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Do you want to live a longer life in good health? Simple practices can make some difference, such as exercise or calorie restriction. But over the long haul all that really matters is progress in medicine: building new classes of therapy to repair and reverse the known root causes of aging. The sooner these treatments arrive, the more lives will be saved. Find out how to help ยป
April 15th, 2022
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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.
April 15th, 2022
Permalink No Comments Yet Add a Comment Posted by Reason
An interesting commentary here notes the extended life span in flies that results from the upregulation of the Mask gene in dopaminergenic neurons only. This is accompanied by extended reproductive life span as well, indicating an overall improvement in health along with extended life. In short-lived species there are many examples of this sort of single gene alteration that results in overall improvement, demonstrating that the processes of evolution do not optimize for life span. Should we expect to find analogous single gene alterations in humans? That question is complicated by the fact that long-lived species such as our own exhibit life spans that are much less plastic in response to metabolic and environmental factors when compared to the life spans of short-lived species. Mice can live 40% longer in response to calorie restriction , 70% longer in response to growth hormone receptor knockout , but in humans neither of those states appears to result in more than a few years gained.
Dopaminergic neurons are critical modulators for essential brain functions such as learning and memory, reward and addiction, motor control , and metabolism . My recent work identified a novel function of dopaminergic neurons in regulating aging and longevity in flies. I demonstrated that overexpressing the putative scaffolding protein Mask in small subsets of dopaminergic neurons significantly extends the lifespan in flies. Interestingly, the prolonged lifespan of the Mask-overexpressing flies is accompanied by sustained reproductive activities, contradicting the long-acknowledged inverse relation between reproduction and longevity.
This prevalent negative correlation between reproduction and longevity has been explained by the disposability theory that posits a competing allocation of energy between reproduction and somatic maintenance. However, my work, together with a few other findings in flies, suggested that extension of both lifespan and reproduction can be induced simultaneously by a variety of specific genetic manipulations. Moreover, such a co-extension also occurs in nature - the reproductive females of eusocial insects acquire physiological transformations that enable the expansion of both their reproduction capacity and lifespan.
It seems that a common mechanism may exist to actively induce adaptations to cope with the reproductive demands of the animals, which also at the same time intervenes the aging process and extends the lifespan. Inspired by this notion, I propose a reproduction-centered theory that explains the seemingly contradictory relationships of reproduction and longevity. The success of reproduction is essential for the survival of the species. From such a reproduction-centered perspective, the maintenance of the somatic tissues is not just critical for the survival of individuals but is, more importantly, essential for the fulfillment of reproduction. Therefore, I postulate that somatic tissues possess the ability to adapt to, instead of competing with, the animal's reproduction states and that such adaptations can consequentially impact aging and longevity.