Ammonium is a key determinant on the dietary restriction of yeast chronological aging in culture medium

Abstract

New evidences have recently emerged from studies in yeast and in higher eukaryotes showing the importance of nutrient balance in dietary regimes and its effects on longevity regulation. We have previously shown that manipulation ofammoniumconcentration in the culture and/or aging medium can drastically affect chronological lifespan (CLS) of Saccharomyces cerevisiae, especially in amino acid restricted cells. Here we describe that the CLS shortening under amino acid restriction can be completely reverted by removing ammonium from the culture medium. Furthermore, the absence of ammonium, and of any rich nitrogen source, was so effective in extending CLS that no beneficial effect could be observed by further imposing calorie restriction conditions. When present in the culture medium,ammoniumimpaired the consumption of theauxotrophy-complementing amino acidsand caused in an improper cell cycle arrest of the culture. TOR1 deletion reverted ammonium effects both in amino acid restricted and non-restricted cultures, whereas, Ras2p and Sch9p seem to have only a milder effect in the mediation ofammonium toxicity under amino acid restriction and no effect on non-restricted cultures. Our studies highlight ammonium as a key effector in the nutritional equilibrium between rich and essential nitrogen sources and glucose required for longevity promotion.

Dietary Restriction and Nutrient Balance in Aging

“…Furthermore, the negative effects of NH 4 + are mediated by Tor1p, Ras2p, and Sch9p. These results further establish NH 4 + as a key factor involved in the nutritional balance required between nitrogen sources and glucose, to achieve longevity promotion in yeast [ 12 ]. A schematic illustration of dietary balance in yeast is provided in Figure 2 .…”

“…Sch9p seems to be directly involved in nutritional balance in yeast as a new study reports antagonistic effects of SCH9 deletion on yeast cells grown in synthetic complete medium and natural grape juice, where the nitrogen : carbon ratio significantly differs [ 91 ]. In line with these latest results, the CLS shortening under amino acid restriction can be completely reverted by removing nonlimiting good nitrogen sources (NH 4 + or glutamine) from the medium and furthermore NH 4 + is a necessary nutrient for the beneficial effects of CR on longevity to occur [ 12 ]. The presence of ammonium is responsible for inducing replicative stress and blocking the consumption of essential amino acids.…”

“…Since then many studies have demonstrated the beneficial effects of CR on lifespan extension of multiple organisms (yeast, flies, worms, fish, rodents, and rhesus monkeys), as well as on the improvement of overall health in rodent models. However, new evidences have recently emerged from studies in yeast [ 11 , 12 ] and in higher eukaryotes [ 13 – 15 ] showing the importance of nutrient balance in dietary regimens and its effects on longevity regulation, challenging the notion that the indiscriminate reduction of caloric intake per se extends lifespan. These studies increasingly suggest that not only caloric restriction but rather a balance of different nutrients and their ratios have a pivotal role in regulating lifespan [ 13 , 14 , 16 – 18 ].…”

Similar environments but diverse fates: Responses of budding yeast to nutrient deprivation

“…Similarly, cyclin expression also blocks the establishment and maintenance of quiescence 79. Finally, once cells do enter quiescence, higher quality N sources accelerate ageing relative to lower quality sources 173.…”

An optimized competitive-aging method reveals gene-drug interactions underlying the chronological lifespan of Saccharomyces cerevisiae

“…While this may be explained in part by differences in genotypic background, media composition, and subtle environmental variations 17 , the large fraction of false positives and little overlap may also suggest that available large-scale CLS phenotyping approaches are still lacking enough technical replicability. Moreover, changes in specific controlled and uncontrolled environmental conditions are known to be important modifiers of CLS phenotypes and may be confounding causes of aging 12,[17][18][19][20] . Hence, a combination of high throughput and good resolution is needed to correctly determine not only genetic aging factors, but also to quantitatively derive their interactions with nutrimental, chemical, or pharmacological environments.…”