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 of ammonium concentration 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,ammonium impaired the consumption of the auxotrophy-complementing amino acids and 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 of ammonium 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.
Highlights
The budding yeast Saccharomyces cerevisiae is a highly exploited model to study environmental and genetic factors affecting longevity
We have previously established that NH4+ at the concentration commonly used in SD medium [0.5%, (NH4)2SO4], is toxic for aging yeast when grown under amino acid restriction conditions, leading to cell death in a concentration dependent manner, with a www.impactjournals.com/oncotarget significant increase in cell survival being observed when the NH4+ concentration in the medium was decreased to 0.01% [31]
The results indicated that, like for NH4+, cells grown in LAA medium with glutamine lost viability fast displaying a very short chronological lifespan (CLS), as compared with that of cells grown in LAA medium in the absence of a good nitrogen source (Fig. 1A and 1B)
Summary
The budding yeast Saccharomyces cerevisiae is a highly exploited model to study environmental and genetic factors affecting longevity. The aging process is conserved from yeasts to mammals, with several studies showing that reducing growth factors/nutrients intake has profound positive effects in extension of life span and improves overall health by delaying or reducing aged-related diseases in mammals [1]. Studies using CR show that reducing glucose concentration in culture media is sufficient to increase replicative and chronological life span (CLS) [4,5,6,7,8]. Further studies have revealed that the major nutrientsignaling pathways TOR, SCH9 and RAS/AC/PKA are involved in longevity regulation by glucose, promoting cell division and growth in response to nutrients while inhibiting the general stress response and autophagy [6, 9]
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