Evolution of natural lifespan variation and molecular strategies of extended lifespan in yeast.

Alaattin Kaya,Weiqiang Liu,Xiaqing Zhao,Xuming Zhou,Theo K Bammler,Mitchell Lee,Brian M Wasko,Matt Kaeberlein,Benjamin Barre,Lu Wang,Siming Ma,Daniel El Promislow,Benjamin R Harrison,Alexander Tyshkovskiy,Cheryl Zi Jin Phua,Vadim N Gladyshev

doi:10.7554/elife.64860

Abstract

To understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan (RLS). Phylogenetic analyses pointed to genes and environmental factors that strongly interact to modulate the observed aging patterns. We then identified genetic networks causally associated with natural variation in RLS across wild yeast isolates, as well as genes, metabolites, and pathways, many of which have never been associated with yeast lifespan in laboratory settings. In addition, a combined analysis of lifespan-associated metabolic and transcriptomic changes revealed unique adaptations to interconnected amino acid biosynthesis, glutamate metabolism, and mitochondrial function in long-lived strains. Overall, our multiomic and lifespan analyses across diverse isolates of the same species shows how gene-environment interactions shape cellular processes involved in phenotypic variation such as lifespan.

Highlights

Diverse selective forces generate enormous variation within and among species (Via and Lande, 1985; Li et al, 2018)
Most wild isolates grew faster than the diploid laboratory wild-type (WT) BY4743 strain under both conditions, with an average doubling time of 65 min in YPD and 125 min in YPG (Figure 1A, Supplementary file 1). Most of these strains grew at a similar rate on YPD, and variation in growth rate on YPG was relatively small among them, indicating that these laboratory-optimized culture conditions are suitable for supporting nutritional needs of these strains and for replicative lifespan (RLS) analysis (Figure 1A)
To assess if any of our transcript hits were previously implicated in yeast lifespan, we extended our list of significant genes to 357 genes by selecting a cutoff at padj = 0.05 and compared these with the genes associated with RLS in laboratory WT strain listed in the GenAge database

Summary

Introduction

Diverse selective forces (mutation, selection, and drift) generate enormous variation within and among species (Via and Lande, 1985; Li et al, 2018). Genetic variation in natural populations of many organisms can differentially affect their neural and endocrine functions, leading to variation in quantitative life-h istory traits such as fitness and age at maturation (Bonier et al, 2009; Finch and Rose, 1995). Variation in another fitness trait, lifespan, has attracted much attention (Arking et al, 1996; Libert and Pletcher, 2007; Ratikainen and Kokko, 2019). Longevity varies among individuals of the same species, indicating that variability of lifespan is not constrained at the level of species, and that the molecular determinants of lifespan vary within the same genetic pool (Finch and Pike, 1996; Klass, 1983; Kaya et al, 2015; Ma et al, 2018; Dato et al, 2018; Wright et al, 2019)

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