OK, let’s take a look. Note that the claim about senescent cells being protected from AP in the colon and liver is not from a review article—the citation is to an orginal research article on Nature. They don’t talk about correcting for multiple comparisons, although it’s possible that this was left unstated or is dealt with automatically via Prism, the software they used for analysis. I’ll contact the authors and ask.
This is the relevant figure (extended data figure 3). Red bars are no AP treatment, pink bars are with AP treatment (which ought to kill senescent cells). Eyeballing it, we see fairly consistent equal or higher expression levels across the range of senescence markers in the no AP group, and then this pattern vanishes in the liver and colon with the exception of p21 in the liver, which seems like it’s “trending toward significance” (my words, not theirs). Based on my visual spot-checking, I would have said that the liver and colon really do seem to respond differently to AP than other organs. And that’s a perfectly normal, expected outcome for any drug.
Error bars indicate s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001 (unpaired two-tailed t-tests). Asterisks above individual bars in a denote significant changes to 2-month-old mice; asterisks above brackets denote significant differences between 18-month-old vehicle and AP-treated mice.
In the statistical analysis section, we have:
Prism software was used for statistical analysis and generation of survival, cataract and tumour latency curves… Investigators were blinded to allocation during experiments and outcome assessment, except for rare instances where blinding was not possible.
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.
OK, let’s take a look. Note that the claim about senescent cells being protected from AP in the colon and liver is not from a review article—the citation is to an orginal research article on Nature. They don’t talk about correcting for multiple comparisons, although it’s possible that this was left unstated or is dealt with automatically via Prism, the software they used for analysis. I’ll contact the authors and ask.
This is the relevant figure (extended data figure 3). Red bars are no AP treatment, pink bars are with AP treatment (which ought to kill senescent cells). Eyeballing it, we see fairly consistent equal or higher expression levels across the range of senescence markers in the no AP group, and then this pattern vanishes in the liver and colon with the exception of p21 in the liver, which seems like it’s “trending toward significance” (my words, not theirs). Based on my visual spot-checking, I would have said that the liver and colon really do seem to respond differently to AP than other organs. And that’s a perfectly normal, expected outcome for any drug.
In the statistical analysis section, we have:
Cool, I buy the basic result.
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.