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

Benjamin P Lee,Rong Yuan,David Melzer,Florence Emond,Luigi Ferrucci,Kevin Flurkey,George A Kuchel,Lorna W Harries,David E Harrison,Luke C Pilling,Luanne L Peters

doi:10.1111/acel.12499

Abstract

SummaryDysregulation of splicing factor expression and altered alternative splicing are associated with aging in humans and other species, and also with replicative senescence in cultured cells. Here, we assess whether expression changes of key splicing regulator genes and consequent effects on alternative splicing are also associated with strain longevity in old and young mice, across 6 different mouse strains with varying lifespan (A/J, NOD.B10Sn‐H2b/J, PWD.Phj, 129S1/SvlmJ, C57BL/6J and WSB/EiJ). Splicing factor expression and changes to alternative splicing were associated with strain lifespan in spleen and to a lesser extent in muscle. These changes mainly involved hnRNP splicing inhibitor transcripts with most changes more marked in spleens of young animals from long‐lived strains. Changes in spleen isoform expression were suggestive of reduced cellular senescence and retained cellular proliferative capacity in long‐lived strains. Changes in muscle isoform expression were consistent with reduced pro‐inflammatory signalling in longer‐lived strains. Two splicing regulators, HNRNPA1 and HNRNPA2B1, were also associated with parental longevity in humans, in the InCHIANTI aging study. Splicing factors may represent a driver, mediator or early marker of lifespan in mouse, as expression differences were present in the young animals of long‐lived strains. Changes to alternative splicing patterns of key senescence genes in spleen and key remodelling genes in muscle suggest that correct regulation of alternative splicing may enhance lifespan in mice. Expression of some splicing factors in humans was also associated with parental longevity, suggesting that splicing regulation may also influence lifespan in humans.

Highlights

Aging is a dynamic, multisystem process, which is highly heterogeneous in humans with some people surviving disease-free until advanced age whilst others succumb to age-related conditions in mid-life
We found associations between strain lifespan and the expression of the Hnrnpa1, Hnrnpa2b1, Hnrnpk, Hnrnpm, Hnrnpul2, Sf3b1, Srsf3 and Tra2b genes
When data were assessed by binary logistic regression to allow for nonlinearity of response, all but one (Hnrnpul2) of the splicing regulators associated with lifespan in spleen remained associated with median strain lifespan (Table S10)

Summary

Introduction

Multisystem process, which is highly heterogeneous in humans with some people surviving disease-free until advanced age whilst others succumb to age-related conditions in mid-life. Breakdown in the regulation of mRNA splicing is a prominent feature in many age-related diseases such as Alzheimer’s disease, Parkinson’s disease and several tumour types (Scuderi et al, 2014; Danan-Gotthold et al, 2015; Lisowiec et al, 2015; Lu et al, 2015). 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. Regulated splice sites demonstrating temporal, spatial or reactive expression are less likely to show species conservation (Garg & Green, 2007)

Results

Discussion

Conclusion