Fight Aging!

Multiple proteins can be assembled from the blueprint of a any given gene, depending on which of the intron sequences (usually removed) and exon sequences (usually retained) within the overall gene sequence are included in the final protein. Splicing is the part of the gene expression process that determines this outcome, and regulation of splicing is one of the many aspects of cellular biochemistry that becomes disarrayed with age. It is an open question as to how important this is versus other processes in aging, as well as how far downstream from the root causes of aging splicing dysfunction might be, but splicing changes might be relevant in the pace of creation of senescent cells, to pick one example.

Naked mole-rats are exceptionally long-lived for their size as rodents, and by comparing their biochemistry to that of similarly sized mice, researchers have found a range of mechanisms that might contribute to this longevity. Naked mole-rats exhibit very good DNA repair; naked mole-rat senescent cells do not secrete damaging and inflammatory signals; cancer suppression mechanisms are very effective; and so forth. Researchers here add stability of splicing regulation to the list. Naked mole-rats do not exhibit the age-related changes in splicing factor expression observed in other mammals, and splicing thus remains stable throughout most of life.

Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation

Naked mole-rats (NMRs) have amongst the longest lifespans relative to body size of any known, non-volant mammalian species. They also display an enhanced stress resistance phenotype, negligible senescence and very rarely are they burdened with chronic age-related diseases. Alternative splicing (AS) dysregulation is emerging as a potential driver of senescence and ageing. We hypothesised that the expression of splicing factors, important regulators of patterns of AS, may differ in NMRs when compared to other species with relatively shorter lifespans.

We designed assays specific to NMR splicing regulatory factors and also to a panel of pre-selected brain-expressed genes known to demonstrate senescence-related alterations in AS in other species, and measured age-related changes in the transcript expression levels of these using embryonic and neonatal developmental stages through to extreme old age in NMR brain samples. We also compared splicing factor expression in both young mouse and NMR spleen and brain samples. Both NMR tissues showed approximately double the expression levels observed in tissues from similarly sized mice. Furthermore, contrary to observations in other species, following a brief period of labile expression in early life stages, adult NMR splicing factors and patterns of AS for functionally relevant brain genes remained remarkably stable for at least two decades.

These findings are consistent with a model whereby the conservation of splicing regulation and stable patterns of AS may contribute to better molecular stress responses and the avoidance of senescence in NMRs, contributing to their exceptional lifespan and prolonged healthspan.