Astaxanthin and meclizine extend lifespan in UM-HET3 male mice (Harrison et al. 2024 — ITP)
TL;DR
NIA Interventions Testing Program (ITP) multi-site lifespan cohort testing nine compounds in genetically heterogeneous UM-HET3 mice. Astaxanthin extended median male lifespan by 12% (p=0.003); meclizine by 8% (p=0.03) — both male-specific, not significant in females. Fisetin failed to extend lifespan in either sex at 600 ppm under two dosing schedules (continuous or cyclic); a separate biomarker sub-cohort showed fisetin also failed to reduce p16^Ink4a mRNA in kidney, brain, or liver. The remaining five compounds (SG1002, dimethyl fumarate, mycophenolic acid, 4-phenylbutyrate) were also null. The fisetin null result is a direct rebuttal to yousefzadeh-2018-fisetin-senolytic under the more stringent ITP design.
⚠️ Replication status (2026): the astaxanthin and meclizine positives did NOT replicate. The next ITP cohort — Korstanje et al. 2026 (GeroScience; same program, UM-HET3) — reported that astaxanthin and meclizine do not increase lifespan (its title lists both among eight null compounds) 1. An apparent astaxanthin female-lifespan-harm signal in the pooled 3-site analysis did not survive a 2-site sensitivity reanalysis excluding JAX (where anomalously long control-female survival inflated it) — so it is likely a site artifact, not genuine toxicity (mitoglitazone and pioglitazone female harm did persist). Both compounds are therefore now single-positive-cohort + failed-replication → contested (#gap/contradictory-evidence). The fisetin null, by contrast, is consistent across cohorts. This is the ITP’s false-positive-control design working as intended — a single-cohort ITP positive is a lead, not a verdict. See korstanje-2026-itp-null-cohort, astaxanthin, meclizine.
ITP Design Rationale
The NIA Interventions Testing Program (ITP) is considered the highest-rigor preclinical lifespan testing platform available. Key design features:
- Three independent sites conducting identical protocols simultaneously: The Jackson Laboratory (JAX), UT Health San Antonio, and University of Michigan (UM). A positive result must be consistent across sites to be credited.
- Genetically heterogeneous UM-HET3 mice: four-way F1 cross (BALB/cByJ × C57BL/6J) × (C3H/HeJ × DBA/2J). This stock captures polygenic variation similar to outbred humans, reducing the risk of strain-specific artifacts that plague inbred strains. Results generalize more broadly than C57BL/6 inbred data.
- Both sexes tested in all arms, enabling detection of sex-specific effects.
- Rigor over throughput: ITP deliberately runs fewer compounds per cohort to maintain large n and multi-site replication, accepting false-negative risk in exchange for false-positive reduction.
Compounds Tested and Schedules
| Compound | Dose (target ppm) | Dose (achieved ppm) | Diet start age | Schedule |
|---|---|---|---|---|
| Astaxanthin (Asta) | 4000 | ~1840 (46% of target) | 12 months | Continuous |
| Meclizine (Mec) | 800 | ~544 (68% of target) | 12 months | Continuous |
| Fisetin (Fis_On) | 600 | ~594 (99% of target) | 20 months | Continuous |
| Fisetin (Fis_Cyc) | 600 | ~594 (99% of target) | 20 months | Cyclic: 3 days on / 11 days off |
| SG1002 (H₂S donor) | 240 | Not measurable | 18 months (C2018); 5–9 months (C2019) | Continuous |
| Dimethyl fumarate (DMF_early) | 120 | ~42 (35% of target) | 10 months | Continuous |
| Dimethyl fumarate (DMF_16) | 120 | ~42 (35% of target) | 16 months | Continuous |
| Mycophenolic acid (MPA) | 6.7 | ~6.1 (91% of target) | 9 months | Continuous |
| 4-Phenylbutyrate (PBA) | 1000 | ~1070 (107% of target) | 9 months | Continuous |
Note: astaxanthin achieved only ~46% of target concentration — the drug is difficult to incorporate homogeneously into rodent chow. The paper reports this as the actual diet ppm, not the intended amount.
Key Results
Positive: Astaxanthin (males only)
astaxanthin extended median male lifespan by 12% (pooled across 3 sites; log-rank test p=0.003). Site-specific effects were consistent: JAX +11%, UT +11%, UM +14% — a hallmark of ITP credibility. The 90th percentile lifespan (maximum lifespan proxy) showed a non-significant +6% increase (Wang-Allison test p=0.19).
Female astaxanthin: median lifespan +3%, p=0.64 — not significant. The male specificity is unexplained but mirrors patterns seen with other ITP compounds (e.g., rapamycin shows larger male benefit in some cohorts).
Positive: Meclizine (males only)
meclizine extended median male lifespan by 8% (pooled; log-rank test p=0.03). Site effects: JAX +15%, UM +11%, UT 0% — less consistent than astaxanthin, with UT contributing a null. Plasma blood levels confirmed exposure: males 174 ± 77 ng/ml, females 115 ± 100 ng/ml. The lower female exposure may partly explain sex specificity, though pharmacokinetic differences between sexes are common for antihistamines. The 90th percentile lifespan showed a non-significant +6% (Wang-Allison p=0.14).
Meclizine is an H1 antihistamine historically used for motion sickness; its mechanism of lifespan extension is not established in this paper and represents a potential discovery target. gap/no-mechanism
Null: Fisetin (both sexes, two dosing schedules)
fisetin at 600 ppm (99% target dose achieved) — the highest fidelity of any tested compound in this cohort — did not extend lifespan in males or females under either a continuous (Fis_On) or cyclic 3-day-on/11-day-off (Fis_Cyc) schedule:
| Arm | Sex | Median Δ | Log-rank p |
|---|---|---|---|
| Fis_On | Male | −5% | p=0.85 |
| Fis_Cyc | Male | +7% | p=0.54 |
| Fis_On | Female | +1% | p=0.37 |
| Fis_Cyc | Female | −1% | p=0.75 |
Dosing started at 20 months (late-life initiation). The paper does not report an explicit mg/kg/day conversion for 600 ppm in UM-HET3 mice; no such figure appears in the text. By standard mouse food-intake estimates (~3–4 g/day at ~30 g body weight), 600 ppm corresponds to approximately 60–80 mg/kg/day — well above the threshold used in Yousefzadeh 2018 (~60 mg/kg/day at 500 ppm) and within the range expected to reach pharmacologically relevant concentrations if fisetin’s senolytic activity were operative in this context.
Fisetin p16^Ink4a Biomarker Sub-cohort
In a separate sub-cohort of mice aged 22–24 months treated for 2–4 months on the same Fis_On and Fis_Cyc schedules, the paper performed qPCR of p16^Ink4a mRNA in kidney, brain, and liver — three tissues that show aging-associated p16 induction:
“Neither of the two groups of Fis-treated mice had significantly lower numbers of p16^Ink4a-positive cells, compared to age-matched untreated control mice.”
(Terminology note: the paper uses the phrase “numbers of p16^Ink4a-positive cells” but the actual assay was qPCR measuring p16^Ink4a mRNA levels, expressed as cycle threshold (CT) values — not an IHC cell count or flow-cytometric cell enumeration. No individual senescent cells were counted. The paper’s own language is imprecise; the finding is that fisetin did not significantly reduce bulk tissue p16^Ink4a mRNA compared to untreated aged controls.)
p21^Cip1 showed no age-related increase in these tissues, making it an insensitive endpoint. The p16 qPCR failure for fisetin is a direct biomarker-level challenge to the senolytic mechanism proposed in Yousefzadeh 2018, which showed p16+ cell clearance in C57BL/6 mice at 100 mg/kg gavage. Key differences between experiments:
- Strain: UM-HET3 heterogeneous (Harrison 2024) vs inbred C57BL/6 (Yousefzadeh 2018)
- Dosing route: dietary 600 ppm (Harrison 2024) vs gavage 100 mg/kg × 5 days (Yousefzadeh 2018)
- Age at start: 20 months (Harrison 2024) vs 22–24 months (Yousefzadeh 2018)
- Duration: 2–4 months continuous or cyclic (Harrison 2024) vs acute 5-day course (Yousefzadeh 2018)
Whether strain background, bioavailability from chow vs gavage, or dosing regimen explains the discrepancy is unresolved. gap/contradictory-evidence
Null: SG1002 (Hydrogen Sulfide Donor)
SG1002 at 240 ppm (achieved concentration not measurable by plasma assay) did not extend lifespan in either sex in two separate cohort-years (C2018 starting at 18 months; C2019 starting at 5–9 months). The inability to confirm tissue exposure limits interpretability. gap/dose-response-unclear
Null: Dimethyl Fumarate
Dimethyl fumarate (DMF) at 120 ppm target achieved only ~35% of target (~42 ppm actual), in both early-start (10 months) and late-start (16 months) arms. No lifespan extension in either sex. Authors note the low achieved concentration may explain the null result — not a definitive rejection of DMF as an aging intervention. gap/dose-response-unclear
Null: Mycophenolic Acid
Mycophenolic acid at 6.7 ppm (91% target achieved) did not extend lifespan. Full target dose achieved; null result is interpretively cleaner than DMF.
Null: 4-Phenylbutyrate (with Female Harm Signal)
4-Phenylbutyrate at 1000 ppm (107% target achieved) did not extend lifespan in males. It reduced female median lifespan by 2% (p=0.01) — a small but statistically significant harm signal in one sex. The mechanism for sex-specific harm is not established.
Extrapolation to Humans
| Dimension | Status | Notes |
|---|---|---|
| Pathway conserved in humans? | yes | Oxidative stress, senescence biology, and the general aging biology tested here are conserved |
| Phenotype conserved in humans? | unknown | Lifespan extension in heterogeneous mice is closer to human biology than inbred data, but direct human evidence absent for these compounds in aging |
| Replicated in humans? | no | No human aging trials for astaxanthin/meclizine as lifespan interventions; fisetin human senolytic trials underway (see fisetin) but prior to ITP null |
Limitations
- All findings are in mice; zero human aging evidence.
- Astaxanthin target dose was poorly achieved (46% of intended); actual effective ppm is lower than planned. Positive result stands but optimal dose is uncertain.
- Meclizine’s lifespan effect shows site heterogeneity (UT site 0% effect); the pooled result is significant but less robust than astaxanthin’s cross-site consistency.
- Fisetin was tested starting at 20 months (late-life); earlier initiation might yield different results, though the Yousefzadeh 2018 result that this replicates used a similarly late 85-week (~20-month) start.
- DMF null result is confounded by low achieved dietary concentration.
- The p16 sub-cohort for fisetin used qPCR on bulk tissue RNA, which may be less sensitive than single-cell or flow-cytometric approaches for detecting small reductions in rare p16+ cell populations.
- Meclizine mechanism of action unknown; cannot rule out off-target effects explaining lifespan result.
- ITP does not measure cause-specific mortality, body composition changes, or molecular biomarkers as part of its standard lifespan protocol beyond the designated sub-cohorts.
Implications for the Wiki
This paper is the critical counter-data point for the fisetin compound page’s senolytic claims. The Yousefzadeh 2018 finding that fisetin extends lifespan in mice came from small n (8–9/group), a single inbred background (C57BL/6), and a single lab — exactly the conditions the ITP is designed to stress-test. The ITP null at comparable dose and start age, with biomarker confirmation of no p16 reduction, substantially weakens the case for fisetin as a mouse lifespan extender and argues against direct translation of the 2018 result to aging-relevant human trials.
The astaxanthin and meclizine positive results in males represent two new ITP-validated compounds warranting mechanism studies and potential human aging trial design, though neither currently has a compound page in this wiki. gap/stub astaxanthin meclizine
Cross-References
- fisetin — compound page; human trial status; see Limitations for ITP vs Yousefzadeh 2018 discordance
- cellular-senescence — proposed mechanism for fisetin arm
- yousefzadeh-2018-fisetin-senolytic — the 2018 study whose lifespan claim is challenged here
- deregulated-nutrient-sensing — potential mechanism for astaxanthin (Nrf2/oxidative stress axis)
- mtor — potential pathway for meclizine effects (see gap/no-mechanism above)
Citations
Footnotes
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korstanje-2026-itp-null-cohort · doi:10.1007/s11357-026-02201-2 · PMID 41843349 · Korstanje R, Strong R, Salmon AB, … Harrison DE, … Miller RA · GeroScience 2026 (online 2026-03-17) · in-vivo, NIA Interventions Testing Program (UM-HET3) · title: “Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice” — direct non-replication of the astaxanthin + meclizine positives in this cohort; possible female harm signal for astaxanthin · seeded 2026-06-30, verified: false (full-text/dose-detail verifier pass pending). ↩