Hormonal
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.
This study highlights a critical nuance in longevity pharmacology: NRF-2 activation must be carefully titrated. While low-level activation (via low-dose lithium) extends lifespan, excessive activation (mimicking strong stress responses) can shorten it. This suggests that future anti-aging drugs targeting NRF-2 must be precisely dosed to stay within the 'hormetic zone' of benefit, avoiding the toxic zone of over-activation.
These results suggest that the level of activation of CncC that maximizes extension of lifespan is considerably lower than that which maximizes protection against toxic doses of lithium and paraquat... stronger induction is detrimental for lifespan.
Why this rating
Supported by genetic interaction studies (Keap1 deletion + Lithium).
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
- 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.Strong
- Low-dose lithium supplementation (1-25 mM in Drosophila) extends median and maximum lifespan and healthspan independently of sex and genetic background.Good
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