scholarly journals Cellular Senescence in Adrenocortical Biology and Its Disorders

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3474
Author(s):  
Xin Gao ◽  
Faping Li ◽  
Bin Liu ◽  
Yuxiong Wang ◽  
Yishu Wang ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Zona Glomerulosa ◽  
Adrenal Androgen ◽  
Senescent Phenotype ◽  
Age Related ◽  
Endocrine Organs ◽  
Age Dependent ◽  
Sexual Characteristics

Cellular senescence is considered a physiological process along with aging and has recently been reported to be involved in the pathogenesis of many age-related disorders. Cellular senescence was first found in human fibroblasts and gradually explored in many other organs, including endocrine organs. The adrenal cortex is essential for the maintenance of blood volume, carbohydrate metabolism, reaction to stress and the development of sexual characteristics. Recently, the adrenal cortex was reported to harbor some obvious age-dependent features. For instance, the circulating levels of aldosterone and adrenal androgen gradually descend, whereas those of cortisol increase with aging. The detailed mechanisms have remained unknown, but cellular senescence was considered to play an essential role in age-related changes of the adrenal cortex. Recent studies have demonstrated that the senescent phenotype of zona glomerulosa (ZG) acts in association with reduced aldosterone production in both physiological and pathological aldosterone-producing cells, whereas senescent cortical-producing cells seemed not to have a suppressed cortisol-producing ability. In addition, accumulated lipofuscin formation, telomere shortening and cellular atrophy in zona reticularis cells during aging may account for the age-dependent decline in adrenal androgen levels. In adrenocortical disorders, including both aldosterone-producing adenoma (APA) and cortisol-producing adenoma (CPA), different cellular subtypes of tumor cells presented divergent senescent phenotypes, whereby compact cells in both APA and CPA harbored more senescent phenotypes than clear cells. Autonomous cortisol production from CPA reinforced a local cellular senescence that was more severe than that in APA. Adrenocortical carcinoma (ACC) was also reported to harbor oncogene-induced senescence, which compensatorily follows carcinogenesis and tumor progress. Adrenocortical steroids can induce not only a local senescence but also a periphery senescence in many other tissues. Therefore, herein, we systemically review the recent advances related to cellular senescence in adrenocortical biology and its associated disorders.

scholarly journals Development of the human adrenal zona reticularis: morphometric and immunohistochemical studies from birth to adolescence

2009 ◽  
Vol 203 (2) ◽  
pp. 241-252 ◽  
Author(s):  
Xiao-Gang Hui ◽  
Jun-ichi Akahira ◽  
Takashi Suzuki ◽  
Masaki Nio ◽  
Yasuhiro Nakamura ◽  
...  
Keyword(s):  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Adrenal Androgen ◽  
Zona Reticularis ◽  
Age Related ◽  
Morphometric Analyses ◽  
Proliferation And Apoptosis ◽  
Age Dependent ◽  
Autopsy Specimens ◽  
Immunohistochemical Studies

Age-related morphologic development of human adrenal zona reticularis (ZR) has not been well examined. Therefore, in this study, 44 human young adrenal autopsy specimens retrieved from large archival files (n=252) were examined for immunohistochemical and morphometric analyses. Results demonstrated that ZR became discernible around 4 years of age, and both thickness and ratio per total cortex of ZR increased in an age-dependent fashion thereafter, although there was no significant increment in total thickness of developing adrenal cortex. We further evaluated immunoreactivity of both KI67 and BCL2 in order to clarify the equilibrium between cell proliferation and apoptosis in the homeostasis of developing human adrenals. Results demonstrated that proliferative adrenocortical cells were predominantly detected in the zona glomerulosa and partly in outer zona fasciculata (ZF) before 4 years of age and in ZR after 4 years of age, but the number of these cells markedly decreased around 20 years of age. The number of BCL2-positive cells increased in ZR and decreased in ZF during development. Adrenal androgen synthesizing type 5 17β-hydroxysteroid dehydrogenase (HSD17B5 or AKR1C3 as listed in the Hugo Database) was almost confined to ZR of human adrenals throughout development. HSD17B5 immunoreactivity in ZR became discernible and increased from around 9 years of age. Results of our present study support the theory of age-dependent adrenocortical cell migration and also indicated that ZR development is not only associated with adrenarche, but may play important roles in an initiation of puberty.

scholarly journals Human Adrenal Cortical Zone Changes With Aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A69-A69
Author(s):  
Yuta Tezuka ◽  
Nanako Atsumi ◽  
Amy Blinder ◽  
Juilee Rege ◽  
Thomas J Giordano ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Adult Life ◽  
Rank Correlation ◽  
Zona Glomerulosa ◽  
Zona Fasciculata ◽  
Strong Positive Correlation ◽  
Adult Life Span ◽  
Functional Changes ◽  
Morphological Studies ◽  
Age Related

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.

scholarly journals p53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions

2019 ◽  
Vol 20 (23) ◽  
pp. 6023 ◽  
Author(s):  
Kaori Fujita
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Full Length ◽  
Protein Isoforms ◽  
Specific Cell ◽  
Gene Expressions ◽  
Related Disorder ◽  
Immune System Activation ◽  
Age Related ◽  
P53 Isoforms

Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases.

scholarly journals Protein Oxidative Damage at the Crossroads of Cellular Senescence, Aging, and Age-Related Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Martin A. Baraibar ◽  
Liang Liu ◽  
Emad K. Ahmed ◽  
Bertrand Friguet
Keyword(s):  
Lipid Peroxidation ◽  
Protein Modification ◽  
Replicative Senescence ◽  
Human Fibroblasts ◽  
Potential Effect ◽  
Senescent Phenotype ◽  
Intermediate Metabolism ◽  
Age Related ◽  
Cellular Pathways

Protein damage mediated by oxidation, protein adducts formation with advanced glycated end products and with products of lipid peroxidation, has been implicated during aging and age-related diseases, such as neurodegenerative diseases. Increased protein modification has also been described upon replicative senescence of human fibroblasts, a valid model for studying agingin vitro. However, the mechanisms by which these modified proteins could impact on the development of the senescent phenotype and the pathogenesis of age-related diseases remain elusive. In this study, we performedin silicoapproaches to evidence molecular actors and cellular pathways affected by these damaged proteins. A database of proteins modified by carbonylation, glycation, and lipid peroxidation products during aging and age-related diseases was built and compared to those proteins identified during cellular replicative senescencein vitro. Common cellular pathways evidenced by enzymes involved in intermediate metabolism were found to be targeted by these modifications, although different tissues have been examined. These results underscore the potential effect of protein modification in the impairment of cellular metabolism during aging and age-related diseases.

scholarly journals Latent Adrenal Insufficiency: From Concept to Diagnosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Nada Younes ◽  
Isabelle Bourdeau ◽  
Andre Lacroix
Keyword(s):  
Adrenal Insufficiency ◽  
Adrenal Cortex ◽  
Standard Dose ◽  
Signs And Symptoms ◽  
Serum Cortisol ◽  
Zona Glomerulosa ◽  
Adrenocortical Function ◽  
Adrenal Crisis ◽  
Zona Fasciculata ◽  
Adrenal Androgen

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

Age-related effects on the zona glomerulosa cells of the rat adrenal cortex

1998 ◽  
Vol 1 (4) ◽  
pp. 254-263
Author(s):  
H. Almeida ◽  
M. C. Magalhaes ◽  
M. M. Magalhaes
Keyword(s):  
Adrenal Cortex ◽  
Zona Glomerulosa ◽  
Age Related ◽  
Glomerulosa Cells ◽  
Zona Glomerulosa Cells

Age-related changes in the morphology and function of the zona glomerulosa of the rat adrenal cortex

1992 ◽  
Vol 24 (6) ◽  
pp. 835-842 ◽  
Author(s):  
A.S. Belloni ◽  
P. Rebuffat ◽  
L.K. Malendowicz ◽  
G. Mazzocchi ◽  
S. Rocco ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Zona Glomerulosa ◽  
Age Related ◽  
And Function ◽  
Age Related Changes

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

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.

scholarly journals Deep Learning Shows Cellular Senescence Is a Barrier to Cancer Development

2021 ◽  
Author(s):  
Indra Heckenbach ◽  
Michael Ben Ezra ◽  
Garik V Mkrtchyan ◽  
Jakob Sture Madsen ◽  
Malte Hasle Nielsen ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Protective Role ◽  
Premature Aging ◽  
Cancer Development ◽  
Malignant Neoplasms ◽  
Age Related ◽  
Murine Liver ◽  
Exclusive Or

Cellular senescence is a critical component of aging and many age-related diseases, but understanding its role in human health is challenging in part due to the lack of exclusive or universal markers. Using neural networks, we achieve high accuracy in predicting senescence state and type from the nuclear morphology of DAPI-stained human fibroblasts, murine astrocytes and fibroblasts derived from premature aging diseases in vitro. After generalizing this approach, the predictor recognizes an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies. Evaluating corresponding medical records reveals that individuals with increased senescent cells have a significantly decreased rate of malignant neoplasms, lending support for the protective role of senescence in limiting cancer development. In sum, we introduce a novel predictor of cellular senescence and apply it to diagnostic medical images, indicating cancer occurs more frequently for those with a lower rate of senescence.

scholarly journals Nuclear morphology is a deep learning biomarker of senescence across tissues and species

2021 ◽  
Author(s):  
Indra Heckenbach ◽  
Garik Mkrtchyan ◽  
Michael Ben Ezra ◽  
Daniela Bakula ◽  
Jakob Madsen ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Positive Association ◽  
Protective Role ◽  
Premature Aging ◽  
Malignant Neoplasms ◽  
Nuclear Morphology ◽  
Age Related ◽  
Murine Liver ◽  
Exclusive Or

Abstract Cellular senescence is a critical component of aging and many age-related diseases, but understanding its role in human health is challenging in part due to the lack of exclusive or universal markers. Using neural networks, we achieve high accuracy in predicting senescence state and type from the nuclear morphology of DAPI-stained human fibroblasts, murine astrocytes, murine neurons, and fibroblasts derived from premature aging diseases in culture. After generalizing this approach, the predictor recognizes an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies, suggesting that alterations in nuclear morphology is a universal feature of senescence. Evaluating corresponding medical records reveals that individuals with a higher rate of senescent cells have a significantly decreased rate of malignant neoplasms, lending support for the protective role of senescence in limiting cancer development. Additionally, we find a positive association with lower significance for other conditions, including osteoporosis, osteoarthritis, hypertension, cerebral infarction, hyperlipidemia, and hypercholesteremia. In sum, we introduce a predictor of cellular senescence based on nuclear morphology that is applicable across tissues and species and is associated with health outcomes in humans.

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