Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing

Abstract

Summary Aging is a major risk factor for chronic disease in the human population, but there is little human data on gene expression alterations that accompany the process. We examined human peripheral blood leucocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30 to 104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n = 458), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. Of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (Area Under the Curve in replication set; 95%). The focussed nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in Gene Set Enrichment Analysis (GSEA), notably including the processing of messenger RNAs (mRNAs); (p<0.002, FDR q<0.05). This is supported by our observation of age-associated disruption to the balance of alternatively-expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging.

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

“…Splicing factor expression has been shown to be conclusively associated with chronological age in humans (Harries et al ., 2011) and also with cellular senescence in multiple human primary cell lines in culture (Holly et al ., 2013), indicating that these factors may be linked with cellular plasticity and adaptability during the aging process. Here, we have assessed the potential relationships between splicing factor expression and alternative splicing with strain longevity across 6 mouse strains of variable medium to long lifespans, in both young and old animals.…”

“…Hnrnpa1 is also downregulated with greater lifespan in mouse splenocytes, but the HNRNPA2B1 effect in humans is reversed compared to what we observe in the mice. This may be because the association between Hnrnpa2b1 expression and longevity is most marked in the young animals of the long‐lived strains, and our human subjects are mostly elderly, with a mean age of approximately 75 years (Harries et al ., 2011). Interestingly, both Hnrnpa2b1 and Hnrnpa1 are known to be determinants of lifespan in Drosophila species, by virtue of their regulation of the TDB‐43 protein (Romano et al ., 2014).…”

“…Our previous work suggests that splicing factor expression is strongly associated with age in humans and with cellular senescence in human cell models (Harries et al ., 2011; Holly et al ., 2013). In our human work, the per‐year age‐related changes in splicing factor expression were also relatively small (beta coefficients ranging from −0.01 to 0.005) (Holly et al ., 2013), which may explain why strong effects were not seen in the current mouse study where our sample numbers were much smaller.…”

“…Whilst this is a possibility, the links between splicing factor expression and aging in humans and other animals are well documented from our previous work (Harries et al ., 2011; Holly et al ., 2013) and that of other groups (Meshorer & Soreq, 2002). Our observation that the lifespan‐associated expression changes relating to Hnnrpa2b1 and Hnrnpa1 we observe in mice are also translatable to humans is also supportive of our conclusions.…”

“…This may indicate that defects in the splicing machinery may cause the cellular response to stress to be less specific, with effects on cellular resiliency and accumulation of DNA damage. We have previously identified deregulation of splicing factor expression and alternative splicing as a key factor in normal human and cellular aging (Harries et al ., 2011; Holly et al ., 2013). Alternatively expressed isoforms also demonstrate tissue‐specific differences in aging, as they do for many other phenomena (Holly et al ., 2013).…”