Background Both aging and inappropriate secretion of aldosterone increase the risk for developing cardiovascular disease; however, the influence of aging on aldosterone secretion and physiology is not well understood. Methods The relationship between age and adrenal aldosterone synthase (CYP11B2) expression was evaluated in 127 normal adrenals from deceased kidney donors (age 9mo-68y). Following immunohistochemistry, CYP11B2 expressing area and areas of abnormal foci of CYP11B2 expressing cells, called aldosterone-producing cell clusters (APCCs), were analyzed. In a separate ancillary clinical study of 677 participants without primary aldosteronism, who were studied on both high and restricted sodium diets (age 18-71y), we used multivariable linear regression to assess the independent associations between age and renin-angiotensin-aldosterone system physiology. Results In adrenal tissue, the total CYP11B2 expressing area was negatively correlated with age (r=−0.431, P <0.0001), whereas the total APCC area was positively correlated with age (r=0.390, P<0.0001). The integrated ratio of APCC to CYP11B2 expressing area was most strongly and positively correlated with age (r=0.587, P < 0.0001). When participants in the clinical study were maintained on a high sodium balance, renin activity progressively declined with older age, whereas serum and urinary aldosterone did not significantly decline. Correspondingly, the aldosterone-to-renin ratio (ARR) was positively and independently associated with older age (adjusted β=+5.54 ng/dL per ng/mL/h per 10 years, P<0.001). In contrast, when participants were assessed under sodium restricted conditions, physiologic stimulation of aldosterone was blunted with older age (β=−4.6 ng/dL per 10 years, P<0.0001). Conclusion Aging is associated with a pattern of decreased normal zona glomerulosa CYP11B2 expression and increased APCC expression. This histopathologic finding parallels an age-related autonomous aldosteronism and abnormal aldosterone physiology that provides one potential explanation for age-related cardiovascular risk.

Context GH and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD). Objective To assess relationships between hepatic expression of IGF1 and IGF binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH releasing hormone (GHRH) on circulating IGFBPs. Design Analysis of data from a randomized clinical trial of GHRH. Setting Two US academic medical centers. Participants 61 men and women 18-70yo with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy. Main Outcome Measures Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis. Results Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBP’s, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6. Conclusions These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.

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