The life-extension-skeptical theory I find most credible is "there is no conserved metabolic pathway governing lifespan that can be altered without serious harm to the organism. Aging is just overall damage/entropy; there is no "master switch" regulating its rate."
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It looks like the effect of CR on lifespan diminishes in larger organisms. In rhesus monkeys, CR doesn't seem to increase median lifespan, though it does improve other health outcomes.
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Replying to @diachronist
By "larger" I mean like monkeys rather than mice. Larger species tend to be longer-lived. When a change (like growth hormone deficiency) is known to extend life in multiple species, the effect size is larger in worms & flies than in mice, and probably smaller still in monkeys.
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Therefore, a reasonable concern about any life-extending intervention is whether the effects will "fade out" to nothing by the time you get to humans. This is why I'm not very excited by small life-extending effect sizes in mice, even if well-replicated.
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