scholarly journals Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 32-33
Author(s):  
Alaattin Kaya
Keyword(s):  
Caloric Restriction ◽  
Genetic Basis ◽  
Epigenetic Landscape ◽  
Intermediary Metabolites ◽  
Replicative Lifespan ◽  
Nad Metabolism ◽  
Wild Yeast ◽  
Lifespan Variation ◽  
Extended Lifespan ◽  
Selective Forces

Abstract To understand the genetic basis and the selective forces acting on longevity, it is useful to employ ecologically diverse individuals of the same species, widely different in lifespan. This way, we may capture the experiment of Nature that modifies the genotype arriving at different lifespans. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered wide diversity of lifespan. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. By identifying genes, proteins and metabolites that correlate with longevity across these isolates, we found that long-lived strains elevate intermediary metabolites, differentially regulate genes involved in NAD metabolism and adjust control of epigenetic landscape through conserved, rare histone modifier. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness.

scholarly journals Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

2020 ◽  
Author(s):  
Alaattin Kaya ◽  
Cheryl Zi Jin Phua ◽  
Mitchell Lee ◽  
Lu Wang ◽  
Alexander Tyshkovskiy ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Epigenetic Landscape ◽  
Intermediary Metabolites ◽  
Closely Related Species ◽  
Nad Metabolism ◽  
Lifespan Variation ◽  
Extended Lifespan ◽  
Selective Forces ◽  
Biology Of Aging ◽  
Species Lifespan

ABSTRACTThe question of why and how some species or individuals within a population live longer than others is among the most important questions in the biology of aging. A particularly useful model to understand the genetic basis and selective forces acting on the plasticity of lifespan are closely related species or ecologically diverse individuals of the same species widely different in lifespan. Here, we analyzed 76 diverse wild isolates of two closely related budding yeast species Saccharomyces cerevisiae and Saccharomyces paradoxus and discovered a diversity of natural intra-species lifespan variation. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. We identified sets of genes and metabolites to regulate aging pathways, many of which have not been previously associated with lifespan regulation. We also identified and characterized long-lived strains with elevated intermediary metabolites and differentially regulated genes for NAD metabolism and the control of epigenetic landscape through chromatin silencing. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness. Overall, our study shows how the environment and natural selection interact to shape diversity of lifespan.

scholarly journals Evolution of natural lifespan variation and molecular strategies of extended lifespan

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alaattin Kaya ◽  
Cheryl Zi Jin Phua ◽  
Mitchell Lee ◽  
Lu Wang ◽  
Alexander Tyshkovskiy ◽  
...  
Keyword(s):  
Natural Variation ◽  
Phylogenetic Analyses ◽  
Replicative Lifespan ◽  
Cellular Processes ◽  
Wild Yeast ◽  
Gene Environment ◽  
Lifespan Variation ◽  
Extended Lifespan ◽  
Selective Forces ◽  
Transcriptomic Changes

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. 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 replicative lifespan 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 multi-omic 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.

scholarly journals Author response: The genetic basis of aneuploidy tolerance in wild yeast

2019 ◽  
Author(s):  
James Hose ◽  
Leah E Escalante ◽  
Katie J Clowers ◽  
H Auguste Dutcher ◽  
DeElegant Robinson ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Author Response ◽  
Wild Yeast

scholarly journals The genetic basis of aneuploidy tolerance in wild yeast

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
James Hose ◽  
Leah E Escalante ◽  
Katie J Clowers ◽  
H Auguste Dutcher ◽  
DeElegant Robinson ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Drug Treatment ◽  
Genetic Basis ◽  
Rna Binding ◽  
Laboratory Strain ◽  
Pathogenic Fungi ◽  
Wild Type ◽  
Wild Yeast ◽  
Mechanistic Understanding

Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi – what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of Saccharomyces cerevisiae tolerate chromosome amplification while laboratory strains used as a model for aneuploid syndromes do not. Here, we mapped the genetic basis to Ssd1, an RNA-binding translational regulator that is functional in wild aneuploids but defective in laboratory strain W303. Loss of SSD1 recapitulates myriad aneuploidy signatures previously taken as eukaryotic responses. We show that aneuploidy tolerance is enabled via a role for Ssd1 in mitochondrial physiology, including binding and regulating nuclear-encoded mitochondrial mRNAs, coupled with a role in mitigating proteostasis stress. Recapitulating ssd1Δ defects with combinatorial drug treatment selectively blocked proliferation of wild-type aneuploids compared to euploids. Our work adds to elegant studies in the sensitized laboratory strain to present a mechanistic understanding of eukaryotic aneuploidy tolerance.

scholarly journals An epigenetic landscape governs early fate decision in cellular aging

2019 ◽  
Author(s):  
Yang Li ◽  
Yanfei Jiang ◽  
Julie Paxman ◽  
Richard O’Laughlin ◽  
Lorraine Pillus ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Quantitative Model ◽  
Cellular Aging ◽  
Multiple Equilibrium ◽  
Epigenetic Landscape ◽  
Genetically Engineer ◽  
Different Types ◽  
Extended Lifespan ◽  
Fate Decision

AbstractChromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which cell fate arises in isogenic cells is unknown. Here, we show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape with multiple equilibrium states that represent different types of terminal cellular states. Interestingly, the structure of the landscape drives single-cell differentiation towards one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise. Guided by a quantitative model of the aging landscape, we genetically engineer a new “long-lived” equilibrium state that is characterized by a dramatically extended lifespan.

scholarly journals Lifespan Extension in Long-Lived Vertebrates Rooted in Ecological Adaptation

2021 ◽  
Vol 9 ◽  
Author(s):  
Olatunde Omotoso ◽  
Vadim N. Gladyshev ◽  
Xuming Zhou
Keyword(s):  
Natural Selection ◽  
Genetic Factors ◽  
Physiological Function ◽  
Evolutionary Model ◽  
Comparative Biology ◽  
Genetic Changes ◽  
Theories Of Aging ◽  
Lifespan Variation ◽  
Extended Lifespan ◽  
Mechanisms Of Adaptation

Contemporary studies on aging and longevity have largely overlooked the role that adaptation plays in lifespan variation across species. Emerging evidence indicates that the genetic signals of extended lifespan may be maintained by natural selection, suggesting that longevity could be a product of organismal adaptation. The mechanisms of adaptation in long-lived animals are believed to account for the modification of physiological function. Here, we first review recent progress in comparative biology of long-lived animals, together with the emergence of adaptive genetic factors that control longevity and disease resistance. We then propose that hitchhiking of adaptive genetic changes is the basis for lifespan changes and suggest ways to test this evolutionary model. As individual adaptive or adaptation-linked mutations/substitutions generate specific forms of longevity effects, the cumulative beneficial effect is largely nonrandom and is indirectly favored by natural selection. We consider this concept in light of other proposed theories of aging and integrate these disparate ideas into an adaptive evolutionary model, highlighting strategies in decoding genetic factors of lifespan control.

scholarly journals HIGH THROUGHPUT YEAST REPLICATIVE LIFESPAN SCREEN UNCOVERS HISTONE DEACETYLASE HDA AS NOVEL REGULATOR OF AGING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S876-S876
Author(s):  
Ruofan Yu ◽  
Xiaohua Cao ◽  
Weiwei Dang
Keyword(s):  
Stress Response ◽  
Histone Deacetylase ◽  
High Throughput ◽  
High Throughput Screening ◽  
Screening Method ◽  
Replicative Lifespan ◽  
New Genes ◽  
Extended Lifespan ◽  
As Stress ◽  
Time And Energy

Abstract In this work, we set out to develop a high throughput screening method, SEBYL (SEquencing Based Yeast replicative Lifespan screen), in order to identify new aging regulators in budding yeast. By utilizing SEBYL on yeast knockout collection, we were able to identify 285 long-lived gene deletions, of which a significant portion was proven to have extended lifespan by previous classical experiments. To demonstrate the ability of our method to discover new genes and pathways involved in aging process, we focused on characterizing one newly identified long-lived candidate emerged from the screening, histone deacetylase complex HDA, and found it regulates aging through mediating stress response pathways, especially DNA damage stress response. Presence of HDA complex inhibits expression of trehalose metabolism genes, which act as stress protectant. When HDA complex is mutated, trehalose genes are de-repressed, enhancing stress response and eventually promotes longevity. In summary, we conclude SEBYL to be time and energy saving, robust, and suitable for discovery of aging regulating genes using various preexisting yeast mutant collection resource.

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