Metabolic adaptation of short‐living growth hormone transgenic mice to methionine restriction and supplementation

Abstract

Extension of mammalian health and life span has been achieved using various dietary interventions. We previously reported that restricting dietary methionine (MET) content extends life span only when growth hormone signaling is intact (no life span increase in GH deficiency or GH resistance). To understand the metabolic responses of altered dietary MET in the context of accelerated aging (high GH), the current study evaluated MET and related pathways in short-living GH transgenic (GH Tg) and wild-type mice following 8 weeks of restricted (0.16%), low (0.43%), or enriched (1.3%) MET consumption. Liver MET metabolic enzymes were suppressed in GH Tg compared to diet-matched wild-type mice. MET metabolite levels were differentially affected by GH status and diet. SAM:SAH ratios were markedly higher in GH Tg mice. Glutathione levels were lower in both genotypes consuming 0.16% MET but reduced in GH Tg mice when compared to wild type. Tissue thioredoxin and glutaredoxin were impacted by diet and GH status. The responsiveness to the different MET diets is reflected across many metabolic pathways indicating the importance of GH signaling in the ability to discriminate dietary amino acid levels and alter metabolism and life span.

Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress

“…Previous reports showed that 80% MetR increases the level of GSH in erythrocytes in rats [ 7 , 64 ]. Although MetR decreases the GSH levels in several tissues, including the liver [ 7 , 64 , 65 , 66 , 67 , 68 , 69 ], oxidative stress is not enhanced. The low levels of hepatic GSH induced by MetR are compensated by increased antioxidative capacity, including increased erythroid 2-like 2 transcription factor (NFE2L2)-induced antioxidative responses [ 65 ].…”

Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice

“…Indeed, unpublished studies from the Orentreich Foundation found that GH injections abrogate the MR phenotype of methionine-restricted rats (not shown). In addition, Brown-Borg et al recently demonstrated that short-lived GH-overexpressing transgenic mice show an impaired response to MR ( Brown-Borg et al, 2018 ). Accordingly, we hypothesized that any intervention that reduces IGF-1 levels (or otherwise impairs IGF-1 signaling) will produce MR-like healthspan benefits.…”

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

“…Moreover, the SAM:SAH ratio is markedly increased, while liver and kidney gnmt mRNA levels are decreased in the short-lived growth hormone transgenic mice (GH-Tg). Methionine restriction reverses the SAM:SAH ratio in GH-Tgs but not to wt levels [ 118 ]. In flies, genetic suppression of two out of three AHCY homologs, systemically or in a tissue-specific manner, reduces age-related SAH accumulation and leads to lifespan extension [ 80 ].…”