We investigated age-related alterations in hypothalamic-pituitary-thyroid function in a series of in vivo and in vitro studies in 2-, 8-, 18-, and 24-month-old male Fischer 344/N (F344/N) rats. Thyroid histology showed progressive follicular loss with advancing age; this was associated with significant and progressive decrements in plasma levels of free T4 and free T3, but not immunoreactive TSH, which remained unchanged with age. This was accompanied by a progressive age-dependent loss in in vivo responsivity of the thyrotroph to synthetic TRH and a paradoxically augmented response of GH to this peptide in the oldest rats. Steady state levels of prepro-TRH mRNA in the hypothalamic paraventricular nucleus were decreased with age, whereas TRH content in and in vitro secretion by whole hypothalami remained unchanged. Both anterior pituitary steady state TSH beta-subunit mRNA levels and TSH content were decreased with age. Taken together, these data suggest that aging in male F344/N rats is associated with a progressive, centrally mediated decrease in thyroid function. The relative contributions to this phenomenon of age-related alterations in supra-hypothalamic and/or hypothalamic vs. pituitary thyrotropic function remain to be determined, as do the relationships between changes in hypothalamic-pituitary-thyroid function and those in aging per se.