Alternative splicing in aging and longevity

Abstract

Alternative pre-mRNA splicing increases the complexity of the proteome that can be generated from the available genomic coding sequences. Dysregulation of the splicing process has been implicated in a vast repertoire of diseases. However, splicing has recently been linked to both the aging process itself and pro-longevity interventions. This review focuses on recent research towards defining RNA splicing as a new hallmark of aging. We highlight dysfunctional alternative splicing events that contribute to the aging phenotype across multiple species, along with recent efforts toward deciphering mechanistic roles for RNA splicing in the regulation of aging and longevity. Further, we discuss recent research demonstrating a direct requirement for specific splicing factors in pro-longevity interventions, and specifically how nutrient signaling pathways interface to splicing factor regulation and downstream splicing targets. Finally, we review the emerging potential of using splicing profiles as a predictor of biological age and life expectancy. Understanding the role of RNA splicing components and downstream targets altered in aging may provide opportunities to develop therapeutics and ultimately extend healthy lifespan in humans.

Figure 1:. Regulation of RNA processing and disruption with age and disease.

RNA processing fidelity is maintained at multiple points between transcription and translation in normal physiology. With advanced age, disruption of RNA homeostasis can compromise cellular/tissue function and contribute to development of age-related diseases. Depicted are some of the points of dysregulation in RNA homeostasis including splicing factor expression changes, and modifications affecting splicing factor localization, spliceosome dysfunction, aberrant splicing, defective RNA surveillance and aberrant mRNA translation.

Figure 2:. Constitutive and alternative splicing events.

Seven types of alternative splicing are cassette exon, alternative 5’ splice site, alternative 3’ splice site, mutually exclusive exons, intron retention, alternative promoter and alternative polyadenylation. Boxes represent exons and lines represent introns.

Figure 3:. Regulation of alternative splicing by nutrient sensing signaling pathways.

Examples of nutrient sensing factors, implicated in the mechanisms of aging and longevity, impacting splicing factor regulatory protein phosphorylation, localization and levels. Extracellular signals including insulin/IGF activate growth factor receptors and impact signaling to a number of different pathways. Activated Ras causes a signaling cascade that involves MAPK/ERK signaling to increase SRSF1 expression and subsequent increase in exon inclusion of the insulin receptor (INSR) transcript to form insulin receptor beta (INSR-B). PI3K signaling downstream of insulin increases AKT mediated phosphorylation of SR protein kinases (SRPKs) or SR proteins directly. Phosphorylation induces nuclear localization and can alter splicing of transcripts including PKC exon inclusion to form PKC beta isoform. Lastly, mTORC1 signaling increases phosphorylation of S6K which phosphorylates SRPK2 and leads to nuclear translocation. SRPK2 then phosphorylates SR proteins. The impact of these splicing regulatory factor-mediated changes in alternative splicing is alterations in isoform expression and cellular functions including lipogenesis and glucose uptake. Lastly, nutrient sensing and alternative splicing are important for survival in yeast as nutrient depletion leads to an accumulation of stable introns in a TORC1-dependent manner that protect cells from starvation by downregulating ribosomal biogenesis.

Figure 4:. Core and regulatory splicing factors are implicated in longevity.

Longevity associated splicing factors participating at different stages of the splicing process are depicted in red. Expression of Hnrnpk, Hnrnpul2, Hnrnpm, Hnrnpd, Hnrnpa0, Hnrnpul1, Sf3b1, Srsf3 and Tra2β are associated with strain longevity in mice (Lee et al. 2016). Hnrnpa1 and Hnrnpa2b1 levels are associated with strain longevity in mice as well as parental longevity in humans (Lee et al. 2016) while expression of PRP-38 is required for mediating longevity in C. elegans (Curran 2007). Notably, splicing factors SF1/SFA-1, SF3A2/REPO-1 (Heintz et al. 2017) and HNRNPUL1/HRPU-1 (Tabrez et al. 2017) are required for DR-mediated longevity in C. elegans.