I agree with you that we are probably seeing AP being selectively broken down by the liver and colon. It therefore fails to reach the normal senescent cells in these tissues, and does not trigger their destruction. This causes a higher level of senescent cells to remain in these tissues after AP administration stops. If those liver and colon senescent cells can go on to trigger senescence in neighboring cells, that may explain why a temporary administration of senolytics fails to provide lasting protection against aging, despite the accumulation of senescent cells being a root cause of aging.
Under this hypothesis, senescent cells are a root cause of aging, as they trigger conversion of other cells to senescence—as suggested in the ODE model paper you linked—but this root cause can only be controlled in a lasting way by ensuring that senolytics eliminates senescent cells in a non-tissue selective manner. We can’t leave any pockets of them hanging out in the liver and colon, for example, or they’ll start spreading senescence to other nearby organs again as soon as you stop senolytics. Or alternatively, they might simply leave the mouse with an aged liver and colon, which might be enough to kill the mouse consistently, so that there’s no real lifespan benefit.
Edit: Sorry if I’m responding to a rebuttal you changed your mind about :)
Edit: Sorry if I’m responding to a rebuttal you changed your mind about :)
Yeah, sorry, I went back and looked at the context of the earlier comments and was like “oh, right, I see what the claim is” and then updated my comment.
I agree with you that we are probably seeing AP being selectively broken down by the liver and colon. It therefore fails to reach the normal senescent cells in these tissues, and does not trigger their destruction. This causes a higher level of senescent cells to remain in these tissues after AP administration stops. If those liver and colon senescent cells can go on to trigger senescence in neighboring cells, that may explain why a temporary administration of senolytics fails to provide lasting protection against aging, despite the accumulation of senescent cells being a root cause of aging.
Under this hypothesis, senescent cells are a root cause of aging, as they trigger conversion of other cells to senescence—as suggested in the ODE model paper you linked—but this root cause can only be controlled in a lasting way by ensuring that senolytics eliminates senescent cells in a non-tissue selective manner. We can’t leave any pockets of them hanging out in the liver and colon, for example, or they’ll start spreading senescence to other nearby organs again as soon as you stop senolytics. Or alternatively, they might simply leave the mouse with an aged liver and colon, which might be enough to kill the mouse consistently, so that there’s no real lifespan benefit.
Edit: Sorry if I’m responding to a rebuttal you changed your mind about :)
Yeah, sorry, I went back and looked at the context of the earlier comments and was like “oh, right, I see what the claim is” and then updated my comment.