Decoding and rejuvenating human ageing genomes: Lessons from mosaic chromosomal alterations

Dai, Xueqin; Guo, Xihan

doi:10.1016/j.arr.2021.101342

Cited by 27 publications

(13 citation statements)

References 227 publications

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“…Furthermore, X chromosome aneuploidy or X chromosome loss/monosomy [46] (i.e., CIN specifically affecting chromosome X [35]) has been found to hallmark the Alzheimer's disease brain. It is of note that X chromosome loss is the most documented cytogenetic (chromosomal) biomarker of human aging [2,4]. CNVs, resulting from somatic recombination and selectively affecting the APP gene, have also been found to produce genomic or subchromosomal instability in the Alzheimer's disease brain [47].…”

Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

“…Sixty years ago, intercellular changes in chromosome numbers were demonstrated to be a possible cellular mechanism of human aging [1]. Later on, aging was systematically associated with the accumulation of aneuploid cells (i.e., cells exhibiting the loss/gain of whole chromosomes) and, occasionally, with chromosome instability (CIN) [2][3][4]. Furthermore, the rates of the latter were found to increase throughout ontogeny, as documented by studying the variability of cancer genomes [5,6].…”

Section: Introductionmentioning

confidence: 99%

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Chromosome Instability, Aging and Brain Diseases

Iourov

Yurov

Vorsanova

et al. 2021

Cells

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Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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Section: Cin In the Diseased Brain: An Aging Perspectivementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chromosome Instability, Aging and Brain Diseases

Iourov

Yurov

Vorsanova

et al. 2021

Cells

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“…Mosaic chromosomal alterations (mCAs) are large clonal structural somatic alterations detected in the whole blood-derived DNA, which are characterized by whole-chromosomal or sub-chromosomal level changes, including gain, loss, and copy-neutral loss of heterozygosity (CN-LOH). In addition to the crucial role of aging in the exponential increase of mCAs 26,27 , several other factors have also been reported to help shape the mCA landscapes, such as ambient air pollutants 28 , hazardous chemicals 29,30 , radiation 31 , and unhealthy lifestyles 32,33,34,35 , suggesting that mCAs can be viewed as an internal genomic signature associated with both internal and external exposures 36 . In the past decades, large population-based studies have established the effect of chromosomal mosaicism on early human embryogenesis 37,38 , birth defects 39,40 and a broad range of adult diseases 41,42 and cancers 26,27,31,43,44,45 .…”

Section: Introductionmentioning

confidence: 99%

Interplay between mosaic chromosomal alterations and polygenic risk score increases risk of non-small cell lung cancer

Qin

Chen

Liu

et al. 2022

Preprint

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We investigated autosomal mosaic chromosomal alterations (mCAs) in 10,248 non-small cell lung cancer (NSCLC) cases and 9,298 cancer-free controls of Chinese ancestry. Mosaic loss and copy-neutral loss of heterozygosity were associated with an increased risk of NSCLC, while mosaic gain was associated with a decreased risk of NSCLC, especially those spanning telomeres. The increased cell fraction of mCAs was also correlated with an increasing NSCLC risk in the affected individuals. Both multiplicative and additive interactions were observed between polygenic risk score (PRS) and the presence of mosaic loss, where carriers of mosaic loss events with cell fractions ≥5% among the high genetic risk group had the greatest risk for developing NSCLC. These findings suggest that mCA events may act as a new endogenous indicator for risk of NSCLC and have the potential to be jointly used with PRS to optimize risk stratification of NSCLC.

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“…Aging could be described as the periodic and progressive loss of molecular, cellular, physiological functioning of body leading to several chronic pathological conditions [1]. Alzheimer's disease (AD) is one of the most recurrent neurodegenerative conditions linked to aging, and is challenging to diagnose.…”

Section: Introductionmentioning

confidence: 99%

DAF-16 and SKN-1 mediate Anti-aging and Neuroprotective efficacies of “thai ginseng” Kaempferia parviflora Rhizome extract in Caenorhabditis elegans

Prasanth

Malar

Brimson

et al. 2022

Nutrition and Healthy Aging

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BACKGROUND: The rhizomes of Kaempferia parviflora (KP), have been traditionally used for treating various ailments with 5,7-dimethoxyflavone (DMF) as a prominent compound. OBJECTIVE: To investigate the anti-aging and neuroprotective properties of KP and DMF in Caenorhabditis elegans. METHODS: C. elegans (wild-type (N2), transgenic and mutant strains) were treated with KP and DMF and were monitored for lifespan and neuroprotection through physiological assays, fluorescence microscopy and qPCR analysis. Molecular docking studies were employed to identify the interaction mode of DMF with DAF-16 and SKN-1. RESULTS: KP and DMF significantly increased the lifespan of N2 along with modulating pharyngeal pumping and lipofuscin accumulation. They also exhibited neuroprotection in Aβ transgenic strains by improving lifespan and delaying paralysis. Further, they reduced ROS accumulation significantly in worms exposed to UV-A, thereby exhibiting anti-photoaging potential. KP and DMF could activate SKN-1, DAF-16 which was evident from molecular docking and qPCR analysis. The DAF-2 and DAF-16 mutants did not exhibit any variations in lifespan upon treatment with KP and DMF suggesting the involvement of the DAF-16 mediated pathway in regulating the anti-aging and neuroprotective effects. CONCLUSION: Our findings suggest that KP with DMF as an active ingredient is a potential nutraceutical for aging and associated disorders.

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Decoding and rejuvenating human ageing genomes: Lessons from mosaic chromosomal alterations

Cited by 27 publications

References 227 publications

Chromosome Instability, Aging and Brain Diseases

Chromosome Instability, Aging and Brain Diseases

Interplay between mosaic chromosomal alterations and polygenic risk score increases risk of non-small cell lung cancer

DAF-16 and SKN-1 mediate Anti-aging and Neuroprotective efficacies of “thai ginseng” Kaempferia parviflora Rhizome extract in Caenorhabditis elegans

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