Identifying longevity associated genes by integrating gene expression and curated annotations

Townes, F. William; Carr, Kareem; Miller, Jeffrey W.

doi:10.1371/journal.pcbi.1008429

Cited by 10 publications

(11 citation statements)

References 67 publications

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“…TORC1 positively regulates aging, and its inhibition increases lifespan in various eukaryotic organisms including yeast and mammalian 13,26,27,29,30 . The drug rapamycin, initially discovered as an antifungal natural product produced by Streptomyces hygroscopicus , inhibits TORC1 and increases lifespan (Figures S1A and S1B) 13,17,19,21,23,25,29 .…”

Section: Resultsmentioning

confidence: 99%

“…Since rapamycin increases the lifespan by an inhibitory effect on TORC1 activity 13,17,19,21,23,25,29 , it appears most interesting to focus on AAGs with a deletion phenotype of increased CLS/RLS and being down-regulated by rapamycin application. A manual analysis of these gene lists reveals that, among the uncharacterized or severely understudied AAGs, there is a single one known to increase both CLS and RLS upon deletion and being downregulated by rapamycin treatment.…”

Section: Resultsmentioning

confidence: 99%

“…The gene lists were extracted, after processing, from downloaded files (as of 8 th November 2022) using the databases SGD 22 and GenAge 23 . The actual gene lists are available in Additional File 1'.…”

Section: Table 1 Numbers Of Known Aging Associated Genes (Aags) Repor...mentioning

confidence: 99%

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Uncharacterized yeast geneYBR238C,an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging viaHAP4- andRMD9-dependent mechanisms

Alfatah,

Lim,

Zhang

et al. 2023

Preprint

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Uncovering the regulators of cellular aging will unravel the complexity of aging biology and identify potential therapeutic interventions to delay the onset and progress of chronic, aging-related diseases. In this work, we systematically compared gene sets involved in regulating the lifespan of Saccharomyces cerevisiae (a powerful model organism to study the cellular aging of humans) and those with expression changes under rapamycin treatment. Among the functionally uncharacterized genes in the overlap set, YBR238C stood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show that YBR238C and its paralogue RMD9 oppositely affect mitochondria and aging. YBR238C deletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect of YBR238C is largely explained by HAP4- and RMD9-dependent mechanisms. Further, we find that genetic or chemical-based induction of mitochondrial dysfunction increases TORC1 (Target of Rapamycin Complex 1) activity that, subsequently, accelerates cellular aging. Notably, TORC1 inhibition by rapamycin (or deletion of YBR238C) improves the shortened lifespan under these mitochondrial dysfunction conditions in yeast and human cells. The growth of mutant cells (a proxy of TORC1 activity) with enhanced mitochondrial function is sensitive to rapamycin, whereas the growth of defective mitochondrial mutants is largely resistant to rapamycin compared to the wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TORC1-MItochondria-TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Uncharacterized yeast geneYBR238C,an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging viaHAP4- andRMD9-dependent mechanisms

Alfatah,

Lim,

Zhang

et al. 2023

Preprint

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“…Such analytical approach can overcome inherent constraints of conventional single-database enrichment analyses (i.e. intrinsic domain limitation, annotation biases, and small number of genes with annotations of interest), often requiring a posteriori clustering of complex lists of heterogeneous terms ( 51 , 52 , 53 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

PolyQ length co-evolution in neural proteins

Vaglietti

Fiumara

2021

NAR Genomics and Bioinformatics

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Intermolecular co-evolution optimizes physiological performance in functionally related proteins, ultimately increasing molecular co-adaptation and evolutionary fitness. Polyglutamine (polyQ) repeats, which are over-represented in nervous system-related proteins, are increasingly recognized as length-dependent regulators of protein function and interactions, and their length variation contributes to intraspecific phenotypic variability and interspecific divergence. However, it is unclear whether polyQ repeat lengths evolve independently in each protein or rather co-evolve across functionally related protein pairs and networks, as in an integrated regulatory system. To address this issue, we investigated here the length evolution and co-evolution of polyQ repeats in clusters of functionally related and physically interacting neural proteins in Primates. We observed function-/disease-related polyQ repeat enrichment and evolutionary hypervariability in specific neural protein clusters, particularly in the neurocognitive and neuropsychiatric domains. Notably, these analyses detected extensive patterns of intermolecular polyQ length co-evolution in pairs and clusters of functionally related, physically interacting proteins. Moreover, they revealed both direct and inverse polyQ length co-variation in protein pairs, together with complex patterns of coordinated repeat variation in entire polyQ protein sets. These findings uncover a whole system of co-evolving polyQ repeats in neural proteins with direct implications for understanding polyQ-dependent phenotypic variability, neurocognitive evolution and neuropsychiatric disease pathogenesis.

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“…In addition, differentially expressed genes during senescence/immortalization were shown to be key regulators of interferon-and insulin growth factor-related processes, pRB/p53associated cell cycle regulation, as well as MAP kinase, cytoskeletal, and oxidative stress pathways [14][15][16]. Certain transcriptomic changes observed in aging organisms were linked to longevity [17][18][19][20][21]; however, how these gene expression changes contribute to aging-related pathologies is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Transcriptomics Reveals the Expression of Aging- and Senescence-Associated Genes in Distinct Cancer Cell Populations

Saul

Kosinsky

2021

Cells

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The human aging process is associated with molecular changes and cellular degeneration, resulting in a significant increase in cancer incidence with age. Despite their potential correlation, the relationship between cancer- and ageing-related transcriptional changes is largely unknown. In this study, we aimed to analyze aging-associated transcriptional patterns in publicly available bulk mRNA-seq and single-cell RNA-seq (scRNA-seq) datasets for chronic myelogenous leukemia (CML), colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer (LC), and pancreatic ductal adenocarcinoma (PDAC). Indeed, we detected that various aging/senescence-induced genes (ASIGs) were upregulated in malignant diseases compared to healthy control samples. To elucidate the importance of ASIGs during cell development, pseudotime analyses were performed, which revealed a late enrichment of distinct cancer-specific ASIG signatures. Notably, we were able to demonstrate that all cancer entities analyzed in this study comprised cell populations expressing ASIGs. While only minor correlations were detected between ASIGs and transcriptome-wide changes in PDAC, a high proportion of ASIGs was induced in CML, CRC, HCC, and LC samples. These unique cellular subpopulations could serve as a basis for future studies on the role of aging and senescence in human malignancies.

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Identifying longevity associated genes by integrating gene expression and curated annotations

Cited by 10 publications

References 67 publications

Uncharacterized yeast geneYBR238C,an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging viaHAP4- andRMD9-dependent mechanisms

Uncharacterized yeast geneYBR238C,an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging viaHAP4- andRMD9-dependent mechanisms

PolyQ length co-evolution in neural proteins

Single-Cell Transcriptomics Reveals the Expression of Aging- and Senescence-Associated Genes in Distinct Cancer Cell Populations

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