Digging Deeper into the Mechanisms of Calorie Restriction in Yeast

Calorie restriction promotes longevity, slowing the progression aging via sweeping metabolic changes across an entire organism. The metabolic changes it produces in cells are very similar in all species studied to date. This is one of the reasons why calorie restriction is so well studied: one can carry out low-cost experiments in yeast and nonetheless learn something that is likely relevant to human biochemistry. Still, it is well established that calorie restriction is much better at extending life in short-lived species. In humans there are clear improvements to long-term health, but nowhere near the same degree of life extension observed in calorie restricted mice.

Caloric restriction and the tor1Δ mutation are robust geroprotectors in yeast and other eukaryotes. Lithocholic acid is a potent geroprotector in Saccharomyces cerevisiae. Here, we used liquid chromatography coupled with tandem mass spectrometry method of non-targeted metabolomics to compare the effects of these three geroprotectors on the intracellular metabolome of chronologically aging budding yeast. Yeast cells were cultured in a nutrient-rich medium. Our metabolomic analysis identified and quantitated 193 structurally and functionally diverse water-soluble metabolites implicated in the major pathways of cellular metabolism.

We show that the three different geroprotectors create distinct metabolic profiles throughout the entire chronological lifespan of S. cerevisiae. We demonstrate that caloric restriction generates a unique metabolic pattern. Unlike the tor1Δ mutation or lithocholic acid, it slows down the metabolic pathway for sulfur amino acid biosynthesis from aspartate, sulfate, and 5-methyltetrahydrofolate. Consequently, caloric restriction significantly lowers the intracellular concentrations of methionine, S-adenosylmethionine, and cysteine. We also noticed that the low-calorie diet, but not the tor1Δ mutation or lithocholic acid, decreases intracellular ATP, increases the ADP:ATP and AMP:ATP ratios, and rises intracellular ADP during chronological aging.

These findings suggest a hypothetical model of how the observed CR-specific remodeling of cellular metabolism delays the chronological aging of yeast. The key aspects of this model are as follows: 1) a life-long decline in the intracellular concentrations of cysteine and methionine weakens tRNA thiolation, thus slowing down the pro-aging process of protein synthesis, 2) a decrease of intracellular methionine throughout the chronological lifespan attenuates a direct methionine-driven stimulation of the pro-aging Tor1 pathway, thereby lowering the inhibitory effect of Tor1 on autophagy and other anti-aging processes, 3) a deterioration in intracellular methionine concentration at diverse stages of chronological aging also weakens a methionine-dependent suppression of the proteasomal degradation of damaged and dysfunctional proteins, a known anti-aging process, 4) a decline in S-adenosylmethionine concentration throughout the chronological lifespan lowers the ability of the protein phosphatase Ppa2p to stimulate the pro-aging Tor1 pathway, and 5) a rise in the ADP:ATP and AMP:ATP ratios on most days of yeast chronological lifespan indirectly (i.e., independent of AMP or ATP binding to Snf1) stimulates the anti-aging protein kinase complex Snf1; Snf1 can also be activated directly, via an ADP binding-dependent protection of Snf1 from inactivating dephosphorylation.

Link: https://doi.org/10.18632/oncotarget.27926


As an avid bread baker, whatever life extension gained by the yeast when the dough goes sour is wasted on them ;)

Posted by: Thomas Mark Schaefer at May 25th, 2021 7:33 AM

It is always good to have more and deeper knowledge. This knowledge might bring some interesting intervention targets.

But we can explain CR even at high-school level by reduced production of Reactive Oxygen Species(ROS) due to slowing down the metabolism, increased Autophagy and by the principle of faster procreation when the resources are plentiful , which leads to the "burning of the candle from both ends" . On top of that it seems that the periods of reduced calorie availability are the rest/repair/downtime for the organisms. Like a workshop or store which can perform the maintenance only when there are no paying customers, but as long as you have customers you cannot stop or risk losing them...

Posted by: Cuberat at May 25th, 2021 8:30 AM
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