Glucose, Methionine, and the Study of Calorie Restriction in Yeast

Beneficial changes to metabolism take place in response to a lowered intake of nutrients, upregulating cell maintenance processes and extending life span. This evolved a very long time ago indeed, a way to ensure greater odds of survival in the face of famine. As a consequence of its distant origins, the mechanisms of the calorie restriction response are similar in near all species, from single celled yeast through to higher animals such as mammals.

The research noted here reinforces this point: calorie restriction in yeast cells in culture is usually achieved by reducing the surrounding amount of glucose, a far cry from the sort of diet and dietary restriction found in mammals. Nonetheless, researchers show that this glucose restriction causes a loss of methionine in the yeast cells, and the downstream reaction to that loss of methionine includes the usual beneficial adaptation to a lack of nutrients. In mammals, methionine is an essential amino acid that must be obtained from the diet, and it is the lack of methionine that is the primary trigger for the response to calorie restriction. Thus the cellular response in the two very different species is nonetheless quite similar.

Since the discovery in the early 1930s that reduced food intake extends the life span of rats, caloric restriction (CR), defined as a reduction in calorie intake without causing malnutrition, has been shown to extend the life span of a range of species. While the effect on life span for humans remains to be determined, studies in nonhuman primates indicate that CR confers health benefits and possibly extends life span in rhesus monkeys, and short-term CR studies in humans evoke metabolic health benefits.

While the life span phenotype of CR was first observed in laboratory rats, much of the insight into molecular mechanisms has derived from simpler model organisms including the budding yeast Saccharomyces cerevisiae. Budding yeast has been a canonical model for aging research due to its short replicative life span (defined as the number of daughter cells produced by a mother cell prior to senescence) and ease of genetic manipulation. In addition, yeast cells can grow on synthetic media of precisely controlled composition, making it possible to isolate the effect of an individual nutrient on life span. For example, CR has been implemented by simply reducing the glucose concentration of the media without affecting other nutrients.

In this work, we investigate the molecular mechanism of life span extension by glucose restriction (GR) in yeast, using an approach that combines global gene expression profiling, microfluidics-based single-cell analysis, and candidate-based genetic manipulations. Using ribosome profiling and RNA-seq, we systematically compared the translational and transcriptional profiles of cells grown in GR and normal media, uncovering groups of functionally related genes that are up- or down-regulated. We observed a cross-talk from glucose sensing to the regulation of intracellular methionine: methionine biosynthetic enzymes and transporters were significantly down-regulated by GR, leading to the decreased intracellular methionine level, and external supplementation of methionine cancels the life span extension by GR without affecting the life span in the normal media. With additional evidence from systematic manipulations of methionine pathway genes and bioinformatic analyses of other long-lived mutants, we were able to place intracellular methionine at a central position for life span regulation.



@JohnD: Unless they are just failing to remove significant numbers of senescent cells, it bears out the thesis that systemic inflammatory signaling is important, and that senolytics should be applied systemically rather than locally.

Posted by: Reason at August 17th, 2020 9:28 AM

@JohnD That's a shame. Last I heard, OneSkin still on track to release it's topical skin senolytic in October and am eager to try that. (@Reason. Yes, that's another reason am interested in the skin stuff, being a significant source of systemic inflammation, as others have noted.)

Posted by: dtkamp at August 17th, 2020 9:39 AM

Local application can use much higher dose safely. Also it seems that each tissue has different types of ScC.

Posted by: Cuberat at August 17th, 2020 1:23 PM

UBX closed down 66% today. Supposedly this phase 2 trial was Unity's low dose trial. And that a high dose trial is still in phase 1b. But I can not find dose details on the high dose trial. The 4mg used in the low dose trial seems exceedingly low to me.

Posted by: JohnD at August 17th, 2020 4:25 PM

Here is an article about UBX seno trial.

For people following the UBX trial this news is not the least surprising.

Apparently knee arthritis has more complex nature and simple Senolytics don't help in advanced stages. Let's hope that their compounds will work better for the eyes.

Posted by: Cuberat at August 17th, 2020 7:35 PM

FWIW, I have had successful treatment of osteoarthritis with MSCs (left knee), and Exosomes (right knee). Though It is not permanent, I think it is something that has to be redone every 2-3 years, as my left knee which I had done 2 years ago is starting to complain.

Posted by: JohnD at August 17th, 2020 11:44 PM
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