The plasma proteins GSN, F2, CRTAC1, and HP reflect multigenerational health, longevity, and resilience

Putter, P. C., Beekman, M., Lakenberg, N., Lackmann, J.-W., Mueller, S., Mueller, R.-U., Deelen, J., Slagboom, P. E., Antczak, P., van den Berg, N. M. A.

Molecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical CentreMolecular Epidemiology, Dept. of Biomedical Data Sciences, Leiden University Medical Centre · medrxiv

Paper

Abstract

Background The risk of chronic diseases and multimorbidity increases with age, yet, individuals of the same age can strongly differ in healthspan, ranging from early manifestation of age-related disease to robust health into very old age. Plasma biomarkers, including metabolites and proteins, can capture intrinsic health status, thereby providing insights into the nature of this variation. These biomarkers have been widely explored to understand chronic and early disease risk but less so for disease resilience in mid- and late-life survival (i.e. after 90 years), or for multigenerational longevity. Methods We quantified 326 plasma proteins using data-independent mass spectrometry in two generations of the Leiden Longevity Study cohort: F1 nonagenarian siblings (late-life; age [≥]89; N=852) and F2 offspring and their partners (mid-life; age 30-80; N=2,282). Baseline plasma protein levels were tested for association with mid- and late-life survival, with up to 22 years of follow-up, and cardiometabolic healthspan, with up to 16 years of follow-up. By comparing F2 offspring and partners, we tested for plasma proteins associating with familial longevity. Findings Four proteins: GSN, F2, CRTAC1, and HP, consistently associated with increased mid- and late-life survival, prolonged cardiometabolic healthspan, and familial longevity; representing overall resilience. Moreover, six proteins: APCS, C7, FCN2, HPR, GSN, and PIGR, associated with mortality independent of MetaboHealth, a well-established metabolomics-based mortality score. Interpretation We identified GSN, F2, CRTAC1, and HP as promising candidate indicators of healthy aging and resilience, meriting further study. Funding ZonMw, LUF, BBMRI-NL, VOILA, Joerg Bernards-Stiftung, Koeln Fortune, and CECAD

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Research summary

The study identifies specific plasma proteins associated with mid- and late-life survival and resilience, suggesting potential biomarkers for healthy aging. The research focuses on understanding the biological indicators of longevity and resilience, which aligns with the goals of longevity research.

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