Age-Related Autonomous Aldosteronism

Abstract

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 adrenal glands from deceased kidney donors (age, 9 months to 68 years). Following immunohistochemistry, CYP11B2-expressing area and areas of abnormal foci of CYP11B2-expressing cells, called aldosterone-producing cell clusters, 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, 18-71 years), 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 aldosterone-producing cell cluster area was positively correlated with age (r=0.390, P<0.0001). The integrated ratio of aldosterone-producing cell cluster 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 was positively and independently associated with older age (adjusted β=+5.54 ng/dL per ng/mL per hour per 10 years, P<0.001). In contrast, when participants were assessed under sodium-restricted conditions, physiological stimulation of aldosterone was blunted with older age (β=-4.6 ng/dL per 10 years, P<0.0001).

Conclusions: Aging is associated with a pattern of decreased normal zona glomerulosa CYP11B2 expression and increased aldosterone-producing cell cluster expression. This histopathologic finding parallels an age-related autonomous aldosteronism and abnormal aldosterone physiology that provides 1 potential explanation for age-related cardiovascular risk.

Keywords: aging; aldosterone; aldosterone-producing cell cluster; cytochrome P-450 CYP11B2; primary aldosteronism; renin.

Figure 1. Continuous and discontinuous adrenal CYP11B2 expression during aging

A-C. Representative histological findings of young adrenal (9 year-old, male) showing continuous CYP11B2 expression in the zona glomerulosa (CYP11B2, brown in A and C). Boxed area in A indicates the captured region for high magnification view. D-F. Representative histological findings of older age adrenal (53 year-old, female) showing discontinuous CYP11B2 expression in the zona glomerulosa with APCCs (CYP11B2, brown in D and F). Boxed area in D indicates the captured region of APCC for high magnification view. A and D. Low magnification scan of adrenal with CYP11B2 IHC. Scale bars, 5 mm. B and E. Hematoxylin and eosin staining. Scale bars, 100 μm. C and F. CYP11B2 IHC. Scale bars, 100 μm. G. Distribution of continuous and discontinuous CYP11B2 expression pattern across age groups. Black bar, continuous CYP11B2 expression; Gray bar, discontinuous CYP11B2 expression.

Figure 2. CYP11B2 expression patterns in normal human adrenals across aging

A. Correlation between age and total CYP11B2 expressing area normalized to adrenal cortex area (%). B. Correlation between age and normal zona glomerulosa CYP11B2 expressing area (%). Normal zona glomerulosa CYP11B2 expressing area was calculated by subtracting APCC areas from total CYP11B2 expressing area. C. Correlation between sum of APCC areas normalized to adrenal cortex (%). D. Correlation between age and ratio of APCC area to total CYP11B2 expressing area (%).

Figure 3. Age and aldosterone dysregulation

A. The relationship between age and the aldosterone-to-renin ratio under sodium loading conditions. For graphical purposes, the aldosterone-to-renin ratio is log transformed. B. The relationship between age and the sodium-modulated aldosterone suppression-to-stimulation index (SASSI). For graphical purposes, the SASSI is log transformed. The solid green line represents the mean regression and is surrounded by dashed green lines that represent the 95% confidence intervals for the mean regression. The dotted green lines represent the 95% confidence intervals for the observed values.