Serine- and Threonine/Valine-Dependent Activation of PDK and Tor Orthologs Converge on Sch9 to Promote Aging

Abstract

Dietary restriction extends longevity in organisms ranging from bacteria to mice and protects primates from a variety of diseases, but the contribution of each dietary component to aging is poorly understood. Here we demonstrate that glucose and specific amino acids promote stress sensitization and aging through the differential activation of the Ras/cAMP/PKA, PKH1/2 and Tor/S6K pathways. Whereas glucose sensitized cells through a Ras-dependent mechanism, threonine and valine promoted cellular sensitization and aging primarily by activating the Tor/S6K pathway and serine promoted sensitization via PDK1 orthologs Pkh1/2. Serine, threonine and valine activated a signaling network in which Sch9 integrates TORC1 and Pkh signaling via phosphorylation of threonines 570 and 737 and promoted intracellular relocalization and transcriptional inhibition of the stress resistance protein kinase Rim15. Because of the conserved pro-aging role of nutrient and growth signaling pathways in higher eukaryotes, these results raise the possibility that similar mechanisms contribute to aging in mammals.

Parsing the life-shortening effects of dietary protein: effects of individual amino acids

“…Thus, we further explored the individual role of each amino acid on the high-protein toxicity and we found that the over-representation of methionine (Met), serine (Ser), threonine (Thr) and phenylalanine (Phe) were especially harmful. These amino acids when in excess decrease growth and/or lifespan in a wide variety of life forms such as unicellular algae (Met, Thr and Ser [45]), yeasts (Met, Thr and Ser [46][47][48]), roundworms (Phe [49]), flies (Met [50,51]), rodents (Met, Thr, Ser and Phe [46,[52][53][54]), and even cancer tumour cells (Met and Phe [55]) and other human cells (Met [46]). Methionine is proposed to be related to oxidative stress processes [56].…”

Protein and amino acid restriction, aging and disease: from yeast to humans

“…Both glucose and AA restriction are sufficient to extend the yeast lifespan [13, 14]. AA scarcity drives the accumulation of uncharged tRNAs resulting in activation of general control nonderepressible 2 (GCN2), a protein kinase and important regulator of the general AA control pathway, leading to slow growth [14].…”

“…However, a screen for the ability of each AA to sensitize cells to oxidative stress, a phenotype consistently correlated with reduced longevity, three amino acids previously not associated with aging were shown to have the most potent effect on cellular protection, DNA damage and lifespan [18]. When cells were sensitized to oxidative stress by glucose in a Ras-dependent manner, AAs serine (Ser), threonine (Thr) and valine (Val) were the only three that caused a strong sensitization of cells to oxidative stress and promoted aging [13]. In particular, serine activated the Pkh1/2 (PDK1/2 orthologs) while threonine and valine activated TOR signaling, both of which converged to activate the S6 kinase (S6K) ortholog, Sch9 (Fig.…”

“…1). The lack of these AAs was sufficient to extend lifespan but also to decrease age-dependent DNA damage [13, 16]. Notably, in yeast, glucose has a pro-aging effect that is more pronounced than that caused by AAs but also cooperates with AAs to accelerate cell damage and death.…”

Genomewide mechanisms of chronological longevity by dietary restriction in budding yeast

“…This was also the case for their cell cycle arrest defects: Similar gene deletion phenotypes were observed in the cell cycle dynamics triggered by both nitrogen and carbon starvation. This is relevant in the context that dietary restriction responses depend on nutrient composition (Wu, Liu & Huang, 2013) and that different sensing pathways underlie longevity by glucose or amino acid restriction (Mirisola et al., 2014). But the fact that several protocols of dietary restriction result in lifespan extension, including restriction of glucose, reduced nitrogen levels, and restriction of specific amino acids suggests that the underlying response involves overlapping mechanisms (Kennedy, Steffen & Kaeberlein, 2007).…”