Role of Secretome in Age-related Changes in the Male Reproductive System: An Add-on Review on the Gut-Brain Axis
DOI:
https://doi.org/10.22225/wmj.10.2.10116.110-116Keywords:
mesenchymal secretome, infertility, degenerative medicine, gut-brain axisAbstract
Humans are unable to prevent the ageing process. The secretome is a group of bioactive molecules released by cells that may exert paracrine effects on adjacent cells. Recent research indicates that the cellular secretome of mesenchymal stem cells (MSCs) may be useful in the management of idiopathic male infertility. This narrative review was derived from journal articles retrieved through various search engines, including PubMed, Google Scholar, and EBSCO, which were used to compile the reference list. Subsequently, relevant information and journals were collected and reviewed by the authors. The secretome can be examined from multiple perspectives. It may be linked to morphological, histological, and physiological changes in the male reproductive system associated with ageing. These processes may be improved by incorporating the secretome as an anti-inflammatory, anti-apoptotic, and anti-aging agent. Normal gut–testis microbial cooperation supports overall health. Food intake or illness can disrupt the gut microbiota, triggering a cascade that affects fertility. Dysbiotic conditions increase inflammatory markers and damage the gut epithelium, allowing bacteria and inflammatory cytokines to enter the circulation. The secretome also plays a role in balancing the microbiome within the gut–brain axis, thereby contributing to the prevention of fertility impairment. The presence of the secretome may serve as a modulatory factor for age-related changes in male reproductive function, particularly fertility components. Further investigation through additional related studies and systematic reviews is needed to enhance understanding of the relationship between these variables.
References
1. Aitken RJ. Male reproductive ageing: a radical road to ruin. Human Reproduction [Internet]. 2023 Oct 3 [cited 2025 Nov 2];38(10):1861–71. Available from: https://academic.oup.com/humrep/article/38/10/1861/7241578
2. Kaltsas A, Moustakli E, Zikopoulos A, Georgiou I, Dimitriadis F, Symeonidis EN, et al. Impact of Advanced Paternal Age on Fertility and Risks of Genetic Disorders in Offspring. Genes [Internet]. 2023 Feb 14 [cited 2025 Nov 2];14(2):486. Available from: https://www.mdpi.com/2073-4425/14/2/486
3. Collodel G, Ferretti F, Masini M, Gualtieri G, Moretti E. Influence of age on sperm characteristics evaluated by light and electron microscopies. Sci Rep [Internet]. 2021 Mar 2 [cited 2025 Nov 2];11(1):4989. Available from: https://www.nature.com/articles/s41598-021-84051-w
4. Margiana R, Pilehvar Y, Amalia FL, Lestari SW, Supardi S, I’tishom R. Mesenchymal stem cell secretome: A promising therapeutic strategy for erectile dysfunction? Asian Journal of Urology [Internet]. 2024 Jul [cited 2025 Nov 2];11(3):391–405. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2214388224000146
5. Datrianto D, Budipitojo T, Prihatno S. Secretome improves testosterone and androgen-binding protein production in testicular dysfunction rats induced by cisplatin. J Adv Vet Anim Res [Internet]. 2021 [cited 2024 May 20];8(4):1. Available from: https://www.ejmanager.com/fulltextpdf.php?mno=49307
6. Gunes S, Hekim GNT, Arslan MA, Asci R. Effects of aging on the male reproductive system. J Assist Reprod Genet [Internet]. 2016 Apr [cited 2024 May 20];33(4):441–54. Available from: http://link.springer.com/10.1007/s10815-016-0663-y
7. Monakova A, Sagaradze G, Basalova N, Popov V, Balabanyan V, Efimenko A. Novel Potency Assay for MSC Secretome-Based Treatment of Idiopathic Male Infertility Employed Leydig Cells and Revealed Vascular Endothelial Growth Factor as a Promising Potency Marker. IJMS [Internet]. 2022 Aug 20 [cited 2024 May 20];23(16):9414. Available from: https://www.mdpi.com/1422-0067/23/16/9414
8. Luongo FP, Perez Casasus S, Haxhiu A, Barbarulo F, Scarcella M, Governini L, et al. Exposure to Cumulus Cell Secretome Improves Sperm Function: New Perspectives for Sperm Selection In Vitro. Cells [Internet]. 2023 Sep 25 [cited 2024 May 20];12(19):2349. Available from: https://www.mdpi.com/2073-4409/12/19/2349
9. Simionescu G, Ilie OD, Ciobica A, Doroftei B, Maftei R, Grab D, et al. Mini-Review on the Possible Interconnections between the Gut-Brain Axis and the Infertility-Related Neuropsychiatric Comorbidities. Brain Sciences [Internet]. 2020 Jun 17 [cited 2024 May 20];10(6):384. Available from: https://www.mdpi.com/2076-3425/10/6/384
10. Li T, Shao W, Wang Y, Zhou R, Yun Z, He Y, et al. A two-sample mendelian randomization analysis investigates associations between gut microbiota and infertility. Sci Rep [Internet]. 2023 Jul 15 [cited 2024 May 20];13(1):11426. Available from: https://www.nature.com/articles/s41598-023-38624-6
11. Sagaradze G, Monakova A, Basalova N, Popov V, Balabanyan V, Efimenko A. Regenerative medicine for male infertility: A focus on stem cell niche injury models. Biomedical Journal [Internet]. 2022 Aug [cited 2024 May 20];45(4):607–14. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2319417022000269
12. Serefoglu EC, Kolbasi B, Bulbul MV, Karabulut S, Cakici C, Gundogdu Ozdemir RZ, et al. Therapeutic Effects of Mesenchymal Stem Cell Conditioned Medium in Rat Varicocele Model. World J Mens Health [Internet]. 2025 [cited 2025 Nov 2];43(2):437. Available from: https://wjmh.org/DOIx.php?id=10.5534/wjmh.240059
13. Prihatno SA, Padeta I, Larasati AD, Sundari B, Hidayati A, Fibrianto YH, et al. Effects of secretome on cisplatin-induced testicular dysfunction in rats. Vet World [Internet]. 2018 Sep [cited 2024 May 20];11(9):1349–56. Available from: http://www.veterinaryworld.org/Vol.11/September-2018/24.html
14. Khasanah LM, Fibrianto YH, Budipitojo T, Wijayanto H. MECHANISM OF SPERMATOGENESIS REGENERATION IN TESTICULAR DYFUNCTION RAT USING SECRETOME [Disertation]. [Indonesia]: Universitas Gadjah Mada; 2022.
15. Soleimani MZ, Khorsandi L, Asadi-Fard Y, Rezaei-Tazangi F, Ashtari A. Protective Effects of Adipose Mesenchymal Stem Cell Secretome On Oxidative Stress-Induced Bisphenol-A in Isolated Rat Testes Mitochondria and Sperm Quality. JBRA [Internet]. 2024 [cited 2025 Nov 2]; Available from: https://www.jbra.com.br/trab/pub/download_trabalho.php?fileSource=/var/www/vhosts/jbra.com.br/media/trab/arq_6052&fileName=9-2942%20-%20Protective.pdf&id_trabalho=2513
16. Bader R, Ibrahim JN, Mourad A, Moussa M, Azoury J, Azoury J, et al. Improvement of Human Sperm Vacuolization and DNA Fragmentation Co-Cultured with Adipose-Derived Mesenchymal Stem Cell Secretome: In Vitro Effect. IJSC [Internet]. 2019 Nov 30 [cited 2025 Nov 2];12(3):388–99. Available from: http://www.ijstemcell.com/journal/view.html?doi=10.15283/ijsc19047
17. Yue D, Wang F, Han Y, Xiong C, Yang R. Exosomes derived from umbilical cord mesenchymal stem cells ameliorate male infertility caused by busulfan in vivo and in vitro. Ecotoxicology and Environmental Safety [Internet]. 2024 Mar [cited 2025 Nov 2];272:116063. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0147651324001386
18. Kavaldzhieva K, Mladenov N, Markova M, Belemezova K. Mesenchymal Stem Cell Secretome: Potential Applications in Human Infertility Caused by Hormonal Imbalance, External Damage, or Immune Factors. Biomedicines [Internet]. 2025 Feb 27 [cited 2025 Nov 2];13(3):586. Available from: https://www.mdpi.com/2227-9059/13/3/586
19. Hsiao CH, Ji ATQ, Chang CC, Chien MH, Lee LM, Ho JHC. Mesenchymal stem cells restore the sperm motility from testicular torsion-detorsion injury by regulation of glucose metabolism in sperm. Stem Cell Res Ther [Internet]. 2019 Dec [cited 2025 Nov 2];10(1):270. Available from: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-019-1351-5
20. Araújo B, Silva RC, Domingues S, Salgado AJ, Teixeira FG. Mesenchymal Stem Cell Secretome: A Potential Biopharmaceutical Component to Regenerative Medicine?. In: Haider, K.H. (eds) Handbook of Stem Cell Therapy. Springer, Singapore. 2022;
21. Zhankina R, Baghban N, Askarov M, Saipiyeva D, Ibragimov A, Kadirova B, et al. Mesenchymal stromal/stem cells and their exosomes for restoration of spermatogenesis in non-obstructive azoospermia: a systemic review. Stem Cell Res Ther [Internet]. 2021 Dec [cited 2025 Nov 2];12(1):229. Available from: https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02295-9
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