A team of scientists has examined how younger and older mice heal from wounds and found that more robust senescent cell activation in younger animals helps them heal faster.
A double-edged sword
Multiple experiments have found that senescent cells and proper wound healing are intrinsically linked. Zebrafish are well-known to completely regenerate tissue, but an experiment found that the blanket removal of senescent cells impairs this ability [1]. Removing senescent cells from 2-month-old mice impaired their wound healing as well [2].
However, it is well-known that older people heal slower from wounds while having more cellular senescence throughout the body. These researchers decided to take a closer look at this phenomenon at the cellular level.
When young people have more senescent cells
In the first experiment, the researchers cut one-centimeter wounds through the back fat of 2-month-old and 24-month-old mice, which were given painkillers and kept from infection. Unsurprisingly, the wounds of the older mice healed much slower than those of the younger mice; by week 18, the wounds of the younger mice had fully closed, while it took the older mice 24 days to heal.
This was linked to the transient activation of senescent cells. Before the wound, the aged mice had more senescent cells in the area than the younger mice did, as measured by the two well-known biomarkers p16 and SA-β-gal; a week after wounding, however, only the younger mice exhibited sharp upregulations of both of these biomarkers, and this was confirmed by an examination of p16 mRNA gene expression. Another senescence-associated biomarker, p21, was upregulated only in the young mice two weeks after wounding, which was also confirmed by an mRNA analysis.
The SASP had similar temporary changes. In the younger mice, the increase in senescent cells within a week was matched by transient increases in well-known inflammatory factors, including tumor necrosis factor (TNF) and IL-6, along with factors that remodel the extracellular matrix. In the aged mice, however, the increase in IL-6 was prolonged compared to the young mice, the matrix-remodeling factor MMP8 was also elevated for longer, and many of the other factors were not significantly elevated at all.
Going senescent for a reason
Looking closely at the cells at the wound site, the researchers isolated a “defined senescent” population. These were cells that had upregulated p16 and p21 levels and did not express the proliferation marker Mki67. Most of these cells were fibroblasts, although other immune and tissue cells were present in this population as well. The authors described the fibroblasts as having a ‘transcriptionally active program’ that led to upregulated SASP factors.
Rather than inflammation, most of these upregulated factors were related to matrix regulation and growth, which clearly play significant roles in wound healing. These findings were corrobrated with human data: a public dataset of RNA sequencing data derived from younger people’s wounds found similar upregulations in ECM remodeling and deposition.
Unsurprisingly, these upregulated factors were less present in older animals. The older mice had a less robust response at the cellular level; their senescent cells were less heterogenous. Unlike the younger mice, they were more prone to expressing inflammatory factors as part of the SASP, and there was less activation of matrix-deposition factors. The older cells’ signaling, according to the authors, suggests “a dysfunctional, stressed state rather than a reparative one”.
In sum, young senescent wound fibroblasts mount a prorepair chemokine and ECM-remodeling program and broadcast it to their neighbors, whereas aged senescent wound fibroblasts lose that reparative signaling and instead exhibit proteotoxic/inflammatory features that fail to promote efficient healing.
Just as there is a difference between acute inflammation and the chronic inflammation known as inflammaging, this study’s results show a clear difference between transient and permanent senescence. A “senescent cell” is simply one that no longer divides, and there is obviously a distinction between cells that become activated to become senescent to perform a specific task and cells that have been gradually driven senescent through aging. Promoting the former while eliminating the latter is a difficult but necessary job in dealing with this aspect of aging.
Literature
[1] Da Silva‐Álvarez, S., Guerra‐Varela, J., Sobrido‐Cameán, D., Quelle, A., Barreiro‐Iglesias, A., Sánchez, L., & Collado, M. (2020). Cell senescence contributes to tissue regeneration in zebrafish. Aging cell, 19(1), e13052.
[2] Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., … & Campisi, J. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733.
View the article at lifespan.io
