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Senolytics may work better on some "zombie" cells than others depending on cell cycle status

Posted by coastaldiego in Longevity & Anti-Aging - 1 points, 4 comments.

https://www.eurekalert.org/news-releases/1099324

New paper in Aging-US looking at how senescent cells in different cell cycle states respond to senolytic drugs. Basically the researchers found that whether a zombie cell gets killed off depends a lot on where it sits in the cell cycle when you hit it with the senolytic. Some senescent cells just shrug it off.

This one actually feels useful to me because most of the senolytic stuff i've seen treats "senescent cells" like one homogeneous thing. They're not. If a big chunk of the cells you're trying to clear are resistant based on cell cycle state, that changes how you'd think about dosing and timing. Fwiw this lines up with why combo approaches keep performing better than single drugs in the preclinical data 🕰️

Anyone following the senolytic space closely? Curious if anyone's seen follow up work on whether timing senolytics around circadian rhythm or fasting windows actually matters, or if that's just wishful thinking at this point.

Comments

  • grace_squats: For what it is worth, I've been digging into the cell cycle heterogeneity angle for a while now and I think you're onto something the preclinical folks have been hinting at but rarely spelling out. From my own digging, the most stubborn senescent populations seem to be the quiescent ones, the ones sitting in G0, not the actively cycling ones. That actually fits with why senolytics like D+Q work intermittently. D triggers apoptosis more in cells that are primed for it, and a cell parked in G0 ju
  • coastaldiego: Yeah the G0 angle makes a lot of sense actually, thats kinda what i was getting at but you explained it better. If a chunk of the target cells are just sitting there in quiescence not primed for apoptosis at all, intermittent dosing would logically miss them some percentage of the time. Fwiw that makes me wonder if there's any work on whether you could push quiescent senescent cells back into cycle before hitting them with the senolytic. Like is there a priming step people have tried?
  • fasted_scientist: Quiescent G0 cells being harder to clear actually tracks with what I've seen people report anecdotally, some feel a response early in a senolytic protocol then nothing. Could be the cycling pool gets nuked first and you're left with the stubborn lot. I'd want to see them pair D+Q with something that pushes G0 cells back into cycle before treating. Do you know if anyone's tried that combo in the preclinical literature, or is it still all theory at this point?
  • coastaldiego: Yeah the cycling pool getting cleared first thing actually makes a lot of sense, kinda like how antibiotics hit the active bacteria first and leave persisters behind. Hadn't thought about it that way but it fits. On your question, i've seen a few papers mention senomorphic approaches that basically try to push senescent cells out of that G0 stuck state before hitting them, but honestly most of it is still pretty preclinical. Dasatinib + quercetin is the usual combo people talk about. Some resea

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