The interconnections between gerontogen, aging, and senotherapy

Rahma Rahma; Agian Jeffilano Barinda

doi:10.7324/JAPS.2024.184140

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Abstract

Aging causes various degenerative diseases in the older adult population. Senescence, a state of permanent cell-cycle arrest accompanied by the production of various pro-inflammatory factors known as senescence-associated secretory phenotype (SASP), is considered a significant contributor to the aging process and its chronic diseases. Ample evidence showed that various stressors could induce senescence, including DNA damage, telomere shortening and damage, activation of oncogenes, and mitochondrial dysfunction. Numerous credible findings indicate that environmental agents can induce senescence, including UV radiation, a high-fat diet, heavy metal exposure, cigarette smoke, and adverse social environment. These findings posed the possibility that many more environmental agents may induce senescence and accelerate aging but remain unidentified. Senescence also becomes more intriguing due to its promising future as a pharmacological target to blunt the detrimental effects of aging and prevent aging-related diseases, either by eliminating the senescent cells or by controlling the SASP. On the other hand, investigating senescence has become more intricate due to the need for a multimarker approach and translation in vivo analysis. This review will discuss senescence and its biomarkers, how to identify gerontogens in vivo, recent research about gerontogen, and also the development of senotherapy.

Keyword: Aging senescence toxicology gerontogen senotherapy

Citation:

Rahma R, Barinda, AJ. The interconnections between gerontogen, aging, and senotherapy. J Appl Pharm Sci. 2024. Online First. http://doi.org/10.7324/JAPS.2024.184140

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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1. Litke R, Garcharna LC, Jiwani S, Neugroschl J. Modifiable risk factors in Alzheimer disease and related dementias: a review. ClinTher. 2021;43(6):953-65. https://doi.org/10.1016/j.clinthera.2021.05.006

2. Wu J, Li T, Song X, Sun W, Zhang Y, Liu Y, et al. Prevalence anddistribution of hypertension and related risk factors in Jilin Province,China 2015: a cross-sectional study. BMJ Open. 2018;8(3):e020126. https://doi.org/10.1136/bmjopen-2017-020126

3. Nguyen CT, Pham NM, Lee AH, Binns CW. Prevalence ofand risk factors for type 2 diabetes mellitus in Vietnam: asystematic review. Asia Pac J Public Health. 2015;27(6):588-600. https://doi.org/10.1177/1010539515595860

4. Arafat HM, Omar J, Muhamad R, Al-Astani TAD, Shafii N, Al LahamNA, et al. Breast cancer risk from modifiable and non-modifiablerisk factors among palestinian women: a systematic review andmeta-analysis. Asian Pac J Cancer Prev. 2021;22(7):1987-95. https://doi.org/10.31557/APJCP.2021.22.7.1987

5. Nguyen H, Manolova G, Daskalopoulou C, Vitoratou S,Prince M, Prina AM. Prevalence of multimorbidity incommunity settings: a systematic review and meta-analysis of observational studies. J Comorb. 2019;9:2235042X1987093. https://doi.org/10.1177/2235042X19870934

6. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709-13. https://doi.org/10.1016/j.cell.2014.10.039

7. Sorrentino JA, Sanoff HK, Sharpless NE. Defining the toxicology of aging. Trends Mol Med. 2014;20(7):375-84. https://doi.org/10.1016/j.molmed.2014.04.004

8. Salam R, Saliou A, Bielle F, Bertrand M, Antoniewski C, Carpentier C, et al. Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma. Nat Commun. 2023;14(1):441. https://doi.org/10.1038/s41467-023-36124-9

9. Matsudaira T, Nakano S, Konishi Y, Kawamoto S, Uemura K, Kondo T, et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Commun Biol. 2023;6(1):665. https://doi.org/10.1038/s42003-023-05027-2

10. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019;179(4):813-27. https://doi.org/10.1016/j.cell.2019.10.005

11. Gasek NS, Kuchel GA, Kirkland JL, Xu M. Strategies for targeting senescent cells in human disease. Nat Aging. 2021;1(10):870-9. https://doi.org/10.1038/s43587-021-00121-8

12. Mario Gonzalez-Meljem J, Haston S, Carreno G, Apps JR, Pozzi S, Stache C, et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat Commun. 2017;8(1):1819. https://doi.org/10.1038/s41467-017-01992-5

13. Dou X, Fu Q, Long Q, Liu S, Zou Y, Fu D, et al. PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy. Nat Metab. Published online November 1, 2023;5(11):1887-910. https://doi.org/10.1038/s42255-023-00912-w

14. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes live cancer through senescence secretome. Nature. 2013;499(7456):97-101. https://doi.org/10.1038/nature12347

15. Barinda AJ, Ikeda K, Nugroho DB, Wardhana DA, Sasaki N, Honda S, et al. Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype. Nat Commun. 2020;11(1):1-13. https://doi.org/10.1038/s41467-020-14387-w

16. Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL. Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes. 2015;64(7):2289-98. https://doi.org/10.2337/db14-1820

17. Frescas D, Hall BM, Strom E, Virtuoso LP, Gupta M, Gleiberman AS, et al. Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent. Cell Cycle. 2017;16(16):1526-33. https://doi.org/10.1080/15384101.2017.1339850

18. Zonari A, Brace LE, Al-Katib K, Porto WF, Foyt D, Guiang M, et al. Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models. npj Aging. 2023;9(1):10. https://doi.org/10.1038/s41514-023-00109-1

19. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16 Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-6. https://doi.org/10.1038/nature10600

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