In a recent study, researchers injected rats with mesenchymal stromal cells. They observed improvements in aging-related biomarkers and phenotypes in many organs [1].
The rejuvenating role of MSCs
Mesenchymal stromal cells (MSCs) can be obtained from diverse sources, including bone marrow, adipose tissue, perinatal tissue, and dental tissues [2].
MSCs have been shown to have multiple beneficial effects. Previous research has found that they can “alleviate oxidative stress and inflammatory responses, promote tissue repair, and restore proper immunological functions” [3, 4], stimulate angiogenesis [5], extend murine lifespan and healthspan, and have a protective effect against stem cell and fibroblast aging [6]. MSCs’ safety and efficacy have been shown in Phase I and II clinical trials investigating aging-related frailty [7].
Positive impact on aging biomarkers
This study aimed to comprehensively evaluate the impact of human-derived umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on senescence in rats.
The researchers used ten naturally aged male rats (24 months old) and five young male rats (8 weeks old). They treated them with four weekly tail vein injections of UC-MSCs. The authors stated that they wished to have more animals in the study, but they were limited due to the scarcity of naturally aged animals.
The researchers observed a significant increase in p16, p21, SA-β-gal, and lipofuscin, which are aging-related factors and biomarkers of aging and senescence, in the heart, brain, lung, kidney, liver, spleen, intestinal tissues, and peripheral blood of aged rats. Depending on the tissue, this was observed for some or all of the markers. MSC treatment significantly reduced those markers.
The authors also measured oxidative stress markers. The levels of SOD, an enzyme that plays a role in preventing the toxic effects of free radicals, were decreased in the multiple tested organs and peripheral blood of aged rats. MSC treatment led to a significant increase in SOD levels.
Levels of MDA, a biomarker of lipid oxidative damage, significantly increased in multiple organs, brain tissue, and peripheral blood of aged rats, but MSC treatment resulted in a decrease in MDA.
The third marker, the antioxidant GSH, wasn’t consistent between different organs of aged rats. Still, the MSC treatment always increased its levels in measured tissues (but not always significantly) compared to aged controls.
The next group of measured biomarkers consisted of aging-related biomarkers related to the immune system: an antibody IgG (Immunoglobulin G) and two pro-inflammatory cytokines, IL-1β and IL-6.
The authors observed decreased levels of IgG in the brain, multiple organs, and peripheral blood of old rats compared to young rats. The difference in brain, liver, lungs, kidneys, and peripheral blood was statistically significant, and following MSC treatment, those levels increased.
In the lungs, kidneys, liver, and peripheral blood of aged rats, the researchers observed an increase in IL-1β and IL-6. MSC treatment decreased both of the cytokines in the lungs and kidneys and IL-1β in the liver.
The researchers summarize that there is an increase in aging-related factors, oxidative stress, and chronic inflammation in multiple organs of old rats. However, MSC treatment can significantly ameliorate these aging-related phenotypes.
Rejuvenating organs and the microbiome
Starting with the brain, the researchers investigated changes in two regions: the prefrontal cortex and the hippocampus. Previous research linked aging-related changes in those brain regions “to cognitive deficits, intellectual decline, sleep disorders, and circadian rhythm disruptions” [8].
The study’s authors observed aging-related phenotypes in those regions, for example, a significant decrease in the number of neurons, which was increased following MSC treatment along with improvement in other aging-related phenotypes.
Other organs also suffered from aging-related changes. Compared to young cells, aged heart cells exhibited age-related phenotypes, including accumulation of collagen fibers and increase in cellular size (hypertrophy). MSC treatment helped improve both of them.
The heart, along with the liver, also suffered from an age-related increase in the deposition of fats. Following MSC treatment, those fat depositions decreased in the old rats, suggesting that MSCs have an impact on lipid metabolism.
It is known that aging affects microbiota and that gut diversity in the elderly is lower compared to young people [9]. In this study, the researchers observed aging-related changes in the microbiomes of rats.
MSC treatment of older rats helped to increase microbial diversity and rejuvenate the microbiome towards that of younger animals. The authors suggest that such alterations might have broader effects on other organs through the modulation of amino acid and carbohydrate metabolism.
Rejuvenating the immune system
Aging is associated with the decline of the proper functioning of the immune system in a process known as immunosenescence. One of the manifestations of aging immune systems is a change in different types of immune cells, specifically ”changes in the ratio of naïve T cells and memory T cells, imbalanced CD4 + T cells and CD8 + T cells” [10].
In this study, the researchers observed those and other aging-related phenotype in the aged rats. Those included, reduced CD4 + T/CD8 + T ratio in peripheral blood, disordered structure of spleen, lower number of spleen cells, and higher number of apoptotic spleen cells. MSCs treatment improved those phenotypes in the aged rats.
More comprehensive, but not long-term
While the anti-aging benefits of MSCs were studied previously, the authors emphasize that their study is more comprehensive than the previous research and shows “that MSCs can modulate the entire organism’s aging process and achieve deceleration of aging through reciprocal interactions among different organs and systems.”
However, further research is needed into the molecular mechanisms of MSCs’ anti-aging action. There is also a need to assess such treatment’s long-term effects and possible side effects.
Literature
[1] Wang, L., Deng, Z., Li, Y., Wu, Y., Yao, R., Cao, Y., Wang, M., Zhou, F., Zhu, H., & Kang, H. (2024). Ameliorative effects of mesenchymal stromal cells on senescence associated phenotypes in naturally aged rats. Journal of translational medicine, 22(1), 722.
[2] Galipeau, J., & Sensébé, L. (2018). Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell stem cell, 22(6), 824–833.
[3] He, Y., Chen, D., Yang, L., Hou, Q., Ma, H., & Xu, X. (2018). The therapeutic potential of bone marrow mesenchymal stem cells in premature ovarian failure. Stem cell research & therapy, 9(1), 263.
[4] Wang, L., Li, Y., Xu, M., Deng, Z., Zhao, Y., Yang, M., Liu, Y., Yuan, R., Sun, Y., Zhang, H., Wang, H., Qian, Z., & Kang, H. (2021). Regulation of Inflammatory Cytokine Storms by Mesenchymal Stem Cells. Frontiers in immunology, 12, 726909.
[5] Xiao, X., Xu, M., Yu, H., Wang, L., Li, X., Rak, J., Wang, S., & Zhao, R. C. (2021). Mesenchymal stem cell-derived small extracellular vesicles mitigate oxidative stress-induced senescence in endothelial cells via regulation of miR-146a/Src. Signal transduction and targeted therapy, 6(1), 354.
[6] Dorronsoro, A., Santiago, F. E., Grassi, D., Zhang, T., Lai, R. C., McGowan, S. J., Angelini, L., Lavasani, M., Corbo, L., Lu, A., Brooks, R. W., Garcia-Contreras, M., Stolz, D. B., Amelio, A., Boregowda, S. V., Fallahi, M., Reich, A., Ricordi, C., Phinney, D. G., Huard, J., … Robbins, P. D. (2021). Mesenchymal stem cell-derived extracellular vesicles reduce senescence and extend health span in mouse models of aging. Aging cell, 20(4), e13337.
[7] Zhu, Y., Ge, J., Huang, C., Liu, H., & Jiang, H. (2021). Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics. Theranostics, 11(12), 5675–5685.
[8] Satoh, A., Imai, S. I., & Guarente, L. (2017). The brain, sirtuins, and ageing. Nature reviews. Neuroscience, 18(6), 362–374.
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[10] Goronzy, J. J., & Weyand, C. M. (2013). Understanding immunosenescence to improve responses to vaccines. Nature immunology, 14(5), 428–436.
