Estrogen receptor-alpha immunoreactivity in the arcuate hypothalamus of young and middle-aged female mice.

BACKGROUND: Changes in the neuroendocrine regulation of gonadal function, via altered hypothalamic sensitivity to peripheral hormones, are known to schedule reproductive maturation in the young and influence reproductive senescence. Estrogen (E) is a key hormone in this process. While changes in circulating levels of E over the life span are well documented, less is known about the corresponding changes in E sensitivity over the lifespan, especially during middle-age, when the initial signs of reproductive senescence emerge. OBJECTIVE: Taking Estrogen Receptor (ER)-alpha-immunoreactive cells as an index of hypothalamic sensitivity to E, this investigation aims to quantify alterations occurring at middle age in comparison to young age. METHODS: We counted ER-alpha-immunoreactive (IR) cells in the Arcuate hypothalamus of 6-week-old (young) and 18-month-old (middle-aged) C57BL/6J female mice, sacrificed at vaginal opening and diestrous, respectively. An automated imaging microscopy system (AIMS) was employed to generate counts of ER-alpha-IR cells for each sampled section of the Arcuate nucleus (ARC). RESULTS: This study shows a 21% reduction in the number of ER-alpha-IR cells and an 18% reduction in total ARC cell populations with aging. However, the calculated percentage of ER-alpha IR cells is similar in both young and middle aged mice, 30% and 29%, respectively. CONCLUSIONS: Both ER-alpha IR cell populations and total cell populations within the ARC hypothalamus decline by middle age in comparison to young age. Despite such a significant decrease in ER-alpha immunoreactive and total cells, both young and middle age mice maintain a similar ratio of ER-alpha IR cells to total cells in the ARC hypothalamus.

Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice.

Life-long calorie restriction (CR) remains the most robust and reliable means of extending life span in mammals. Among the several theories to explain CR actions, one variant of the neuroendocrine theories of aging postulates that changing hypothalamic sensitivity to endocrine feedback is the clock that times phenotypic change over the life span. If the feedback sensitivity hypothesis is correct, CR animals should display a significantly different pattern of hormone-sensitive cell density and distribution in the hypothalamus. Of the many endocrine signal receptors that may be involved in maintaining hypothalamic feedback sensitivity, our study has selected to begin mapping those for estrogen (E). Altered hypothalamic sensitivity to E is known to schedule reproductive maturation and influence reproductive senescence. Taking estrogen receptor-alpha (ERalpha) immunoreactivity as an index of sensitivity to E, we counted ERalpha immunoreactive and non-immunoreactive cells in the pre-optic hypothalamus of young (6 weeks), ad-libitum (Old-AL) fed old (22 months), and calorie restricted (Old-CR) old (22 months) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each sampled section of pre-optic hypothalamus. Results show a 38% reduction in ERalpha immunoreactive cells and an 18% reduction in total cell numbers in AL-old mice in comparison to young mice. However, CR mice only show a 19% reduction in ERalpha immunoreactive cells and a 13% reduction in total cell numbers in comparison to young mice. This indicates CR prevents age-related cell loss and maintains estrogen sensitivity in the pre-optic hypothalamus of old female B6D2F1 mice.

The ageing phenome: caloric restriction and hormones promote neural cell survival, growth, and de-differentiation.

The phenome represents the observable properties of an organism that have developed under the continued influences of both genome and environmental factors. Phenotypic properties are expressed through the functions of cells, organs and body systems that operate optimally, close to equilibrium. In complex organisms, maintenance of the equilibrium is achieved by the interplay of several regulatory mechanisms. In the elderly, dynamic instability may lead to progressive loss of normal function, failure of adaptation and increased pathology. Extensive research (reported elsewhere in this journal) has demonstrated that genetic manipulations of endocrine signaling in flies, worms and mice increase longevity. Another effective strategy for prolonging the lifespan is caloric restriction: in data presented here, the persistence of estrogen-sensitive cells in the hypothalamus of caloric restricted 22-month-old female mice, may explain the persistence of reproductive function at an age, when reproductive function has long ceased in ad libitum fed controls. Still another strategy utilizes the effects of epidermal growth factor (EGF) to promote in vitro proliferation of neuroglia, astrocytes and oligodendrocytes. Their subsequent de-differentiation generates immature precursor cells potentially capable of differentiating into neuroblasts and neurons. These and other examples suggest that, in terms of functional outcomes, "the genome proposes but the phenome disposes".