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

==== 3. Preclinical evidence: health / longevity-relevant domains ====

===== 3.1 Neurodegeneration and brain aging =====

Huntington’s disease (HD) models
* In HD transgenic mice, chronic oral JM6 (peripheral KMO inhibitor) increased brain KYNA, decreased extracellular glutamate and microglial activation, preserved synapses, and extended lifespan and improved motor performance vs. control. PMC<ref>{{cite web|title=PMC|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC3118409/|publisher=pmc.ncbi.nlm.nih.gov|access-date=2025-12-28}}</ref>
* In a Drosophila HD model, both genetic and pharmacologic inhibition of KMO (e.g., Ro 61-8048, UPF 648) reduced neurodegeneration and improved survival and motor function. Nature<ref>{{cite web|title=Nature|url=https://www.nature.com/articles/s42003-019-0520-5|publisher=nature.com|access-date=2025-12-28}}</ref>

Note: the lifespan extension was demonstrated in disease models, not normal aging mice.

Alzheimer’s disease and synaptic protection
* JM6 treatment reduced synapse loss and microglial activation in an AD mouse model while elevating KYNA, interpreted as KMO-mediated protection from excitotoxicity. PMC<ref>{{cite web|title=PMC|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC3118409/|publisher=pmc.ncbi.nlm.nih.gov|access-date=2025-12-28}}</ref>

Ischemia / stroke / surgical brain injury
* Ro 61-8048 reduced dystonia severity in rodent models and showed neuroprotection in ischemia models (reduced neuronal damage and seizures) via kynurenine pathway modulation. ScienceDirect<ref>{{cite web|title=ScienceDirect|url=https://www.sciencedirect.com/science/article/abs/pii/S0014299908002379|publisher=sciencedirect.com|access-date=2025-12-28}}</ref>
* In a mouse stroke model, KMO inhibition with Ro 61-8048 (40 mg/kg/day) immediately post-stroke reduced infarct volume and improved outcomes in preliminary work. Circulation Research<ref>{{cite web|title=Circulation Research|url=https://www.ahajournals.org/doi/10.1161/str.54.suppl_1.TMP113|publisher=Circulation Research|access-date=2025-12-28}}</ref>
* In surgical brain injury models, Ro 61-8048 increased KYNA, reduced QUIN, apoptosis markers, and improved histologic outcomes; these effects were reversed by a KAT II inhibitor, confirming mechanism. PubMed<ref>{{cite web|title=PubMed|url=https://pubmed.ncbi.nlm.nih.gov/31257634/|publisher=pubmed.ncbi.nlm.nih.gov|access-date=2025-12-28}}</ref>

Takeaway (neuro):
KMO inhibition is consistently neuroprotective across HD, AD, ischemia, surgical brain injury, and other excitotoxic/oxidative models. It improves survival in HD and some fly models; it does not yet have evidence that it extends normal mammalian lifespan.

===== 3.2 Systemic inflammation, organ injury and frailty =====
* Reviews on pancreatitis and acute inflammatory conditions note that higher KMO activity and 3-HK correlate with greater organ dysfunction and worse outcomes, and that KMO inhibition reduces tissue injury, oxidative stress, and inflammatory damage in animal models (e.g., pancreatitis, sepsis). 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>
* Kynurenine pathway reviews in aging humans show that higher KYN/TRP and downstream metabolites (3-HK, 3-HAA, QUIN) associate with sarcopenia, frailty, and functional decline. Interventions that normalize KP (not necessarily KMO inhibition) are proposed as a geroscience target but remain untested in RCTs. 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>

Takeaway (systemic):
Preclinical data suggest KMO overactivation is harmful in acute inflammatory settings and that inhibition is organ-protective. Translational data in humans are still observational and pathway-level, not KMO-drug–specific.

===== 3.3 Aging, neuromuscular function, and geroscience-specific data =====
* In a chronic inflammation/aging mouse model, elevated neurotoxic kynurenines (3-HK, QUIN) were shown to mediate neuromuscular dysfunction; treating motor neurons with these metabolites induced neurite degeneration. JCI Insight<ref>{{cite web|title=JCI Insight|url=https://insight.jci.org/articles/view/136091|publisher=JCI Insight|access-date=2025-12-28}}</ref>
* A 2025 review argues that age-related KP dysregulation—shifting toward the KMO branch—may be a driver of habituation and learning deficits with aging. MDPI<ref>{{cite web|title=MDPI|url=https://www.mdpi.com/2073-4409/14/22/1786|publisher=mdpi.com|access-date=2025-12-28}}</ref>
* In C. elegans, downregulation of several KP enzymes (TDO, KYNU, HAAO) extends lifespan and improves late-life function; the common theme is reduced production of downstream oxidative/excitotoxic metabolites. 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>

But: there is no direct demonstration that KMO inhibition in otherwise healthy mammals extends lifespan or compresses morbidity.