Human Adrenal Cortical Zone Changes With Aging

Abstract Background: Previous adrenal morphological studies have shown that the zona reticularis (ZR) and the zona glomerulosa (ZG) decrease in size with aging. Although several lines of evidence indicate that the hypothalamic-pituitary-adrenal axis becomes hyperactive in elderly, little is known about age-related transformations of the adrenal zona fasciculata (ZF). Objectives: To investigate the morphological and functional changes of the adrenal cortex across the adult life span, with emphasis on: 1) the understudied ZF, and 2) potential sexual dimorphisms. Methods: We used immunohistochemistry to evaluate the expression of several cortical proteins: aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 11β-hydroxylase (CYP11B1) and cytochrome b5 type A (CYB5A). The ZF area was estimated by subtracting the VSNL1-positive (a ZG marker) area from the HSD3B2-expressing area (ZG and ZF). All captured images were quantitated by ImageJ. In addition, we employed liquid chromatography-tandem mass spectrometry to quantify the morning serum concentrations of 6 steroids: cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone (17OHP4), 11-deoxycorticosterone (DOC), corticosterone, and androstenedione (A4). The Mann-Whitney U test and Spearman’s rank correlation coefficients were used for statistical analysis, as appropriate. Results: We included 60 adrenal glands from 30 men and 30 women, with ages between 18–86 years. The total cortical area was positively correlated with age (r=0.34, p=0.008), and this association was significant only in men (p=0.02). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined abruptly with aging in men (r=-0.57 and -0.76, p=0.001 and p<0.0001, respectively), but not women (p=0.06 and 0.27, respectively). The CYB5A-positive area, marking the ZR, correlated negatively with age (r=-0.76, p<0.0001) in both sexes. In contrast, the estimated ZF area showed a strong positive correlation with age both in men (r=0.59, p=0.0006) and women (r=0.49, p=0.007), while CYP11B1-positive area remained stable across ages (p=0.86). Finally, we measured morning levels of 6 steroids in 149 men and 149 women, with ages between 21–95 years, matched for age and body mass index. Serum cortisol, corticosterone, and DOC levels remained relatively stable across ages (p=0.38, 0.64 and 0.25, respectively), while 11dF levels increased slightly with age (r=0.16 and p=0.007), particularly so in men (p=0.005). Expectedly, 17OHP4 and A4 declined with aging (r=-0.37 and -0.37, p<0.0001 for both). Conclusions: In contrast with the ZG and ZR, the ZF and the total adrenal cortex area enlarge with aging. An abrupt decline of the ZG occurs with age in men, but not in women, possibly contributing to sexual dimorphism in cardiovascular risk.

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The Age-Dependent Changes of the Human Adrenal Cortical Zones Are Not Congruent

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab007 ◽

2021 ◽

Author(s):

Yuta Tezuka ◽

Nanako Atsumi ◽

Amy R Blinder ◽

Juilee Rege ◽

Thomas J Giordano ◽

...

Keyword(s):

Adrenal Cortex ◽

Adrenal Glands ◽

Cytochrome B5 ◽

Serum Cortisol ◽

Zona Fasciculata ◽

Serum Concentrations ◽

Functional Changes ◽

Sexual Dimorphisms ◽

Age Related ◽

Age Dependent

Abstract Background While previous studies indicate that the zonae reticularis (ZR) and glomerulosa (ZG) diminish with aging, little is known about age-related transformations of the zona fasciculata (ZF). Objectives To investigate the morphological and functional changes of the adrenal cortex across adulthood, with emphasis on (i) the understudied ZF and (ii) sexual dimorphisms. Methods We used immunohistochemistry to evaluate the expression of aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3β-hydroxysteroid dehydrogenase type II (HSD3B2), 11β-hydroxylase (CYP11B1), and cytochrome b5 type A (CYB5A) in adrenal glands from 60 adults (30 men), aged 18 to 86. Additionally, we employed mass spectrometry to quantify the morning serum concentrations of cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, and androstenedione in 149 pairs of age- and body mass index–matched men and women, age 21 to 95 years. Results The total cortical area was positively correlated with age (r = 0.34, P = 0.008). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined with aging in men (r = −0.57 and −0.67, P < 0.01), but not in women. The CYB5A-positive area declined with age in both sexes (r = −0.76, P < 0.0001). In contrast, the estimated ZF area correlated positively with age in men (r = 0.59, P = 0.0006) and women (r = 0.49, P = 0.007), while CYP11B1-positive area remained unchanged across ages. Serum cortisol, corticosterone, and 11-deoxycorticosterone levels were stable across ages, while 11dF levels increased slightly with age (r = 0.16, P = 0.007). Conclusion Unlike the ZG and ZR, the ZF and the total adrenal cortex areas enlarge with aging. An abrupt decline of the ZG occurs with age in men only, possibly contributing to sexual dimorphism in cardiovascular risk.

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Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation

International Journal of Endocrinology ◽

10.1155/2016/7834356 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 16

Author(s):

Koshiro Nishimoto ◽

Tsugio Seki ◽

Yuichiro Hayashi ◽

Shuji Mikami ◽

Ghaith Al-Eyd ◽

...

Keyword(s):

Adrenal Cortex ◽

Zona Glomerulosa ◽

Statistical Analyses ◽

Cell Cluster ◽

Zona Fasciculata ◽

Undifferentiated Cell ◽

Immunohistochemical Detection ◽

Cluster Generation ◽

Over Time ◽

Cell Zone

Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time.Purposes. To investigate changes in human adrenocortical zonation with age.Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm2) were calculated by four examiners. Average values were used in statistical analyses.Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals.Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults.

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Electrical responses in cat adrenal cortex: possible relation to aldosterone secretion.

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1979.237.2.e158 ◽

1979 ◽

Vol 237 (2) ◽

pp. E158 ◽

Cited By ~ 3

Author(s):

E Natke ◽

E Kabela

Keyword(s):

Membrane Potential ◽

Angiotensin Ii ◽

Adrenal Cortex ◽

Adrenal Glands ◽

Membrane Depolarization ◽

Zona Glomerulosa ◽

Membrane Potentials ◽

Zona Fasciculata ◽

Aldosterone Secretion ◽

Stimulus Secretion Coupling

The effects of secretagogues for aldosterone release were studied on the membrane potential of cells in the adrenal cortex of the cat. Adrenal glands were excised, sliced, and continuously superfused. Membrane potentials were recorded from both zona glomerulosa and zona fasciculata-reticularis. Secretagogues, angiotensin II (1 microgram/ml) and 20 mM KCl, were found to depolarize cells rapidly. Ouabain (10(-5) M) also depolarized the membrane potential although the response was sluggish. Samples of the superfusate were collected and analyzed by radioimmunoassay for their aldosterone and cortisol content. Depolarizing concentrations of angiotensin II, KCl, and ouabain seemed to increase aldosterone release. Cortisol output was more variable. Saralasin blocked the effects of angiotensin II on the membrane potential. These experiments suggest that membrane depolarization plays a role in the stimulus-secretion coupling of mineral corticoids.

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Mechanisms of age-related decline in memory search across the adult life span.

Developmental Psychology ◽

10.1037/a0032272 ◽

2013 ◽

Vol 49 (12) ◽

pp. 2396-2404 ◽

Cited By ~ 18

Author(s):

Thomas T. Hills ◽

Rui Mata ◽

Andreas Wilke ◽

Gregory R. Samanez-Larkin

Keyword(s):

Life Span ◽

Adult Life ◽

Memory Search ◽

Adult Life Span ◽

Age Related

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The Functional Glomerulosa Cells Define the Unicity of the Adult Human Adrenal Cortex

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.146 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A72-A73

Author(s):

Pamela Camponova ◽

Céline Duparc ◽

Malanie Roy ◽

Herve Lefebvre ◽

Michael Thomas

Keyword(s):

Adrenal Cortex ◽

Caspase 3 ◽

Organ Transplant ◽

Zona Glomerulosa ◽

University Hospital ◽

Central Vein ◽

Zona Fasciculata ◽

Cortical Cells ◽

Ki 67 ◽

Steroidogenic Cells

Abstract The zonation of the human adrenal cortex has long been established morphologically and histologically as three distinct layers of cells. The outer zona glomerulosa (ZG) comprises densely packed cells arranged in clusters that produce aldosterone; the zona fasciculata (ZF) is composed of cells with large cytoplasm, containing lipid droplets arranged in radial columns that synthetize cortisol; and the zona reticularis is composed of compact and pigmented cells producing androgens. The main purpose of this work was to study the expression of aldosterone synthase (CYP11B2 which catalyzes the last steps of aldosterone synthesis) and 11β-hydroxylase (CYP11B1 which catalyzes the last step of cortisol synthesis) in normal adrenal glands to address issues regarding the zonation and the fate of the cells constitutive of each zone through the expression of Ki-67 and cleaved Caspase-3. Thirty eight normal human adrenals (16 females, 22 males, ranging in age from 22 to 81 years old with a median age of 52 years old) were obtained from brain-dead organ donors (kindly provided by the Organ Transplant Clinics, University Hospital of Rouen). As early as 22 years old, we found that the histological ZG (h-ZG) does not correspond to the functional ZG (f-ZG) expressing CYP11B2. Moreover, the h-ZG CYP11B2- cells were CYP11B1+ showing that these cells ascribed to the h-ZG are in fact cortisol producing cells. The progressive replacement of CYP11B2+ cells by CYP11B1+ cells in the h-ZG might demonstrate the role of the extracellular matrix in the morphological maintenance of the adrenal cortex. Our analysis also showed that steroidogenic cells were either CYP11B1 or CYP11B2 positive. By immunofluorescence, we observed in many cases isolated or clusters of CYP11B2+ cells located deeply in the h-ZF and sometimes in the vicinity of the central vein. We were able to show that those cells were probably issued from CYP11B2+ cell clusters located in h-ZG which migrated centripetally. Ki-67 immunoreactivity was highly variable and observed throughout the entire cortex. We also found a positive correlation between the steroidogenic and endothelial cells proliferation. It is interesting to note that some Ki-67+ cells located in the h-ZG were CYP11B1+. Cortical cells positive for cleaved Caspase-3 were extremely rare but detected in all zones when present. These findings challenge the classic view of lineage conversion of differentiated ZG cells and show a new pathway where the CYP11B2+ cells migrate without changing their phenotype.

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Temporal clusters of age-related behavioral alterations captured in smartphone touchscreen interactions

10.1101/2021.12.24.474105 ◽

2021 ◽

Author(s):

Enea Ceolini ◽

Ruchella Kock ◽

Gijsbert Stoet ◽

Guido Band ◽

Arko Ghosh

Keyword(s):

Real World ◽

Temporal Dynamics ◽

Probability Distributions ◽

Adult Life ◽

Cognitive Tests ◽

Behavioral Alterations ◽

Adult Life Span ◽

Adult Lifespan ◽

Age Related ◽

Common Notion

Cognitive and behavioral abilities alter across the adult life span. Smartphones engage various cognitive functions and the corresponding touchscreen interactions may help resolve if and how the behavior is systematically structured by aging. Here, in a sample spanning the adult lifespan (16 to 86 years, N = 598, accumulating 355 million interactions) we analyzed a range of interaction intervals - from a few milliseconds to a minute. We used probability distributions to cluster the interactions according to their next inter-touch interval dynamics to discover systematic age-related changes at the distinct temporal clusters. There were age-related behavioral losses at the clusters occupying short intervals (~ 100 ms, R2 ~ 0.8) but gains at the long intervals (~ 4 s, R2 ~ 0.4). These correlates were independent of the years of experience on the phone or the choice of fingers used on the screen. We found further evidence for a compartmentalized influence of aging, as individuals simultaneously demonstrated both accelerated and decelerated aging at distant temporal clusters. In contrast to these strong correlations, cognitive tests probing sensorimotor, working memory, and executive processes revealed rather weak age-related decline. Contrary to the common notion of a simple behavioral decline with age based on conventional cognitive tests, we show that real-world behavior does not simply decline and the nature of aging systematically varies according to the underlying temporal dynamics. Of all the imaginable factors determining smartphone interactions in the real world, age-sensitive cognitive and behavioral processes can dominatingly dictate smartphone temporal dynamics.

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Incorporating Ecological Momentary Assessment into multi-level investigations of adult development and aging: Promise and practical considerations

10.31234/osf.io/pc8tj ◽

2020 ◽

Author(s):

Jennifer Lee Crawford ◽

Tammy English ◽

Todd Samuel Braver

Keyword(s):

Adult Development ◽

Ecological Momentary Assessment ◽

Adult Life ◽

Individual Variability ◽

Aging Research ◽

Adult Life Span ◽

Age Related ◽

Development And Aging ◽

Ecological Momentary ◽

Momentary Assessment

Ecological momentary assessment (EMA) represents a promising approach to study adult development and aging. In contrast to laboratory-based studies, EMA involves the repeated sampling of experiences in daily life contexts, enabling investigators to gain access to dynamic processes (e.g., situational contexts, intra-individual variability) that are likely to strongly contribute to age-related change across the adult life-span. As such, EMA approaches complement the prevailing research methods to study age differences (e.g., experimental paradigms, neuroimaging), and offer the potential to replicate and extend findings from the laboratory to more naturalistic contexts. Following an overview of the methodological and conceptual strengths of EMA approaches in adult development and aging research, we provide a guide for researchers interested in implementing EMA studies. Together, this work will highlight the tremendous potential in combining EMA methods with other laboratory-based approaches in order to increase the robustness, replicability, and real-world implications of research findings.

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In vitro conversion of cholesterol into aldosterone and cortisol in different zones of the bovine adrenal cortex

Acta Endocrinologica ◽

10.1530/acta.0.1010436 ◽

1982 ◽

Vol 101 (3) ◽

pp. 436-441 ◽

Cited By ~ 3

Author(s):

Karl-Eric Karlmar

Keyword(s):

Adrenal Cortex ◽

Total Content ◽

Zona Glomerulosa ◽

Zona Fasciculata ◽

Oxidoreductase Activity ◽

Chain Cleavage ◽

Specific Fraction ◽

The Individual ◽

Cytochrome P 450

Abstract. The individual steps in the formation of aldosterone and cortisol from cholesterol were assayed in different subcellular preparations from the inner and outer zones of bovine adrenal cortex. In zona glomerulosa the 11β-, 18- and 21-hydroxylase activities were relatively high, whereas the 17α-hydroxylase activity was relatively low. Cholesterol side-chain cleavage and 3β-hydroxysteroid-Δ5-oxidoreductase activity were similar in zona glomerulosa and zona fasciculata-reticularis. The differences were however only quantitative. In no case one specific fraction was totally devoid of enzyme activity. The total content of mitochondrial cytochrome P-450 was relatively high in zona fasciculata-reticularis whereas the content of microsomal cytochrome P-450 was similar in the two fractions. In view of the relatively small differences observed, it seems likely that other factors than distribution of the above enzymes are of major importance for the specific production of gluco- and mineralocorticoids in the two layers.

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Intrafetal Insulin-Like Growth Factor-I Infusion Stimulates Adrenal Growth But Not Steroidogenesis in the Sheep Fetus during Late Gestation

Endocrinology ◽

10.1210/en.2006-1573 ◽

2007 ◽

Vol 148 (11) ◽

pp. 5424-5432 ◽

Cited By ~ 11

Author(s):

J. T. Ross ◽

I. C. McMillen ◽

F. Lok ◽

A. G. Thiel ◽

J. A. Owens ◽

...

Keyword(s):

Mrna Expression ◽

Adrenal Cortex ◽

Plasma Cortisol ◽

Zona Glomerulosa ◽

Late Gestation ◽

Zona Fasciculata ◽

Synthetic Enzymes ◽

Fetal Plasma ◽

Igf I ◽

Sheep Fetus

We investigated the effects of an intrafetal infusion of IGF-I on adrenal growth and expression of the adrenal steroidogenic and catecholamine-synthetic enzyme mRNAs in the sheep fetus during late gestation. Fetal sheep were infused for 10 d with either IGF-I (26 μg/kg·h; n = 14) or saline (n = 10) between 120 and 130 d gestation, and adrenal glands were collected for morphological analysis and determination of the mRNA expression of steroidogenic and catecholamine-synthetic enzymes. Fetal body weight was not altered by IGF-I infusion; however, adrenal weight was significantly increased by 145% after IGF-I infusion. The density of cell nuclei within the fetal adrenal cortex (the zona glomerulosa and zona fasciculata), and within the adrenaline synthesizing zone of the adrenal medulla, was significantly less in the IGF-I-infused fetuses compared with the saline-infused group. Thus, based on cell-density measurements, there was a significant increase in cell size in the zona glomerulosa and zona fasciculata of the adrenal cortex and in the adrenaline-synthesizing zone of the adrenal medulla. There was no effect of IGF-I infusion on the adrenal mRNA expression of the steroidogenic or catecholamine-synthetic enzymes or on fetal plasma cortisol concentrations. In summary, infusion of IGF-I in late gestation resulted in a marked hypertrophy of the steroidogenic and adrenaline-containing cells of the fetal adrenal in the absence of changes in the mRNA levels of adrenal steroidogenic or catecholamine-synthetic enzymes or in fetal plasma cortisol concentrations. Thus, IGF-I infusion results in a dissociation of adrenal growth and function during late gestation.

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