Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging

Alternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome-wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus and white adipose tissue from wild-type C57BL6/J male mice (4 and 18-months-old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone and white adipose tissue between the different age groups (ranging from 27-246 AS genes corresponding to 0.3-3.2% of the total number of genes analyzed). For skin, skeletal muscle and bone we included a later age group (28-month-old) that showed the number of alternatively spliced genes increased with age in all three tissues (P<0.01). Analysis of alternatively spliced genes across all tissues by gene-ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson-Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with impaired developmental splicing. As progerin accumulates the number of genes with AS increases compared to in wild-type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.