The life history of sea urchins is fundamentally different from that of traditional models of aging and therefore they provide the opportunity to gain new insight into this complex process. Sea urchins grow indeterminately, reproduce throughout their life span and some species exhibit negligible senescence. Using a microarray and qRT-PCR, age-related changes in gene expression were examined in three tissues (muscle, esophagus and nerve) of the sea urchin species Strongylocentrotus purpuratus. The results indicate age-related changes in gene expression involving many key cellular functions such as the ubiquitin–proteasome pathway, DNA metabolism, signaling pathways and apoptosis. Although there are tissue-specific differences in the gene expression profiles, there are some characteristics that are shared between tissues providing insight into potential mechanisms that promote lack of senescence in these animals. As an example, there is an increase in expression of genes encoding components of the Notch signaling pathway with age in all three tissues and a decrease in expression of the Wnt1 gene in both muscle and nerve. The interplay between the Notch and Wnt pathways may be one mechanism that ensures continued regeneration of tissues with advancing age contributing to the general lack of age-related decline in these animals.