SummaryThe Shc family of proteins participates in mitogenic and survival signalling through binding to receptor tyrosine kinases. We report here on the expression of Shc in forebrain, spinal cord and hind limb muscles from 30‐month‐old rats with different degrees of sensorimotor impairment. ShcA (mRNA and protein) is up‐regulated in skeletal muscles and spinal cord of aged rats, and this change relates to biological age, i.e. degree of behavioural incapacitation, rather than to chronological age. Western blot and RT‐PCR revealed that the increase in ShcA selectively affected the p46 isoform in the spinal cord, whereas in muscle tissue a robust increase of p66ShcA was also evident. Furthermore, in parallel with the up‐regulation of ShcA, an increase of p75NTR mRNA in the aged animals was observed. ShcB mRNA showed a tendency for down‐regulation in both spinal cord and skeletal muscles, whereas the expression of ShcC was unaltered. Our data show that the regulation of Shc mRNAs in senescence is region as well as isoform specific. The regulatory changes may reflect changes in mitogenic/survival signalling induced by age‐related cell and tissue damage. The coup‐regulation of p66ShcA and p75NTR is interesting since both molecules have been associated with apoptosis.