---
canonical_name: 17-DMAG
alternate_names: Alvespimycin, Alvespimycin Hydrochloride, 17-Dimethylaminoethylamino-17-demethoxygeldanamycin, KOS-1022, NSC 707545, DMAG
canonical_topic: 17-DMAG for Health & Longevity
short_topic_lc: 17_dmag
creation_date: 2026-0718-1651
creator_ai_fullname: Opus 4.8
ep_keywords: HSP90 Inhibitors, Heat Shock Protein 90 Inhibitors, Senolytics, Geldanamycin Analogs
---

# 17-DMAG for Health & Longevity

Evidence Review created on 07/18/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** Alvespimycin, Alvespimycin Hydrochloride, 17-Dimethylaminoethylamino-17-demethoxygeldanamycin, KOS-1022, NSC 707545, DMAG

## Motivation

17-DMAG (also called alvespimycin) is a laboratory-made compound that blocks a cellular "helper" protein which many damaged and cancerous cells depend on to stay alive. It was first built as an experimental cancer drug, but it later drew attention in aging research for a different reason: it appears able to selectively destroy worn-out cells that build up in the body over a lifetime.

These worn-out cells, sometimes called "zombie" cells, accumulate as we age and leak substances that inflame and damage the tissue around them. In studies using fast-aging mice, giving this compound lowered the number of such cells and delayed several signs of aging. Because clearing these cells has become one of the most closely watched ideas in longevity science, an old cancer drug suddenly looked like a possible tool for extending healthy lifespan.

This review examines what is actually known about 17-DMAG through a health and longevity lens: how it works, what the animal and early human evidence shows, its considerable safety concerns, how it has been dosed, and the wide gap between promising laboratory findings and any proven benefit in people.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section collects high-level, directly relevant overviews of 17-DMAG and its therapeutic category — heat shock protein 90 (HSP90) inhibitors used as senolytics (drugs that selectively clear worn-out "senescent" cells).

* [Senolytics: A Major Anti-Aging Advance](https://www.lifeextension.com/magazine/2021/6/senolytics-anti-aging-advance) - Michael Downey

  An accessible overview of the senolytic strategy that gives the longevity context in which HSP90 inhibitors such as 17-DMAG are studied, explaining why clearing senescent cells is thought to slow aspects of aging.

* [HSP90 Inhibitors as Another New Class of Potential Senolytic Drug Compounds](https://www.fightaging.org/archives/2017/09/hsp90-inhibitors-as-another-new-class-of-potential-senolytic-drug-compounds/) - Reason

  A longevity-focused commentary on the discovery that HSP90 inhibitors selectively kill senescent cells, placing 17-DMAG within the broader landscape of senolytic drug development and noting the trade-off between potency and side effects.

* [Identification of HSP90 inhibitors as a novel class of senolytics](https://pubmed.ncbi.nlm.nih.gov/28871086/) - Fuhrmann-Stroissnigg et al., 2017

  The primary research paper that first showed 17-DMAG extends healthspan and delays age-related symptoms in fast-aging mice; it is the single most important source for the compound's longevity relevance.

* [Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art](https://pubmed.ncbi.nlm.nih.gov/29602128/) - Mellatyar et al., 2018

  A narrative review devoted specifically to 17-DMAG, summarizing its mechanism, preclinical data, and clinical-trial experience across cancers and inflammatory conditions.

* [Re-examining HSPC1 inhibitors](https://pubmed.ncbi.nlm.nih.gov/28255900/) - Lee et al., 2017

  A critical narrative review of the HSP90 inhibitor field that helps a reader weigh why so many compounds in this class, 17-DMAG included, showed activity yet stalled in development.

A note on sources: after both web and on-platform searches, no directly relevant, in-depth content on 17-DMAG or HSP90-inhibitor senolytics was found from Rhonda Patrick, Peter Attia, Andrew Huberman, or Chris Kresser, so academic and longevity-publication sources were used to reach five high-quality items.

## Grokipedia

* [17-Dimethylaminoethylamino-17-demethoxygeldanamycin](https://grokipedia.com/page/17_dimethylaminoethylamino_17_demethoxygeldanamycin)

  The dedicated Grokipedia article for the compound, covering its chemistry as a water-soluble geldanamycin derivative, its HSP90-inhibiting mechanism, and its clinical-development history.

## Examine

No Examine.com article exists for this intervention. Examine.com focuses on dietary supplements and nutrition, and does not typically cover investigational prescription-type drugs such as 17-DMAG.

## ConsumerLab

No ConsumerLab article exists for this intervention. ConsumerLab tests consumer supplements and does not typically cover investigational prescription-type drugs such as 17-DMAG.

## Systematic Reviews

This section lists the systematic review that formally evaluates 17-DMAG among clinically tested HSP90 inhibitors.

* [Hsp90 inhibitors in breast cancer: a systematic review](https://pubmed.ncbi.nlm.nih.gov/23870456/) - Zagouri et al., 2013

  A PRISMA-guided systematic review of HSP90 inhibitors in breast cancer that formally includes alvespimycin (17-DMAG) among the reviewed agents; it is relevant as the only systematic review capturing 17-DMAG's human clinical data, though its focus is oncology rather than longevity, where the evidence remains preclinical.

## Mechanism of Action

17-DMAG works by inhibiting heat shock protein 90 (HSP90), a molecular chaperone — a protein whose job is to help other proteins fold correctly and stay stable. Many of HSP90's "client" proteins are the very drivers that damaged, cancerous, and senescent (worn-out) cells rely on to survive, including signaling proteins in the AKT (a pro-survival pathway) and ERK (a growth-signaling pathway) networks. By binding the ATP-binding pocket at the N-terminal (front) end of HSP90, 17-DMAG stops the chaperone from working, so its client proteins become unstable and are broken down.

* **Senolytic mechanism:** Senescent cells depend on HSP90-stabilized survival signals to resist their own self-destruction (apoptosis, or programmed cell death). Removing this support tips them toward apoptosis while largely sparing healthy cells, which is the basis for the compound's longevity interest.

* **Heat-shock feedback:** Inhibiting HSP90 releases a control switch called HSF1 (heat shock factor 1), triggering a protective stress response that raises other chaperones such as HSP70 (heat shock protein 70). This same feedback both signals that the drug is engaging its target and can blunt its effect.

The explanation above is intended to be enough for a non-specialist without cataloguing every client protein.

* **Competing mechanistic views:** Whether HSP90 inhibition helps or harms tissues over the long term is genuinely debated. One view holds that clearing senescent cells and destabilizing cancer-driving proteins is net-protective; a competing view notes that HSP90 also supports normal, healthy proteins, so broad inhibition may stress non-senescent cells and cause the toxicities seen in trials.

Key pharmacological properties (17-DMAG is a small-molecule drug):

* **Selectivity:** Binds the ATP pocket of both major HSP90 forms (HSP90-alpha and HSP90-beta) with high-nanomolar potency; it is not selective for a single tissue.

* **Half-life:** Human studies report an elimination half-life on the order of roughly half a day to a day.

* **Tissue distribution:** Widely distributed, more water-soluble than its predecessor 17-AAG (tanespimycin), with limited penetration into the central nervous system (CNS, the brain and spinal cord).

* **Metabolism:** Undergoes less liver metabolism than 17-AAG; it is partly processed by CYP3A4 (a major liver drug-metabolizing enzyme) and reduced by NQO1 (NAD(P)H quinone dehydrogenase 1, an enzyme that converts this drug class to a more active hydroquinone form), with a substantial share cleared unchanged by the kidneys and bile.

## Historical Context & Evolution

* **Original intended use:** 17-DMAG began as an anticancer agent. It is a semi-synthetic derivative of geldanamycin, a natural product isolated in 1970 from the bacterium *Streptomyces hygroscopicus*. Geldanamycin itself was too toxic to the liver for clinical use, which spurred a search for safer analogs.

* **Why it evolved:** The first clinical analog, 17-AAG (tanespimycin), had poor water solubility and formulation problems. 17-DMAG was engineered to be water-soluble and orally available, with reportedly less liver toxicity, higher potency, and less extensive metabolism than 17-AAG. It was advanced through early-phase cancer trials by the U.S. National Cancer Institute, the Institute of Cancer Research (United Kingdom), and industry sponsors Kosan Biosciences and Bristol-Myers Squibb.

* **The findings, not just the reception:** In human phase 1 cancer trials, 17-DMAG confirmed HSP90 inhibition in tumor and blood samples and produced occasional durable responses (for example, in prostate cancer and melanoma), but also dose-limiting gastrointestinal, liver, and eye toxicities, including one treatment-related death at the highest dose. Company development was ultimately discontinued; no HSP90 inhibitor of this chemical family has been approved.

* **Standing of the evidence:** The compound was not "debunked." Its cancer development stalled on a narrow safety-versus-benefit margin rather than a disproof of mechanism. In 2017 the same properties were repurposed conceptually when researchers identified HSP90 inhibitors, 17-DMAG among them, as a new class of senolytics that extended healthspan in fast-aging mice.

* **What changed and why:** The scientific view shifted from "failed oncology drug" toward "proof-of-concept senolytic tool." This is not a settled conclusion — the longevity evidence emerged entirely in cells and mice, and the same toxicity concerns that limited cancer use remain unresolved for any human longevity application.

## Expected Benefits

The benefits below are framed for health- and longevity-oriented adults. A crucial caveat applies to every item: no benefit of 17-DMAG has been demonstrated for human aging outcomes. All longevity-relevant evidence is preclinical (cells and mice), which caps every item at the lower evidence levels.

A dedicated search of clinical, preclinical, and expert sources was performed for the full benefit profile before writing this section.

### Low 🟩

#### Selective Clearance of Senescent Cells

The central longevity claim is that 17-DMAG selectively kills senescent cells — worn-out cells that stop dividing but resist dying and accumulate with age. By destabilizing HSP90-supported survival proteins, it pushes these cells into apoptosis (self-destruction). The evidence is a cell-screening study in mouse and human cells showing preferential killing of senescent over non-senescent cells; there are no human data. For a longevity-minded reader this is the mechanism of interest, but it remains a laboratory finding.

**Magnitude:** In cell studies, senescent cells were preferentially killed at concentrations that spared most non-senescent cells; no human quantitative estimate exists.

#### Healthspan Extension in Accelerated-Aging Mouse Models

Intermittent 17-DMAG treatment of Ercc1-deficient mice — a model of accelerated aging — reduced markers of senescence, lowered p16INK4a (a protein marker of senescent cells), and delayed the onset of several age-related symptoms, extending the period of healthy life. The evidence basis is a single controlled study in a progeroid (premature-aging) model, which is suggestive but does not establish benefit in normally aging animals or in people.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Suppression of Chronic Inflammatory (SASP) Signaling

Senescent cells release a mix of inflammatory molecules known as the senescence-associated secretory phenotype (SASP), which drives "inflammaging" — the low-grade chronic inflammation of aging. By removing the cells that produce it, 17-DMAG could indirectly lower this inflammatory burden. This is mechanistically plausible and consistent with senolytic theory, but it has not been directly measured for 17-DMAG in humans, so the basis is mechanistic only.

#### Preservation of Stem-Cell and Tissue Function

Senolytics as a class have improved stem-cell function and physical performance in aged mice, and clearing senescent cells is proposed to relieve neighboring healthy cells and stem cells from toxic signaling. Whether 17-DMAG specifically preserves stem-cell or tissue function is inferred from the broader senolytic literature rather than demonstrated for this compound; the basis is mechanistic and analogical.

#### Activation of a Protective Heat-Shock (Cellular Stress) Response

Blocking HSP90 releases HSF1 and raises protective chaperones such as HSP70, a response linked in other contexts to improved protein quality control. It is speculated that a brief, controlled version of this stress could be beneficial, but for 17-DMAG this is untested in aging contexts and rests on mechanism and isolated laboratory observations only.

## Benefit-Modifying Factors

* **Genetic makeup (NQO1 status):** The enzyme NQO1 activates geldanamycin-class drugs to a more potent form. A common low-activity variant (NQO1*2, the C609T change) reduces this activation and could blunt the compound's cellular effect, potentially lowering any benefit in carriers.

* **Baseline senescent-cell burden:** A senolytic can only help to the extent that senescent cells are present. Individuals with a higher accumulated burden of senescent cells (typically older or with more tissue damage) would in theory have more to gain than those with a low burden, in whom benefit may be negligible.

* **Sex-based differences:** No sex-specific benefit data exist for 17-DMAG. Sex differences in HSP90 biology, drug metabolism, and senescent-cell accumulation are plausible but unstudied for this compound, so any benefit difference by sex is currently unknown.

* **Pre-existing health conditions:** Because the proposed benefit is clearing senescent cells, conditions marked by high senescent-cell load (such as advanced tissue fibrosis or metabolic disease) are where benefit is hypothesized to concentrate; this remains untested in humans.

* **Age:** Senescent-cell accumulation rises with age, so older adults within the target audience are the group in whom a senolytic effect would theoretically matter most — while also being the group most vulnerable to the compound's toxicities.

## Potential Risks & Side Effects

The risks below are framed for a health- and longevity-oriented reader considering a compound whose only human data come from cancer patients receiving it intravenously. A dedicated search of clinical-trial reports and drug-reference sources was performed for the full side-effect profile before writing this section. The overriding risk is that these are the toxicities that limited 17-DMAG in oncology, and no safe longevity dose has ever been established.

### High 🟥 🟥 🟥

#### Gastrointestinal Toxicity

Nausea, vomiting, and diarrhea were among the most common adverse events across phase 1 trials and contributed to dose-limiting toxicity. The proposed mechanism is disruption of HSP90-dependent proteins in the fast-dividing gut lining. Severity ranged from manageable to dose-limiting, and events were generally reversible on stopping the drug, but they defined the practical ceiling on dosing.

**Magnitude:** Gastrointestinal events were dose-limiting at 106 mg/m² weekly intravenously and were among the most frequent toxicities at effective doses.

#### Hepatotoxicity (Liver Injury)

Reversible elevations in liver enzymes were repeatedly observed, consistent with the liver toxicity that plagued the parent compound geldanamycin. The mechanism involves stress to liver cells that depend on HSP90 client proteins and, for this drug class, formation of reactive metabolites. Although 17-DMAG was designed to be less liver-toxic than 17-AAG, a treatment-related death occurred at the highest tested dose, underscoring that liver risk is real and potentially serious.

**Magnitude:** Liver-enzyme elevations were common at active doses; a treatment-related death occurred at 106 mg/m² weekly.

### Medium 🟥 🟥

#### Ocular Toxicity (Visual Disturbances)

Eye-related effects such as blurred vision and other visual disturbances have been reported with 17-DMAG and are a recognized class effect of HSP90 inhibitors, thought to arise from stress to light-sensing retinal cells that rely on HSP90. Reported cases were generally a minority of patients and often reversible, but the possibility of retinal injury makes this a distinctive and closely monitored risk for the class.

**Magnitude:** Not quantified in available studies.

#### Constitutional Symptoms (Fatigue and Muscle Aches)

Fatigue, muscle aches (myalgia), and general malaise were frequently reported, likely reflecting the systemic cellular stress of broad HSP90 inhibition and the accompanying heat-shock response. These effects are usually not dangerous but can meaningfully reduce day-to-day function, which is especially relevant for an audience using an intervention electively rather than for cancer.

**Magnitude:** Not quantified in available studies.

#### Bone Marrow Suppression

Reductions in blood counts, including white cells and platelets, were seen in trials, particularly in blood-cancer studies and combination regimens. The mechanism is toxicity to fast-dividing bone-marrow precursor cells. Lowered counts raise the risk of infection and bleeding and require laboratory monitoring.

**Magnitude:** Not quantified in available studies.

### Low 🟥

#### Cardiac Effects (Potential Heart-Rhythm Changes)

Several HSP90 inhibitors can affect the heart's electrical recovery time (the QT interval, seen on an electrocardiogram), raising a theoretical risk of dangerous rhythm disturbances. Direct evidence specific to 17-DMAG is limited, but the class signal warrants caution, particularly with other rhythm-affecting drugs.

**Magnitude:** Not quantified in available studies.

#### Kidney and Electrolyte Effects

Because a meaningful fraction of 17-DMAG is cleared by the kidneys, and because rapid destruction of many cells can stress the kidneys and shift electrolytes, kidney function and electrolyte changes are a plausible lower-frequency concern. Reported renal events in trials were uncommon relative to gastrointestinal and liver effects.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Unknown Risks of Chronic Senolytic Dosing

All human safety data come from short-course cancer treatment. The long-term consequences of repeatedly inhibiting HSP90 in an otherwise healthy person — including possible harm to normal cells that also depend on HSP90 — are unknown. This concern rests on mechanism and the absence of any long-term human data rather than on reported events.

## Risk-Modifying Factors

* **Genetic makeup (NQO1 and CYP3A4):** The NQO1*2 low-activity variant alters how much active drug is formed and could shift both benefit and toxicity. Variation in CYP3A4 activity (genetic or drug-induced) changes how quickly 17-DMAG is cleared, potentially raising exposure and side effects in slow metabolizers.

* **Baseline biomarker levels:** Individuals starting with abnormal liver enzymes, low blood counts, or reduced heart function have less physiological reserve and are more likely to cross into dangerous territory if the corresponding toxicity occurs.

* **Sex-based differences:** No sex-specific safety data exist for 17-DMAG. Known sex differences in drug metabolism and body composition could influence exposure and toxicity, but this is unquantified for this compound.

* **Pre-existing health conditions:** Liver disease, significant heart disease, retinal (eye) disease, and kidney impairment each map directly onto the compound's known toxicities and would amplify the corresponding risk.

* **Age:** Older adults, the group most drawn to senolytics, generally have reduced organ reserve and more concurrent medications, both of which increase the likelihood and consequences of adverse effects.

## Key Interactions & Contraindications

* **Prescription drug interactions:** Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) can raise 17-DMAG levels and toxicity, while strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin) can lower its levels. Severity: caution to avoid. Clinical consequence: excess toxicity or loss of effect. Mitigating action: avoid strong inhibitors/inducers or separate and adjust dose under supervision.

* **Over-the-counter medication interactions:** Over-the-counter hepatotoxic agents, chiefly high-dose acetaminophen, add to liver-injury risk. Severity: caution. Clinical consequence: additive liver toxicity. Mitigating action: minimize concurrent acetaminophen and monitor liver enzymes.

* **Supplement interactions:** St. John's Wort is a strong CYP3A4 inducer and can reduce drug levels; grapefruit-derived supplements inhibit CYP3A4 and can raise them. Severity: caution. Clinical consequence: altered exposure. Mitigating action: avoid these supplements during use.

* **Supplements with additive effects:** Other senolytics and potentially hepatotoxic supplements (for example fisetin and quercetin used as senolytics, high-dose green-tea catechins, kava) could add to senescent-cell clearance or to liver stress. Severity: caution. Clinical consequence: additive cellular stress or liver toxicity. Mitigating action: avoid stacking multiple senolytic or liver-stressing agents.

* **Other intervention interactions:** QT-prolonging drugs (amiodarone, sotalol, ondansetron, certain antibiotics) may combine with the class cardiac signal. Severity: caution to avoid. Clinical consequence: heart-rhythm disturbance. Mitigating action: avoid combinations and check an electrocardiogram.

* **Populations who should avoid it:** People who are pregnant or breastfeeding (embryo-fetal harm is expected for this drug class), those with significant liver disease, significant heart disease, or active retinal disease should not use 17-DMAG.

* **Populations to avoid — specific thresholds:** Moderate-to-severe liver impairment (Child-Pugh Class B or C, a clinical liver-severity score), reduced heart pumping function (left-ventricular ejection fraction below about 50%), a baseline corrected QT interval above roughly 470–480 milliseconds, or pregnancy are practical exclusion thresholds drawn from how HSP90-inhibitor trials screened participants.

## Risk Mitigation Strategies

* **Baseline organ screening before any use:** Obtain liver enzymes, blood counts, kidney function, an electrocardiogram, and an eye exam before starting, to prevent unrecognized liver, cardiac, or retinal problems from being worsened.

* **Low starting dose with slow escalation:** Because gastrointestinal and liver toxicities are dose-limiting, any use would start well below the oncology maximum (which was 80 mg/m² weekly intravenously, with dose-limiting toxicity at 106 mg/m²) and escalate cautiously, to reduce the chance of severe gastrointestinal or liver injury.

* **Intermittent rather than continuous dosing:** Senolytic theory favors short, spaced courses ("hit-and-run") rather than daily dosing, which limits cumulative exposure and lowers the risk of chronic organ stress.

* **Scheduled liver and blood monitoring:** Check liver enzymes and blood counts before each course and periodically during use (for example weekly during active dosing), to catch hepatotoxicity or bone-marrow suppression early.

* **Ophthalmologic surveillance:** Given the class risk of retinal injury, arrange an eye exam at baseline and prompt evaluation of any new visual symptoms, to prevent progression of ocular toxicity.

* **Medication and supplement review:** Remove strong CYP3A4 inhibitors/inducers, QT-prolonging drugs, and additional liver-stressing or senolytic agents beforehand, to prevent avoidable drug interactions that magnify toxicity.

## Therapeutic Protocol

No standard protocol exists for using 17-DMAG for health or longevity; it has never been approved or used in clinical practice for that purpose. The only human dosing frameworks come from early-phase cancer trials, presented here for context, not as a usable longevity regimen.

* **Standard (oncology) protocol:** In the phase 1 solid-tumor study led by Pacey and colleagues at the Institute of Cancer Research, the recommended dose was 80 mg/m² given intravenously once weekly, the highest dose without dose-limiting toxicity. This is the closest thing to a "standard" human dose and was defined for cancer, not aging.

* **Competing approaches:** Twice-weekly intravenous schedules were explored by the U.S. National Cancer Institute (for example in advanced malignancies and in acute myeloid leukemia, a fast-growing blood cancer), and oral and combination regimens (with trastuzumab, a HER2-targeting antibody used in HER2-positive — a growth-receptor-positive — breast cancer) were tested by industry sponsors. No approach is framed here as preferred, since none was validated for longevity.

* **Popularizing experts/clinics:** The intravenous weekly schedule was popularized by the Cancer Research UK program (Workman and colleagues) and by U.S. National Cancer Institute investigators; the senolytic concept was introduced by the Scripps/Mayo Clinic aging groups.

* **Best time of day:** No time-of-day optimum has been established for 17-DMAG.

* **Half-life consideration:** With an elimination half-life on the order of half a day to a day, weekly or twice-weekly dosing was used in trials rather than daily dosing.

* **Single versus split dosing:** Trials used single weekly infusions or twice-weekly infusions; there is no evidence favoring split daily dosing for a senolytic goal.

* **Genetic polymorphisms:** NQO1 status (the low-activity NQO1*2 variant) may influence how much active drug is formed and is the most relevant pharmacogenetic factor; CYP3A4-affecting variants and co-medications also alter exposure.

* **Sex-based differences:** No sex-specific dosing has been defined; differences in metabolism and body composition could matter but are unstudied.

* **Age-related considerations:** Older adults may clear the drug more slowly and tolerate toxicity less well, arguing for more conservative dosing at the older end of the target range.

* **Baseline biomarkers:** Liver enzymes, blood counts, kidney function, and cardiac markers should guide whether dosing is appropriate at all and at what level.

* **Pre-existing conditions:** Liver, heart, eye, and kidney disease each argue against use or for markedly reduced exposure.

## Discontinuation & Cycling

* **Lifelong versus short-term:** 17-DMAG is not a maintenance therapy. The senolytic model is inherently short-term and intermittent — brief courses intended to reduce senescent-cell burden, then stop — rather than continuous lifelong dosing.

* **Withdrawal effects:** No withdrawal syndrome has been described. Because senolytics are proposed to clear cells and then be discontinued, stopping is not expected to cause rebound, though this has not been formally studied in humans for 17-DMAG.

* **Tapering:** No taper is described or expected; the drug was given in defined courses and simply stopped, and dose-limiting toxicity, not dependence, governed discontinuation in trials.

* **Cycling for efficacy:** Cycling is effectively the intended pattern. Senolytic dosing is hypothesized to be repeated only periodically (for example spaced courses as senescent cells re-accumulate), which also limits cumulative toxicity — but no validated cycle length exists for 17-DMAG.

* **Practical discontinuation triggers:** In practice, any liver-enzyme rise, cytopenia (low blood counts), visual change, or rhythm change would be a reason to stop, reflecting how trials handled dose-limiting toxicity.

## Sourcing and Quality

* **Availability:** 17-DMAG is not available as an approved medicine. Its pharmaceutical development was discontinued, so there is no legitimate consumer or clinical supply for human use; it exists mainly as a research-grade chemical sold for laboratory work.

* **What to look for:** For any legitimate laboratory purchase, a certificate of analysis documenting identity and purity (typically 98% or higher) and third-party analytical confirmation would be the minimum quality signals — but research-grade material is explicitly not manufactured to standards suitable for human use.

* **Purity and formulation concerns:** Research chemicals carry no assurance of sterility, endotoxin control, or accurate dosing needed for an injectable human product, which is the form used in all human trials.

* **Reputable sources:** No reputable compounding pharmacy or manufacturer supplies 17-DMAG for human administration; the compound used in trials came from controlled clinical manufacturing under regulatory oversight that no longer applies.

## Practical Considerations

* **Time to effect:** Unknown for any longevity outcome. In laboratory models, senolytic killing of senescent cells occurs within days, but no human timeframe for a health benefit has ever been demonstrated.

* **Common pitfalls:** The central pitfall is treating strong mouse and cell-culture results as if they were proven human benefits; others include underestimating the liver, eye, and gastrointestinal toxicities that limited the drug, and assuming a research chemical is equivalent to a clinical-grade medicine.

* **Regulatory status:** 17-DMAG is investigational and was never approved by the U.S. Food and Drug Administration (FDA) or other regulators; its development was halted. There is no approved or off-label human use, and marketing it for human consumption is not permitted.

* **Cost and accessibility:** It is not commercially available as a medicine at any price. Access for human use is effectively nonexistent, which is itself a decisive practical barrier.

## Interaction with Foundational Habits

* **Sleep:** Direction — indirect, likely negative during dosing. The systemic cellular stress and fatigue reported with HSP90 inhibition, plus gastrointestinal side effects, could disrupt sleep during active treatment. No sleep-improving effect has been shown, and there is no evidence of a beneficial interaction; practically, side-effect burden is the relevant consideration.

* **Nutrition:** Direction — indirect and interaction-driven. Grapefruit (a CYP3A4 inhibitor) can raise drug levels, so it should be avoided; a nutrient-dense diet supporting liver health is sensible given the hepatotoxicity risk. No specific diet enhances efficacy, and no nutrient depletion is documented, so the practical point is avoiding foods that alter drug metabolism.

* **Exercise:** Direction — potentially potentiating at the biology level, unproven in practice. Exercise itself induces heat-shock proteins and clears some senescent cells, mechanistically overlapping with the drug's target, but whether combining the two adds benefit or compounds cellular stress is unknown. During active dosing, fatigue and low blood counts may limit exercise capacity, so timing hard training away from dosing is prudent.

* **Stress management:** Direction — indirect. Blocking HSP90 activates a cellular stress response; there is no evidence it changes cortisol or psychological stress, but managing overall stress supports recovery and tolerability. No specific interaction with stress-management practices has been demonstrated.

## Monitoring Protocol & Defining Success

Because 17-DMAG has no approved use, the monitoring below is adapted from how HSP90-inhibitor trials safeguarded participants; it is oriented toward catching toxicity rather than confirming a longevity benefit. Baseline testing should be completed before any dosing, covering liver, blood, kidney, cardiac, and eye status as described in the table.

Ongoing monitoring cadence: liver enzymes and blood counts before each course and roughly weekly during active dosing; kidney function and electrocardiogram before each course; an eye exam at baseline and promptly with any visual symptom, otherwise periodically (for example every 3–6 months) during repeated use.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
| --- | --- | --- | --- |
| ALT / AST (liver enzymes) | ALT and AST roughly 10–26 U/L | Detects liver injury, the key dose-limiting toxicity | Conventional labs flag only above ~40 U/L; functional practitioners watch tighter ranges. Fasting sample preferred; recheck before each course |
| Total bilirubin | 0.3–1.0 mg/dL | Flags impaired liver clearance | Pair with liver enzymes; morning fasting draw |
| Complete blood count (CBC) | Neutrophils >1.5 ×10⁹/L; platelets >150 ×10⁹/L | Detects bone-marrow suppression (infection/bleeding risk) | Check before each course and weekly during dosing |
| eGFR (estimated kidney filtration) | >90 mL/min/1.73m² | Kidney clearance affects drug exposure | "eGFR" estimates how well kidneys filter; hydration and recent meat intake can shift creatinine-based values |
| Corrected QT interval (QTc, from an ECG) | <440 ms | Screens for heart-rhythm risk, a class concern | Electrocardiogram (ECG) records the heart's electrical activity; avoid with other QT-prolonging drugs |
| Left-ventricular ejection fraction (LVEF) | ≥55% | Confirms adequate heart pumping before use | Measured by echocardiogram; conventional "normal" starts ~50% |
| Dilated eye (retinal) exam | No retinal changes | Screens for ocular toxicity of the drug class | Baseline and with any visual change; best paired with symptom review |

Qualitative markers of how someone is faring:

* **Energy and fatigue:** Worsening fatigue can signal toxicity rather than benefit and should prompt review.

* **Vision:** Any blurring or visual change is a warning sign for retinal toxicity.

* **Digestive comfort:** Persistent nausea, vomiting, or diarrhea indicates the dose is poorly tolerated.

* **General well-being:** Overall stamina and recovery between courses give a practical read on tolerability.

## Emerging Research

For a longevity-minded reader, the honest state of play is that 17-DMAG has no active clinical trials and no human longevity studies; the near-term signal comes from where the senolytic field is heading rather than from new trials of this specific compound.

* **No ongoing 17-DMAG trials:** As of July 2026, no clinical trials are actively evaluating 17-DMAG for aging or any other indication; its registered trials are completed or terminated.

* **Completed reference trial (solid tumors/lymphoma):** A U.S. National Cancer Institute phase 1 study established human safety and HSP90 target engagement — [NCT00089271](https://clinicaltrials.gov/study/NCT00089271), phase 1, roughly 60 participants, now completed.

* **Completed reference trial (blood cancer):** A phase 1 study in relapsed chronic lymphocytic leukemia (a slow-growing blood cancer) — [NCT01126502](https://clinicaltrials.gov/study/NCT01126502), phase 1, about 30 participants, terminated — informs dosing and toxicity in a non-solid-tumor setting.

* **Completed combination trial:** A phase 1 study combined intravenous alvespimycin with trastuzumab (a HER2-targeting antibody) — [NCT00803556](https://clinicaltrials.gov/study/NCT00803556), phase 1, about 29 participants, completed — relevant to how the drug behaves alongside other agents.

* **Future direction that could strengthen the case:** The foundational senolytic finding — that 17-DMAG extends healthspan in fast-aging mice — points to studies in normally aging animals and, eventually, carefully dosed human proof-of-concept work; see [Fuhrmann-Stroissnigg et al., 2017](https://pubmed.ncbi.nlm.nih.gov/28871086/).

* **Future direction that could weaken the case:** The same body of work highlights the narrow gap between senolytic effect and organ toxicity, so research into safer, tissue-targeted next-generation HSP90 inhibitors could render 17-DMAG itself obsolete rather than validate it; the class review by [Mellatyar et al., 2018](https://pubmed.ncbi.nlm.nih.gov/29602128/) documents this development challenge.

## Conclusion

17-DMAG is an experimental compound that blocks a cellular helper protein many damaged and worn-out cells rely on to survive. Built decades ago as a cancer drug, it later became interesting for longevity because it can selectively destroy the aged, "zombie" cells that accumulate over time and inflame nearby tissue. In fast-aging mice, it lowered the number of these cells and delayed some signs of aging, which is the source of its appeal.

The evidence, however, is thin and one-sided. Every longevity-relevant result comes from cells and mice; there is no human data showing it slows aging or improves health, and its only human testing was in cancer patients. That testing revealed the central problem: meaningful toxicity to the gut, liver, and eyes, with a narrow margin between effect and harm. The compound was never approved, its development was stopped, and it is not available as a medicine.

Taken together, 17-DMAG is best understood as a proof-of-concept tool that helped establish an idea — that clearing worn-out cells might extend healthy life — rather than a usable intervention. The gap between its laboratory promise and any proven, safe human benefit remains very wide and genuinely uncertain.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**


---
canonical_name: 3HAA
alternate_names: 3-Hydroxyanthranilic Acid, 3-HAA, 3HANA, 2-Amino-3-hydroxybenzoic acid
canonical_topic: 3HAA for Health & Longevity
short_topic_lc: 3haa
creation_date: 2026-0625-1328
creator_ai_fullname: Opus 4.8
ep_keywords: Kynurenine Pathway Metabolites, Tryptophan Catabolites, Tryptophan Metabolites
---

# 3HAA for Health & Longevity

Evidence Review created on 06/25/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** 3-Hydroxyanthranilic Acid, 3-HAA, 3HANA, 2-Amino-3-hydroxybenzoic acid

## Motivation

A small molecule the body makes when it breaks down a building block of dietary protein, 3HAA (3-hydroxyanthranilic acid) was for decades viewed as a fleeting, throwaway step on the way to making cellular energy carriers. Recent work has reframed it as a substance that, when its levels are raised, appears to switch on the cell's own defenses against damage.

Interest grew after laboratory animals lived markedly longer and stayed healthier into old age when 3HAA was allowed to accumulate, either by blocking the enzyme that destroys it or by adding it to the diet. A separate line of work found that the same molecule rises in the blood of middle-aged people after months of regular exercise, hinting it may be one of the chemical messengers behind some benefits of physical activity.

This review examines what is known about 3HAA as a potential health and longevity intervention. It surveys the proposed biological actions, the strength of the evidence for benefits and risks, the practical realities of supplementation, and the open questions that current research is still working to answer.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section lists high-level resources that give an accessible overview of 3HAA and its emerging role in aging biology.

* [On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging](https://pubmed.ncbi.nlm.nih.gov/38097593/) - Dang et al., 2023

  The foundational primary-research report showing that raising 3HAA extends lifespan by roughly 30% in worms and that long-lived effects carry into mice; the most complete single source on the longevity hypothesis.

* [3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity](https://pubmed.ncbi.nlm.nih.gov/38786006/) - Hull et al., 2024

  An accessible primary study extending the 3HAA story to neurodegeneration models, showing delayed paralysis in worms engineered to mimic Alzheimer's and Huntington's disease.

* [Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities](https://pubmed.ncbi.nlm.nih.gov/39304346/) - Pocivavsek et al., 2024

  A narrative review that situates 3HAA within the broader kynurenine pathway, explaining how its parent and neighboring metabolites influence the brain and why the pathway's enzymes are drug targets.

* [Unlocking Longevity: The Role of 3-Hydroxyanthranilic Acid (3HAA) in Aging](https://www.sunybiotech.com/news-show-196.html) - SunyBiotech

  A plain-language overview written for a general audience that summarizes the key animal findings and the proposed oxidative-stress mechanism without requiring a research background.

* [The tryptophan metabolite 3-hydroxyanthranilic acid lowers plasma lipids and decreases atherosclerosis in hypercholesterolaemic mice](https://pubmed.ncbi.nlm.nih.gov/22711758/) - Zhang et al., 2012

  An earlier primary study, predating the longevity work, demonstrating that 3HAA reduces plaque and blood lipids in mice, providing context for its cardiovascular and anti-inflammatory actions.

_Note: No dedicated, by-name content on 3HAA was found from the priority experts (Rhonda Patrick, Peter Attia, Andrew Huberman, Chris Kresser, or Life Extension Magazine). 3HAA is an early-stage research metabolite rather than a mainstream supplement, so the list above draws on the strongest available primary research, a narrative review, and one accessible lay summary instead._

## Grokipedia

[3-Hydroxyanthranilic acid](https://grokipedia.com/page/3_hydroxyanthranilic_acid)

The dedicated Grokipedia entry summarizes the compound's chemistry, its place in the kynurenine pathway, and its biological roles, serving as a concise structured reference.

## Examine

No Examine.com article exists for 3HAA. Examine.com focuses on consumer dietary supplements and ingredients with marketed products and human trial data; 3HAA is a research-grade endogenous metabolite without a consumer supplement profile, so it is not covered.

## ConsumerLab

No ConsumerLab.com article exists for 3HAA. ConsumerLab tests and reviews commercially marketed supplement products for quality and label accuracy; 3HAA is not sold as a finished consumer supplement, so no product review is available.

## Systematic Reviews

The following systematic reviews and meta-analyses address 3HAA within the broader kynurenine pathway, as no review focuses on 3HAA supplementation alone.

* [Dynamic changes in metabolites of the kynurenine pathway in Alzheimer's disease, Parkinson's disease, and Huntington's disease: A systematic Review and meta-analysis](https://pubmed.ncbi.nlm.nih.gov/36263032/) - Fathi et al., 2022

  Pooled data from 30 studies comparing kynurenine pathway metabolites, including 3HAA, between neurodegenerative-disease patients and controls; useful for understanding how 3HAA levels shift in age-associated brain disease.

* [A systematic review and meta-analysis of the kynurenine pathway of tryptophan metabolism in rheumatic diseases](https://pubmed.ncbi.nlm.nih.gov/37936702/) - Mangoni & Zinellu, 2023

  A meta-analysis of 24 studies that, notably, found no significant difference in 3HAA between patients with rheumatic disease and controls, helping to delineate which conditions 3HAA does and does not track with.

## Mechanism of Action

3HAA is a downstream product of the kynurenine pathway (KP), the main route by which the body breaks down the amino acid tryptophan to ultimately make NAD⁺ (nicotinamide adenine dinucleotide, a coenzyme essential for cellular energy and repair). It is produced from 3-hydroxykynurenine by the enzyme kynureninase and is normally destroyed within seconds by the enzyme HAAO (3-hydroxyanthranilic acid 3,4-dioxygenase), which converts it toward quinolinic acid.

The leading explanation for 3HAA's benefits is an oxidative-stress-response (hormetic) mechanism. When 3HAA accumulates, it activates the SKN-1 transcription factor in worms — the equivalent of NRF2 (a master regulator that switches on the cell's antioxidant and detoxification genes) in mammals. This raises the cell's defenses against reactive oxygen species (unstable molecules that damage proteins, lipids, and DNA). Paradoxically, 3HAA can itself directly break down hydrogen peroxide, acting as a free-radical scavenger; the modest stress it imposes is thought to "train" the cell's protective systems. Alterations in iron homeostasis and improved protein homeostasis (the cell's ability to keep proteins correctly folded) have also been proposed as contributors.

A competing mechanistic view treats 3HAA as a potential pro-oxidant and toxin rather than a protector. Under certain conditions — particularly in the presence of copper or transition metals — 3HAA generates superoxide and hydrogen peroxide and can enhance metal-driven toxicity, and it sits one enzymatic step upstream of quinolinic acid, an excitotoxin (a molecule that can overstimulate and damage nerve cells). Whether 3HAA is net-protective or net-harmful appears to depend heavily on dose, tissue, and local redox conditions, and both views are supported by experimental data.

As 3HAA is a small endogenous molecule rather than a conventional drug, classical pharmacological properties are not well characterized in humans. In its role as the HAAO substrate it has an extremely short biological half-life — on the order of seconds to minutes — because HAAO rapidly clears it; it is water-soluble, distributes through plasma and tissues, and is metabolized chiefly by HAAO toward quinolinic acid and NAD⁺ synthesis. No cytochrome P450 (CYP, the liver's main drug-metabolizing enzyme family) pathway is a primary route for its clearance.

## Historical Context & Evolution

3HAA was originally of interest purely as a biochemical waypoint — a transient intermediate identified in the mid-twentieth century during the mapping of how the body converts tryptophan into NAD⁺. For most of its history it had no "intended use"; it was simply a metabolite measured by biochemists studying the kynurenine pathway, with no therapeutic ambitions attached.

The reasons it came to be considered for health optimization emerged in two waves. First, in the 2000s and 2010s, researchers studying immune regulation and cardiovascular disease found that 3HAA had anti-inflammatory actions in animal models of autoimmune disease and atherosclerosis, where it lowered blood lipids and reduced arterial plaque. Second, and more decisively, aging researchers screening kynurenine pathway genes discovered that blocking the enzyme that destroys 3HAA extended lifespan in invertebrates — reframing the molecule from metabolic byproduct to candidate longevity agent.

The scientific opinion on 3HAA has genuinely shifted and remains unsettled rather than settled. Early literature emphasized its potential toxicity and pro-oxidant chemistry, especially in the brain; newer work emphasizes hormetic, protective, and lifespan-extending effects. What changed was the introduction of genetic tools to raise 3HAA at physiological levels (rather than flooding cells with high concentrations) and longevity assays in worms and mice. Both bodies of evidence stand, and the field has not converged on a single verdict; 3HAA is best characterized as a metabolite whose net effect is context-dependent and actively debated.

## Expected Benefits

A dedicated search of primary research and expert sources was performed to assemble the benefit profile below.

### High 🟩 🟩 🟩

(No benefits qualify for the High evidence level. All current evidence for 3HAA is preclinical or observational; none rests on human clinical trials.)

### Medium 🟩 🟩

(No benefits qualify for the Medium evidence level.)

### Low 🟩

#### Lifespan and Healthspan Extension

In *Caenorhabditis elegans*, knocking down the HAAO enzyme (which raises physiological 3HAA) extends lifespan by approximately 30% and delays age-associated declines in movement and vigor; in pilot mouse studies, female HAAO-knockout mice and aging male mice fed 3HAA-supplemented diets were also longer-lived. The proposed mechanism is activation of the SKN-1/NRF2 oxidative-stress response and improved protein homeostasis with age. The evidence basis is robust invertebrate work plus small, preliminary mouse cohorts; no human lifespan data exist, and the mouse results were described by the authors as pilot-scale.

**Magnitude:** ~30% median lifespan extension in *C. elegans*; mouse effects reported as positive but pilot-scale and not precisely quantified.

#### Reduced Atherosclerosis and Improved Blood Lipids

In atherosclerosis-prone mice, eight weeks of 3HAA treatment reduced arterial lesion size, lowered plasma cholesterol and triglycerides, and blunted local and systemic inflammation, partly by reducing macrophage uptake of oxidized LDL (low-density lipoprotein, the "bad" cholesterol carrier; its uptake is the early step in artery-clogging foam-cell formation). The proposed mechanism involves modulation of PPAR signaling (peroxisome proliferator-activated receptors, master switches for fat and inflammation control). The evidence basis is a single well-conducted mouse study; results have not been replicated in humans.

**Magnitude:** Significant reduction in aortic lesion size and plasma lipids in mice; exact percentage not generalizable to humans.

#### Anti-Inflammatory and Immune-Modulating Effects

Across autoimmune-disease models, including experimental autoimmune encephalomyelitis (a mouse model of multiple sclerosis), 3HAA dampens harmful immune activation; in aging worms it improves immune function and acts against gram-negative bacteria. The proposed mechanism includes induction of heme oxygenase-1 (a protective, anti-inflammatory enzyme) and broad modulation of immune-cell signaling. The evidence basis is multiple animal and cell-culture studies; human immune data are limited to observational metabolite measurements.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Protection Against Neurodegeneration

In worms engineered to express amyloid-beta or polyglutamine (mimicking Alzheimer's and Huntington's disease), raising 3HAA delayed age-associated paralysis, an effect that occurred even without reduced protein aggregation; 3HAA is also predicted to bind amyloid-beta and reduce its clumping in test-tube experiments. The basis is mechanistic and limited to invertebrate models and in-vitro prediction, with no controlled mammalian or human studies, so this benefit remains hypothetical for people.

#### Mediation of Exercise Benefits

In middle-aged adults, six months of endurance exercise raised blood 3HAA by 85–134%, and 3HAA levels track inversely with measures associated with aging, raising the possibility that 3HAA is one chemical signal carrying some longevity benefits of physical activity. This is an association from a small human study rather than evidence that supplemental 3HAA reproduces exercise benefits; the causal link is unproven and the idea is speculative.

## Benefit-Modifying Factors

* **Genetic variation in pathway enzymes:** Activity of HAAO and upstream enzymes (KYNU, kynureninase, which produces 3HAA; and KMO, kynurenine 3-monooxygenase, which routes tryptophan toward 3HAA's precursor) varies between individuals and could determine baseline 3HAA levels and how much accumulates; those with naturally lower HAAO activity might already sit at higher 3HAA and respond differently.

* **Baseline biomarker levels:** People with already-high oxidative stress, inflammation, or a high kynurenine-to-tryptophan ratio may have a different response than those with low baseline values, since the proposed mechanism is a hormetic (stress-response) one that depends on starting conditions.

* **Sex-based differences:** The pilot mouse longevity data were strongest in female HAAO-knockout mice, while the dietary-supplementation lifespan effect was reported in aging males, suggesting sex may modify which delivery route or outcome is most affected; the basis is preliminary.

* **Pre-existing health conditions:** Cardiovascular disease, autoimmune conditions, and neurodegenerative disease are the contexts where animal benefits appeared, so individuals with these conditions are the ones in whom benefits have been modeled — though only in animals.

* **Age:** Benefits in animals were specifically tied to aging — effects on healthspan, immune function, and proteotoxicity appeared in older animals, suggesting older adults at the upper end of the target range may be the most relevant population, while effects in the young are untested.

## Potential Risks & Side Effects

A dedicated search of toxicology, pharmacology, and primary literature was performed for the risk profile below.

### High 🟥 🟥 🟥

(No risks qualify for the High evidence level. There are no human safety trials of 3HAA, so no risk is supported by high-quality human evidence.)

### Medium 🟥 🟥

(No risks qualify for the Medium evidence level.)

### Low 🟥

#### Pro-Oxidant Toxicity in the Presence of Metals

In cell-culture studies, 3HAA generates superoxide and hydrogen peroxide and enhances copper-induced toxicity in brain astrocytes, reducing cell viability and mitochondrial function. The proposed mechanism is metal-catalyzed redox cycling, in which 3HAA reduces copper or iron and drives production of damaging reactive oxygen species. The evidence basis is rat astrocyte and biochemical studies; relevance to whole-body human supplementation at physiological doses is unknown, and the same redox chemistry underlies its proposed benefits, making context critical.

**Magnitude:** Not quantified in available studies.

#### Conversion Toward Quinolinic Acid

3HAA sits one enzymatic step upstream of quinolinic acid, an excitotoxin implicated in neurodegeneration and neuroinflammation. Supplying extra 3HAA could in principle increase flux toward quinolinic acid, though raising 3HAA specifically by blocking its breakdown would instead reduce downstream quinolinic acid. The evidence basis is pathway biochemistry rather than direct toxicity studies of 3HAA supplementation; the net effect on quinolinic acid in humans is unestablished.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Unknown Effects of Chronic Human Supplementation

No human has been studied taking 3HAA as a chronic supplement, so the entire long-term safety profile — including effects on liver, kidney, immune tolerance, and cancer-relevant immune signaling — is unknown. Because the kynurenine pathway also participates in immune suppression and tumor immune evasion, shifting pathway metabolites chronically carries theoretical, unquantified risk. This concern rests on mechanistic reasoning and the absence of data rather than on observed harm.

#### Disruption of Immune Balance

Kynurenine pathway metabolites help regulate immune tolerance, and 3HAA can induce apoptosis (programmed cell death) in certain immune cells under pathophysiological conditions. Chronically altering 3HAA might therefore shift immune function in unintended directions, for example over-suppressing or over-activating immune responses. This is an isolated-report and mechanistic concern with no controlled human data.

## Risk-Modifying Factors

* **Genetic variation in pathway and metal-handling genes:** Variants in the kynurenine pathway enzymes (HAAO, KYNU, KMO) could set how much 3HAA accumulates and therefore how much pro-oxidant load a given exposure produces, while variants in iron- and copper-handling genes (HFE, linked to hereditary hemochromatosis; ATP7B, linked to Wilson's disease) raise tissue metal levels and could amplify 3HAA's metal-catalyzed toxicity; none of this has been tested directly for 3HAA risk.

* **Metal status (copper and iron):** Because 3HAA's toxic redox chemistry is metal-catalyzed, individuals with copper or iron overload (e.g., hemochromatosis or Wilson's disease) could plausibly be at higher risk of pro-oxidant harm; those with normal metal status may face less of this specific concern.

* **Baseline oxidative stress and antioxidant capacity:** People with depleted glutathione or impaired NRF2 signaling might tolerate the pro-oxidant aspect of 3HAA poorly, whereas robust antioxidant defenses could buffer it.

* **Sex-based differences:** Animal data hint that sex modifies kynurenine pathway handling, but no sex-specific human risk data exist; this remains an open question rather than a documented difference in side effects.

* **Pre-existing neurological or autoimmune conditions:** Those with neurodegenerative disease or active autoimmunity sit closest to the pathways 3HAA influences, and could in principle experience either benefit or harm; the direction is unestablished.

* **Age:** Older adults, the primary target population, generally have higher baseline kynurenine pathway activity and oxidative burden, which could amplify either the protective or the harmful arm of 3HAA's action; this is inferred, not measured.

## Key Interactions & Contraindications

* **Prescription drug interactions:** No human interaction studies exist. Theoretical caution applies with drugs that affect the kynurenine pathway or metal handling, including IDO/TDO-modulating agents used in oncology (the enzymes that open the pathway) and copper-chelating drugs such as penicillamine and trientine; the consequence would be unpredictable shifts in pathway metabolites.

* **Over-the-counter medication interactions:** No documented interactions. High-dose iron or copper supplements are a theoretical concern because 3HAA's pro-oxidant toxicity is metal-catalyzed; combining them could in principle increase reactive-oxygen-species generation. Caution and separation are reasonable.

* **Supplement interactions:** No documented interactions. Antioxidant supplements (e.g., N-acetylcysteine, vitamin C) could theoretically blunt the hormetic, NRF2-activating mechanism thought to drive 3HAA's benefits, while metal-containing supplements could amplify its pro-oxidant risk.

* **Additive effects:** Other NRF2-activating compounds (e.g., sulforaphane from broccoli sprouts, curcumin from *Curcuma longa*) could have additive effects on the same antioxidant-response pathway 3HAA is proposed to engage, with unknown combined consequences.

* **Other intervention interactions:** Endurance exercise itself raises 3HAA, so combining supplementation with intensive training would stack two inputs to the same metabolite, with effects that have not been studied.

* **Populations who should avoid it:** Pregnant or breastfeeding individuals, children, people with copper or iron overload disorders, and anyone with active cancer or significant neurodegenerative or autoimmune disease should avoid 3HAA, given the complete absence of human safety data and the pathway's involvement in immune regulation.

* **Severity and consequence:** All interactions above are classified as caution-level and theoretical, because no clinical interaction has been observed; the potential clinical consequence is increased oxidative damage or unpredictable immune modulation.

* **Specific thresholds:** Because no human dosing or toxicity thresholds exist, the only defensible classifications are categorical — avoid entirely in the populations listed above and in anyone with diagnosed iron-overload (e.g., ferritin and transferrin saturation in the hemochromatosis range) or copper-overload conditions.

## Risk Mitigation Strategies

* **Separation from metal supplements:** Because 3HAA's pro-oxidant toxicity is copper- and iron-catalyzed, the relevant mitigation is non-coadministration with high-dose iron or copper supplements; separating any unavoidable metal intake by several hours reduces metal-driven reactive-oxygen-species generation.

* **Baseline metal-status screening:** Measuring baseline ferritin, transferrin saturation, and copper before any exposure identifies individuals with undiagnosed iron or copper overload, the group at greatest theoretical risk of pro-oxidant harm.

* **Lowest conceivable exposure:** With no established human dose, the mitigation favored in the literature is the smallest amount and infrequent use, since the hormetic mechanism implies that modest, not maximal, exposure is what may benefit cells — reducing the risk of tipping 3HAA from protective into toxic, pro-oxidant territory.

* **Exercise as an alternative lever:** Endurance training raised blood 3HAA by 85–134% over six months with an established safety record, offering a way to elevate the metabolite that sidesteps the unknown risks of unstudied oral supplementation.

* **Exclusion of vulnerable populations:** Excluding pregnant or breastfeeding people, children, and those with cancer, active autoimmunity, or neurodegenerative disease limits exposure in groups where the kynurenine pathway's role in immune and neural regulation makes unintended harm most plausible.

* **Symptom surveillance:** Because of the theoretical link to quinolinic-acid excitotoxicity, surveillance for new neurological symptoms (headache, cognitive changes), with discontinuation if they arise, addresses the risk of unrecognized downstream toxicity.

## Therapeutic Protocol

There is no validated human therapeutic protocol for 3HAA. The points below describe what is and is not known, framed for readers evaluating a frontier intervention.

* **Standard protocol used by practitioners:** None exists. 3HAA is not an established clinical or supplement intervention; no leading practitioner or clinic publishes a 3HAA dosing protocol, because human use has not been studied.

* **Competing approaches:** Two conceptual routes to raising 3HAA are discussed in the research literature without either being framed as standard — direct dietary supplementation of 3HAA (used in aging mice) versus inhibiting the HAAO enzyme so endogenous 3HAA accumulates (modeled genetically in worms and mice). A third, indirect route is endurance exercise, which raises 3HAA naturally in humans.

* **Expert or clinic that popularized each approach:** The lifespan-extension and dietary-supplementation work was led by the Sutphin laboratory (University of Arizona) in collaboration with The Jackson Laboratory; the human exercise findings come from the Zimmer/Joisten groups at TU Dortmund and the University of Göttingen. No clinic offers 3HAA therapeutically.

* **Best time of day:** Unknown; no chronobiology data exist for 3HAA dosing.

* **Expected half-life:** As the substrate of HAAO, free 3HAA is cleared within seconds to minutes, which is a central practical obstacle — orally supplied 3HAA would be rapidly metabolized, a key reason researchers have explored HAAO inhibition rather than supplementation alone.

* **Single versus split dosing:** Undetermined. The very short half-life implies that any sustained elevation would require either continuous delivery or enzyme inhibition rather than a single oral dose, but no human dosing schedule has been tested.

* **Genetic polymorphisms:** Variants in HAAO, KYNU, and KMO could influence baseline 3HAA and the response to any intervention, but no pharmacogenetic dosing guidance exists.

* **Sex-based differences:** Pilot mouse data suggested sex influenced which route produced longevity effects (HAAO knockout in females, dietary 3HAA in aging males), but this has not been translated into human dosing guidance.

* **Age-related considerations:** Animal benefits were concentrated in older animals, so older adults are the population in whom any future protocol would most plausibly be aimed; no age-specific human dosing is established.

* **Baseline biomarker levels:** Baseline oxidative-stress markers and kynurenine-to-tryptophan ratio could in theory guide who might respond, but no biomarker-guided protocol has been validated.

* **Pre-existing health conditions:** The cardiovascular, autoimmune, and neurodegenerative contexts where animal benefits appeared would shape any future indication, but no condition-specific human protocol exists.

## Discontinuation & Cycling

* **Lifelong versus short-term use:** Undetermined. Animal benefits derived from chronic elevation (genetic knockout or continuous dietary supplementation), suggesting sustained exposure may be required for longevity effects, but no human data define an appropriate duration.

* **Withdrawal effects:** None are known or expected; 3HAA is a normal endogenous metabolite that the body continuously produces and clears, so stopping supplementation would simply return levels toward baseline. No withdrawal syndrome has been described.

* **Tapering protocol:** Not applicable; given rapid clearance and the absence of dependence, no taper would be physiologically necessary. This is inferred from its short half-life rather than from human studies.

* **Cycling:** Whether cycling preserves any hormetic benefit is unstudied. Because the proposed mechanism is a stress-response that could theoretically adapt with constant exposure, intermittent use is a reasonable hypothesis, but there is no evidence to recommend a specific cycling pattern.

## Sourcing and Quality

* **Source and form:** 3HAA is available only as a research-grade laboratory chemical (e.g., from chemical-reagent suppliers), not as a regulated dietary supplement manufactured for human consumption; this is the central sourcing limitation and a strong reason for caution.

* **What to look for:** Because no human-grade product exists, there is no third-party-tested consumer supplement to evaluate; research chemicals carry purity certificates (e.g., ≥98% by HPLC, high-performance liquid chromatography, a standard lab method for measuring purity) intended for laboratory use, not assurances of safety or suitability for ingestion.

* **Purity and contamination concerns:** Research-grade material may contain residual solvents, heavy metals, or synthesis byproducts not screened to food-supplement standards; the metal-contamination concern is amplified by 3HAA's metal-catalyzed pro-oxidant chemistry.

* **Reputable brands or compounding pharmacies:** No reputable supplement brand or compounding pharmacy is known to produce 3HAA for human use; the absence of a legitimate consumer supply chain is itself a key finding of this section.

## Practical Considerations

* **Time to effect:** Unknown in humans. In animals, longevity and healthspan effects were measured over the lifespan, and atherosclerosis benefits appeared over eight weeks of treatment in mice; no human time-to-benefit has been established.

* **Common pitfalls:** The most common conceptual error is treating 3HAA as a ready-to-use longevity supplement — it is an early-stage research metabolite with no human dosing, rapid breakdown in the body, and no consumer-grade product. Another pitfall is assuming "more is better," when the proposed mechanism is hormetic and excessive amounts may be pro-oxidant or toxic.

* **Regulatory status:** 3HAA is not approved or regulated as a drug or dietary supplement for human use by the FDA or comparable agencies; it exists in a regulatory gap as a research chemical, and any human use is entirely off-label and unsanctioned.

* **Cost and accessibility:** As a research reagent, 3HAA is relatively inexpensive per gram but is not sold through normal supplement channels; accessibility for legitimate, safe human use is effectively nil, which is the dominant practical barrier rather than cost.

## Interaction with Foundational Habits

* **Sleep:** Indirect interaction. The kynurenine pathway connects to serotonin and melatonin metabolism through shared tryptophan precursor, so shifting tryptophan toward the kynurenine branch could in theory affect sleep-related metabolites; no direct evidence shows 3HAA itself improves or disrupts sleep, so the practical effect is unknown.

* **Nutrition:** Direct interaction. 3HAA is made from dietary tryptophan, so protein and tryptophan intake set the raw material for the whole pathway; additionally, dietary copper and iron are practically important because they catalyze 3HAA's pro-oxidant chemistry, making it sensible to avoid taking 3HAA alongside high-metal meals or supplements.

* **Exercise:** Direct, potentiating interaction. Endurance exercise raised blood 3HAA by 85–134% over six months in middle-aged adults, meaning exercise and 3HAA push the same metabolite in the same direction; this makes exercise both a natural way to raise 3HAA and a confounder for anyone trying to attribute effects to supplementation. Timing relative to any dosing is unstudied.

* **Stress management:** Indirect interaction. Psychological stress and inflammation activate the kynurenine pathway (via cortisol and immune signaling), which can raise pathway metabolites including 3HAA; whether managing stress meaningfully changes 3HAA levels or its effects is not established, so the proposed mechanism is plausible but unproven.

## Monitoring Protocol & Defining Success

Because 3HAA has no validated human use, the monitoring framework below is precautionary, aimed at detecting harm and tracking the biological systems 3HAA is proposed to influence rather than confirming an approved therapeutic effect.

Before any experimental use, baseline testing should establish metal status and the markers of oxidative stress and inflammation that the kynurenine pathway influences, so that any change can be interpreted and so that contraindicated individuals (iron or copper overload) are identified. Ongoing monitoring, if used at all, should occur at baseline, at roughly 4–8 weeks, and then every 3–6 months, with prompt re-checking if any new symptom arises.

* **Baseline labs:** ferritin, transferrin saturation, serum copper/ceruloplasmin, high-sensitivity CRP (C-reactive protein), complete blood count, and comprehensive metabolic panel.

* **Ongoing labs:** repeat the inflammatory and metal markers and liver and kidney function on the cadence above.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
|-----------|--------------------------|-----------------|---------------|
| Ferritin | 30–150 ng/mL (women), 50–200 ng/mL (men) | Screens for iron overload that amplifies 3HAA pro-oxidant risk | Acute-phase reactant; pair with transferrin saturation; conventional upper limit (~300–400) is far higher than the functional ceiling |
| Transferrin saturation | 20–40% | Detects iron overload (hemochromatosis) before symptoms | Fasting morning draw preferred; >45% warrants avoidance of 3HAA |
| Serum copper / ceruloplasmin | Copper 70–140 µg/dL | Identifies copper excess that catalyzes 3HAA toxicity | Interpret together; supplement metals separately from any 3HAA |
| hs-CRP (high-sensitivity C-reactive protein) | <1.0 mg/L | Tracks systemic inflammation 3HAA is proposed to lower | Avoid testing during acute illness; fasting not required |
| ALT/AST | <25 U/L | Surveillance for unstudied hepatic effects | Liver enzymes; conventional reference upper limit (~40) is higher than the optimal functional ceiling |
| eGFR | >90 mL/min/1.73m² | Surveillance for unstudied renal effects | Estimated glomerular filtration rate, a measure of kidney function; affected by hydration and recent high protein intake |

* **Qualitative markers:**

  - Energy and vitality through the day
  - Cognitive clarity and absence of new neurological symptoms (a precaution against theoretical quinolinic-acid effects)
  - Sleep quality
  - Exercise recovery and tolerance

Defining success is necessarily provisional: in the absence of approved endpoints, "success" would mean stable or improved inflammatory and metabolic markers, no deterioration in liver, kidney, or neurological status, and subjective wellbeing — not any proven extension of human lifespan, which current evidence cannot demonstrate.

## Emerging Research

Research on 3HAA is at an early, rapidly evolving stage, and the items below reflect studies and directions that could strengthen or weaken the case for it.

* **No interventional human trials registered:** A search of ClinicalTrials.gov found no registered trials testing 3HAA supplementation or HAAO inhibition as an intervention in humans; current human-facing studies measure kynurenine pathway metabolites observationally rather than dosing 3HAA. This absence is itself a key finding and a barrier to translation.

* **Translation of the longevity mechanism to mammals:** The pivotal report by [Dang et al., 2023](https://pubmed.ncbi.nlm.nih.gov/38097593/) established the worm lifespan effect and pilot mouse data; the central future question is whether adequately powered mammalian lifespan studies confirm the effect — a result that could substantially strengthen the case. The same work could weaken it if larger mouse cohorts fail to replicate the pilot findings.

* **Neurodegeneration models:** [Hull et al., 2024](https://pubmed.ncbi.nlm.nih.gov/38786006/) showed 3HAA delays proteotoxic paralysis in worm Alzheimer's and Huntington's models; future research extending this to mammalian neurodegeneration models will determine whether the protective signal survives in more complex nervous systems, and the pro-oxidant/quinolinic-acid literature provides the counter-hypothesis that it may not.

* **Immune and aging biology:** A bioRxiv preprint by [Espejo et al., 2024](https://pubmed.ncbi.nlm.nih.gov/38260592/) (not yet peer-reviewed) reported that 3HAA improves aging immune function and has antimicrobial activity in worms via tissue compartmentalization; whether an analogous, evolutionarily conserved immune role exists in mammals is an open area that could cut either way given the pathway's dual role in immune tolerance and tumor immune evasion.

* **Exercise as a natural lever:** [Joisten et al., 2025](https://pubmed.ncbi.nlm.nih.gov/40178293/) demonstrated that endurance training raises human 3HAA by 85–134%, opening the question of whether 3HAA mediates measurable longevity benefits of exercise; confirming a causal mediating role would strengthen interest, while finding it is merely a passive marker would weaken the supplementation rationale.

* **Enzyme-targeting drug development:** Reviews such as [Pocivavsek et al., 2024](https://pubmed.ncbi.nlm.nih.gov/39304346/) highlight HAAO and other kynurenine pathway enzymes as emerging pharmacological targets; future selective HAAO inhibitors could test the "raise endogenous 3HAA" hypothesis more cleanly than supplementation, and their safety profiles will be decisive.

## Conclusion

3HAA is a small molecule the body naturally makes when it breaks down a dietary protein building block. Long dismissed as a throwaway step, it has drawn fresh attention because raising its levels made laboratory worms and mice live longer and stay healthier, and because the same molecule rises in people's blood after months of regular exercise. The most striking proposed action is that 3HAA switches on the body's built-in defenses against cellular damage, while also directly mopping up a harmful reactive chemical.

The evidence, however, is early and mixed. Every claim of benefit — longer life, healthier arteries, calmer inflammation, protection of nerve cells — rests on animal, cell, or test-tube work, with no human trials of 3HAA as a supplement. At the same time, the very chemistry behind its benefits can turn harmful in the presence of certain metals, and it sits just upstream of a nerve-damaging compound, so its overall effect appears to depend heavily on dose and circumstance and is genuinely debated.

Practically, 3HAA is broken down within seconds in the body, exists only as a research chemical rather than a tested supplement, and has no human dosing or safety record. It is best understood today as a promising but unproven research metabolite, with raising it through exercise being the one approach backed by human data.

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