Methionine Restriction Extends Lifespan in Progeroid Mice and Alters Lipid and Bile Acid Metabolism

Abstract

SummaryDietary intervention constitutes a feasible approach for modulating metabolism and improving the health span and lifespan. Methionine restriction (MR) delays the appearance of age-related diseases and increases longevity in normal mice. However, the effect of MR on premature aging remains to be elucidated. Here, we describe that MR extends lifespan in two different mouse models of Hutchinson-Gilford progeria syndrome (HGPS) by reversing the transcriptome alterations in inflammation and DNA-damage response genes present in this condition. Further, MR improves the lipid profile and changes bile acid levels and conjugation, both in wild-type and in progeroid mice. Notably, treatment with cholic acid improves the health span and lifespan in vivo. These results suggest the existence of a metabolic pathway involved in the longevity extension achieved by MR and support the possibility of dietary interventions for treating progeria.

Dietary Methionine Restriction Reduces Inflammation Independent of FGF21 Action

“…The coordinated downregulation of inflammatory genes known to be regulated by STAT3 suggests that the MR‐dependent anti‐inflammatory responses in WAT are being mediated by MR‐dependent inhibition of STAT3 activity . Another group used microarray analyses and found that MR also downregulated STAT3 signaling in the liver of a mouse model of Hutchinson‐Gilford progeria syndrome . To determine whether MR affects STAT3 activity, we measured STAT3 phosphorylation in liver and EWAT of WT and Fgf21 ‐/‐ mice fed a HFD or HFD + MR for 8 weeks (Figure ).…”

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

“…Therapeutic treatments and their effect in Lmna G609G/G609G mice. Given the impressive benefit of the HFD in this mouse model, the finding that methionine restriction (MR), a mimicker of calorie restriction, also extended lifespan seemed puzzling [84]. There, methionine restriction, starting at seven weeks of age in Lmna G609G/G609G mice, increased median lifespan by 20%.…”

Methionine restriction for improving progeria: another autophagy-inducing anti-aging strategy?

“…In an attempt to extend their health span and lifespan, progeroid mice (with either the Lmna G609G/G609G or zmpste24 −/genotypes) were subjected to lifelong methionine restriction from weaning to death [1]. Although this dietary intervention reduces the growth rate of the mice, it does prolong their median and maximum longevity by approximately 20%, commensurate with the observation that methionine restriction also attenuates signs of premature aging such as skeletal aberrations (lordokyphosis and osteoporosis) or fibrosis of the aorta and skeleton muscles.…”