Hormonal
Lithium extends lifespan and stress resistance by inhibiting GSK-3 (Shaggy in flies), which subsequently activates the transcription factor NRF-2 (CncC), leading to hormetic stress resistance.
The longevity benefits of lithium are mechanistically linked to the inhibition of GSK-3 and the subsequent activation of NRF-2. This pathway enhances cellular stress resistance (hormesis) without requiring autophagy. This suggests that GSK-3 inhibitors or NRF-2 activators could be viable anti-aging strategies, provided they are dosed to avoid over-activation of NRF-2, which can be detrimental to lifespan.
The life-extending mechanism involves the inhibition of glycogen synthase kinase-3 (GSK-3) and activation of the transcription factor nuclear factor erythroid 2-related factor (NRF-2)... Genetic or pharmacological inhibition of GSK-3 activates NRF-2... NRF-2 activation is required for the longevity effects of lithium
Why this rating
Genetic epistasis experiments (RNAi knockdowns, overexpression) confirm the causal pathway.
Source
Lithium Promotes Longevity through GSK3/NRF2-Dependent Hormesis
Jorge Iván Castillo-Quan et al. · Cell Reports · 2016
DOI 10.1016/j.celrep.2016.03.041
More from this paper
- Low-dose lithium supplementation (1-25 mM in Drosophila) extends median and maximum lifespan and healthspan independently of sex and genetic background.Good
- There is a hormetic curve for NRF-2 activation: low-level activation extends lifespan, while high-level activation (e.g., via Keap1 deletion combined with lithium) shortens lifespan or provides no additional longevity benefit, though it increases stress resistance.Good
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