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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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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