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J-147

J147 · Abrexa J-147

C
Animal replicated
Research chemicalSmall MoleculeNootropicATP Synthase Modulator
RouteOralGray-market only
C
Evidence grade: Animal replicated

Effect demonstrated in multiple animal studies; human data sparse or extrapolated. Grades summarize evidence quality, not whether a compound is appropriate, legal, or risk-free.

At a glance
What it is
Curcumin Derivative / ATP Synthase Modulator — Salk Institute — Neuroprotective Longevity Small Molecule — Small Molecule, Nootropic, ATP Synthase Modulator.
Why people use it
Used primarily for cognitive support and longevity and anti-aging.
If you only read one thing

J-147's story has two layers of tension. The first is pharmacological: a compound discovered by phenotypic screening without knowing its target turned out to hit one of the most fundamental biological clocks in living organisms — ATP synthase, the enzyme that had already been shown to control aging in worms, flies, and was now being implicated in Alzheimer's through J-147. This is the discovery narrative that makes J-147 scientifically significant. The second tension is translational: the mouse data is among the most compelling in the longevity pharmacology literature — reversed brain aging biomarkers, prevented hippocampal transcriptome aging, extended Drosophila lifespan, reversed cognitive impairment in old Alzheimer's mice at an age equivalent to late human Alzheimer's. A Phase 1 human safety trial has been conducted. And yet no Phase 2 efficacy trial has been announced or initiated. The compound has been in development for over a decade with extraordinary preclinical data and no human efficacy evidence. Understanding why the clinical development has been slow is part of understanding J-147's position in the field.

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Published literature
1human RCT0human studies5animal4in vitro

Human evidence is limited to Phase 1 safety/pharmacology; no published Phase 2 efficacy trial validates the Alzheimer's, cognition, or longevity claims in humans.

Evidence reality check
Human evidence
1 human study
1 randomized; 0 observational.
Preclinical base
9 lab signals
5 animal; 4 in-vitro/mechanistic.
Risk posture
No major flags listed
Review route-specific cautions before use.
Categories
Cognition & MoodLongevity & Anti-agingMitochondrial & Energy
Properties
Active malignancy: cautionWADA S4✓ Human RCTNot injectable
Evidence
CAnimal replicated
The Discovery Method — Phenotypic Screening
J-147 was discovered by screening thousands of compounds for their ability to reverse cellular hallmarks of brain aging in a cell-based assay — not by designing a molecule to hit a known target. The assay measured protection against multiple neurotoxicities associated with aging: oxidative stress, loss of neurotrophic support, metabolic stress. J-147 emerged as a potent hit. This phenotypic approach was deliberate: Schubert's group argued that the dominant target-based approach to Alzheimer's drug development (focusing on amyloid-beta and tau) had repeatedly failed, and that screening for compounds that reverse the biology of aging itself would produce better Alzheimer's candidates. This strategy produced J-147 — and its unexpected target (ATP synthase) later proved the argument correct.
The ATP Synthase Target
For 7 years after J-147's discovery, its molecular target was unknown. In 2018, Goldberg et al. (Aging Cell) used thermal proteome profiling and chemical proteomics to identify the molecular target: the alpha subunit of the F1 component of mitochondrial ATP synthase (ATP5A). ATP synthase (Complex V) is the enzyme that synthesizes ATP from ADP using the proton gradient across the inner mitochondrial membrane. J-147 binds the F1-ATP5A subunit and modulates its activity, triggering a downstream cascade: increased intracellular Ca2+ → activation of CAMKK2 (calcium/calmodulin-dependent protein kinase kinase beta) → activation of AMPK → modulation of mTOR → neuroprotection, BDNF upregulation, mitochondrial stabilization. ATP synthase had already been shown to control aging in C. elegans and Drosophila — making it a biologically validated aging target in model organisms.
Key Preclinical Findings
Prior et al. 2013 (Alzheimer's Research & Therapy): reversed cognitive impairment in 20-month-old Alzheimer's transgenic mice (APPswe/PS1ΔE9 — one of the most established AD mouse models); Y-maze, water maze, fear conditioning all significantly improved vs untreated old AD mice. Currais et al. 2019 (Aging Cell): SAMP8 rapidly-aging mice (models sporadic AD/aging); J-147 prevented age-associated drift of hippocampal transcriptome and plasma metabolome — treated old mice had gene expression and metabolic profiles resembling young mice. Goldberg 2018 (Aging Cell): extended lifespan in Drosophila. Lapchak 2013 (CeeTox safety): EC50/toxicity ratio 782-3600 fold — significant therapeutic safety window.
Human Trial and Status
Phase 1 NCT03838185 (Abrexa Pharmaceuticals): randomized, double-blind, placebo-controlled; single ascending dose (SAD) in healthy young and elderly subjects; safety and pharmacokinetics primary endpoints. The trial was designed to assess what J-147 does in humans — not to test efficacy. As of mid-2026, the Phase 1 trial appears to have completed enrollment, but full peer-reviewed results have not been published. Community: oral 25-50 mg/day; accessible from some research chemical vendors; used primarily for cognitive aging support and longevity.
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