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Several reports have demonstrated that cerebral blood flow decreases with age and may contribute to neurodegenerative changes found in aging animals and man. Because GH and insulin-like growth factor 1 (IGF-1) decrease with age and have an important role in vascular maintenance and remodeling, we hypothesized that the decrease in cerebral blood flow is associated with a rarefaction of cerebral blood vessels resulting from a decline in GH and IGF-1. Measurements of vascular density (number of vessels/cortical surface area) in both Brown-Norway and Fisher 344/Brown-Norway rats were made at 5, 13, and 29 months of age using chronic cranial window chambers that allowed viewing of the cortical surface and its corresponding vasculature. Correlations were made with plasma levels of IGF-1. In Brown-Norway rats, arteriolar density decreased from 15.53 +/- 1.08 to 9.49 +/- 0.62 endpoints/mm2 in 7- and 29-month-old animals, respectively (P < 0.05). A decline was observed also in arteriolar anastomoses [3.05 +/- 0.21 to 1.42 +/- 0.24 connections/mm2 in 7- and 29-month-old animals (P< 0.05)]. Venular density did not decrease with age. Similar changes were observed in Fisher 344/Brown-Norway rats. The number of cortical surface arterioles was correlated with plasma IGF-1 levels at the time of vascular mapping (r = 0.772, P < 0.05), and injection of bovine GH (0.25 mg/kg, s.c., twice daily for 35 days) to 30-month-old animals increased both plasma IGF-1 and the number of cortical arterioles. These data indicate that: 1) vascular density on the surface of the cortex decreases with age; 2) vascular density is correlated with plasma levels of IGF-1; and 3) injection of GH increases cortical vascular density in older animals. We conclude that GH and IGF-1 have an important role in the decline in vascular density with age and suggest that decreases in vascular density may have important implications for the age-related decline in cerebral blood flow and brain function.

Moderate caloric restriction (60% of ad libitum intake) is an important model to investigate potential mechanisms of biological aging. This regimen has been reported to decrease the number of pathologies and increase life span in all species tested to date. Although moderate caloric restriction induces a wide range of physiological changes within the organism, adaptive changes within the endocrine system are evident and serve to maintain blood levels of glucose. These alterations include an increase in growth hormone secretory dynamics and a decline in plasma levels of IGF-1. These endocrine compensatory mechanisms can be induced at any age, and we have proposed that these alterations mediate some of the beneficial aspects of moderate caloric restriction. Numerous studies indicate that growth hormone and IGF-1 decrease with age and that administration of these hormones ameliorates the deterioration of tissue function evident in aged ad libitum-fed animals, suggesting that the absence of these hormones contributes to the phenotype of aging. Nevertheless, IGF-1 is an important risk factor in age-related pathologies including lung, breast, and prostate cancer. From these studies, we propose that endocrine compensatory mechanisms induced by moderate caloric restriction (including increased growth hormone and decreased IGF-1) decrease the stimulus for cellular replication, resulting in a decline in pathologies and increased life span observed in these animals. These findings have important implications for potential mechanisms of moderate caloric restriction and suggest that neuroendocrine compensatory mechanisms exert a key role on the actions of moderate caloric restriction on life span.

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Research studies clearly indicate that age-related changes in cellular and tissue function are linked to decreases in the anabolic hormones, growth hormone and insulin-like growth factor (IGF)-1. Although there has been extensive research on the effects of these hormones on bone and muscle mass, their effect on cerebrovascular and brain ageing has received little attention. We have also observed that in response to moderate calorie restriction (a treatment that increases mean and maximal lifespan by 30-40 %), age-related decreases in growth hormone secretion are ameliorated (despite a decline in plasma levels of IGF-1) suggesting that some of the effects of calorie restriction are mediated by modifying the regulation of the growth hormone\IGF-1 axis. Recently, we have observed that microvascular density on the surface of the brain decreases with age and that these vascular changes are ameliorated by moderate calorie restriction. Analysis of cerebral blood flow paralleled the changes in vasculature in both groups. Administration of growth hormone for 28 d was also found to increase microvascular density in aged animals and further analysis indicated that the cerebral vasculature is an important paracrine source of IGF-1 for the brain. In subsequent studies, administration of GHRH (to increase endogenous release of growth hormone) or direct administration of IGF-1 was shown to reverse the age-related decline in spatial working and reference memory. Similarly, antagonism of IGF-1 action in the brains of young animals impaired both learning and reference memory. Investigation of the mechanisms of action of IGF-1 suggested that this hormone regulates age-related alterations in NMDA receptor subtypes (e.g. NMDAR2A and R2B). The beneficial role of growth hormone and IGF-1 in ameliorating vascular and brain ageing are counterbalanced by their wellrecognised roles in age-related pathogenesis. Although research in this area is still evolving, our results suggest that decreases in growth hormone and IGF-1 with age have both beneficial and deleterious effects. Furthermore, part of the actions of moderate calorie restriction on tissue function and lifespan may be mediated through alterations in the growth hormone\IGF-1 axis.

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The mammalian proximal tubule is an important mediator of the renal adaptive response to systemic acidosis. In chronic metabolic and respiratory acidosis the bicarbonate reabsorptive (or proton secretory) capacity is increased. This increase is mediated, at least in part, by an increase in Vmax of the luminal Na/H antiporter. To determine whether this adaptation involves increased mRNA expression, Na/H antiporter mRNA levels were measured by Northern analysis in renal cortex of rats with metabolic (6 mmol/kg body wt NH4Cl for 2 or 5 d) and respiratory (10% CO2/air balanced for 2 or 5 d) acidosis and of normal, pair-fed rats. Na/H antiporter mRNA levels were unchanged after 2 d of both metabolic and respiratory acidosis. After 5 d, however, Na/H antiporter mRNA expression was increased 1.76 +/- 0.12-fold in response to metabolic acidosis (P less than 0.005, n = 8), but was not different from normal in response to respiratory acidosis: 1.1 +/- 0.2 (NS, n = 8). Thus, the renal adaptive response to metabolic acidosis involves increased cortical Na/H antiporter mRNA levels. In contrast, the enhanced proximal tubule Na/H antiporter activity and bicarbonate reabsorption in respiratory acidosis seem to involve mechanisms other than increased Na/H antiporter gene expression.

In this study, we examined the effects of age and growth hormone replacement on both coronary blood flow and capillary density. Blood flow was measured by using [(14)C]-iodoantipyrine in three groups of anesthetized Brown Norway x Fischer 344 rats: young vehicle-treated animals (6 months; n = 13), old vehicle treated animals (30 months; n = 9), and old animals treated with bovine growth hormone (200 microg/kg) twice a day for 30 days (30 months; n = 7). Capillary density was measured by color segmentation analysis of sections stained for platelet endothelial cell adhesion molecule-1. In all regions examined, coronary blood flow decreased with age, and growth hormone administration resulted in an increase in flow compared to vehicle-treated animals. Capillary density decreased with age in the apex and the left ventricular middle segment. In response to growth hormone administration, capillary density increased significantly in the apex but not in other regions of the heart. Our results demonstrate that growth hormone enhances regional myocardial blood flow in the aged heart and suggest that part of this effect could be due to an increase in capillary density.