A recent paper noted that the dramatic enlargement in senescent cells relative to their non-senescent counterparts isn't just a side-effect of the senescent state, but actually necessary for the inflammatory signaling that is characteristic of senescent cells. In delving into some of the mechanisms involve in this link, the researchers demonstrated that preventing enlargement also largely prevented inflammatory signaling. Since this inflammatory signaling is the mechanism by which accumulating senescent cells contribute to age-related disease, this line of research might lead to novel forms of therapy.
We should bear in mind that the activities of senescent cells are useful in the proper context, as is the case for all inflammatory signaling. Senescent cells serve to draw the attention of the immune system to potentially cancerous cells, as well as coordinate regeneration following injury. Suppress the senescent cell inflammation that contributes to aging, and those benefits are suppressed as well. It all runs through the same pathways and regulatory mechanisms. Separating desirable from undesirable activity may never be a practical concern in the context of applying small molecules or gene therapies to change cell behavior. The only alternative is to address the underlying causes that produce undesirable activation of inflammation or undesirable accumulation of senescent cells.
Following up on the question of senescent cell size, we have today's open access paper, which also describes interesting discoveries regarding specific mechanisms that link senescent cell enlargement to inflammatory signaling. The authors of today's paper are a little quick to use the word "rejuvenation", but it makes for an interesting addition to the discussion, including additional molecule targets for those who feel inclined to develop therapies based on preventing cell enlargement as a means to reduce the impact of senescent cells. For my part, I remain inclined to think that selectively destroying senescent cells via senolytic drugs remains a better option. Senolytic treatments can be intermittent, and thus less costly, and also avoid suppression of the necessary functions of senescent cells between treatments.
AP2A1 modulates cell states between senescence and rejuvenation
Aging proceeds with the accumulation of senescent cells in multiple organs. These cells exhibit increased size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. The regulation of cell morphology and migration is closely associated with the state of stress fibers. Stress fibers are actomyosin-based bundles, which are composed mainly of actin filaments cross-linked by α-actinin and non-muscle myosin II. Stress fibers localize between separate cell adhesion sites to generate contractile force on the underlying extracellular matrix - points of anchorage.
The organization of stress fibers is known to be altered in cells undergoing senescence. While the proteome of stress fibers has only been partly investigated, our group recently revealed that those in human fibroblasts are comprised of at least 135 proteins, and 63 of them are upregulated with replicative senescence. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of enlarged stress fibers.
Using human fibroblasts undergoing replicative senescence, we found that the expression level of AP2A1 modulates the extent of the senescence progression, specifically influencing the expression of senescence markers, morphological, and migratory phenotypes, and thickness and turnover of individual stress fibers. Notably, knockdown of AP2A1 reversed senescence-associated phenotypes, exhibiting features of cellular rejuvenation. Similar functions of AP2A1 were identified not only in replicative senescence but also in UV-induced or drug-induced senescence and were found in epithelial cells as well as fibroblasts.
We also showed that AP2A1 plays a role in integrin β1 translocation along the length of stress fibers, a process enhanced in aged fibroblasts to strengthen cell adhesions. These results suggest that senescent cells maintain their large size by reinforcing their effective anchorage through integrin β1 translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin β1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.
View the full article at FightAging
