S-adenosyl-L-homocysteine Supplementation as a Methionine Restriction Mimetic Strategy

Methionine restriction produces benefits to health and longevity in animal studies. This involves minimizing the dietary intake of the essential amino acid methionine while maintaining all of the other necessary nutrients. Much of the nutrient sensing that alters downstream cellular activities in response to a lower intake of calories is based upon assessment of methionine levels. Thus methionine restriction without calorie restriction triggers a sizable fraction of the same beneficial upregulation of cell maintenance processes, leading to improved tissue function, slowed aging, and so forth.

In comparison to the practice of calorie restriction, achieving a meaningful degree of methionine restriction, without reducing calories, is a harder dietary undertaking. The publicly available data on methionine levels is of poor quality and far from complete. Near all staple food choices contain a lot of methionine. There are medical diets manufactured with low methionine levels, used to treat a few uncommon conditions, but they are neither easily obtained nor easily reverse engineered. These issues could be bypassed given a suitable business venture focused on manufacturing such a diet for the public rather than for patients, but it is unclear that producing low methionine foods outside the medical diet industry is in any way commercially viable.

Thus we come to whether or not methionine-based nutrient sensing can be triggered by other means. In today's open access paper, researchers take a look at one of the options on the table. Memetics will never be as good as the real thing, but it is in principle possible that any given mimetic could be good enough to merit time and effort on the part of the research community. Certainly, the quality of calorie restriction mimetics varies widely, and we might expect the same to be true of methionine restriction mimetics.

S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects

Dietary restriction, including methionine restriction (MetR) , is an effective strategy for promoting longevity and counteracting age-related morbidities. In addition, genetic manipulation or pharmacological inhibition of methionine (Met) metabolic pathways and a Met-restricted diet prolong lifespan. Several studies indicate that a MetR diet is possible for humans, but long-term compliance to such a diet is considered problematic. Previously, we showed that a yeast mutant that accumulates S-adenosyl-L-methionine (SAM) to high levels exhibited reduced intracellular Met and lifespan extension mediated through AMPK activation. We also showed that in a wild-type (WT) strain, supplementation with S-adenosyl-L-homocysteine (SAH) increased SAM levels, activating AMPK, and extending lifespan.

To investigate the basis for SAH-mediated longevity, we performed metabolomics analysis of a WT yeast strain. As previously reported, SAH administration increased levels of SAH and SAM, a methyl group donor. SAH is a potent competitive inhibitor of SAM-dependent methyltransferases, and SAH accumulation thereby impairs cell growth. we speculate that SAH supplementation can increase SAM synthesis through an unknown mechanism. Since SAM synthesis requires Met, stimulating SAM production can decrease the quantity of intracellular Met. Notably, among the amino acids, Met exhibited significantly reduced levels after SAH supplementation.

The lower Met content in SAH-treated cells suggests that longevity from SAH supplementation can induce a MetR state. Hence, since MetR extends chronological lifespan (CLS) in an autophagy-dependent manner, we investigated the effect of SAH on autophagy. SAH treatment increased degradation of an autophagy marker, suggesting that SAH administration promotes autophagy.

Subsequently, to determine whether SAH acts as an anti-aging metabolite in a metazoan, we investigated its effects on the nematode C. elegans. SAH treatment extended the lifespan of WT animals in a concentration-dependent manner,. Notably, SAH did not affect food consumption, brood size, or viability. SAH also partially prevented the aging-associated decrease in physical capacity. Altogether, these results suggest that SAH mediates phylogenetically conserved anti-aging effects.

In conclusion, our results suggest that SAH extends lifespan by inducing MetR or mimicking its downstream effects. Since the lifespan-extending effects of SAH are conserved in yeast and nematodes, and MetR extends the lifespan of many species, exposure to SAH is expected to have multiple benefits across evolutionary boundaries. Our findings offer the enticing possibility that in humans the benefits of a MetR diet can be achieved by promoting Met reduction with SAH. The use of endogenous metabolites, such as SAH, is considered safer than drugs and other substances, suggesting that it may be one of the most feasible ways to prevent age-related diseases.

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