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Cellular Senescence and Lifespan

12/16/22
 

One targeted pathway to longevity is through cellular senescence. Cellular senescence is when normal cells no longer divide in response to stress or other factors. Senescent cells are known as a hallmark of aging, and evidence is demonstrating a relationship between senescence, age related disease and lifespan. On the other hand, cellular senescence is positively associated with wound healing, cancer suppression, and fibrosis.

The reason why cells can become senescent involves mitochondrial dysfunction, stresses, genetic dysfunction such as compromised chromosome formation over expression of cancer genes and DNA damage (1, 2, 3, 4). This leads to a senescent phenotype that changes the levels of cancer, inflammation, growth, and lipid related genes (2, 3, 6). Therefore, this process may serve as a worthy therapeutic target for future drug development.

Options include strengthening the overall immune system, or targeting specific cellular functions which are involved decreasing senescent cells. Specifically, engineering our T-cells to eliminate the senescent cells is an option, this has been highly promising in innovative cancer therapies. Increasing the cell’s surface receptors, or increasing the level of binding of the receptors to immune cells could also be effective (2).

A growing body of senolytics (drugs that will kill only the senescent cells), exists and are being further researched and optimized (2), to better exhibit their desired action.

Another type of drug called SASP inhibitors (senomorphics), instead suppress the chemokines, growth factors, proteases, and cytokines which senescent cells release. Antibodies which neutralize the activity of these molecules also exist as senomorphics (2).

Strengthening the immune system is another way decrease senescent cells because decreased immune function is associated with higher levels of senescent cells. As we age the thymus becomes less active, and immune response strength decreases. The thymus creates white blood cells including T-Cells, and also hormones that could deter aging (8).

More research is needed before senolytics or senomorphics are administered in the general population (9).

Over-the-counter products such as poly-phenols (resveratrol, fisetin), flavonoids, and tocotrienols with quercetin (compounds from vitamin e), are being studied, but we lack enough research to recommend them for senolytic use in the general population.

A healthy diet (10), exercise, and stress reduction are a great start to preventing pre-mature cellular senescence.

Resources:

1. Miwa S, Kashyap S, Chini E, von Zglinicki T. Mitochondrial dysfunction in cell senescence and aging. J Clin Invest. 2022 Jul 1;132(13):e158447. doi: 10.1172/JCI158447. PMID: 35775483; PMCID: PMC9246372. https://pubmed.ncbi.nlm.nih.gov/35775483/

2. von Kobbe C. Targeting senescent cells: approaches, opportunities, challenges. Aging (Albany NY). 2019 Nov 30;11(24):12844-12861. doi: 10.18632/aging.102557. Epub 2019 Nov 30. PMID: 31789602; PMCID: PMC6949083. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949083/#:~:text=SUPPRESS%20SENESCENT%20CELLS-,Senolytics,is%20extensive%20and%20continuously%20growing.

3. https://www.frontiersin.org/articles/10.3389/fcell.2021.645593/full

4. He S, Sharpless NE. Senescence in Health and Disease. Cell. 2017 Jun 1;169(6):1000-1011. doi: 10.1016/j.cell.2017.05.015. PMID: 28575665; PMCID: PMC5643029. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643029/

5. Csekes E, Račková L. Skin Aging, Cellular Senescence and Natural Polyphenols. Int J Mol Sci. 2021 Nov 23;22(23):12641. doi: 10.3390/ijms222312641. PMID: 34884444; PMCID: PMC8657738. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657738/#:~:text=Senescent%20cells%20are%20characterized%20by,related%20skin%20changes%20and%20pathologies.

6. Lopes-Paciencia S, Saint-Germain E, Rowell MC, Ruiz AF, Kalegari P, Ferbeyre G. The senescence-associated secretory phenotype and its regulation. Cytokine. 2019 May;117:15-22. doi: 10.1016/j.cyto.2019.01.013. Epub 2019 Feb 16. PMID: 30776684. https://pubmed.ncbi.nlm.nih.gov/30776684/#:~:text=The%20senescence%2Dassociated%20secretory%20phenotype%20(SASP)%20defines%20the%20ability,growth%20factors%20and%20bioactive%20lipids. tissue regeneration

7. Miwa S, Kashyap S, Chini E, von Zglinicki T. Mitochondrial dysfunction in cell senescence and aging. J Clin Invest. 2022 Jul 1;132(13):e158447. doi: 10.1172/JCI158447. PMID: 35775483; PMCID: PMC9246372. https://pubmed.ncbi.nlm.nih.gov/35775483/

8. Csaba, G. (2016). The Immunoendocrine Thymus as a Pacemaker of Lifespan, Acta Microbiologica et Immunologica Hungarica, 63(2), 139-158. doi: https://doi.org/10.1556/030.63.2016.2.1. https://akjournals.com/configurable/content/journals$002f030$002f63$002f2$002farticle-p139.xml?t:ac=journals%24002f030%24002f63%24002f2%24002farticle-p139.xml

9. Malavolta M, Pierpaoli E, Giacconi R, Costarelli L, Piacenza F, Basso A, Cardelli M, Provinciali M. Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals. Curr Drug Targets. 2016;17(4):447-59. doi: 10.2174/1389450116666150907105104. PMID: 26343116. https://pubmed.ncbi.nlm.nih.gov/26343116/

10. Domaszewska-Szostek A, Puzianowska-Kuźnicka M, Kuryłowicz A. Flavonoids in Skin Senescence Prevention and Treatment. Int J Mol Sci. 2021 Jun 25;22(13):6814. doi: 10.3390/ijms22136814. PMID: 34201952; PMCID: PMC8267725. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267725/


By: Evan Redmond, Pharm.D.



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