Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing.
Level 5 - mechanism / opinion, no new human data
Mechanistic laboratory and animal research (in vitro, nematodes, flies, mice) without human data.
PubMed 39695235 · doi:10.1038/s41586-024-08348-2
What was done
Researchers investigated the molecular pathway through which lithocholic acid (LCA) activates AMP-activated protein kinase (AMPK). Using co-immunoprecipitation proteomics with sirtuin 1 (SIRT1), they identified TUB-like protein 3 (TULP3) as an LCA receptor. They assessed downstream deacetylation of vacuolar H+-ATPase (v-ATPase) and tested the physiological effects of a muscle-specific deacetylation-mimic mutant (V1E1 3KR) in aged mice, as well as LCA treatment in nematode (*Caenorhabditis elegans*) and fruit fly (*Drosophila*) models.
What was found
No quantitative effect sizes or numerical values are reported in the abstract. Mechanistically, LCA-bound TULP3 allosterically activated sirtuins to deacetylate the V1E1 subunit of v-ATPase at residues K52, K99, and K191, inhibiting v-ATPase and triggering AMPK activation via lysosomal glucose-sensing. In aged mice, expressing the 3KR mutant in muscle activated AMPK and rejuvenated muscle tissue. In nematodes and flies, LCA extended lifespan and healthspan in a manner dependent on the TULP3 homologues *tub-1* and *ktub*, respectively.
Why it matters
The study identifies a specific bile-acid-sensing molecular cascade (TULP3-sirtuin-v-ATPase-AMPK) that mimics the longevity and metabolic benefits of calorie restriction in preclinical models.
Limits
The abstract provides no sample sizes, effect sizes, survival curves, or statistical metrics. All findings are restricted to cell, invertebrate, and rodent models; translation to human biology, dosing, and safety is untested.
Cited by
- supports Fasting increases bile secretion, and the microbiome converts cholic acid from bile into a metabolite that enters the bloodstream and directly binds to and activates SIRT1.