New York Times article explains how killing p16-INK4a positive senescent cells can help keep the surrounding cells vigorous.

So here's my question: why is p16-INK4a expressed in most cells other than heart and liver cells? What would happen if we knocked it out everywhere?

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    $\begingroup$ do you have a reference for CDKN2A (p16-INK4a) not being expressed in heart/liver tissues? On GeneCards it looks to me like it has been found to be expressed there. $\endgroup$ – Luke May 2 '12 at 15:58
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    $\begingroup$ That's a good question. The Nature paper referenced in the NYT article says it, but with no citation, and their tissue work backs it up. The GeneCard data does run counter to that, though. I'd add the caveat that the Nature paper is talking about mice, and mice handle senescence differently than humans do. For one thing, they don't turn off their telomerase. $\endgroup$ – Transcriptase May 2 '12 at 21:14

p16-INK4a is a part of a very important checkpoint mechanism. It's the "bad guy" in the context of aging because it induces senescence, and too much senescence leads to aging-related tissue degradation.

But senescence is important. It's one of the responses cells take when something goes wrong-- DNA damage, viral infection, telomere depletion, that sort of thing. Senescent cells have stopped proliferating. We have a word for cells that don't stop proliferating, and that word is "cancer". So, p16-INK4a is a major tumor suppressor. A universal p16-INK4a knockout would have a much harder time shutting down the proliferation of cells that had undergone DNA damage, and would therefore be much more prone to cancer. You'd have very young-looking tissues filled with tumors.

So, the headline question is why INK4a is not expressed in the heart or liver if it's so important. This is speculation on my part, but I think it's because those tissues are especially prone to being damaged by fibrosis, and a build-up of senescent cells would lead to increased fibrosis. Senescence is just one possible response to DNA damage, though. Another is apoptosis. If the senescence-induction pathways aren't active in heart and lung tissue, I'd expect the apoptosis-induction pathways to be pretty active.

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  • $\begingroup$ nice answer; care to elaborate/speculate further on why senescence in favourable over apoptosis in other tissues? Or could the removal of senescent cells simply be an un-selected-for trait (by this I mean that reproduction has generally happened prior to the buildup of senescent cells) $\endgroup$ – Luke May 2 '12 at 16:18
  • $\begingroup$ Yeah, that's an interesting question. I'd say main advantage of senescence in most tissues is that the cell gets to hang around and do its job. If it goes through apoptosis, it's going to need to be replaced. Senescence as a strategy, then, would keep overall proliferation rates lower in the tissue as a whole, which could have upsides, like limiting the potential for errors to creep in. Which one gets selected for in which tissue could definitely be influenced by the balance of those factors compared to reproduction time. $\endgroup$ – Transcriptase May 2 '12 at 16:36

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