Editing Openai/692df380-fd64-8008-b788-94e93ef3ff89 (section)

==== 2. Mechanistic rationale for health and longevity ====

The KMO branch of the kynurenine pathway is attractive for longevity for several interconnected reasons:
# Neurotoxicity and neurodegeneration 3-HK and QUIN generate reactive oxygen species and promote excitotoxic neuronal death; KYNA is neuroprotective in many models. In aging and neurodegenerative disease, the balance shifts toward 3-HK/QUIN. PMC<ref>{{cite web|title=PMC|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC8747024/|publisher=pmc.ncbi.nlm.nih.gov|access-date=2025-12-28}}</ref>
# Inflammation and organ injury KMO is upregulated by inflammatory cytokines (e.g., IFN-γ) and is implicated in acute pancreatitis, sepsis, and multiple organ dysfunction, where higher 3-HK relates to worse outcomes. MDPI<ref>{{cite web|title=MDPI|url=https://www.mdpi.com/2073-4409/13/15/1259|publisher=mdpi.com|access-date=2025-12-28}}</ref>
# Aging biology / frailty Multiple human cohorts link high KYN, high KYN/TRP ratio, and high downstream metabolites (including 3-HK) with frailty, disability, and mortality in older adults. ScienceDirect<ref>{{cite web|title=ScienceDirect|url=https://www.sciencedirect.com/science/article/abs/pii/S0531556519305704|publisher=sciencedirect.com|access-date=2025-12-28}}</ref>
# Geroscience angle: modulating the kynurenine pathway extends lifespan in invertebrates Reducing flux through various KP enzymes (TDO, KYNU, HAAO) extends lifespan and delays functional decline in C. elegans, with ~30% lifespan extension reported for haao-1 knockdown and similar effects for tdo-2 / kynu-1 downregulation. Nature<ref>{{cite web|title=Nature|url=https://www.nature.com/articles/s41467-023-43527-1|publisher=nature.com|access-date=2025-12-28}}</ref> This demonstrates that some dampening of KP activity can be pro-longevity, even though KMO itself has not yet been directly tied to lifespan extension in wild-type mammals.

The logical but unproven longevity hypothesis is that partial, well-timed KMO inhibition might:
* Reduce chronic neuroinflammation and excitotoxicity
* Mitigate inflammaging-driven organ damage
* Possibly improve neuromuscular aging by lowering toxic KP metabolites

All of that is still speculative at the human lifespan level.