Mark A. Voelker

Age-dependent loss of insulin-like growth factor-1 receptor immunoreactive cells in the supraoptic hypothalamus is reduced in calorically restricted mice.

Both life‐long caloric restriction (CR) and the suppression of insulin‐like growth factor‐1 (IGF‐1) signaling reliably extend the mammalian lifespan. The neuroendocrine system, regulated by the hypothalamus, remains the most convincing site of action for both these modes of life extension. Yet, determining whether CR actions are mediated by the modulation of neuroendocrine IGF‐1 signaling remains unclear. Of the hypothalamic nuclei that express the IGF‐1 receptor (IGF‐1R), the cells of the supraoptic nucleus (SON) display some of the most robust IGF‐1R expression. Taking IGF‐1R immunoreactivity as an index of sensitivity to IGF‐1, we counted IGF‐1R immunoreactive and non‐immunoreactive cells in the SON of young‐ad‐libitum fed (young‐Al, 6 weeks), old‐ad‐libitum fed (Old‐Al, 22 months), and old‐calorie‐restricted (Old‐CR, 22 months) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each section of supraoptic hypothalamus. Results show that while the total number of cells in the SON of ad‐libitum fed mice does not change significantly with aging, a significant reduction in IGF‐1R immunoreactive cells does occur in ad‐libitum fed mice with aging. In contrast to this, calorie restricted mice show both a decline in the total number of cells and IGF‐1R immunoreactive cells in the SON with age, but with the decrease in the latter being notably attenuated when compared to the degree of loss seen in ad‐libitum fed mice. Thus, while CR induces greater loss in the total number of cells in the SON with age, it reduces the degree of age‐dependent loss seen in IGF‐1R expressing cells. As a result, when compared to Old‐AL mice, the SON of Old‐CR mice displays a greater proportion of IGF‐1R cells and thus possibly enhanced IGF‐1 sensitivity with aging.

Resuscitating hypothermic dogs after 2 hours of circulatory arrest below 6 degrees C.

BACKGROUND Ultraprofound hypothermia may have a place in trauma rescue and resuscitation. We describe resuscitation of dogs after asanguineous perfusion and circulatory arrest of 2 hours at 2 degrees to 4 degrees C. METHODS Nine dogs were cooled using a bypass apparatus and their circulating blood replaced with bicarbonated Hextend (Abbott, North Chicago, IL). Perfusion was continued to 2 degrees to 4 degrees C, and 60 mL of 2 mol/L KCl and 20 mL of 50% MgSO(4).7H(2)O were infused intra-arterially, and circulation was arrested for 2 hours. The dogs were then rewarmed, transfused, defibrillated, weaned from bypass, and allowed to awaken. Preoperative and postoperative biochemistry and hematology were compared. RESULTS Six dogs recovered fully. One of these dogs died of an infection 2 weeks later. Three other dogs never recovered because of technical or procedural difficulties. Biochemical and hematologic parameters were normal by 3 weeks. CONCLUSION Hypothermic blood substitution with Hextend allows resuscitation after 2 hours of ice-cold circulatory arrest in dogs.

Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice

The mammalian lifespan is dramatically extended by both caloric restriction (CR) and insulin‐like growth factor‐1 (IGF‐1) suppression. Both interventions involve neuroendocrine alterations directed by the hypothalamus. Yet, it remains unclear whether CR exerts its affects by altering central IGF‐1 sensitivity. With this question in mind, we investigated the influence of CR and normal aging on hypothalamic IGF‐1 sensitivity, by measuring the changes in IGF‐1 receptor (IGF‐1R) populations. Taking IGF‐1 receptor (IGF‐1R) immunoreactivity as an index of sensitivity to IGF‐1, we counted IGF‐1R immunoreactive and non‐immunoreactive cells in the paraventricular nucleus (PVN) of Young‐ad libitum fed (Young‐Al, 6 weeks old), Old‐ad libitum fed (Old‐Al, 22 months old), and old calorically restricted (Old‐CR, 22 months old) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each cross‐section of PVN hypothalamus. Ad libitum fed mice show a 37% reduction in IGF‐1R immunoreactive cells and a 12% reduction in the total cell population of the PVN with aging. In comparison, caloric‐restricted mice show a 33% reduction in IGF‐1R immunoreactive cells and a notable 24% decrease in the total cell population with aging. This selective maintenance of IGF‐1R expressing cells coupled with the simultaneous loss of non‐immunoreactive cells, results in a higher percentage of IGF‐1R immunoreactive cells in the PVNs of CR mice. Thus, the decline in the percentage of IGF‐1 sensitive cells in the PVN with age is attenuated by CR.