This open access review looks over present opinions on whether or not alternative splicing is important in aging, and in the creation and harmful activities of senescent cells in particular. Alternative splicing refers to the fact that a single gene can code for different proteins. Changes in the ratio of production for these alternative proteins for any specific gene might be either a form of disarray caused by molecular damage or a reaction to rising levels of cell and tissue damage – essentially another form of genetic regulation that, like epigenetic decorations to DNA, changes with age.
The summary in this paper is that the picture is very complicated and poorly understood at present, as is the case for much of the detail level of cellular metabolism and the ways in which it changes over the course of aging. Fortunately we don’t need a full understanding in order to produce significant benefits by selectively destroying the lingering senescent cells found in old tissues; this is the great advantage of therapeutic approaches that target the known root causes of aging. A full accounting of the way in which these causes contribute to aging, in detail, over time, is unnecessary for first generation therapies, making this a much faster and cheaper road to treating aging as a medical condition.
At the cellular and molecular levels, the aging phenotype varies between tissues but can include common hallmarks such as genomic and epigenetic instability, mitochondrial dysfunction, telomere attrition, and the accumulation of senescent cells. Considered as one of the causes of age-related tissue degeneration, cellular senescence is an irreversible and programmed cell-cycle arrest that occurs in most diploid cell types. Senescence is associated with large-scale changes affecting a variety of processes such as cytokine secretion through the senescence-associated secretory phenotypes (SASPs), alterations in gene expression, and alternative splicing, as well as chromatin remodeling that includes senescence-associated heterochromatin foci (SAHF).
Although replicative senescence is linked to telomere attrition, telomere shortening is not necessarily required for the onset of senescence, implying the existence of different senescent programs. Consistent with this view, telomere-independent senescence can be controlled by pathways triggered by insults (stress-induced senescence), as well as by other intrinsic signals that occur during embryonic development and tissue repair. Notably, senescence can also be engaged by the hyperactivation of factors, such as RAS, that promote cell growth, a process known as oncogene-induced senescence that may be linked to telomere dysfunction. While the exact connection between senescence and organismal aging is still much debated, it has become increasingly clear that cellular senescence plays a role in some age-related diseases and in tissue degeneration associated with aging.
As senescence and aging are characterized by global cellular and molecular changes, it is fair to expect that splicing control will also be subjected to alterations. The challenge is to determine whether these changes are collateral or direct effects, and how they contribute to senescence and aging. Several reviews have recently presented splicing defects linked to age-associated diseases, such as neurodegenerative disorders and cancer. Given the challenges associated with maintaining homeostasis in cells and tissues subjected to constant internal and external insults, we can anticipate that a subset of mutations and epigenetic changes may alter the expression or activity of spliceosome components and splicing regulatory factors. These changes may, in turn, alter the splicing profile in several transcripts, resulting in a cascade of alterations that may either activate senescence, promote apoptosis, or elicit tumor formation. Although senescence and apoptosis may protect against tumor formation, the gradual accumulation of senescent cells will elicit tissue degeneration and organ dysfunction. While progressive age-related disturbances in homeostasis do indeed correlate with a broad range of alterations in alternative splicing, the current challenge is to determine whether a specific splicing change contributes to the aging phenotype or is simply a consequence with little or no functional impact.
Although we reviewed the impact of selected splice variants on aging, regulatory networks likely coordinate the production of splice variants from different genes to maximize functional outcomes that determine cell fate, and ultimately the aging phenotype. Consistent with this proposition, the activity of p53 in senescence and apoptosis can be modulated by SIRT1 and ING1, in turn affecting ING1 signaling and SIRT1 activity. Extending these relationships to the full repertoire of splice variants for all the components of the extended p53 regulatory network may be required to determine how important is the level of coordination and feedback involved in the production of splice variants contributing to aging. Already, the splicing regulatory proteins SRSF1, SRSF2, SRSF3, and SRSF6 are emerging as central players coordinating multiple splicing decisions in age-relevant and senescent transcripts. To help clarify the contribution of an expanding list of splice variants and regulators associated with aging, it would be useful to combine expression assays with the monitoring of phenotypes like cell growth and the production of senescent markers. Likewise, it would be informative to determine whether and how SASP components produced by senescent cells reprogram the splicing profiles of neighboring cells.