I’ve been commenting in various groups (including here) for a long time on why I don’t think aging is fundamentally programmed, even though gene regulation clearly strongly influences how aging progresses.
I recently wrote a longer piece that lays out this argument in more detail, including why cellular reprogramming alone cannot address all age-related damage. I’m posting it here in case it’s of interest.
This debate has been happening on twitter recently. I therefore asked three LLMs for a definition of programmed aging and posted the results here:
As people probably know Olafur and I disagree about these issues.
I think Aging is fundamentally programmed as part of an aging and development process driven by nuclear acetylation levels which are driven mainly by mitochondrial citrate export.
This is a link through to the discussion on twitter/x
Just to clarify for readers: the article isn’t arguing that gene regulation (including cellular reprogramming) is not important, but that regulatory explanations alone cannot account for accumulated non-cellular damage, which in turn places hard limits on what reprogramming can fix.
Thanks mate. I’ll read more carefully to address the points you make later. For now I’m more interested in the points you don’t make. To wit, you spend a lot of energy arguing against certain interpretations of programmed aging, but as an alternative you only hint at some nebulous “damage” (yes, this is a common term, and I hate it for imprecision). You’re clear that this refers to some subset of ongoing stochastic changes. Which ones (you refer to ECM changes, but as one in many), and why do you think they are sufficient to explain the phenomenon of aging?
You seem to be arguing some combination of
As to the first point, I’m inclined to agree that tissue level matrix regulation is central to aging. I’m skeptical that it’s stochastic in nature, for two reasons. First, in general, the repeated failure of all attempts to modify aging by preventing various forms of stochastic changes, from antioxidants to anti-crosslinking agents. Second, the fact that despite there being a host of identified proteins composing the ECM, no progeroid syndrome is associated with mutations of them, AFAIK. Surely some of the defective matrices would be more prone to “damage”?
The second point is surely not what you meant to argue, and just my misunderstanding the text. After all, different animals’ matrices change at different rates, so either the rate of accumulation of “damage” or the rate of its clearance is under genetic control. Could you elaborate on the meaning of paragraph 3, especially, in this context?