Associations of cardiovascular biomarkers and plasma albumin with exceptional survival to the highest ages

Takumi Hirata,Toru Takebayashi,Yukiko Abe,Hiroki Inagaki,Shinsuke Yuasa,Kimio Yoshimura,Yasumichi Arai,Tetsuo Adachi,Nobuyoshi Hirose,Michiyo Takayama,Yuichi Oike,Takashi Sasaki,Jun Morinaga,Motoyoshi Endo,Akira Kunitomi,Hideyuki Okano

doi:10.1038/s41467-020-17636-0

Abstract

Supercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness. Identifying specific biomarkers conducive to exceptional survival might provide insights into counter-regulatory mechanisms against aging-related disease. Here, we report associations between cardiovascular disease-related biomarkers and survival to the highest ages using a unique dataset of 1,427 oldest individuals from three longitudinal cohort studies, including 36 supercentenarians, 572 semi-supercentenarians (105–109 years), 288 centenarians (100–104 years), and 531 very old people (85–99 years). During follow-up, 1,000 participants (70.1%) died. Overall, N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6, cystatin C and cholinesterase are associated with all-cause mortality independent of traditional cardiovascular risk factors and plasma albumin. Of these, low NT-proBNP levels are statistically associated with a survival advantage to supercentenarian age. Only low albumin is associated with high mortality across age groups. These findings expand our knowledge on the biology of human longevity.

Highlights

IntroductionSupercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness
Supercentenarians are approaching the current human longevity limit by preventing or surviving major illness
We hypothesize that survival into the current highest age at death (≥110 years) in low-mortality countries is supported by protection against cardiovascular disease, as this system is intrinsically more susceptible to oxidative stress and inflammation with aging, and plays a central role in maintaining oxygen and metabolite delivery to major organ systems

Summary

Introduction

Supercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness. Recent electrocardiography (ECG) studies have reported that a substantial subpopulation of centenarians exhibits ECG abnormalities, such as left ventricular hypertrophy, abnormal Q waves, or atrial fibrillation, which are associated with increased mortality beyond 100 years of age[9,10] These findings raise the fundamental question of whether clinical and subclinical cardiovascular disease is an inevitable consequence of extended longevity, even in the absence of modifiable risk factors. Cystatin C is selected because it shows a much higher correlation with age than does creatinine in approximately 5000 healthy individuals ranging from 25 to 110 years[27] These nine candidate biomarkers are assessed for associations with survival in multiple cohorts of centenarians, (semi)-supercentenarians, and very old individuals, compared with traditional cardiovascular risk factors and plasma albumin, which are independent predictors of mortality in older adults[28]. Only the relationship between NT-proBNP and all-cause mortality is robust against adjustment for traditional risk factors, inflammation, and organ reserve

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Conclusion