Two conserved epigenetic regulators prevent healthy ageing

Yuan, Jie; Chang, Siyuan; Yin, Shigang; Liu, Zhi‐Yang; Cheng, Xiu; Liu, Xi-Juan; Jiang, Qiang; Gao, Ge; Lin, De-Ying; Kang, Xin-Lei; Ye, Shiwei; Chen, Zheng; Yin, James Q.; Hao, Pei; Jiang, Lubin; Cai, Shi-Qing

doi:10.1038/s41586-020-2037-y

Cited by 74 publications

(85 citation statements)

References 47 publications

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“…[3][4][5][6] For instance, genome-wide RNA-interference-based screening in Caenorhabditis elegans revealed a conserved epigenetic mechanism, which implicated 59 genes as modulators of age-related behavioural deterioration rate. 7 Two neuronal genes were among the most prominent hits: epigenetic reader (BAZ-2) and histone 3 lysine 9 methyltransferase (SET-6), which could accelerate behavioural deterioration by repressing the expression of nuclear-encoded mitochondrial proteins. Importantly, the expression of human orthologues (BAZ2B and EHMT1) in the frontal cortex increases with age and correlates with Alzheimer disease (AD) progression.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

2020

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The number of age predictors based on DNA methylation (DNAm) profile is rising due to their potential in predicting healthspan and application in age-related illnesses, such as neurodegenerative diseases. The cumulative assessment of DNAm levels at age-related CpGs (DNAm clock) may reflect biological aging. Such DNAm clocks have been developed using various training models and could mirror different aspects of disease/aging mechanisms. Hence, evaluating several DNAm clocks together may be the most effective strategy in capturing the complexity of the aging process. However, various confounders may influence the outcome of these age predictors, including genetic and environmental factors, as well as technical differences in the selected DNAm arrays. These factors should be taken into consideration when interpreting DNAm clock predictions. In the current review, we discuss 15 reported DNAm clocks with consideration for their utility in investigating neurodegenerative diseases and suggest research directions towards developing a more optimal measure for biological aging.

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Section: Introductionmentioning

confidence: 99%

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

2020

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“…Certain conditions that activate the UPR mt are associated with extended lifespan and require ATFS-1 or other regulators of this stress response pathway. This includes mitonuclear imbalance [3], ETC dysfunction [12], and more recently from the loss of two neuronal epigenetic regulators [34]. Contrary to these findings, ATFS-1 had no role in regulating the lifespan increase observed with RNAi knockdown of the cytochrome c oxidase 1 gene cco-1, despite it reducing the expression of the UPR mt reporter [5].…”

Section: Plos Geneticsmentioning

confidence: 83%

A novel gene-diet interaction promotes organismal lifespan and host protection during infection via the mitochondrial UPR

et al. 2020

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Cells use a variety of mechanisms to maintain optimal mitochondrial function including the mitochondrial unfolded protein response (UPRmt). The UPRmt mitigates mitochondrial dysfunction by differentially regulating mitoprotective gene expression through the transcription factor ATFS-1. Since UPRmt activation is commensurate with organismal benefits such as extended lifespan and host protection during infection, we sought to identify pathways that promote its stimulation. Using unbiased forward genetics screening, we isolated novel mutant alleles that could activate the UPRmt. Interestingly, we identified one reduction of function mutant allele (osa3) in the mitochondrial ribosomal gene mrpl-2 that activated the UPRmt in a diet-dependent manner. We find that mrpl-2(osa3) mutants lived longer and survived better during pathogen infection depending on the diet they were fed. A diet containing low levels of vitamin B12 could activate the UPRmt in mrpl-2(osa3) animals. Also, we find that the vitamin B12-dependent enzyme methionine synthase intersects with mrpl-2(osa3) to activate the UPRmt and confer animal lifespan extension at the level of ATFS-1. Thus, we present a novel gene-diet pairing that promotes animal longevity that is mediated by the UPRmt.

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“…Both proteins when overexpressed in aged worms increased the levels of H3K9Me3, the triple methylated state of the protein, thus inhibiting UPR MT activation in the H3K9-protected loci ( Figure 1 ). Loss of function of SET-6 or BAZ-2 increased healthspan but not longevity, a phenotype that was inhibited downregulating UBL-5 or ATFS-1 (Yuan et al, 2020 ). Histone 3 methylation appears then as a key epigenetic mediator for UPR MT throughout the lifespan (Merkwirth et al, 2016 ; Tian et al, 2016 ; Ono et al, 2017 ).…”

Section: The Role and Regulation Of Upr Mt In Aginmentioning

confidence: 99%

“…It would be noteworthy to determine the temporality of this increased expression to understand whether it is an early program persistently activated throughout the disease progression, or a late response triggered by an overall mitochondrial dysfunction. This is especially relevant considering that the expression of the epigenetic regulators of UPR MT EHMT1 and BAZ2B, and therefore inhibition of UPR MT , correlates positively with the progression of AD (Zhang et al, 2013 ; Yuan et al, 2020 ). Therefore, future studies should try to clarify whether both inhibition and persistent activation of UPR MT contribute to ND pathomechanisms.…”

Section: Upr Mt In Aging Neurons and Neurodegeneramentioning

confidence: 99%

The Mitochondrial Unfolded Protein Response: A Hinge Between Healthy and Pathological Aging

Muñoz-Carvajal

Sanhueza

2020

Front. Aging Neurosci.

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Aging is the time-dependent functional decline that increases the vulnerability to different forms of stress, constituting the major risk factor for the development of neurodegenerative diseases. Dysfunctional mitochondria significantly contribute to aging phenotypes, accumulating particularly in post-mitotic cells, including neurons. To cope with deleterious effects, mitochondria feature different mechanisms for quality control. One such mechanism is the mitochondrial unfolded protein response (UPR MT ), which corresponds to the transcriptional activation of mitochondrial chaperones, proteases, and antioxidant enzymes to repair defective mitochondria. Transcription of target UPR MT genes is epigenetically regulated by Histone 3-specific methylation. Age-dependency of this regulation could explain a differential UPR MT activity in early developmental stages or aged organisms. At the same time, precise tuning of mitochondrial stress responses is crucial for maintaining neuronal homeostasis. However, compared to other mitochondrial and stress response programs, the role of UPR MT in neurodegenerative disease is barely understood and studies in this topic are just emerging. In this review, we document the reported evidence characterizing the evolutionarily conserved regulation of the UPR MT and summarize the recent advances in understanding the role of the pathway in neurodegenerative diseases and aging.

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Two conserved epigenetic regulators prevent healthy ageing

Cited by 74 publications

References 47 publications

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

A novel gene-diet interaction promotes organismal lifespan and host protection during infection via the mitochondrial UPR

The Mitochondrial Unfolded Protein Response: A Hinge Between Healthy and Pathological Aging

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