Tier 3 — preclinical

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestradiol, and late-start canagliflozin

Miller RA, Harrison DE, Cortopassi GA, Dehghan I, Fernandez E, Garratt M, Geisler JG, Ginsburg BC, Han ML, Jiang N, Kaczorowski CC, Kumar N, Leiser SF, Lopez-Cruzan M, Milne G, Mitchell JR, Nelson JF, Reifsnyder PC, Salmon AB, Xu Z, Korstanje R, Rosenthal N, Strong R
GeroScience 2024 46(5):4657-4670

Bibliography

PubMed
PMID 38753230
PubMed Central
PMC11336000
DOI
10.1007/s11357-024-01176-2
Funding
Supported by NIH grants AG022308 (David E. Harrison), AG022303 (Richard A. Miller), AG022307 and AG013319 (Randy Strong), and AG062817 (Gino A. Cortopassi).
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 studied across three independent ITP sites.
SampleLarge multi-site ITP lifespan cohort; sex- and site-specific group sizes are reported in the paper.
InterventionDietary alpha-ketoglutarate at 20,000 ppm starting at 18 months of age.
DurationFrom 18 months of age until death.
EndpointsMedian lifespan; Survival distribution; Sex-specific lifespan effects

What the study showed, in plain terms

This 2024 Interventions Testing Program paper tested alpha-ketoglutarate in genetically heterogeneous UM-HET3 mice, a more diverse and highly standardized model than the inbred C57BL/6J mice used in the widely cited 2020 Ca-AKG lifespan study.

AKG was provided in food at 20,000 ppm beginning at 18 months of age. Unlike the earlier report, the ITP experiment found no lifespan benefit in either sex.

For Ca-AKG claims, this is important replication evidence: a lifespan signal in one mouse background did not reproduce in a large, multi-site genetically heterogeneous mouse program.

Key findings

  • AKG at 20,000 ppm started at 18 months did not increase lifespan in either male or female UM-HET3 mice.
  • The experiment was run across the three NIA ITP sites, reducing dependence on a single laboratory or inbred strain.
  • The null result directly qualifies broad statements that AKG 'extends lifespan in mice'.

What this study can and cannot tell us

  • This is preclinical evidence and does not test Ca-AKG supplementation in humans.
  • AKG was started late in life, at 18 months, so it does not exclude an effect from earlier lifelong exposure.
  • The paper tested several interventions simultaneously; AKG was one arm within a broader ITP study.

Citation network

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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