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

BackgroundThe 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. MethodsWe 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. FindingsFour 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. InterpretationWe identified GSN, F2, CRTAC1, and HP as promising candidate indicators of healthy aging and resilience, meriting further study. FundingZonMw, LUF, BBMRI-NL, VOILA, Jorg Bernards-Stiftung, Koln Fortune, and CECAD Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAs the population ages, implementing biomarkers that are able to distinguish vulnerable individuals from highly resilient ones may help to alleviate the burden on our healthcare system. Several studies have shown that plasma-derived proteins change with chronological age and can be used to discern those at risk of disease or early mortality. However, most plasma proteome studies to date have focused either on cross-sectional analyses, short follow-up periods, and/or cohorts with a narrow age range, often centered around mid-life. These studies therefore do not capture the biological factors that contribute to survival up to high ages (longevity), disease resilience and sustained health. In addition, it remains unclear whether the proteins and underlying mechanisms associated with increased survival are consistent across mid and late-life. Added value of this studyThis study set out to investigate the potential of plasma proteins as markers for healthy aging and resilience, and examines the extent to which these associations are consistent across generations. Using the family-based Leiden Longevity Study cohort, including long-lived nonagenarian siblings, their middle-aged offspring, and their partners, we leveraged a unique design to study survival, mid-life health, and multigenerational longevity. We show that prospective (longevity) survival is associated with both age-dependent and age-independent protein effects. Most age-independent proteins displaying consistent associations across life stages. In addition, relative protein level differences were detectable on average ten years before the onset of cardiometabolic disease in mid-life, indicating signatures of future resilience or vulnerability. Four proteins (GSN, CRTAC1, F2, and HP) show consistent association with survival-related outcomes and are proposed as candidate markers of healthy aging. We further observe favorable differences in these proteins in families enriched for longevity, which is indicative of lower disease risk. These identified proteins implicate inflammatory and osteoarthritis related processes. Furthermore, we demonstrate that proteins capture survival domains distinct from those reflected by metabolomic measures, demonstrating the complementary value of plasma proteomics. Implications of all the available evidenceThese findings highlight candidate protein biomarkers of healthy aging and resilience, which may provide improved insight into the mechanisms underlying healthy aging. They also facilitate the development of more sensitive indicators of health, whose implementation may enable earlier and more effective interventions in both population health and clinical care.