The role of autophagy in the regulation of yeast life span

Abstract

The goal of the aging field is to develop novel therapeutic interventions that extend human health span and reduce the burden of age-related disease. While organismal aging is a complex, multifactorial process, a popular theory is that cellular aging is a significant contributor to the progressive decline inherent to all multicellular organisms. To explore the molecular determinants that drive cellular aging, as well as how to retard them, researchers have utilized the highly genetically tractable budding yeast Saccharomyces cerevisiae. Indeed, every intervention known to extend both cellular and organismal health span was identified in yeast, underlining the power of this approach. Importantly, a growing body of work has implicated the process of autophagy as playing a critical role in the delay of aging. This review summarizes recent reports that have identified a role for autophagy, or autophagy factors in the extension of yeast life span. These studies demonstrate (1) that yeast remains an invaluable tool for the identification and characterization of conserved mechanisms that promote cellular longevity and are likely to be relevant to humans, and (2) that the process of autophagy has been implicated in nearly all known longevity-promoting manipulations and thus represents an ideal target for interventions aimed at improving human health span.

Identification of the Genetic Requirements for Zinc Tolerance and Toxicity inSaccharomyces cerevisiae

“…Furthermore, three genes related to amino acids synthesis (APE4, ARO1 and ARO7) and four genes involved in lipid homeostasis (ARV1, SRF1, NEM1 and LEM3), were all required for zinc tolerance. The SNARE (soluble N-ethylmaleimide-sensitive factor attached protein receptor) complex, a protein complex involved in membrane fusion, is also required for autophagy (Tyler and Johnson 2018). In this study, six genes (VAM7, VPS33, VPS51, SEC22, GOS1 and VPS45) encoding proteins belong to the SNARE complex were identified sensitive to zinc stress, indicating their crucial role in the process of autophagy under excess zinc conditions.…”

“…Of these genes, mutants for 8 genes (PTC6, VTC2, GCN2, CCZ1, GCN1, VTC4, PHO85 and VPS45) accumulated higher intracellular zinc than wide-type cells, indicating their important roles in maintaining the intracellular zinc homeostasis. The only identified gene ATG gene in this study, ATG22, encodes a protein involved in transporting small molecules such as amino acids back to the cytosol for protein synthesis and other cellular functions (Tyler and Johnson 2018). Three genes of CCZ1, MON1 and YPT6 were required for the CVT pathway and the autophagy (Cabrera et al 2014;Suda et al 2013).…”

“…immunity and organismal development (Yin et al 2016). There two types of autophagy in yeast, macroautophagy and microautophagy, a nonspecific or direct process, respectively (Tyler and Johnson 2018). The process of autophagy is regulated by nitrogen, glucose depletion, amino acid and phosphate starvation, mitophagy, pexophagy, transcriptional control and lipid metabolisms (Reggiori and Klionsky 2013).…”

The integrated stress response in budding yeast lifespan extension

“…Many of the genes and mechanisms are highly conserved in metazoans, including humans, with abnormalities in higher eukaryote autophagy resulting in the development of aging and age-related diseases, as previously reviewed 29 33 . Elsewhere, we have recently reviewed the contributions of autophagy to yeast lifespan extension 34 . Here, we synthesize the recent studies that link the ISR to lifespan extension in yeast, to support our proposal that the mechanism whereby stress extends lifespan is via induction of the ISR and downstream stress response pathways, including autophagy.…”

Rapid Nuclear Exclusion of Hcm1 in AgingSaccharomyces cerevisiaeLeads to Vacuolar Alkalization and Replicative Senescence

“…Nonetheless, it remains unresolved whether impaired proteolytic function in alkalizing vacuoles is a driving force in aging. Recent literature, however, links the integrative stress response in yeast with enhanced replicative lifespan and autophagy ( Postnikoff et al 2017 ; Tyler and Johnson 2018 ). To address the question of whether proteolytic dysfunction in old, alkalized vacuoles plays a role in aging, we monitored the proteolytic degradation of a human protein in aging yeast cells that forms inclusions in patients with a variety of neurodegenerative diseases (α-synuclein; Yang and Yu 2016 ) and observed that aggregates accumulated within vacuoles as cells age.…”