Commentary Open Access
Volume 2 | Issue 3 | DOI: https://doi.org/10.33696/Neurol.2.046

Impact of Cellular Senescence on Neurodegenerative Diseases during the COVID-19 Pandemic: Suitable Targets Required to Eliminate Cellular Senescence

  • 1Department of Respiratory Medicine, Kanazawa University, Ishikawa, Japan
+ Affiliations - Affiliations

*Corresponding Author

Md Mohiuddin, mohiuddin@med.kanazawa-u.ac.jp

Received Date: August 14, 2021

Accepted Date: September 24, 2021


We recently reviewed the scientific literature that elucidates the impact of cellular senescence on COVID-19 complications [1]. Recent studies have discussed the association of cellular senescence in COVID-19 patients with neurodegenerative diseases [2-5]. Therefore, in the present study, we extend this scientific synopsis to comment on how cellular senescence can promote neurodegenerative diseases and to describe suitable targets for eliminating cellular senescence.

Cellular senescence is a phenomenon characterized by a stable and terminal stage of growth arrest [6]. During cellular senescence, phenotypic changes can occur, known as senescence-associated secretory phenotype (SASP) [7]. Persistent senescent cells cause age-related diseases, while the induction of acute senescence protects against cancer [6]. Thus, targeting senescent cells to limit cellular aging by administering appropriate drugs—called senolytics— could effectively remove senescent cells [8].

The induction of cellular senescence is regulated by excessive ROS production [9]. In contrast, high ROS levels can mediate the activation of p53, which triggers the activation of autophagy [10]. This cellular process triggers mitochondrial dysfunction, which is related to the induction of cellular senescence [11]. ROS have been reported to alter various cellular functions through DNA damage, promoting certain human diseases, such as cancer and neurodegenerative disease [12]. Thus, the implementation of ROS production inhibitors to maintain a correct ROS balance could reduce cellular senescence.

Peripheral immune cells, astrocytes, microglia, and neurons can secrete cytokine molecules into the central nervous system (CNS) [13]. The upregulation of cytokines and their receptors in the brain is characterized as peripheral or central inflammation [14]. Inflammation has been reported to play an important role in the central nervous system for various neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease [15,16]. Notably, interleukin (IL)-6, a pro-inflammatory cytokine, is elevated in patients with Alzheimer’s disease [17]. In addition, β-amyloid (Aβ) peptide deposition promotes a spectrum of activated microglia-mediated brain neuroinflammation, causing the expression of various inflammatory cytokines, including IL-6, tumor necrosis factor-α (TNF-α) and IL-1β [17]. Conversely, proinflammatory cytokines, such as IL-6 and IL-8 are also present in SASP [18]; therefore, cytokine inhibitors could be useful in targeting and eliminating cellular senescence.

NF-κB is a transcription factor involved in the control of a large number of cellular processes, including cell survival, immune and inflammatory responses, and apoptosis [19]. NF-κB has been reported to be activated by cell damage and stress, resulting in increased activity with chronic aging-related diseases [20]. Furthermore, NF-κB signaling is the main inducer of cellular senescence [21]. Aging is the most significant risk factor for the development of Alzheimer’s disease, and recent findings have shown tissue-specific brain inflammation mediated by NF-κB in Alzheimer’s disease [22,23]. Therefore, inhibition of the NF-κB pathway could be a suitable approach to eliminating cellular senescence and targeting the onset of AD.

mTOR is a member of the phosphatidylinositol 3-kinase family of protein kinases [24]. mTOR binds to other proteins and serves as a central component of two distinct protein complexes, mTOR complex 1 and mTOR complex 2, which regulate different cellular processes [25]. Mammalian target of rapamycin complex 1 (mTORC1) and cellular senescence have been reported to be closely related to each other and to organism aging [26]. Furthermore, mTOR regulates cellular senescence by modulating mitochondrial metabolism, autophagy, and protein translation [27]. A previous study claimed that mTOR plays a role in several neurodegenerative diseases, including Down syndrome, Alzheimer’s disease, and Huntington’s disease [28]. Therefore, mTOR inhibition could be a suitable strategy for eliminating cellular senescence.

In conclusion, emerging evidence has demonstrated that cellular senescence is related to neurodegenerative diseases. Furthermore, preliminary studies have indicated that cellular senescence could exacerbate the complications of COVID-19. Due to the COVID-19 pandemic, limited preclinical and clinical studies have investigated the impact of cellular senescence on complications of COVID-19 in patients with neurodegenerative disorders. However, we anticipate that there will soon be greater efforts to fully establish the role of cellular senescence in COVID-19 patients with neurodegenerative disease.

Author contributions

All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

Competing Interests

The authors declare no conflicts of interest in association with the present study.


1. Mohiuddin M, Kasahara K. The emerging role of cellular senescence in complications of COVID-19. Cancer Treatment and Research Communications. 2021 May 15:100399.

2. Sfera A, Osorio C, Maguire G, Rahman L, Azaal J, Cummings M, et al. COVID-19, ferrosenescence and neurodegeneration, a mini-review. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2020 Dec 26:110230.

3. Nehme J, Borghesan M, Mackedenski S, Bird TG, Demaria M. Cellular senescence as a potential mediator of COVID-19 severity in the elderly. Aging Cell. 2020 Oct;19(10):e13237.

4. Camell CD, Yousefzadeh MJ, Zhu Y, Prata LG, Huggins MA, Pierson M, et al. Senolytics reduce coronavirusrelated mortality in old mice. Science. 2021 Jun 8.

5. Hascup ER, Hascup KN. Does SARS-CoV-2 infection cause chronic neurological complications?. Geroscience. 2020 Aug;42:1083-7.

6. Van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May;509(7501):439-46.

7. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathology: Mechanisms of Disease. 2010 Feb 28;5:99-118.

8. Von Kobbe C. Targeting senescent cells: Approaches, opportunities, challenges. Aging (Albany NY). 2019 Dec 31;11(24):12844.

9. Chandrasekaran A, Idelchik MD, Melendez JA. Redox control of senescence and age-related disease. Redox Biology. 2017 Apr 1;11:91-102.

10. Cordani M, Butera G, Pacchiana R, Masetto F, Mullappilly N, Riganti C, et al. Mutant p53-associated molecular mechanisms of ROS regulation in cancer cells. Biomolecules. 2020 Mar;10(3):361.

11. Vasileiou PV, Evangelou K, Vlasis K, Fildisis G, Panayiotidis MI, Chronopoulos E, et al. Mitochondrial homeostasis and cellular senescence. Cells. 2019 Jul;8(7):686.

12. Uttara B, Singh AV, Zamboni P, Mahajan RT.Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Current Neuropharmacology. 2009 Mar 1;7(1):65-74.

13. Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, et al. Role of microglia in central nervous system infections. Clinical Microbiology Reviews. 2004 Oct;17(4):942-64.

14. Galic MA, Riazi K, Pittman QJ. Cytokines and brain excitability. Frontiers in Neuroendocrinology. 2012 Jan 1;33(1):116-25.

15. Amor S, Puentes F, Baker D, Van Der Valk P.Inflammation in neurodegenerative diseases. Immunology.2010 Feb;129(2):154-69.

16. Guerrero A, De Strooper B, Arancibia-Cárcamo IL. Cellular senescence at the crossroads of inflammation and Alzheimer’s disease. Trends in Neurosciences. 2021 Sep; 44(9):714-727.

17. Wang WY, Tan MS, Yu JT, Tan L. Role of pro- inflammatory cytokines released from microglia in Alzheimer’s disease. Annals of Translational Medicine. 2015 Jun;3(10):136.

18. Ortiz-Montero P, Londoño-Vallejo A, Vernot JP. Senescence-associated IL-6 and IL-8 cytokines induce a self-and cross-reinforced senescence/inflammatory milieu strengthening tumorigenic capabilities in the MCF-7 breast cancer cell line. Cell Communication and Signaling. 2017 Dec;15(1):1-8.

19. Oeckinghaus A, Ghosh S. The NF-?B family of transcription factors and its regulation. Cold Spring Harbor Perspectives in Biology. 2009 Oct 1;1(4):a000034.

20. Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL, Reay DP, et al. NF-κB inhibition delays DNA damage– induced senescence and aging in mice. The Journal of Clinical Investigation. 2012 Jul 2; 122(7):2601-12.

21. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-?B signaling in the induction of senescenceassociated secretory phenotype (SASP). Cellular Signalling. 2012 Apr 1;24(4):835-45.

22. Jones SV, Kounatidis I. Nuclear factor-kappa B and Alzheimer disease, unifying genetic and environmental risk factors from cell to humans. Frontiers in Immunology. 2017 Dec 11;8:1805.

23. Kritsilis M, V Rizou S, Koutsoudaki PN, Evangelou K, Gorgoulis VG, Papadopoulos D. Ageing, cellular senescence and neurodegenerative disease. International Journal of Molecular Sciences. 2018 Oct; 19(10):2937.

24. Chiang GG, Abraham RT. Determination of the catalytic activities of mTOR and other members of the phosphoinositide-3-kinase-related kinase family. Methods in Molecular Biology. 2004;281:125-41.

25. Oh WJ, Jacinto E. mTOR complex 2 signaling and functions. Cell Cycle. 2011 Jul 15;10(14):2305-16.

26. Weichhart T. mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology. 2018;64(2):127-34.

27. Xu S, Cai Y, Wei Y. mTOR signaling from cellular senescence to organismal aging. Aging and Disease. 2014 Aug; 5(4):263-73.

28. Talboom JS, Velazquez R, Oddo S. The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease. NPJ Aging and Mechanisms of Disease. 2015 Oct 15;1(1):1-7.

Author Information X