ROS-Induced DNA Damage as an Underlying Cause of Aging

doi:10.20900/agmr20200024

Cited by 8 publications

(7 citation statements)

References 59 publications

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“…However, we found that DNA damage levels were negatively correlated with age for some genes. At face value, our results appear to contradict multiple reports documenting an overall decline in DNA repair with age and, more generally, a strong causal relationship between DNA damage and aging (Campisi, 2013 ; Chen et al., 2020 ; Hoeijmakers, 2009 ; Maynard et al., 2015 ; Ou & Schumacher, 2018 ; Robert & Wagner, 2020 ; Yousefzadeh et al., 2021 ). However, the following interpretative caveats must be considered.…”

Section: Discussioncontrasting

confidence: 95%

Genome‐wide profiles of DNA damage represent highly accurate predictors of mammalian age

Cao,

Deng,

Song

et al. 2024

Aging Cell

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The identification of novel age‐related biomarkers represents an area of intense research interest. Despite multiple studies associating DNA damage with aging, there is a glaring paucity of DNA damage‐based biomarkers of age, mainly due to the lack of precise methods for genome‐wide surveys of different types of DNA damage. Recently, we developed two techniques for genome‐wide mapping of the most prevalent types of DNA damage, single‐strand breaks and abasic sites, with nucleotide‐level resolution. Herein, we explored the potential of genomic patterns of DNA damage identified by these methods as a source of novel age‐related biomarkers using mice as a model system. Strikingly, we found that models based on genomic patterns of either DNA lesion could accurately predict age with higher precision than the commonly used transcriptome analysis. Interestingly, the informative patterns were limited to relatively few genes and the DNA damage levels were positively or negatively correlated with age. These findings show that previously unexplored high‐resolution genomic patterns of DNA damage contain useful information that can contribute significantly to both practical applications and basic science.

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Section: Discussioncontrasting

confidence: 95%

Genome‐wide profiles of DNA damage represent highly accurate predictors of mammalian age

Cao,

Deng,

Song

et al. 2024

Aging Cell

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“…DNA damage induced by oxidative stress, whether by acute injury (as in ischemia/reperfusion( 42 )), or during gradual and stochastic accumulation of genomic errors (as in aging( 43, 44 )), drives cell and tissue dysfunction. Nuclear DNA damage leads to DNA leakage into the cytosol, kickstarting cGAS-STING( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

Ibrahim,

Ciullo,

Miyamoto

et al. 2024

Preprint

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Noncoding RNAs (ncRNAs) are increasingly recognized as bioactive. Here we report the development of TY1, a synthetic ncRNA bioinspired by a naturally-occurring human small Y RNA with immunomodulatory properties. TY1 upregulates TREX1, an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia/reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed either to TY1 or TREX1. Inhibition of TREX1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for TREX1, TY1 attenuated DNA damage in the post-MI heart. This novel mechanism—pharmacologic upregulation of TREX1 in macrophages—establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity.One Sentence SummaryUpregulation of three prime exonuclease, TREX1, in macrophages enhances tissue repair post myocardial infarction.

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“…In the case of ABCA7 LoF neurons, mitochondrial stress may result from catabolism of accumulated triglycerides through increased fatty acid oxidation and result in the detected elevation in ROS ( 62 ). These ROS may then cascade down, producing DNA damage and inflammation ( 63–66 ) observed in ABCA7 LoF ( Fig. S11 ).…”

Section: Discussionmentioning

confidence: 99%

Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances

von Maydell,

Wright,

Bonner

et al. 2023

Preprint

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ABCA7 loss-of-function (LoF) variants dramatically increase the risk of Alzheimer’s disease (AD), yet the pathogenic mechanisms and the cell types affected by this loss remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 humanpost-mortemsamples from the prefrontal cortex (PFC) of ABCA7 LoF carriers and matched control individuals. ABCA7 LoF variants were associated with perturbed gene clusters in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed profound perturbations in gene clusters related to lipid metabolism, mitochondrial function, DNA damage, and NF-kB signaling. Given the known role of ABCA7 as a lipid transporter, we reasoned that ABCA7 LoF may mediate neuronal dysfunction by altering the lipidome, and evaluated lipid changes by untargeted mass-spectrometry. Indeed, ABCA7 LoF inpost-mortemhuman PFC and iPSC-derived neurons showed widespread changes to the lipidome, including increased triacylglycerides and altered abundance of multiple phospholipid species. Consistent with these observations, assays onpost-mortemhuman PFC and iPSC-derived ABCA7 LoF neurons (iNs) showed increased levels of mitochondrial dysfunction, DNA damage, and NF-kB activation, suggesting that ABCA7 LoF is a causal mediator of these disruptions in neurons. This study provides a detailed atlas of ABCA7 LoF in the human brain and suggests that lipid dysregulation in neurons may be an underlying insult by which ABCA7 LoF increases AD risk.One-Sentence SummaryABCA7 loss-of-function, associated with increased risk for Alzheimer’s, causes mitochondrial dysfunction, DNA damage, and lipid disruptions in neurons.

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ROS-Induced DNA Damage as an Underlying Cause of Aging

Cited by 8 publications

References 59 publications

Genome‐wide profiles of DNA damage represent highly accurate predictors of mammalian age

Genome‐wide profiles of DNA damage represent highly accurate predictors of mammalian age

Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury

Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances

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