Exercise may be able to remove senescent cells only if acute inflammation is allowed to occur, according to a new study published in Aging.
Inflammation and senescence
Inflammation is known to be a critical part of aging, and its chronic accumulation has been labeled as a hallmark of aging: inflammaging. The SASP, the cocktail of compounds that senescent cells emit, is a key contributor to inflammaging and drives other cells senescent.
However, there is published evidence that some inflammation works in the other direction. Senescent cells can be removed by immune cells known as macrophages [1], and immune system-based therapies have been investigated for therapeutic use [2].
These researchers have previously reported that p16INK4a, a well-known marker of cellular senescence, decreases in young men 24 hours after high-intensity exercise [3]. Moderate exercise, however, did not have the same effect. They hypothesized that even though chronic inflammation encourages senescence, acute inflammation that results in CD11b-positive immune cells entering tissues discourages it.
Stimulating inflammation with exercise
The researchers recruited a dozen young men (average age of 22 years old) with no history of smoking or drug use to test this hypothesis. Half of the participants were given 400 milligrams of the anti-inflammatory medication ibuprofen, and half were given placebo. The participants cycled at high intensity for 20 seconds and took a 20-second rest for 15 sets. Their muscles were biopsied before exercise and then again 3 and 24 hours afterwards.
After 3 hours, mRNA expression of p16INK4a was decreased in both the ibuprofen and placebo groups, although significantly more in the placebo group, suggesting that the anti-inflammatory effect was also preventing the clearance of senescent cells. This trend continued at the 24-hour mark. However, not all participants responded in the same way, and some participants had significantly more p16INK4a at the beginning of the experiment than others.
Interestingly, CD11b was also decreased by exercise, at a similar rate to p16INK4a. These results were also attenuated by ibuprofen administration. CD11b was found to be directly related to p16INK4a expression in the tissue. There was also a trend towards greater expression of the DNA damage marker γ-H2AX 3 hours afterwards in the ibuprofen group and less expression 24 hours afterwards, but these were not statistically significant.
A limited but possibly valuable study
The researchers note that the total amount of exercise needed to get the observed effects was very low and conducted in short bursts: 10 minutes of exercise resulted in effects that diminished over the course of a full day.
However, this experiment was conducted solely on a relatively small cohort of young men, so it is unknown if these results are applicable to older people or women. There was no follow-up to determine long-term effects. The markers CD11b, p16INK4a, and γ-H2AX were the only metrics used; other senescence biomarkers were not used. A significant amount of future work will need to be conducted to determine if these results apply to other populations and if these findings can be used to develop therapeutic treatments or call for a reduction in anti-inflammatory use with exercise.
Literature
[1] Kay, M. M. (1975). Mechanism of removal of senescent cells by human macrophages in situ. Proceedings of the National Academy of Sciences, 72(9), 3521-3525.
[2] Prata, L. G. L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018, December). Senescent cell clearance by the immune system: Emerging therapeutic opportunities. In Seminars in immunology (Vol. 40, p. 101275). Academic Press.
[3] Jean, W. H., Hsieh, Y. W., Lai, L. F., Dewi, L., Liao, Y. C., Ye, M., … & Kuo, C. H. (2023). Senolytic effect of high intensity interval exercise on human skeletal muscle. Aging (Albany NY), 15(3), 765.
