We have identified a number of genes whose expression in the heart changes with aging. The age-associated shift in cardiac myosin heavy chain isoform expression from predominantly alpha-isoform at 2 months of age to beta-isoform at 24 months 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 decline in thyroid hormone plasma levels and infusion of thyroid hormones to levels many times that in younger animals fails to fully restore thyroid-dependent expression and contractile function. Because the effects of thyroid hormones are mediated by heterodimeric complexes of thyroid hormone receptors (TRs) and retinoid X receptors (RXRs), we measured the level of the mRNA and proteins for the various receptors at 2, 6 , and 24 months. We show that between 2 and 6 months, when alphaMHC mRNA levels fall dramatically, that there is a decrease in TR-erbalpha1 and TR-erbalpha2 mRNA levels, but no change in erbAbeta1 or RXRalpha,beta,or gammamRNA levels. Between 6 and 24 months, however, when bMHC levels increase dramatically, there was a reduction in TR-erbAbeta1 and RXRgamma mRNA and protein levels, but no changes in the other TRs and RXRs. These results suggest that some of the age-related decline in cardiac gene expression may be due to decreased thyroid hormone-dependent intracellular signaling, due to decreased formation of the receptor-transcription complex necessary for thyroid-dependent gene expression. Furthermore, the results suggest that thyroid-dependent changes in the expression of the alpha and beta MHC genes, whose promoters both contain thyroid response elements but are positioned on opposite sides of the transcriptional start site, may be mediated by different TRs and RXRs.
