Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians

• We identify potential drivers of multiple dimensions of the ageing process up to 110 years of age.
• Inflammation is the prime candidate amongst potential determinants of mortality, capability and cognition up to extreme old age.
• Telomere length does not predict successful ageing in the very and extreme old, but centenarians and their offspring maintain telomeres better than non-centenarians.Centenarians are less susceptible to the diseases, functional losses and dependencies of old age than the general public. Why centenarians age differently, i.e. which biological and pathophysiological processes drive ageing at this extreme old age, is not known. We found that chronic systemic inflammation becomes increasingly associated with risk of death, loss of cognitive function and increasing dependency, but did not predict multimorbidity. In contrast, long telomeres might be important to become a centenarian but did not predict the ageing process further on. Suppression of chronic inflammation could be an essential step towards further improvements in human healthy lifespan.

To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively. In linear forward stepwise models, inflammation predicted capability (10.8% variance explained) and cognition (8.6% variance explained) in (semi-)supercentenarians better than chronologic age or gender. The inflammation score was also lower in centenarian offspring compared to age-matched controls with Δ (95% CI) = − 0.795 (− 1.436 to − 0.154). Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans.