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.