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Reversing Signs of Aging via Splicing with Reversalogues

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Review of “Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence” from BMC Cell Biology by Stuart P. Atkinson

Researchers from the laboratories of Elizabeth L. Ostler (University of Brighton, UK) and Lorna W. Harries (University of Exeter, UK) understood that normal human aging and the dysregulated expression of messenger RNA (mRNA) splicing factors [1, 2] the loss of fine control of gene expression [3] go hand in hand. Their new study in BMC Cell Biology now explores the possibility of reversing signs of cellular aging via the activity of newly developed compounds that specifically influence the expression of multiple splicing factors [4]. Could targeting splicing be the key to reversing many of the signs of aging?

Latorre et al. focused on the synthesis of compounds related to the lifespan-extending stilbene compound resveratrol [5] in the hope of encountering a compound that specifically restored normal levels of splicing factor expression with little or no confounding off-target effects. Excitingly, the authors discovered that their newly developed compounds (known as reversalogues) restored splicing factor expression levels to that seen in early passage cells and rescued many signs of cellular aging in senescent cultures of human fibroblasts. Beneficial alterations following reversalogue treatment included increased telomere length, cell-cycle re-entry, and enhanced proliferative potential in previously senescent cells, as well as the return of a “young” pattern of splicing events in the mRNAs of cell senescence-related genes.

Importantly for this study, these compounds did not affect other factors associated with the rescue of age-related cellular decline, including SIRT1 activity, senescence-associated secretory phenotype (SASP) modulation, or the selective removal of senescent cells (senolysis). The lack of an effect on these pathways strongly suggests that the recovery of appropriate splicing factor expression and the fine control of gene expression may be the cause of the beneficial effects observed.

This first demonstration of the importance of splicing factor expression to the reversal of cellular aging will hopefully open the floodgates to new studies exploring this strategy for novel anti-degenerative therapies and to ameliorate aging phenotypes.

To keep up to date with all the new findings related to this exciting new study, stay tuned to the Stem Cells Portal.

References

  1. Harries LW, Hernandez D, Henley W, et al., Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing. Aging Cell 2011;10:868-78.
  2. Lee BP, Pilling LC, Emond F, et al., Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans. Aging Cell 2016;15:903-13.
  3. Stegeman R and Weake VM, Transcriptional Signatures of Aging. J Mol Biol 2017;429:2427-2437.
  4. Latorre E, Birar VC, Sheerin AN, et al., Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biology 2017;18:31.
  5. Markus MA, Marques FZ, and Morris BJ, Resveratrol, by Modulating RNA Processing Factor Levels, Can Influence the Alternative Splicing of Pre-mRNAs. PLOS ONE 2011;6:e28926.