Senescence: A DNA Damage Response and Its Role in Aging and Neurodegenerative Diseases

Overview

Journal Front Aging

Specialty Geriatrics

Date 2024 Apr 10

PMID 38596783

Authors

Tejal Shreeya

Mohd Saifullah Ansari

Prabhat Kumar

Muskan Saifi

Ali A Shati

Mohammad Y Alfaifi

Serag Eldin I Elbehairi

Affiliations

Soon will be listed here.

Abstract

Senescence is a complicated, multi-factorial, irreversible cell cycle halt that has a tumor-suppressing effect in addition to being a significant factor in aging and neurological diseases. Damaged DNA, neuroinflammation, oxidative stress and disrupted proteostasis are a few of the factors that cause senescence. Senescence is triggered by DNA damage which initiates DNA damage response. The DNA damage response, which includes the formation of DNA damage foci containing activated H2AX, which is a key factor in cellular senescence, is provoked by a double strand DNA break. Oxidative stress impairs cognition, inhibits neurogenesis, and has an accelerated aging effect. Senescent cells generate pro-inflammatory mediators known as senescence-associated secretory phenotype (SASP). These pro-inflammatory cytokines and chemokines have an impact on neuroinflammation, neuronal death, and cell proliferation. While it is tempting to think of neurodegenerative diseases as manifestations of accelerated aging and senescence, this review will present information on brain ageing and neurodegeneration as a result of senescence and DNA damage response.

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References

Caldeira C, Cunha C, Vaz A, Falcao A, Barateiro A, Seixas E . Key Aging-Associated Alterations in Primary Microglia Response to Beta-Amyloid Stimulation. Front Aging Neurosci. 2017; 9:277. PMC: 5583148. DOI: 10.3389/fnagi.2017.00277. View

Yates S, Zafar A, Rabai E, Foxall J, Nagy S, Morrison K . The effects of two polymorphisms on p21cip1 function and their association with Alzheimer's disease in a population of European descent. PLoS One. 2015; 10(1):e0114050. PMC: 4308198. DOI: 10.1371/journal.pone.0114050. View

Jackson S, Durocher D . Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell. 2013; 49(5):795-807. DOI: 10.1016/j.molcel.2013.01.017. View

Dimri G, Lee X, Basile G, Acosta M, Scott G, Roskelley C . A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92(20):9363-7. PMC: 40985. DOI: 10.1073/pnas.92.20.9363. View

Wang W, Zheng Y, Sun S, Li W, Song M, Ji Q . A genome-wide CRISPR-based screen identifies as a driver of cellular senescence. Sci Transl Med. 2021; 13(575). DOI: 10.1126/scitranslmed.abd2655. View

Riessland M, Kolisnyk B, Kim T, Cheng J, Ni J, Pearson J . Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons. Cell Stem Cell. 2019; 25(4):514-530.e8. PMC: 7493192. DOI: 10.1016/j.stem.2019.08.013. View

Rodier F, Campisi J . Four faces of cellular senescence. J Cell Biol. 2011; 192(4):547-56. PMC: 3044123. DOI: 10.1083/jcb.201009094. View

Hadar A, Milanesi E, Walczak M, Puzianowska-Kuznicka M, Kuznicki J, Squassina A . SIRT1, miR-132 and miR-212 link human longevity to Alzheimer's Disease. Sci Rep. 2018; 8(1):8465. PMC: 5981646. DOI: 10.1038/s41598-018-26547-6. View

Coppe J, Desprez P, Krtolica A, Campisi J . The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99-118. PMC: 4166495. DOI: 10.1146/annurev-pathol-121808-102144. View

10.

dAdda di Fagagna F . Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008; 8(7):512-22. DOI: 10.1038/nrc2440. View

11.

Gorgoulis V, Adams P, Alimonti A, Bennett D, Bischof O, Bishop C . Cellular Senescence: Defining a Path Forward. Cell. 2019; 179(4):813-827. DOI: 10.1016/j.cell.2019.10.005. View

12.

Chang B, Watanabe K, Broude E, Fang J, Poole J, Kalinichenko T . Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A. 2000; 97(8):4291-6. PMC: 18232. DOI: 10.1073/pnas.97.8.4291. View

13.

Wang S, Ke S, Wu Y, Zhang D, Liu B, He Y . Functional Network of the Long Non-coding RNA Growth Arrest-Specific Transcript 5 and Its Interacting Proteins in Senescence. Front Genet. 2021; 12:615340. PMC: 7987947. DOI: 10.3389/fgene.2021.615340. View

14.

Silva A, Santos A, Farfel J, Grinberg L, Ferretti R, Campos A . Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer's disease. PLoS One. 2014; 9(6):e99897. PMC: 4061071. DOI: 10.1371/journal.pone.0099897. View

15.

Hari P, Millar F, Tarrats N, Birch J, Quintanilla A, Rink C . The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci Adv. 2019; 5(6):eaaw0254. PMC: 6551188. DOI: 10.1126/sciadv.aaw0254. View

16.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

17.

Sherr C, McCormick F . The RB and p53 pathways in cancer. Cancer Cell. 2002; 2(2):103-12. DOI: 10.1016/s1535-6108(02)00102-2. View

18.

Erusalimsky J . Vascular endothelial senescence: from mechanisms to pathophysiology. J Appl Physiol (1985). 2008; 106(1):326-32. PMC: 2636933. DOI: 10.1152/japplphysiol.91353.2008. View

19.

Liu L, Luo G, Yang W, Zhao X, Zheng Q, Lv Z . Activation of the imprinted Dlk1-Dio3 region correlates with pluripotency levels of mouse stem cells. J Biol Chem. 2010; 285(25):19483-90. PMC: 2885227. DOI: 10.1074/jbc.M110.131995. View

20.

Hinterberger M, Fischer P, Huber K, Krugluger W, Zehetmayer S . Leukocyte telomere length is linked to vascular risk factors not to Alzheimer's disease in the VITA study. J Neural Transm (Vienna). 2017; 124(7):809-819. DOI: 10.1007/s00702-017-1721-z. View