The phosphotyrosine signaling followed by various receptor activations conforms a unique signaling platform during metazoan evolution, and is crucial for animal development, maturation, and aging. Shc is the most versatile bipartite phosphotyrosine signal adaptor harboring phosphotrosine-biding (PTB) and Src-homology2 (SH2) domains. Among the Shc adaptor family members, p66-Shc is of potential interest in aging studies, since its deletion in mice resulted in a longer lifespan and/or higher quality of life in later stages of life. However, a few studies have examined the gene expression profiles of p66-Shc in aging tissues. Here, we quantified the expression levels of transcripts of Shc-related isoforms in the liver and brain of young adult, middle-aged, and aged rats, and found that p66-Shc gene expression is specifically up-regulated in the aged liver and brain. In the aged liver tissue, p66-Shc expression was also evident at the protein level, and accumulated in the soluble fraction of the aged tissue. These results indicate that p66-Shc is not only related to animal longevity but also affected during aging, and thus the repression of p66-Shc could become a potential target for an anti-aging strategy. Archives of Gerontology and Geriatrics, 55(3), pp. 744-748; 2012