Mouse on wheel
Researchers publishing in Aging have found a molecule linking exercise to the inhibition of cellular senescence, one of the hallmarks of aging.
Exercise against senescence
We recently reported on a team of researchers looking to protect against chronic obstructive pulmonary disease (COPD) by focusing on possible molecular protections. These researchers have the same target, investigating aging of the lungs, but their target is quite different: this research builds upon previous work demonstrating how senescence and the SASP are connected to this and other lung diseases, such as emphysema [1], noting that fighting senescence appears to mitigate this disease in a mouse model [2].
Exercise, among its many benefits, has been found to fight against COPD [3] and reduce cellular senescence [4]; however, previous work has not discovered the molecular underpinnings of why. These researchers searched for a connection, looking for the exercise-related factor that impedes senescence.
Finding the key protein
The researchers began by cultivating mouse embryonic fibroblasts (MEFs) in either a control medium or a conditioned medium rich with the factors of C2C12 cells, a line of immortalized mouse muscle cells. The cells grown in C2C12-CM performed much better than the control group, having reduced amounts of senescence-related factors, such as SA-β-gal and p16INK4a, along with significantly more robust cellular division.
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Out of 841 candidate proteins in C2C12-CM, 62 had been specifically identified as extracellular factors. Narrowing it down to proteins that had been previously found both to inhibit senescence and to be related to exercise, the researchers found only one that satisfies both criteria: pigment epithelium-derived factor (PEDF) [5, 6].
The researchers tested its effects by comparing cells that had been cultured in C2C12-CM to a group that had been cultured in that medium alongside an antibody against PEDF. The anti-PEDF group had increased amounts of key senescence factors.
Then, the researchers cultured cells in either a control medium or a medium containing recombinant PEDF. Senescence markers in the PEDF group were, as expected, significantly diminished compared to the control group. Looking into the MEFs themselves, the researchers could not recapitulate previous research showing PEDF’s effects on signaling pathways [7]; instead, they found that it reduces reactive oxygen species (ROS) in these cells.
PEDF has positive effects on mice
The researchers then turned to mice, conducting an 8-week experiment in which some mice had running wheels to use while the control group did not. The exercising mice had increased levels of PEDF throughout their bodies and fewer senescence-related factors. mRNA levels of inflammatory cytokines were also decreased in the exercising group.
The researchers then bypassed exercise entirely, injecting recombinant PEDF into mice for 4 weeks. While the effects were not as profound as in the 8-week exercise experiment, PEDF was found to decrease some senescence markers in lung tissues. In another experiment in which 6-month-old mice were subjected to a chemical that causes emphysema, the PEDF-administered group had less markers of emphysema and senescence; the lung collapses that had occurred to the control group had significantly less occurrence in the PEDF group.
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PEDF’s molecular effects were found to be related to the interaction of the microRNA miR-127, which promotes senesence, and BCL-6, a protein that is negatively associated with senescence.
These results offer hope in two ways: they show a likely reason why exercise is beneficial in people with long-term lung disease, and they show the potential of PEDF as a potential drug, particularly for people who are unable to exercise. Of course, these results were in mice, and further work will need to be done to determine if direct PEDF administration is safe for humans.
Literature
[1] Tsuji, T., Aoshiba, K., & Nagai, A. (2006). Alveolar cell senescence in patients with pulmonary emphysema. American journal of respiratory and critical care medicine, 174(8), 886-893.
[2] Mikawa, R., Sato, T., Suzuki, Y., Baskoro, H., Kawaguchi, K., & Sugimoto, M. (2020). p19Arf exacerbates cigarette smoke-induced pulmonary dysfunction. Biomolecules, 10(3), 462.
[3] Amin, S., Abrazado, M., Quinn, M., Storer, T. W., Tseng, C. H., & Cooper, C. B. (2014). A controlled study of community-based exercise training in patients with moderate COPD. BMC pulmonary medicine, 14, 1-8.
[4] Chen, X. K., Yi, Z. N., Wong, G. T. C., Hasan, K. M. M., Kwan, J. S. K., Ma, A. C. H., & Chang, R. C. C. (2021). Is exercise a senolytic medicine? A systematic review. Aging cell, 20(1), e13294.
[5] Norheim, F., Raastad, T., Thiede, B., Rustan, A. C., Drevon, C. A., & Haugen, F. (2011). Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. American Journal of Physiology-Endocrinology and Metabolism, 301(5), E1013-E1021.
[6] Cao, Y., Yang, T., Gu, C., & Yi, D. (2013). Pigment epithelium‐derived factor delays cellular senescence of human mesenchymal stem cells in vitro by reducing oxidative stress. Cell biology international, 37(4), 305-313.
[7] Niyogi, S., Ghosh, M., Adak, M., & Chakrabarti, P. (2019). PEDF promotes nuclear degradation of ATGL through COP1. Biochemical and biophysical research communications, 512(4), 806-811.
