People who retain physical strength in old age show a slower age-related rise in kynurenine, a marker of chronic inflammation, than those who lose strength faster: a preprint from 28 years of follow-up in Rancho Bernardo, San Diego
People who retain physical strength in old age show a slower age-related rise in kynurenine (a marker of chronic inflammation) than those who lose strength faster, according to a preprint from a 28-year follow-up of Rancho Bernardo residents in San Diego
On September 21, researchers from the US and the Netherlands published a preprint: they measured more than 22,000 molecules in blood samples collected across three visits by participants of the Rancho Bernardo Study and compared them with each person's trajectory of grip strength and chair-rise speed. Acylcarnitines were more often elevated in people with low resilience; phosphocholines were higher in those who retained strength.
Older adults with similar baseline health age differently: some maintain strength for years and live independently, while others fall more often, are hospitalized more frequently, and die earlier than their peers. This difference is called physical resilience. Its biochemistry has been barely studied: the only prior work looked at a single class of lipid molecules and found only ceramides.
This preprint took a different approach: instead of one class of molecules, the authors screened nearly the entire serum metabolome, 22,736 features. They needed a cohort with visits spanning many years. The Rancho Bernardo Study has followed 6,726 residents of the community (82% of its adult population) every four years for over forty years since 1972; the same laboratory had already applied the resilience protocol to memory and cognition. From the archive, the authors selected 237 individuals with samples from three visits and computed a resilience score for each.
A statistical model identified 2,810 of the 22,736 molecules as associated with physical resilience. Medium-chain acylcarnitines, carriers of fatty acids into mitochondria, were higher in people with low resilience, a sign of incomplete fat oxidation. On the same day, a separate preprint showed that activating the receptor OR10J5 in aged mice triggered mitochondrial biogenesis and restored grip strength to young-adult levels. Phosphocholines, lipid components of cell membranes, were, by contrast, higher in those who retained resilience.
Of five tryptophan derivatives, only kynurenine showed a different rate of age-related increase between groups: in people with low resilience it rose more steeply across all visits. Kynurenine is produced from tryptophan by an enzyme that is activated during chronic inflammation. In mice fed kynurenine from 16 to 24 months of age (roughly equivalent to human ages 56 to 69), endurance and walking speed declined and frailty increased; kynurenine itself causes bone loss in mice by activating osteoclasts.
To validate the findings outside the cohort, the authors matched the spectra of three acylcarnitines against the tissueMASST database, a repository of mass spectra from independent studies. All three compounds were significantly more frequent in samples from people with Alzheimer's disease than in healthy controls.
In a subset of participants, dexverapamil (an antihypertensive drug) was detected in the blood, and its metabolites were confirmed using human liver microsomes. People with low resilience had higher levels specifically of oxidative metabolites of dexverapamil, while glucuronides, a downstream hepatic product, did not differ between groups. If the liver were more active it would raise both, so the authors attribute the finding to reduced renal function that clears metabolites more slowly; they invoke the same mechanism to explain the steeper rise of kynurenine.
The model explains 10% of the variance in resilience, a moderate but statistically significant association for metabolomics of a complex trait. The authors describe these findings as candidates: smaller studies have already shown that aerobic exercise reduces acylcarnitines, and the authors now propose testing whether these molecules track how exercise repairs mitochondria in aging humans.