Chronological age is a major risk factor for many common diseases including heart disease, cancer and stroke, three of the leading causes of death.
Previously, APOE, FOXO3 and 5q33.3 were the only identified loci consistently associated with longevity.
The discovery stage included six European-ancestry studies (n=7,074 samples) with whole-blood gene expression levels (11,908 genes). The replication stage included 7,909 additional whole-blood samples. A total of 1,497 genes were found to be associated with age, of which 897 are negatively correlated and 600 are positively correlated.
Among the negatively age-correlated genes, three major clusters were identified. The largest group: Cluster #1, consisted of three sub-clusters enriched for (1a) RNA metabolism functions, ribosome biogenesis and purine metabolism; (1b) multiple mitochondrial and metabolic pathways including 10 mitochondrial ribosomal protein (MRP) genes and (1c) DNA replication, elongation and repair, and mismatch repair. Cluster #2 contained factors related to immunity; including T- and B-cell signalling genes, and genes involved in hematopoiesis. Cluster #3 include cytosolic ribosomal subunits.
The positively age-correlated genes revealed four major clusters. Cluster #1: Innate and adaptive immunity. Cluster #2: Actin cytoskeleton, focal adhesion, and tight junctions. Cluster #3: Fatty acid metabolism and peroxisome activity. Cluster #4: Lysosome metabolism and glycosaminoglycan degradation.
DNA methylation, measured by CpG methylation, was not associated with chronological age but associated with the gene expression levels. This result hint at the possibility that DNA methylation could be affecting regulation of gene expression.
Transcriptomic age and epigenetic age (both Hannum and Horvath) were positively correlated, with r-squared values varying between 0.10 and 0.33.