Caloric restriction extends yeast chronological lifespan via a mechanism linking cellular aging to cell cycle regulation, maintenance of a quiescent state, entry into a non-quiescent state and survival in the non-quiescent state.

Anna Leonov,Amanda Piano,Hana Fakim,Mahdi Heshmati-Moghaddam,Rachel Feldman,Vladimir I Titorenko,Negar Roofigari-Esfahani,Harshvardhan Rajen,Leana Rosanelli,Anthony Arlia-Ciommo,Masoumeh Ahmadi,Sarah Elsaser,Sandra Orfali,Vicky Lutchman,Asimah Hussain

doi:10.18632/oncotarget.20614

Abstract

A yeast culture grown in a nutrient-rich medium initially containing 2% glucose is not limited in calorie supply. When yeast cells cultured in this medium consume glucose, they undergo cell cycle arrest at a checkpoint in late G1 and differentiate into quiescent and non-quiescent cell populations. Studies of such differentiation have provided insights into mechanisms of yeast chronological aging under conditions of excessive calorie intake. Caloric restriction is an aging-delaying dietary intervention. Here, we assessed how caloric restriction influences the differentiation of chronologically aging yeast cultures into quiescent and non-quiescent cells, and how it affects their properties. We found that caloric restriction extends yeast chronological lifespan via a mechanism linking cellular aging to cell cycle regulation, maintenance of quiescence, entry into a non-quiescent state and survival in this state. Our findings suggest that caloric restriction delays yeast chronological aging by causing specific changes in the following: 1) a checkpoint in G1 for cell cycle arrest and entry into a quiescent state; 2) a growth phase in which high-density quiescent cells are committed to become low-density quiescent cells; 3) the differentiation of low-density quiescent cells into low-density non-quiescent cells; and 4) the conversion of high-density quiescent cells into high-density non-quiescent cells.

Highlights

A body of knowledge about mechanisms underlying chronological aging of the yeast Saccharomyces cerevisiae has been provided by studies in which yeast cells were cultured in a nutrient-rich liquid medium initially containing 2% glucose [1, 2]
Aging yeast cultured under caloric restriction (CR) conditions in the nutrient-rich 1% yeast extract + 2% peptone (YP) medium initially containing 0.2% glucose lived significantly longer than yeast undergoing chronological aging under noncaloric restriction (non-CR) conditions in YP medium initially supplemented with 2% glucose (Figure 1A)
Even before glucose is depleted from the medium at the diauxic shift, a yeast culture undergoing chronological aging under non-CR conditions is known to differentiate into cell populations with different buoyant densities [6, 8]

Summary

Introduction

A body of knowledge about mechanisms underlying chronological aging of the yeast Saccharomyces cerevisiae has been provided by studies in which yeast cells were cultured in a nutrient-rich liquid medium initially containing 2% glucose [1, 2]. Under these so-called noncaloric restriction (non-CR) conditions yeast cells are not limited in the supply of calories [1, 3, 4]. They are unbudded and uniformly sized, are refractive by phase-contrast microscopy and enclosed by a rigid cell wall, have high buoyant density, store glycogen and trehalose in bulk quantities, are highly metabolically active, exhibit high rates of mitochondrial respiration and low concentrations of reactive oxygen species (ROS), are able to form colonies when plated on fresh solid medium, can re-enter mitosis when nutrients become available following transfer to fresh liquid medium, are resistant to long-term thermal and oxidative stresses, exhibit low rates of mutations that impair www.impactjournals.com/oncotarget mitochondrial functionality, and display a delayed onset of the apoptotic and necrotic modes of programmed cell death (PCD) [5,6,7,8, 10, 11]

Methods

Results

Conclusion