Note that this is a preprint.
It has not yet been peer reviewed by a journal.
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Abstract
Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2-arrested senescent cells feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.
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Not sure this is the first data demonstrating that different senescent cell types react differently to various senolytics.
That was evident in DQ trials where senescence in adipose and endothelial tissues responded to that combination and other tissues did not.
It may be that this study on Navitoclax is very specific and more definitive but this aspect of senescence has been known for a while.
Good to see more research in this area.
Not sure Iād be prepared to try Navitoclax (ABT263) but I would like to try FOXO4-DRI
Both navitoclax and ABT-737 were efficient senolytics in multiple preclinical models. Nevertheless, their translation into clinic as senolytics is impaired by their reported toxicity towards platelets and neutrophils due to the targeting of BCL-xL and BCL-2, respectively, leading to thrombocytopenia and neutropenia
Reading a lot of posts and publications leaves me with the question what will be the advisable order to deal with the process of aging and accumulating senescent cells of various types for someone with a blank history op sirolimus senolytics etc.
I guess when one is young like 25-35 the answer might be improve on healthy habits followed maybe by intermittent sirolimus at low to moderate dose. (assuming generally healthy and not overweight senolitics make no sense?)
Medium age or having health issues or injuries may have caused increase in senescent cells.
should we try to provide cells with more energy like aakg or something else to move some of those cells to the next phase and resume health. After some time of that approach (how long) would it be wise to move on to using senolytic combinations. Or should we start sirolimus before.
Same questions for someone of 70-80 who has not done any thing of this all but is reaonably healthy, with a bmi of 20-22 but being a couch potato. And with probably a lot of senescent cells.
???
what will be the advisable order to deal with the process of aging and accumulating senescent cells
I agree that present age of the person is a very important parameter for the chosen health span or life span intervention.
With respect to senescence a healthy disease free person may not need to address senescence until later in life, say 50. As you noted someone with health issues may need to start earlier or more intensively. That basic concept probably applies to other types of interventions, while some interventions may work best started earlier in life.
That could become a nice project for some AI guru to write some prompts for or dev a cool app.
