes are associated with alterations in serum adiponectin. We also found that DICER controls and is controlled by adiponectin. In mice, DICER plays a role in methionine restriction-induced upregulation of Ucp1 in adipose tissue. In C. elegans, DR and a model of methionine restriction also promote DICER expression in the intestine (an analog of the adipose tissue) and prolong lifespan in a DICER-dependent manner.
Conclusions: We propose an evolutionary conserved mechanism in which dietary sulfur amino acid restriction upregulates DICER levels in adipose tissue leading to beneficial health effects.