Aging accelerates nearly all chronic diseases, so finding common mechanisms to slow aging is crucial for medicine. The ITP program has already identified several substances that extend mouse lifespan, but the molecular footprints of these interventions across different tissues are poorly studied. This work stands somewhat apart: neighboring studies in the archive deal with cellular fluidity, epigenetic aging, and predicting therapy response, but they do not provide a multi-tissue metabolic portrait of longevity.
Male UM-HET3 mice were fed rapamycin, acarbose, 17α-estradiol, canagliflozin, or subjected to 40% caloric restriction starting at 4 months of age. At 12 months, plasma, fat, brain, liver, muscle, and kidney were collected. Metabolites were measured by mass spectrometry. To predict lifespan extension, gradient boosting with XGBoost was used. To ensure that metabolite ranking did not depend on random initial parameters, the model was run 1000 times and median feature importance values were taken.
The model distinguished mice with any of the five interventions from controls in all seven tissues. Among the metabolites explaining half of the predictive power, only two appeared in multiple tissues: ergothioneine and diacylglycerol DG 43:8. Ergothioneine was elevated in brain and plasma under all five interventions, and in muscle under four. Cardiolipin 72:8 increased in muscle under all interventions. In plasma, a shift toward long-chain polyunsaturated triacylglycerols was confirmed.
The work shows that different life-extending approaches cause similar metabolic shifts, although most changes are tissue-specific. Unlike neighboring studies that examined a single tissue or one type of intervention, this study systematically compares seven tissues and five interventions using one method for the first time. This allows separating common markers of longevity from specific effects of a particular drug.
The method can be applied to humans: measure metabolites in blood after a short course of a drug and compare with profiles of long-lived mice. This will speed up the selection of anti-aging drug candidates. Validation on other mouse strains and on drugs that do not extend lifespan will be needed to confirm specificity.
The results will influence gerontology, the pharmacology of aging, and the development of age biomarkers.
Test whether the model can distinguish drugs that do not affect lifespan, and replicate the analysis in females and other mouse strains.
It remains unclear whether the identified metabolites are the cause of slowed aging or a consequence of protective processes. The issue of sex differences is unresolved: in females, the model did not work, pointing to unknown mechanisms of action of the interventions.
Ergothioneine is an antioxidant that mammals cannot synthesize themselves. It is produced by fungi, and mice obtain it from food via a special transporter, OCTN1.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.