Abstract
Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in peripheral blood samples from the InCHIANTI Study of Aging, and assessed longitudinal relationships with human ageing phenotypes (cognitive decline and physical ability) using multivariate linear regression. AKAP17A, HNRNPA0 and HNRNPM transcript levels were all predictively associated with severe decline in MMSE score (p = 0.007, 0.001 and 0.008 respectively). Further analyses also found expression of these genes was associated with a performance decline in two other cognitive measures; the Trail Making Test and the Purdue Pegboard Test. AKAP17A was nominally associated with a decline in mean hand-grip strength (p = 0.023), and further analyses found nominal associations with two other physical ability measures; the Epidemiologic Studies of the Elderly-Short Physical Performance Battery and calculated speed (m/s) during a timed 400 m fast walking test. These data add weight to the hypothesis that splicing dyregulation may contribute to the development of some ageing phenotypes in the human population.
Highlights
There is an intimate relationship between stress responses and successful ageing (Kourtis and Tavernarakis 2011) yet the ability to respond appropriately to stressful environments and to maintain systemic homeostasis declines with age in multiple species (Kirkland et al 2016; Schorr et al 2018; Varadhan et al 2008)
We found that the expression of three splicing factor genes, HNRNPM, HNRNPA0 and AKAP17A may be predictive for change in in this population; all three genes were associated with cognitive decline as measured by the Mini-Mental State Examination (MMSE), Trail-Making Tests part A and B (TMT A/B), and the Purdue Pegboard Test (PPT)
Stars indicated in black denote associations which meet multiple testing thresholds, while those in grey represent nominal associations
Summary
There is an intimate relationship between stress responses and successful ageing (Kourtis and Tavernarakis 2011) yet the ability to respond appropriately to stressful environments and to maintain systemic homeostasis declines with age in multiple species (Kirkland et al 2016; Schorr et al 2018; Varadhan et al 2008). Alternative splicing decisions are made by a series of trans-acting splicing regulatory proteins termed splicing factors. These are the Serine Arginine-rich (SR) family of splicing factors which usually, but not exclusively, promote splice site usage, and the heterogeneous nuclear ribonucleoprotein (HNRNP) family of splicing factors which are usually, but not exclusively, associated with inhibition of splice site usage (Cartegni et al 2002). The expression levels of splicing regulators is known to be associated with ageing; of seven gene ontology pathways robustly associated with age in a large cross-sectional population study of human ageing, six were directly involved in mRNA splicing processes (Harries et al 2011). Splicing factor expression is associated with lifespan in mice and humans (Lee et al 2016)
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