Oct 13, 2025 05:32 PM
https://erictopol.substack.com/p/a-long-...ty-mystery
EXCERPT: I’ve been following the naked mole rat story for decades and it was exciting to see this new report which helps explain what’s behind this legendary animal’s unique healthspan and lifespan. Many other mechanisms have been proposed over the years, but none have had such comprehensive, state-of-the-art assessment in multiple species and a form of independent replication. The convergence of the finding underpinning organismal longevity with the discovery of the cGAS pathway takes the interest to a higher level, no less for potential clinical applications
However, it’s much trickier to translate this to a way to promote healthspan and longevity in humans. The naked mole rat lives underground and has a radically different environmental exposure versus humans. It could theoretically tolerate the inability to sense foreign DNA of pathogens and be so well suited for prioritizing DNA repair and suppressing inflammation.
If we could do a bridge recombination cGAS genome edit of the 4 amino acids, as Patrick Hsu quipped on X, (below) what might be in for? Serious infections? Autoimmune diseases? The very delicate balance of the ongoing clinical trials—to promote or block cGAS-STING—tells us about this tradeoff, and what could turn out to be a very narrow therapeutic window. (MORE - missing details)
EXCERPT: I’ve been following the naked mole rat story for decades and it was exciting to see this new report which helps explain what’s behind this legendary animal’s unique healthspan and lifespan. Many other mechanisms have been proposed over the years, but none have had such comprehensive, state-of-the-art assessment in multiple species and a form of independent replication. The convergence of the finding underpinning organismal longevity with the discovery of the cGAS pathway takes the interest to a higher level, no less for potential clinical applications
However, it’s much trickier to translate this to a way to promote healthspan and longevity in humans. The naked mole rat lives underground and has a radically different environmental exposure versus humans. It could theoretically tolerate the inability to sense foreign DNA of pathogens and be so well suited for prioritizing DNA repair and suppressing inflammation.
If we could do a bridge recombination cGAS genome edit of the 4 amino acids, as Patrick Hsu quipped on X, (below) what might be in for? Serious infections? Autoimmune diseases? The very delicate balance of the ongoing clinical trials—to promote or block cGAS-STING—tells us about this tradeoff, and what could turn out to be a very narrow therapeutic window. (MORE - missing details)