Abstract
Nutrient limitation results in an activation of autophagy in organisms ranging from yeast, nematodes and flies to mammals. Several evolutionary conserved nutrient-sensing kinases are critical for efficient adaptation of yeast cells to glucose, nitrogen or phosphate depletion, subsequent cell-cycle exit and the regulation of autophagy. Here, we demonstrate that phosphate restriction results in a prominent extension of yeast lifespan that requires the coordinated activity of autophagy and the multivesicular body pathway, enabling efficient turnover of cytoplasmic and plasma membrane cargo. While the multivesicular body pathway was essential during the early days of aging, autophagy contributed to long-term survival at later days. The cyclin-dependent kinase Pho85 was critical for phosphate restriction-induced autophagy and full lifespan extension. In contrast, when cell-cycle exit was triggered by exhaustion of glucose instead of phosphate, Pho85 and its cyclin, Pho80, functioned as negative regulators of autophagy and lifespan. The storage of phosphate in form of polyphosphate was completely dispensable to in sustaining viability under phosphate restriction. Collectively, our results identify the multifunctional, nutrient-sensing kinase Pho85 as critical modulator of longevity that differentially coordinates the autophagic response to distinct kinds of starvation.
Highlights
The quantification of cellular viability in the stationary phase using flow-cytometric quantification of propidium iodide staining as a measure of cell death revealed that limiting phosphate to 0.5 mM mildly increased survival during aging, while a further reduction of phosphate availability to
To test whether the induction of autophagy represents a prerequisite for PR-induced longevity, we monitored the lifespan of several autophagy-deficient mutants upon entry longevity, we monitored the lifespan of several autophagy-deficient mutants upon entry into stationary phase driven by glucose versus phosphate exhaustion
We show that a gradual depletion of phosphate, driving entry into stationary phase, results in a prominent extension of yeast lifespan
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Several of the molecular pathways implicated in the aging process are conserved across species, and central nutrient-sensing and -signaling pathways govern the lifespan in organisms ranging from yeast, nematodes and flies, to rodents and humans [1,2,3,4] The downregulation of these nutrient-responsive pathways critically contributes to the beneficial effects of caloric restriction (the reduction of caloric intake without malnutrition), a regime that counteracts age-associated cellular dysfunction in most organisms tested, including yeast [5,6,7]. While the cellular processes and signaling pathways involved in longevity upon glucose or nitrogen restriction are relatively well understood, not much is known about lifespan in phosphate-limited conditions. We demonstrate that Pho has opposing roles in glucose versus phosphate-depleted cells Genetic inactivation of this kinase resulted in mild induction of autophagy and longevity upon glucose exhaustion. Induction of autophagy as well as full lifespan extension via phosphate restriction critically depended on the presence of the Pho85–Pho complex
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
