We have identified a number of genes whose expression in the heart change with aging. The age-associated shift of cardiac myosin heavy chain isoform expression (aMHC to bMHC) is similar to that observed in the hypothyroid heart and indicative of a constellation of changes in the aging heart in which thyroid-dependent gene expression appears to be depressed. Numerous studies, however, have failed to conclusively demonstrate an age-associated decrease in plasma levels of thyroid hormones and infusion of thyroid hormones to levels many times that in younger animals fails to fully restore thyroid-dependent gene expression and contracitle function. Because the effects of thyroid hormones are mediated by a heterodimeric transcription complex of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs), we measured the levels of TRs and RXRs in the young adult (2 and 6 mo) and aging (24 mo) rat heart. The TRs are encoded by the erbA gene: erbAa1 and erbAb1 are plicing variants that encode functional TRs, while erbAa2 is a splicing variant that encode a TR variant that does not bind triiodothyronine. The RXRs, on the other hand, are encoded by three separate genes, RXRa, RXRb, and RXRg. No signficant changes were observed in the mRNAs for the two functional TRs, erbAa1 and erbAb1. On the other hand, the mRNA levels for both RXRb and RXRg decresed signficantly between 6 mo and 24 mo. age, while that of RXRa remained relatively constant. In addition, using an monospecific antibody, we have also observed a significant decrease in RXRg protein levels with age. These results suggest that some of the age-related decline in cardiac gene expression may be due to decreased thyroid hormone-dependent intracellular signalling, due to decreased formation of the receptor-transcription complex necessary for thyroid dependent gene transcription.
