Agreed on the general point that having an overall blueprint is sensible, and that any particular list of targets implies an underlying model.
Note the inclusion of senescent cells. Today, it is clear that senescent cells are not a root cause of aging, since they turn over on a timescale of days to weeks. Senescent cells are an extraneous target. Furthermore, since senescent cell counts do increase with age, there must also be some root cause upstream of that increase—and it seems unlikely to be any of the other items on the original SENS list. Some root cause is missing. If we attempted to address aging by removing senescent cells (via senolytics), whatever root cause induces the increase in senescent cells in the first place would presumably continue to accumulate, requiring ever-larger doses of senolytics until the senolytic dosage itself approached toxicity—along with whatever other problems the root cause induced.
I think this paper ends up supporting this conclusion, but the reasoning as summarized here is wrong. That they turn over on a timescale of days to weeks is immaterial; the core reason to be suspicious of senolytics as actual cure is that this paper finds that the production rate is linearly increasing with age and the removal rate doesn’t keep up. (In their best-fit model, the removal rate just depends on the fraction of senolytic cells.) Under that model, if you take senolytics and clear out all of your senescent cells, the removal rate bounces back, but the production rate is steadily increasing.
You wouldn’t have this result for different models—if, for example, the production rate didn’t depend on age and the removal rate did. You would still see senescent cells turning over on a timescale of days to weeks, but you would be able to use senolytics to replace the natural removal process, and that would be sustainable at steady state.
Agreed on the general point that having an overall blueprint is sensible, and that any particular list of targets implies an underlying model.
I think this paper ends up supporting this conclusion, but the reasoning as summarized here is wrong. That they turn over on a timescale of days to weeks is immaterial; the core reason to be suspicious of senolytics as actual cure is that this paper finds that the production rate is linearly increasing with age and the removal rate doesn’t keep up. (In their best-fit model, the removal rate just depends on the fraction of senolytic cells.) Under that model, if you take senolytics and clear out all of your senescent cells, the removal rate bounces back, but the production rate is steadily increasing.
You wouldn’t have this result for different models—if, for example, the production rate didn’t depend on age and the removal rate did. You would still see senescent cells turning over on a timescale of days to weeks, but you would be able to use senolytics to replace the natural removal process, and that would be sustainable at steady state.
Great point, and nice catch.