Thyroid hormone signaling and homeostasis during aging.

Studies in humans and in animal models show negative correlations between thyroid hormone (TH) levels and longevity. TH signaling is implicated in maintaining and integrating metabolic homeostasis at multiple levels, notably centrally in the hypothalamus but also in peripheral tissues. The question is thus raised of how TH signaling is modulated during aging in different tissues. Classically, TH actions on mitochondria and heat production are obvious candidates to link negative effects of TH to aging. Mitochondrial effects of excess TH include reactive oxygen species and DNA damage, 2 factors often considered as aging accelerators. Inversely, caloric restriction, which can retard aging from nematodes to primates, causes a rapid reduction of circulating TH, reducing metabolism in birds and mammals. However, many other factors could link TH to aging, and it is these potentially subtler and less explored areas that are highlighted here. For example, effects of TH on membrane composition, inflammatory responses, stem cell renewal and synchronization of physiological responses to light could each contribute to TH regulation of maintenance of homeostasis during aging. We propose the hypothesis that constraints on TH signaling at certain life stages, notably during maturity, are advantageous for optimal aging.

Thyroid hormone signaling in the Xenopus laevis embryo is functional and susceptible to endocrine disruption.

Thyroid hormone (TH) is essential for vertebrate brain development. Most research on TH and neuronal development focuses on late development, mainly the perinatal period in mammals. However, in human infants neuromotor development correlates best with maternal TH levels in the first trimester of pregnancy, suggesting that TH signaling could affect early brain development. Studying TH signaling in early embryogenesis in mammals is experimentally challenging. In contrast, free-living embryos, such as Xenopus laevis, permit physiological experimentation independent of maternal factors. We detailed key elements of TH signaling: ligands, receptors (TR), and deiodinases during early X. laevis development, before embryonic thyroid gland formation. Dynamic profiles for all components were found. Between developmental stages 37 and 41 (~48 h after hatching, coincident with a phase of continuing neurogenesis) significant increases in T(3) levels as well as in mRNA encoding deiodinases and TR occurred. Exposure of embryos at this developmental stage for 24 h to either a TH antagonist, NH-3, or to tetrabromobisphenol A, a flame retardant and known TH disruptor, differentially modulated the expression of a number of TH target genes implicated in neural stem cell function or neural differentiation. Moreover, 24-h exposure to either NH-3 or tetrabromobisphenol A diminished cell proliferation in the brain. Thus, these data show first, that TH signaling exerts regulatory roles in early X. laevis neurogenesis and second, that this period represents a potential window for endocrine disruption.

Thyroid status co-regulates thyroid hormone receptor and co-modulator genes specifically in the hypothalamus.

Regulation of Thyrotropin Releasing Hormone (TRH) transcription in the hypothalamus represents the central control point of thyroid function. To examine the expression of potential TRH regulatory components, we simultaneously amplified, by semi-quantitative multiplex PCR system, nine key genes from < or = 100 ng total RNA from two brain areas (hypothalamus and cortex) under different thyroid states. Expression of TR1 and TR2 isoforms, key elements in TRH regulation, was modified by thyroid status in the hypothalamus but not in the cortex. Similarly, hypothyroidism increased specifically hypothalamic levels of three co-modulator genes. This study provides the first demonstration of tissue specific co-regulation of a set of genes by thyroid status within a defined brain area.

Suppression of fever at near term is associated with reduced COX-2 protein expression in rat hypothalamus.

The fever response is blunted at near term. As the enzyme cyclooxygenase-2 (COX-2) plays a critical role in fever development, we measured its expression in rat hypothalamus during pregnancy and lactation. Western blot analysis revealed a 72-kDa COX-2-immunoreactive band in non-immune-challenged, pregnant rats at day 15 of pregnancy. In contrast, it was almost undetectable at near term and at lactation day 5. COX-2 was significantly induced at the 15th day of pregnancy and at the 5th lactating day after intraperitoneal lipopolysaccharide (50 microg/kg). However, this COX-2 induction was significantly reduced at near term compared with values before and after term. The protein levels of the EP3 receptor in the hypothalamus, one of the prostaglandin E(2) (PGE(2)) receptors suggested to be a key receptor for fever induction, were unaffected throughout the pregnancy and lactation in both non-immune-challenged and lipopolysaccharide-treated rats. These data suggest that suppression of fever at near term is associated with a significantly reduced induction of COX-2 by lipopolysaccharide, resulting in a reduced production of PGE(2). Altered expression of the EP3 receptor does not seem to be involved in this fever refractoriness at near term.