An epigenetic palimpsest: the King penguin's blood methylome reveals conserved hematopoietic ageing

Abstract

Age-associated DNA methylation is conserved across vertebrates, but whether epigenetic ageing reflects cellular ageing programmes or age-dependent shifts in cell composition remains unresolved. Here, using 126 whole-blood methylomes from known-age King penguins (Aptenodytes patagonicus), we exploit a vertebrate system in which nucleated erythrocytes dominate peripheral blood, minimizing the influence of leukocyte heterogeneity. We identify a core set of 409 ageing-associated genes showing lifelong, clock-like methylation change. These genes are strongly enriched for regulators of hematopoietic stem and progenitor cell (HSPC) function and niche communication. Integration of methylome, transcriptome and chromatin-accessibility data reveals that many of the strongest ageing signals derive from genes inactive in mature erythrocytes, consistent with the persistence of epigenetic states from ancestral hematopoietic progenitors. A comparison with methylation profiles from 1,501 humans identified a conserved cross-species subset of ageing genes, and a human epigenetic age model constructed solely from orthologues of penguin ageing genes predicts chronological age with high accuracy while remaining largely insensitive to blood cell composition. We propose that blood epigenetic ageing signatures contain a long-lived cellular memory of stem-cell ageing, that may represent an evolutionarily ancient layer of the vertebrate ageing process.