Identification of Splicing-Related Aging Biomarkers

Univ Of Maryland, College Park, College Park MD

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Abstract

DESCRIPTION (provided by applicant): Cellular aging is a powerful in vitro model for exploring molecular mechanisms underlying organismal aging. A popular hypothesis is that, when the telomeres shorten to below a critical point, it acts as a mitotic clock dictating the permanent exit from the cell cycle. Besides telomere shortening, cellular senescence can be triggered prematurely by certain oncogenes or environmental stimuli, such as ?-irradiation. It has also been reported that an aberrant splicing of the pre-mRNA of the lamin A gene (LMNA), due to a de novo mutation in the exon 11, leads to premature cellular senescence and accelerated aging in patients with Hutchinson-Gilford progeria syndrome (HGPS). Interestingly, a small amount of the aberrant splicing product of lamin A in HGPS (named progerin) accumulates in the cells and tissues of healthy individuals as a function of age, suggesting that alterations in mRNA splicing are not necessarily associated with mutations and may also be influenced by age-related factors. Consistent with this line of thinking, a few other genes, including a cell adhesion molecule fibronectin and an intermediate filament protein vimentin, are alternatively spliced in normal senescent cells. This idea is also exemplified in aging-related neurodegenerative diseases, such as Alzheimer's, Parkinson's diseases and tauopathies, all involving aberrations in pre-mRNAs splicing. Based on the above findings, we hypothesize that there are widespread changes in alternative splicing during cellular senescence. Some of these senescence-related isoforms may be unique to senescent cells and functionally important for cells to establishing senescence state, which can be further developed into novel biomarkers for aging. To address this hypothesis, we will conduct a series of investigations including identifying splicing changes in cultured senescent cells using RNA-seq (Aim1), characterizing these senescence-associated isoforms in vitro and in vivo to develop them into aging biomarkers (Aim2).