Tier 3 — preclinical

Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice

Korstanje R, Strong R, Salmon AB, Bogue MA, Curran SP, Diaz V, Fernandez E, Ginsburg B, Han M, Harrison DE, Kaczorowski C, Kaeberlein M, Kennedy BK, Kumar N, LaCroix-Fralish M, Leiser SF, Nelson JF, Polymenis M, Reifsnyder PC, Rosenthal NA, Silva E, Tower J, Miller RA
GeroScience 2026 48(3):3821-3830

Bibliography

PubMed
PMID 41843349
PubMed Central
PMC13356140
DOI
10.1007/s11357-026-02201-2
Funding
Funded in part by NIA grants AG022308 (Ron Korstanje), AG022303 (Richard A. Miller), AG066346 (Mary Bogue), AG022307 and AG013319 (Randy Strong), with facilities supported by CA034196 (The Jackson Laboratory) and AG024824 (University of Michigan). Randy Strong is supported by a Senior Research Career Scientist Award from the U.S. Department of Veterans Affairs Office of Research and Development.
Competing interests
The authors declared no competing interests.

Study snapshot

DesignMulti-site NIA Interventions Testing Program lifespan experiment in genetically heterogeneous UM-HET3 mice.
ModelMale and female UM-HET3 mice across three ITP sites.
SampleLarge multi-site ITP lifespan cohort; detailed sex- and site-specific group sizes are reported in the paper.
InterventionDietary alpha-ketoglutarate at 20,000 ppm starting at 7 months of age.
DurationFrom 7 months of age until death.
EndpointsMedian lifespan; Survival distribution; Sex-specific lifespan effects

What the study showed, in plain terms

This 2026 ITP paper repeated the alpha-ketoglutarate lifespan question with treatment beginning much earlier, at 7 months of age.

AKG was again given at 20,000 ppm in food to genetically heterogeneous UM-HET3 mice across the standardized multi-site ITP network.

The result remained negative: AKG did not increase lifespan. Together with the 2024 late-start ITP experiment, this makes the mouse-longevity literature mixed rather than uniformly positive.

Key findings

  • AKG at 20,000 ppm from 7 months of age did not increase lifespan in either sex.
  • Starting supplementation earlier did not rescue the null lifespan result seen in the prior late-start ITP cohort.
  • This provides an independent, multi-site failure to reproduce the lifespan extension reported in the earlier C57BL/6J study.

What this study can and cannot tell us

  • The finding is specific to the UM-HET3 mouse model and cannot establish human longevity effects.
  • The study tests lifespan, not every possible healthspan or tissue-specific effect of AKG.
  • Dietary AKG in mice is not identical to a commercial delayed-release Ca-AKG capsule.

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Editorial review

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology