Human PBMC scRNA-seq–based aging clocks reveal ribosome to inflammation balance as a single-cell aging hallmark and super longevity

TLDR

Quantifying aging rate is important for evaluating age‑associated decline and mortality, and a blood single‑cell RNA sequencing dataset for seven supercentenarians was recently generated. The study generates a 28‑sample reference aging cohort to compute a single‑cell aging clock and determine the biological age of supercentenarians. The authors compute the aging clock from the cohort and validate that inhibiting ribosomal activity in monocytes confirms its role in balancing inflammation. The clock places the supercentenarians at a biological age between 80.43 and 102.67 years, shows increased naive CD8⁺ T cells, decreased cytotoxic CD8⁺ T cells, memory CD4⁺ T cells, and megakaryocytes, and demonstrates that higher ribosome levels are associated with a low‑inflammation state and slow aging, as confirmed by ribosomal inhibition experiments.

Abstract

Quantifying aging rate is important for evaluating age-associated decline and mortality. A blood single-cell RNA sequencing dataset for seven supercentenarians (SCs) was recently generated. Here, we generate a reference 28-sample aging cohort to compute a single-cell level aging clock and to determine the biological age of SCs. Our clock model placed the SCs at a blood biological age to between 80.43 and 102.67 years. Compared to the model-expected aging trajectory, SCs display increased naive CD8+ T cells, decreased cytotoxic CD8+ T cells, memory CD4+ T cells, and megakaryocytes. As the most prominent molecular hallmarks at the single-cell level, SCs contain more cells and cell types with high ribosome level, which is associated with and, according to Bayesian network inference, contributes to a low inflammation state and slow aging of SCs. Inhibiting ribosomal activity or translation in monocytes validates such translation against inflammation balance revealed by our single-cell aging clock.