|
1
|
Chandra A, Law SF, Pignolo RJ. Changing landscape of hematopoietic and mesenchymal cells and their interactions during aging and in age-related skeletal pathologies. Mech Ageing Dev 2025; 225:112059. [PMID: 40220914 PMCID: PMC12103995 DOI: 10.1016/j.mad.2025.112059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/26/2025] [Accepted: 04/09/2025] [Indexed: 04/14/2025]
Abstract
Aging profoundly impacts mesenchymal and hematopoietic lineage cells, including their progenitors-the skeletal stem cells (SSCs) and hematopoietic stem cells (HSCs), respectively. SSCs are crucial for skeletal development, homeostasis, and regeneration, maintaining bone integrity by differentiating into osteoblasts, adipocytes, and other lineages that contribute to the bone marrow (BM) microenvironment. Meanwhile, HSCs sustain hematopoiesis and immune function. With aging, SSCs and HSCs undergo significant functional decline, partly driven by cellular senescence-a hallmark of aging characterized by irreversible growth arrest, secretion of pro-inflammatory factors (senescence associated secretory phenotype, SASP), and impaired regenerative potential. In SSCs, senescence skews lineage commitment toward adipogenesis at the expense of osteogenesis, contributing to increased bone marrow adiposity , reduced bone quality, and osteoporosis. Similarly, aged HSCs exhibit diminished self-renewal, biased differentiation, and heightened inflammation, compromising hematopoietic output and immune function. In this review, we examine the age-related cellular and molecular changes in SSCs and HSCs, their lineage decisions in the aging microenvironment, and the interplay between skeletal and hematopoietic compartments. We also discuss the role of senescence-driven alterations in BM homeostasis and how targeting cellular aging mechanisms may offer therapeutic strategies for mitigating age-related skeletal and hematopoietic decline.
Collapse
Affiliation(s)
- Abhishek Chandra
- Department of Physiology and Biomedical Engineering, USA; Department of Medicine, Divisions of Hospital Internal Medicine and Section on Geriatric Medicine and Gerontology, USA; Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA.
| | - Susan F Law
- Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA
| | - Robert J Pignolo
- Department of Physiology and Biomedical Engineering, USA; Department of Medicine, Divisions of Hospital Internal Medicine and Section on Geriatric Medicine and Gerontology, USA; Robert and Arlene Kogod Aging Center, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
2
|
Fotopoulou F, Rodríguez-Correa E, Dussiau C, Milsom MD. Reconsidering the usual suspects in age-related hematologic disorders: is stem cell dysfunction a root cause of aging? Exp Hematol 2025; 143:104698. [PMID: 39725143 DOI: 10.1016/j.exphem.2024.104698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 12/28/2024]
Abstract
Aging exerts a profound impact on the hematopoietic system, leading to increased susceptibility to infections, autoimmune diseases, chronic inflammation, anemia, thrombotic events, and hematologic malignancies. Within the field of experimental hematology, the functional decline of hematopoietic stem cells (HSCs) is often regarded as a primary driver of age-related hematologic conditions. However, aging is clearly a complex multifaceted process involving not only HSCs but also mature blood cells and their interactions with other tissues. This review reappraises an HSC-centric view of hematopoietic aging by exploring how the entire hematopoietic hierarchy, from stem cells to mature cells, contributes to age-related disorders. It highlights the decline of both innate and adaptive immunity, leading to increased susceptibility to infections and cancer, and the rise of autoimmunity as peripheral immune cells undergo aging-induced changes. It explores the concept of "inflammaging," where persistent, low-grade inflammation driven by old immune cells creates a cycle of tissue damage and disease. Additionally, this review delves into the roles of inflammation and homeostatic regulation in age-related conditions such as thrombotic events and anemia, arguing that these issues arise from broader dysfunctions rather than stemming from HSC functional attrition alone. In summary, this review highlights the importance of taking a holistic approach to studying hematopoietic aging and its related pathologies. By looking beyond just stem cells and considering the full spectrum of age-associated changes, one can better capture the complexity of aging and attempt to develop preventative or rejuvenation strategies that target multiple facets of this process.
Collapse
Affiliation(s)
- Foteini Fotopoulou
- Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Experimental Hematology Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
| | - Esther Rodríguez-Correa
- Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Experimental Hematology Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany
| | - Charles Dussiau
- Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Experimental Hematology Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany; Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Michael D Milsom
- Division of Experimental Hematology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Experimental Hematology Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany.
| |
Collapse
|
|
3
|
Ali K, Talati J, Mikulas C, Quan A, Reddy P. Testosterone Therapy for the Treatment of Unexplained Anemia in Men With Hypogonadism. Cureus 2024; 16:e66887. [PMID: 39280374 PMCID: PMC11398881 DOI: 10.7759/cureus.66887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 08/12/2024] [Indexed: 09/18/2024] Open
Abstract
Decreased testosterone levels are often under-recognized as a cause of anemia in males with hypogonadism. Men, as a subset, are less likely to seek medical care, especially those who struggle with complex psychiatric and social conditions, where they may lack full autonomy. Increasing testosterone levels leads to erythrocytosis by elevating erythropoietin and soluble transferrin receptor levels and suppressing hepcidin and ferritin levels. While practice guidelines on testosterone therapy for hypogonadism exist, there are no large-scale, randomized clinical trials assessing the use of testosterone replacement therapy in men with hypogonadism to evaluate its effect on anemia. Testosterone replacement therapy is also not wholly benign, and patients may be at increased risk for nonfatal cardiac arrhythmias, venous thromboembolism, and acute kidney injury. We explore two cases of patients with similar prior medical history, both of whom were found to have hypogonadism and anemia that were not otherwise explained. Both patients experienced significant improvement in their anemia following testosterone supplementation.
Collapse
Affiliation(s)
- Kabeer Ali
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Jay Talati
- Internal Medicine, University of Florida College of Medicine, Gainesville, USA
| | - Christopher Mikulas
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Austin Quan
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| | - Pramod Reddy
- Internal Medicine, University of Florida College of Medicine - Jacksonville, Jacksonville, USA
| |
Collapse
|
|
4
|
Bauer MA, Bazard P, Acosta AA, Bangalore N, Elessaway L, Thivierge M, Chellani M, Zhu X, Ding B, Walton JP, Frisina RD. L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice. Hear Res 2024; 446:109004. [PMID: 38608332 PMCID: PMC11112832 DOI: 10.1016/j.heares.2024.109004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 03/25/2024] [Accepted: 04/01/2024] [Indexed: 04/14/2024]
Abstract
The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.
Collapse
Affiliation(s)
- Mark A Bauer
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Parveen Bazard
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA.
| | - Alejandro A Acosta
- School of Medicine, University of Puerto Rico, San Juan, 00925 Puerto Rico; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Nidhi Bangalore
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Lina Elessaway
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Biomedical Sciences - Dept. of Chemistry, University of South Florida, Tampa, FL 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Mark Thivierge
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Moksheta Chellani
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Xiaoxia Zhu
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Bo Ding
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Joseph P Walton
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Department Communication Sciences and Disorders, College of Behavioral & Community Sciences, Tampa, FL 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA
| | - Robert D Frisina
- Department of Medical Engineering, College of Engineering, University of South Florida, Tampa, FL, 33620, USA; Department Communication Sciences and Disorders, College of Behavioral & Community Sciences, Tampa, FL 33620, USA; Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA; Global Center for Hearing and Speech Research, University of South Florida, Tampa, FL 33612, USA.
| |
Collapse
|
|
5
|
Establishment of Hematological and Plasma Biochemical Reference Values and Analysis of Risk Factors for Pet Sugar Gliders ( Petaurus breviceps) in Taiwan. Animals (Basel) 2022; 12:ani12243583. [PMID: 36552503 PMCID: PMC9774594 DOI: 10.3390/ani12243583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Hematological and plasma biochemical examination are crucial in the veterinary care of sugar gliders, which are increasingly popular in Taiwan and the United States. However, published research of the species' reference interval and related influencing factors were rare. The objectives of this study were to establish the hematological and plasma biochemical reference values for captive sugar gliders in Taiwan and to evaluate the influence of factors including age, gender, neuter status, location, season, diet, caging arrangement, and other pets in the household. A total of 42 clinically healthy pet sugar gliders were recruited. Morphometrical measurements and physiological data were collected, and hematological and plasma biochemical examinations were performed. The reference value of each index was calculated using Reference Value Advisor (RVA) software, following the American Society for Veterinary Clinical Pathology (ASVCP) guidelines. Normality of data distribution was tested, and data transformation was conducted. The parametric method and robust method were used to determine reference limits. Univariate analysis was performed, and multiple regression models were built for each hematological and plasma biochemical parameter. Red blood cell, hematocrit, and hemoglobin levels were higher in males, compared to females, while they were lower in the neutered group, compared to the intact group. Relative neutrophil counts were higher in elder sugar gliders, while relative lymphocyte counts were lower. Aspartate transaminase levels were higher in elder sugar gliders, while albumin levels were lower. Blood urea nitrogen levels were highest in spring. The blood profile and related effects presented in this study can provide useful information for veterinary care in pet sugar gliders.
Collapse
|
|
6
|
Stewart AN, Jones LAT, Gensel JC. Improving translatability of spinal cord injury research by including age as a demographic variable. Front Cell Neurosci 2022; 16:1017153. [PMID: 36467608 PMCID: PMC9714671 DOI: 10.3389/fncel.2022.1017153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 11/18/2022] Open
Abstract
Pre-clinical and clinical spinal cord injury (SCI) studies differ in study design, particularly in the demographic characteristics of the chosen population. In clinical study design, criteria such as such as motor scores, neurological level, and severity of injury are often key determinants for participant inclusion. Further, demographic variables in clinical trials often include individuals from a wide age range and typically include both sexes, albeit historically most cases of SCI occur in males. In contrast, pre-clinical SCI models predominately utilize young adult rodents and typically use only females. While it is often not feasible to power SCI clinical trials to test multi-variable designs such as contrasting different ages, recent pre-clinical findings in SCI animal models have emphasized the importance of considering age as a biological variable prior to human experiments. Emerging pre-clinical data have identified case examples of treatments that diverge in efficacy across different demographic variables and have elucidated several age-dependent effects in SCI. The extent to which these differing or diverging treatment responses manifest clinically can not only complicate statistical findings and trial interpretations but also may be predictive of worse outcomes in select clinical populations. This review highlights recent literature including age as a biological variable in pre-clinical studies and articulates the results with respect to implications for clinical trials. Based on emerging unpredictable treatment outcomes in older rodents, we argue for the importance of including age as a biological variable in pre-clinical animal models prior to clinical testing. We believe that careful analyses of how age interacts with SCI treatments and pathophysiology will help guide clinical trial design and may improve both the safety and outcomes of such important efforts.
Collapse
Affiliation(s)
- Andrew N. Stewart
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Linda A. T. Jones
- Center for Outcomes and Measurement, Jefferson College of Rehabilitation Sciences, Thomas Jefferson University, Philadelphia, PA, United States
| | - John C. Gensel
- Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, United States,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States,*Correspondence: John C. Gensel,
| |
Collapse
|
|
7
|
Alcicek FC, Mohaissen T, Bulat K, Dybas J, Szczesny-Malysiak E, Kaczmarska M, Franczyk-Zarow M, Kostogrys R, Marzec KM. Sex-Specific Differences of Adenosine Triphosphate Levels in Red Blood Cells Isolated From ApoE/LDLR Double-Deficient Mice. Front Physiol 2022; 13:839323. [PMID: 35250640 PMCID: PMC8895041 DOI: 10.3389/fphys.2022.839323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 01/27/2022] [Indexed: 12/16/2022] Open
Abstract
In this study for the first time, we investigated the correlation between sex-specific differences in adenosine triphosphate (ATP) levels in red blood cells (RBCs) and their mechanical, biochemical, and morphological alterations during the progression of atherosclerosis in ApoE/LDLR double-deficient (ApoE/LDLR−/−) mice. Our results indicate that both sex and age affect alterations in RBCs of both ApoE/LDLR−/− and C57BL/6J mice. When compared with male RBCs, female RBCs were characterized by lower basal ATP and mean corpuscular hemoglobin concentration (MCHC), higher hemoglobin concentration (HGB), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), deformability, and phosphatidylserine (PS) exposure levels, regardless of age in both, ApoE/LDLR−/− and C57BL/6J mice. ApoE/LDLR−/− mice compared with age-matched controls showed lower basal ATP levels regardless of age and sex. Intracellular ATP level of RBCs was decreased solely in senescent female C57BL/6J mice, while it was elevated in males. Basal extracellular ATP levels were 400 times lower than corresponding intracellular level. In conclusion, basal ATP levels, RBC morphology, deformability, PS exposure levels alterations are sex-dependent in mice. Changes in basal ATP levels were correlated with PS exposure and trends of changes in MCV. Trends of changes of the most RBC parameters were similar in both sexes of ApoE/LDLR−/− mice compared with age-matched controls; however, their kinetics and levels vary greatly between different stages of disease progression.
Collapse
Affiliation(s)
- Fatih Celal Alcicek
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
| | - Tasnim Mohaissen
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
- Chair and Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Katarzyna Bulat
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
- Łukasiewicz Research Network - Krakow Institute of Technology, Krakow, Poland
| | - Jakub Dybas
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
| | - Ewa Szczesny-Malysiak
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
| | - Magdalena Kaczmarska
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
| | - Magdalena Franczyk-Zarow
- Department of Human Nutrition and Dietetics, Faculty of Food Technology, University of Agriculture, Krakow, Poland
| | - Renata Kostogrys
- Department of Human Nutrition and Dietetics, Faculty of Food Technology, University of Agriculture, Krakow, Poland
| | - Katarzyna M. Marzec
- Jagiellonian Centre for Experimental Therapeutics, Jagiellonian University, Krakow, Poland
- Łukasiewicz Research Network - Krakow Institute of Technology, Krakow, Poland
- *Correspondence: Katarzyna M. Marzec,
| |
Collapse
|
|
8
|
Li Z, Wang S, Gong C, Hu Y, Liu J, Wang W, Chen Y, Liao Q, He B, Huang Y, Luo Q, Zhao Y, Xiao Y. Effects of Environmental and Pathological Hypoxia on Male Fertility. Front Cell Dev Biol 2021; 9:725933. [PMID: 34589489 PMCID: PMC8473802 DOI: 10.3389/fcell.2021.725933] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 08/23/2021] [Indexed: 12/28/2022] Open
Abstract
Male infertility is a widespread health problem affecting approximately 6%-8% of the male population, and hypoxia may be a causative factor. In mammals, two types of hypoxia are known, including environmental and pathological hypoxia. Studies looking at the effects of hypoxia on male infertility have linked both types of hypoxia to poor sperm quality and pregnancy outcomes. Hypoxia damages testicular seminiferous tubule directly, leading to the disorder of seminiferous epithelium and shedding of spermatogenic cells. Hypoxia can also disrupt the balance between oxidative phosphorylation and glycolysis of spermatogenic cells, resulting in impaired self-renewal and differentiation of spermatogonia, and failure of meiosis. In addition, hypoxia disrupts the secretion of reproductive hormones, causing spermatogenic arrest and erectile dysfunction. The possible mechanisms involved in hypoxia on male reproductive toxicity mainly include excessive ROS mediated oxidative stress, HIF-1α mediated germ cell apoptosis and proliferation inhibition, systematic inflammation and epigenetic changes. In this review, we discuss the correlations between hypoxia and male infertility based on epidemiological, clinical and animal studies and enumerate the hypoxic factors causing male infertility in detail. Demonstration of the causal association between hypoxia and male infertility will provide more options for the treatment of male infertility.
Collapse
Affiliation(s)
- Zhibin Li
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.,Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, China
| | - Sumin Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Chunli Gong
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yiyang Hu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jiao Liu
- Department of Endoscope, The General Hospital of Shenyang Military Region, Liaoning, China
| | - Wei Wang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yang Chen
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiushi Liao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Bing He
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.,Department of Laboratory Medicine, General Hospital of Northern Theater Command, Shenyang, China
| | - Yu Huang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Qiang Luo
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yongbing Zhao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yufeng Xiao
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| |
Collapse
|
|
9
|
Udroiu I, Sgura A. Growing and aging of hematopoietic stem cells. World J Stem Cells 2021; 13:594-604. [PMID: 34249229 PMCID: PMC8246248 DOI: 10.4252/wjsc.v13.i6.594] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/22/2020] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
In the hematopoietic system, a small number of stem cells produce a progeny of several distinct lineages. During ontogeny, they arise in the aorta-gonad-mesonephros region of the embryo and the placenta, afterwards colonise the liver and finally the bone marrow. After this fetal phase of rapid expansion, the number of hematopoietic stem cells continues to grow, in order to sustain the increasing blood volume of the developing newborn, and eventually reaches a steady-state. The kinetics of this growth are mirrored by the rates of telomere shortening in leukocytes. During adulthood, hematopoietic stem cells undergo a very small number of cell divisions. Nonetheless, they are subjected to aging, eventually reducing their potential to produce differentiated progeny. The causal relationships between telomere shortening, DNA damage, epigenetic changes, and aging have still to be elucidated.
Collapse
Affiliation(s)
- Ion Udroiu
- Department of Science, Roma Tre University, Rome 00146, Italy
| | - Antonella Sgura
- Department of Science, Roma Tre University, Rome 00146, Italy
| |
Collapse
|
|
10
|
Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nat Commun 2021; 12:3208. [PMID: 34050173 PMCID: PMC8163764 DOI: 10.1038/s41467-021-23545-7] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 04/30/2021] [Indexed: 02/04/2023] Open
Abstract
Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD+-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and 13C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD+ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.
Collapse
|
|
11
|
Azad P, Villafuerte FC, Bermudez D, Patel G, Haddad GG. Protective role of estrogen against excessive erythrocytosis in Monge's disease. Exp Mol Med 2021; 53:125-135. [PMID: 33473144 PMCID: PMC8080600 DOI: 10.1038/s12276-020-00550-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 11/12/2020] [Accepted: 11/19/2020] [Indexed: 01/29/2023] Open
Abstract
Monge's disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a+ cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 (p < 0.01) and its target genes (Alas2, BclxL, and Epor, p < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis.
Collapse
Affiliation(s)
- Priti Azad
- Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Francisco C Villafuerte
- Laboratorio de Fisiologia del Transporte de Oxigeno/Fisiología Comparada, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, San Martin de Porres, Lima 31, Peru
| | - Daniela Bermudez
- Laboratorio de Fisiologia del Transporte de Oxigeno/Fisiología Comparada, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, San Martin de Porres, Lima 31, Peru
| | - Gargi Patel
- Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Gabriel G Haddad
- Department of Pediatrics, Division of Respiratory Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
- Rady Children's Hospital, San Diego, CA, 92123, USA.
| |
Collapse
|
|
12
|
Seara FAC, Olivares EL, Nascimento JHM. Anabolic steroid excess and myocardial infarction: From ischemia to reperfusion injury. Steroids 2020; 161:108660. [PMID: 32492466 DOI: 10.1016/j.steroids.2020.108660] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/05/2020] [Accepted: 05/17/2020] [Indexed: 01/06/2023]
Abstract
Anabolic steroids (AS) are synthetic testosterone-derivatives developed by the pharmaceutical industry to mimic testosterone biological effects. So far, AS have been implicated in the treatment of pathological conditions, such as hypogonadism, anemia, and cachexia. Since their discovery, though, AS have been illicitly used by elite and recreational athletes, bodybuilders and weightlifters in order to enhance athletic and aesthetic performance. This practice is characterized by cycles of administration and withdrawal, the combination of different AS compounds, and administration of doses 50 - 1000 times higher than those recommended for therapeutic purposes. AS excess has been correlated to cardiovascular detrimental effects, including cardiac hypertrophy, arrhythmias, and hypertension. Particularly, acute myocardial infarction (AMI) has been extensively reported by clinical and post-mortem studies. Atherosclerosis, hypercoagulability state, increased thrombogenesis and vasospasm have arisen as potential causes of myocardial ischemia in AS users. Additionally, several experimental reports have demonstrated that AS can increase the susceptibility to cardiac ischemia/reperfusion injury, whereas the cardioprotection elicited by physical exercise and ischemic postconditioning is blunted. Altogether, these factors can contribute to increased AMI morbidity and mortality during AS excess, particularly when AS are combined with other compounds, such as thyroid hormones, growth hormones, insulin, and diuretics.
Collapse
Affiliation(s)
- Fernando A C Seara
- Laboratory of Cardiovascular Physiology and Pharmacology, Department of Physiological Sciences, Federal Rural University of Rio de Janeiro, Seropédica, RJ, Brazil; Multicenter Graduate Program in Physiological Sciences, Department of Physiological Sciences, Institute of Biological and Health Sciences, Federal Rural University of Rio de Janeiro, Seropédica, Brazil; Laboratory of Cardiac Electrophysiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Emerson L Olivares
- Laboratory of Cardiovascular Physiology and Pharmacology, Department of Physiological Sciences, Federal Rural University of Rio de Janeiro, Seropédica, RJ, Brazil; Multicenter Graduate Program in Physiological Sciences, Department of Physiological Sciences, Institute of Biological and Health Sciences, Federal Rural University of Rio de Janeiro, Seropédica, Brazil
| | - Jose H M Nascimento
- Laboratory of Cardiac Electrophysiology, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| |
Collapse
|
|
13
|
Stewart AN, MacLean SM, Stromberg AJ, Whelan JP, Bailey WM, Gensel JC, Wilson ME. Considerations for Studying Sex as a Biological Variable in Spinal Cord Injury. Front Neurol 2020; 11:802. [PMID: 32849242 PMCID: PMC7419700 DOI: 10.3389/fneur.2020.00802] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/26/2020] [Indexed: 12/13/2022] Open
Abstract
In response to NIH initiatives to investigate sex as a biological variable in preclinical animal studies, researchers have increased their focus on male and female differences in neurotrauma. Inclusion of both sexes when modeling neurotrauma is leading to the identification of novel areas for therapeutic and scientific exploitation. Here, we review the organizational and activational effects of sex hormones on recovery from injury and how these changes impact the long-term health of spinal cord injury (SCI) patients. When determining how sex affects SCI it remains imperative to expand outcomes beyond locomotor recovery and consider other complications plaguing the quality of life of patients with SCI. Interestingly, the SCI field predominately utilizes female rodents for basic science research which contrasts most other male-biased research fields. We discuss the unique caveats this creates to the translatability of preclinical research in the SCI field. We also review current clinical and preclinical data examining sex as biological variable in SCI. Further, we report how technical considerations such as housing, size, care management, and age, confound the interpretation of sex-specific effects in animal studies of SCI. We have uncovered novel findings regarding how age differentially affects mortality and injury-induced anemia in males and females after SCI, and further identified estrus cycle dysfunction in mice after injury. Emerging concepts underlying sexually dimorphic responses to therapy are also discussed. Through a combination of literature review and primary research observations we present a practical guide for considering and incorporating sex as biological variable in preclinical neurotrauma studies.
Collapse
Affiliation(s)
- Andrew N Stewart
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Steven M MacLean
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Arnold J Stromberg
- Department of Statistics, College of Arts and Sciences, University of Kentucky, Lexington, KY, United States
| | - Jessica P Whelan
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - William M Bailey
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - John C Gensel
- Department of Physiology, University of Kentucky, Lexington, KY, United States.,Spinal Cord and Brain Injury Research Center, College of Medicine, University of Kentucky, Lexington, KY, United States
| | - Melinda E Wilson
- Department of Physiology, University of Kentucky, Lexington, KY, United States
| |
Collapse
|
|
14
|
Guo W, Abou Ghayda R, Schmidt PJ, Fleming MD, Bhasin S. The role of iron in mediating testosterone's effects on erythropoiesis in mice. FASEB J 2020; 34:11672-11684. [PMID: 32667087 DOI: 10.1096/fj.202000920rr] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/15/2020] [Accepted: 06/16/2020] [Indexed: 11/11/2022]
Abstract
Testosterone stimulates iron-dependent erythropoiesis and suppresses hepcidin. To clarify the role of iron in mediating testosterone's effects on erythropoiesis, we induced iron deficiency in mice by feeding low iron diet. Iron-replete and iron-deficient mice were treated weekly with testosterone propionate or vehicle for 3 weeks. Testosterone treatment increased red cell count in iron-replete mice, but, surprisingly, testosterone reduced red cell count in iron-deficient mice. Splenic stress erythropoiesis was stimulated in iron-deficient mice relative to iron-replete mice, and further increased by testosterone treatment, as indicated by the increase in red pulp area, the number of nucleated erythroblasts, and expression levels of TfR1, GATA1, and other erythroid genes. Testosterone treatment of iron-deficient mice increased the ratio of early-to-late erythroblasts in the spleen and bone marrow, and serum LDH level, consistent with ineffective erythropoiesis. In iron-deficient mice, erythropoietin levels were higher but erythropoietin-regulated genes were generally downregulated relative to iron-replete mice, suggesting erythropoietin resistance. Conclusion: Testosterone treatment stimulates splenic stress erythropoiesis in iron-replete as well as iron-deficient mice. However, testosterone worsens anemia in iron-deficient mice because of ineffective erythropoiesis possibly due to erythropoietin resistance associated with iron deficiency. Iron plays an important role in mediating testosterone's effects on erythropoiesis.
Collapse
Affiliation(s)
- Wen Guo
- Research Program in Men's Health: Aging and Metabolism, The Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ramy Abou Ghayda
- Research Program in Men's Health: Aging and Metabolism, The Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paul J Schmidt
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Mark D Fleming
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Shalender Bhasin
- Research Program in Men's Health: Aging and Metabolism, The Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
15
|
Wu FJ, Li IH, Chien WC, Shih JH, Lin YC, Chuang CM, Cheng YD, Kao LT. Androgen deprivation therapy and the risk of iron-deficiency anaemia among patients with prostate cancer: a population-based cohort study. BMJ Open 2020; 10:e034202. [PMID: 32213519 PMCID: PMC7170598 DOI: 10.1136/bmjopen-2019-034202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVES The administration of androgen deprivation therapy (ADT) to patients with metastatic prostate cancer might be associated with some adverse effects such as anaemia; however, few studies have been performed in East Asian populations. This study aimed to investigate the association between ADT and iron-deficiency anaemia (IDA) among patients with prostate cancer in a population-based nationwide cohort. DESIGN Cohort study. SETTING Taiwan. PARTICIPANTS Data for the cohort study were retrieved from the Taiwan National Health Insurance Research Database. Propensity score matching was used to select 7262 patients with prostate cancer who received ADT as the study group and 3631 patients who did not receive ADT as the control group. PRIMARY AND SECONDARY OUTCOME MEASURES This study individually tracked patients over a 3-year study period and identified those who were subsequently diagnosed with IDA following the index date. RESULTS The incidence rates of IDA in the study and control groups were 1.66 (95% CI CI 1.45 to 1.86) and 1.01 per 100 person-years (95% CI 0.78 to 1.25), respectively. Furthermore, proportional Cox regression revealed an HR of 1.62 (95% CI 1.24 to 2.12) for IDA in the study group after adjusting for patients' age, monthly income, geographic location, residential urbanisation level and incidence of hyperlipidaemia, diabetes, hypertension, coronary heart disease, inflammatory bowel disease, other cancers and gastrointestinal bleeding. CONCLUSION Compared with its non-use among patients with prostate cancer, ADT use was associated with a higher risk of IDA.
Collapse
Affiliation(s)
- Fang-Jen Wu
- Department of Pharmacy, West Garden Hospital, Taipei, Taiwan
| | - I-Hsun Li
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Jui-Hu Shih
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Chun Lin
- Research Center of Biostatistics, Taipei Medical University, Taipei, Taiwan
| | - Chin-Min Chuang
- Emergency Department, China Medical University Hospital, Taichung City, Taiwan
| | - Yih-Dih Cheng
- Department of Pharmacy, China Medical University Hospital, Taichung City, Taiwan
| | - Li-Ting Kao
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
| |
Collapse
|
|
16
|
Shibuya S, Toda T, Ozawa Y, Yata MJV, Shimizu T. Acai Extract Transiently Upregulates Erythropoietin by Inducing a Renal Hypoxic Condition in Mice. Nutrients 2020; 12:nu12020533. [PMID: 32092924 PMCID: PMC7071527 DOI: 10.3390/nu12020533] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 02/12/2020] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
Acai (Euterpe oleracea Mart. Palmae, Arecaceae) is a palm plant native to the Brazilian Amazon. It contains many nutrients, such as polyphenols, iron, vitamin E, and unsaturated fatty acids, so in recent years, many of the antioxidant and anti-inflammatory effects of acai have been reported. However, the effects of acai on hematopoiesis have not been investigated yet. In the present study, we administered acai extract to mice and evaluated its hematopoietic effects. Acai treatment significantly increased the erythrocytes, hemoglobin, and hematocrit contents compared to controls for four days. Then, we examined the hematopoietic-related markers following a single injection. Acai administration significantly increased the levels of the hematopoietic-related hormone erythropoietin in blood compared to controls and also transiently upregulated the gene expression of Epo in the kidney. Furthermore, in the mice treated with acai extract, the kidneys were positively stained with the hypoxic probe pimonidazole in comparison to the controls. These results demonstrated that acai increases the erythropoietin expression via hypoxic action in the kidney. Acai can be expected to improve motility through hematopoiesis.
Collapse
Affiliation(s)
- Shuichi Shibuya
- Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi 474-8511, Japan;
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
| | - Toshihiko Toda
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
| | - Yusuke Ozawa
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
| | | | - Takahiko Shimizu
- Aging Stress Response Research Project Team, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi 474-8511, Japan;
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan; (T.T.); (Y.O.)
- Correspondence: ; Tel.: +81-562-44-5651; Fax: +81-562-48-2373
| |
Collapse
|
|
17
|
Wang Z, Khor S, Cai D. Regulation of muscle and metabolic physiology by hypothalamic erythropoietin independently of its peripheral action. Mol Metab 2019; 32:56-68. [PMID: 32029230 PMCID: PMC6938905 DOI: 10.1016/j.molmet.2019.12.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 11/27/2019] [Accepted: 12/02/2019] [Indexed: 12/14/2022] Open
Abstract
Objective The glycoprotein hormone erythropoietin (EPO) is required for erythropoiesis, and the kidney is the primary site of adult EPO synthesis. Limited evidence has suggested that EPO could be detectable in the brain under certain conditions, but it remains unknown if the brain might have its own EPO system for biological functions that are independent of peripheral EPO production and action. We performed this study to address this question using mice under normal conditions versus pathophysiological conditions including aging and dietary obesity. Methods EPO expression was measured in different brain regions as well as in the cerebrospinal fluid. Hypothalamic ventricular EPO was administered to physiologically examine possible therapeutic effects on the conditions of aging and dietary obesity. Body weight, body composition, insulin tolerance, and glucose tolerance were measured to assess the central effects of EPO on metabolic physiology, and muscle strength and histology were analyzed to assess the central effects of EPO on muscle function. In addition, β2-adrenergic receptor knockout bone marrow transplant was employed to determine the potential role of bone marrow in linking the brain to some of these peripheral functions. Results This study revealed that EPO is expressed in the ventromedial hypothalamus in addition to a few other brain regions and is present in the cerebrospinal fluid. Unlike blood EPO concentration, which increased with aging and dietary obesity, hypothalamic EPO decreased in these disease conditions. Therapeutically, aged mice were chronically treated with EPO in the hypothalamic ventricle, showing an increase in lean mass, while body weight and fat mass decreased as a result of a moderate reduction of food intake. Both muscle and metabolic functions were improved by this central treatment, and mechanistically, adrenergic signals to the bone marrow played a role in conveying hypothalamic EPO to these peripheral actions. Dietary obesity was also studied, showing that hypothalamic EPO treatment caused a reduction in food intake and obesity, leading to improved metabolic functions related to decreased fat as well as increased lean mass. Conclusions Hypothalamic EPO plays a role in the central regulation of muscle and metabolic physiology, while its decline contributes to aging and obesity physiology in a manner that is independent of peripheral EPO.
Hypothalamic EPO plays a role in regulating muscle and metabolic physiology independently of its peripheral action. Hypothalamic EPO expression and the cerebrospinal fluid EPO concentration decrease in aging and obesity conditions. Hypothalamic EPO treatment blunts the effects of aging and obesity conditions in impairing muscle and metabolic functions. There exists a connection between the hypothalamus and bone marrow in mediating the physiological effects of central EPO.
Collapse
Affiliation(s)
- Zhouguang Wang
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Sinan Khor
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Dongsheng Cai
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
| |
Collapse
|
|
18
|
Guo W, Schmidt PJ, Fleming MD, Bhasin S. Hepcidin is not essential for mediating testosterone's effects on erythropoiesis. Andrology 2019; 8:82-90. [DOI: 10.1111/andr.12622] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 03/06/2019] [Accepted: 03/07/2019] [Indexed: 12/21/2022]
Affiliation(s)
- W. Guo
- Research Program in Men's Health: Aging and Metabolism The Boston Claude D. Pepper Older Americans Independence Center Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
| | - P. J. Schmidt
- Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA USA
| | - M. D. Fleming
- Department of Pathology Boston Children's Hospital and Harvard Medical School Boston MA USA
| | - S. Bhasin
- Research Program in Men's Health: Aging and Metabolism The Boston Claude D. Pepper Older Americans Independence Center Brigham and Women's Hospital, and Harvard Medical School Boston MA USA
| |
Collapse
|
|
19
|
Abstract
Erythropoietin (EPO) has been linked to cardioprotective effects. However, its effects during the aging process are little known. We investigated the effect of EPO administration on hemodynamic parameters, cardiac function, oxidative damage, and erythropoietin receptor (EPOR) expression pattern in the hypovolemic state. EPO was administered (1000 IU/kg/3 days) and then acute hemorrhage (20% blood loss) was induced in young and adult rats. There was no difference in plasmatic EPO in either age group. The hemodynamic basal condition was similar, without alterations in renal function and hematocrit, in both age groups. After bleeding, both EPO-treated age groups had increased blood pressure at the end of the experimental protocol, being greater in adult animals. EPO attenuated the tachycardic effect. Ejection fraction and fractional shortening were higher in adult EPO-treated rats subjected to hemorrhage. In the left ventricle, young and adult EPO-treated rats subjected to bleeding showed an increased EPOR expression. A different EPOR expression pattern was observed in the adult right atrial tissue, compared with young animals. EPO treatment decreased oxidative damage to lipids in both age groups. EPO treatment before acute hemorrhage improves cardiovascular function during the aging process, which is mediated by different EPOR pattern expression in the heart tissue.
Collapse
|
|
20
|
The relationship between iron deficiency anemia and sexual function and satisfaction among reproductive-aged Iranian women. PLoS One 2018; 13:e0208485. [PMID: 30521614 PMCID: PMC6283628 DOI: 10.1371/journal.pone.0208485] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 11/19/2018] [Indexed: 01/23/2023] Open
Abstract
Iron deficiency anemia (IDA) is a common micronutrient deficiency worldwide, and an important health problem especially in women of reproductive age. This study aimed to determine the relationship between IDA and sexual satisfaction and function among reproductive-aged Iranian women. In this study, 129 women (52 with IDA and 77 non-IDA) with age 18–45 in Mahshahr, Iran were recruited. Data was gathered by a demographic questionnaire, Female Sexual Function Index (FSFI) and Larson Sexual Satisfaction Questionnaire. Data were analyzed using an independent t-test, Mann-Whitney test, Chi-square, and correlation coefficient test. The results of this study showed that the means of hemoglobin (Hb), hematocrit (HCT), serum iron and ferritin were significantly lower in the IDA group than those in the non-IDA group (p<0.01). All dimensions of sexual function and satisfaction were significantly lower in women with IDA compared to the healthy women (p<0.001). Also, all blood indices for IDA had a significant relationship with all sexual function components and sexual satisfaction (p = 0.01) except for pain with Hb and ferritin. Health care providers should provide screening, education, and counseling about anemia and sexual function in reproductive age women.
Collapse
|
|
21
|
Guivier E, Criscuolo F, Zahn S, Bellenger J, Galan M, Faivre B, Sorci G. Early life infection and host senescence. Exp Gerontol 2018; 114:19-26. [PMID: 30366039 DOI: 10.1016/j.exger.2018.10.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 07/20/2018] [Accepted: 10/19/2018] [Indexed: 12/17/2022]
Abstract
Advanced age is often associated with a chronic inflammatory status and inflammatory diseases. It has been suggested that exposure to infectious agents that stimulate the inflammatory response at early ages might have carry over effects in terms of accelerated senescence and increased mortality at late ages. However, not all pathogens and parasites have pro-inflammatory effects. In particular, parasitic nematodes have been shown to dampen the inflammatory response and to prevent or alleviate the symptoms of inflammatory diseases. We, therefore, tentatively predicted that early infection with a parasite that has anti-inflammatory properties might postpone aging. We tested this idea using the association between the nematode Heligmosomoides polygyrus and its rodent host. In addition to the infection with H. polygyrus, we also activated the systemic inflammatory response with an Escherichia coli LPS injection, to explore the effect of H. polygyrus under control and inflammatory conditions. In addition to lifespan, we also assessed several biomarkers of aging, once the infection had been cleared. We found that both treatments (H. polygyrus infection and LPS challenge) reduced longevity. Most of the biomarkers of aging were affected by the previous infection status, suggesting that mice exposed to the nematode had an accentuated senescent phenotype. These results show that infection with immunomodulatory parasites per se does not prolong host lifespan and rather support the view that infection in early life accelerates the rate of aging.
Collapse
Affiliation(s)
- Emmanuel Guivier
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 Boulevard Gabriel, 21000 Dijon, France; Lipides Nutrition Cancer, INSERM UMR 866, Université de Bourgogne Franche-Comté, 6 Boulevard Gabriel, 21000 Dijon, France; Laboratoire IMBE, Université Aix Marseille, Campus St Charles, 13001 Marseille, France.
| | - François Criscuolo
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.
| | - Sandrine Zahn
- Université de Strasbourg, CNRS, IPHC UMR 7178, F-67000 Strasbourg, France.
| | - Jérôme Bellenger
- Laboratoire IMBE, Université Aix Marseille, Campus St Charles, 13001 Marseille, France.
| | - Maxime Galan
- Centre de Biologie pour la Gestion des Populations, 755 avenue du Campus Agropolis, CS 30016, 34988 Montferrier-sur-Lez cedex, France.
| | - Bruno Faivre
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 Boulevard Gabriel, 21000 Dijon, France.
| | - Gabriele Sorci
- Biogéosciences, CNRS UMR 6282, Université de Bourgogne Franche-Comté, 6 Boulevard Gabriel, 21000 Dijon, France.
| |
Collapse
|
|
22
|
Hicks BM, Klil-Drori AJ, Yin H, Campeau L, Azoulay L. Androgen Deprivation Therapy and the Risk of Anemia in Men with Prostate Cancer. Epidemiology 2018; 28:712-718. [PMID: 28768300 DOI: 10.1097/ede.0000000000000678] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND The use of androgen deprivation therapy in prostate cancer may be associated with an increased risk of anemia, but the evidence remains limited. This study aimed to determine if androgen deprivation is associated with increased risk of anemia in patients newly diagnosed with prostate cancer. METHODS This was a population-based cohort study using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository. The cohort consisted of 10,364 men newly diagnosed with nonmetastatic prostate cancer between 1 April 1998 and 30 September 2015. We used time-dependent Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for anemia (hemoglobin <130 g/L) associated with current and past use of androgen deprivation therapy, compared with nonuse. RESULTS There were 3,651 incident anemia events during 31,574 person-years of follow-up (rate: 11.6/100 person-years). Current androgen deprivation therapy use was associated with a nearly three-fold increased hazard of anemia, compared with nonuse (23.5 vs. 5.9 per 100 person-years, respectively; HR: 2.90, 95% CI: 2.67, 3.16). The HR was elevated in the first 6 months of use (HR: 2.20, 95% CI: 1.95, 2.48) and continued to be elevated with longer durations of use. Past androgen deprivation therapy use was associated with a lower estimate (HR: 1.27, 95% CI: 1.12, 1.43), which returned closer to the null ≥25 months after treatment discontinuation (HR: 0.95, 95% CI: 0.79, 1.15). CONCLUSIONS The use of androgen deprivation therapy is associated with increased risk of anemia, which reverses upon treatment discontinuation.
Collapse
Affiliation(s)
- Blánaid M Hicks
- From the aCentre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montréal, QC, Canada; bDepartment of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, QC, Canada; cDivision of Urology, Department of Surgery, McGill University, Montréal, QC, Canada; and dGerald Bronfman Department of Oncology, McGill University, Montréal, QC, Canada
| | | | | | | | | |
Collapse
|
|
23
|
Goetz TG, Mamillapalli R, Sahin C, Majidi-Zolbin M, Ge G, Mani A, Taylor HS. Addition of Estradiol to Cross-Sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE-/- Mice. Endocrinology 2018; 159:754-762. [PMID: 29253190 PMCID: PMC5774248 DOI: 10.1210/en.2017-00884] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Accepted: 12/08/2017] [Indexed: 12/31/2022]
Abstract
The contributions of estradiol and testosterone to atherosclerotic lesion progression are not entirely understood. Cross-sex hormone therapy (XHT) for transgender individuals dramatically alters estrogen and testosterone levels and consequently could have widespread consequences for cardiovascular health. Yet, no preclinical research has assessed atherosclerosis risk after XHT. We examined the effects of testosterone XHT after ovariectomy on atherosclerosis plaque formation in female mice and evaluated whether adding low-dose estradiol to cross-sex testosterone treatments after ovariectomy reduced lesion formation. Six-week-old female ApoE-/- C57BL/6 mice underwent ovariectomy and began treatments with testosterone, estradiol, testosterone with low-dose estradiol, or vehicle alone until euthanized at 23 weeks of age. Atherosclerosis lesion progression was measured by Oil Red O stain and confirmed histologically. We found reduced atherosclerosis in the estradiol- and combined testosterone/estradiol-treated mice compared with those treated with testosterone or vehicle only in the whole aorta (-75%), aortic arch (-80%), and thoracic aorta (-80%). Plaque size was similarly reduced in the aortic sinus. These reductions in lesion size after combined testosterone/estradiol treatment were comparable to those obtained with estrogen alone. Testosterone/estradiol combined therapy resulted in less atherosclerosis plaque formation than either vehicle or testosterone alone after ovariectomy. Testosterone/estradiol therapy was comparable to estradiol replacement alone, whereas mice treated with testosterone only fared no better than untreated controls after ovariectomy. Adding low-dose estrogen to cross-sex testosterone therapy after oophorectomy could improve cardiovascular outcomes for transgender patients. Additionally, these results contribute to understanding of the effects of estrogen and testosterone on atherosclerosis progression.
Collapse
Affiliation(s)
- Teddy G. Goetz
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Cagdas Sahin
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Masoumeh Majidi-Zolbin
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Guanghao Ge
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Arya Mani
- Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Hugh S. Taylor
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| |
Collapse
|
|
24
|
Goetz TG, Mamillapalli R, Devlin MJ, Robbins AE, Majidi-Zolbin M, Taylor HS. Cross-sex testosterone therapy in ovariectomized mice: addition of low-dose estrogen preserves bone architecture. Am J Physiol Endocrinol Metab 2017; 313:E540-E551. [PMID: 28765273 PMCID: PMC5792142 DOI: 10.1152/ajpendo.00161.2017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 07/25/2017] [Accepted: 07/26/2017] [Indexed: 01/17/2023]
Abstract
Cross-sex hormone therapy (XHT) is widely used by transgender people to alter secondary sex characteristics to match their desired gender presentation. Here, we investigate the long-term effects of XHT on bone health using a murine model. Female mice underwent ovariectomy at either 6 or 10 wk and began weekly testosterone or vehicle injections. Dual-energy X-ray absorptiometry (DXA) was performed (20 wk) to measure bone mineral density (BMD), and microcomputed tomography was performed to compare femoral cortical and trabecular bone architecture. The 6-wk testosterone group had comparable BMD with controls by DXA but reduced bone volume fraction, trabecular number, and cortical area fraction and increased trabecular separation by microcomputed tomography. Ten-week ovariectomy/XHT maintained microarchitecture, suggesting that estrogen is critical for bone acquisition during adolescence and that late, but not early, estrogen loss can be sufficiently replaced by testosterone alone. Given these findings, we then compared effects of testosterone with effects of weekly estrogen or combined testosterone/low-dose estrogen treatment after a 6-wk ovariectomy. Estrogen treatment increased spine BMD and microarchitecture, including bone volume fraction, trabecular number, trabecular thickness, and connectivity density, and decreased trabecular separation. Combined testosterone-estrogen therapy caused similar increases in femur and spine BMD and improved architecture (increased bone volume fraction, trabecular number, trabecular thickness, and connectivity density) to estrogen therapy and were superior compared with mice treated with testosterone only. These results demonstrate estradiol is critical for bone acquisition and suggest a new cross-sex hormone therapy adding estrogens to testosterone treatments with potential future clinical implications for treating transgender youth or men with estrogen deficiency.
Collapse
Affiliation(s)
- Teddy G Goetz
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut; and
| | - Ramanaiah Mamillapalli
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut; and
| | - Maureen J Devlin
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | - Amy E Robbins
- Department of Anthropology, University of Michigan, Ann Arbor, Michigan
| | - Masoumeh Majidi-Zolbin
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut; and
| | - Hugh S Taylor
- Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut; and
| |
Collapse
|
|
25
|
Niedernhofer LJ, Kirkland JL, Ladiges W. Molecular pathology endpoints useful for aging studies. Ageing Res Rev 2017; 35:241-249. [PMID: 27721062 DOI: 10.1016/j.arr.2016.09.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 09/15/2016] [Accepted: 09/30/2016] [Indexed: 12/12/2022]
Abstract
The first clinical trial aimed at targeting fundamental processes of aging will soon be launched (TAME: Targeting Aging with Metformin). In its wake is a robust pipeline of therapeutic interventions that have been demonstrated to extend lifespan or healthspan of preclinical models, including rapalogs, antioxidants, anti-inflammatory agents, and senolytics. This ensures that if the TAME trial is successful, numerous additional clinical trials are apt to follow. But a significant impediment to these trials remains the question of what endpoints should be measured? The design of the TAME trial very cleverly skirts around this based on the fact that there are decades of data on metformin in humans, providing unequaled clarity of what endpoints are most likely to yield a positive outcome. But for a new chemical entity, knowing what endpoints to measure remains a formidable challenge. For economy's sake, and to achieve results in a reasonable time frame, surrogate markers of lifespan and healthy aging are desperately needed. This review provides a comprehensive analysis of molecular endpoints that are currently being used as indices of age-related phenomena (e.g., morbidity, frailty, mortality) and proposes an approach for validating and prioritizing these endpoints.
Collapse
Affiliation(s)
- L J Niedernhofer
- Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, United States.
| | - J L Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, United States
| | - W Ladiges
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA 98195, United States
| |
Collapse
|
|
26
|
Feng L, Chen MK, Lukkahatai N, Hsiao CP, Kaushal A, Sechrest L, Saligan LN. Clinical Predictors of Fatigue in Men With Non-Metastatic Prostate Cancer Receiving External Beam Radiation Therapy. Clin J Oncol Nurs 2017; 19:744-50. [PMID: 26583638 DOI: 10.1188/15.cjon.744-750] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Fatigue is one of the most distressing symptoms experienced by people with cancer receiving radiation therapy. OBJECTIVES The goal of this study is to evaluate clinical predictors of worsening fatigue during external beam radiation therapy (EBRT) in men with non-metastatic prostate cancer. METHODS Thirty-five men with non-metastatic prostate cancer scheduled for EBRT were followed at baseline, midpoint, and completion of EBRT. The Functional Assessment of Cancer Therapy-Fatigue scale was administered. Demographic and clinical data were obtained by chart review. Paired t-tests, correlations, general linear models, and logistic regressions were used to determine associations between fatigue scores and clinical data. FINDINGS Red blood cells, hemoglobin, and hematocrit levels were highly intercorrelated and, therefore, were grouped as one composite variable termed heme. Heme levels at baseline and androgen-deprivation therapy (ADT) were significantly correlated with worsening of fatigue symptoms from baseline to midpoint and endpoint. ADT alone did not have a significant correlation with fatigue, but it indirectly affected fatigue levels by influencing heme markers as treatment progressed. These findings provide evidence that hematologic markers and the use of ADT assist in predicting radiation therapy-related fatigue and guide symptom management.
Collapse
Affiliation(s)
- Li Feng
- National Institute of Nursing Research in the National Institutes of Health
| | | | | | | | | | | | - Leorey N Saligan
- National Institute of Nursing Research in the National Institutes of Health
| |
Collapse
|
|
27
|
Guo W, Schmidt PJ, Fleming MD, Bhasin S. Effects of Testosterone on Erythropoiesis in a Female Mouse Model of Anemia of Inflammation. Endocrinology 2016; 157:2937-46. [PMID: 27074351 PMCID: PMC4929557 DOI: 10.1210/en.2016-1150] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The anemia of inflammation is a common problem in inflammatory and autoimmune diseases. We characterized a mouse model of anemia of chronic inflammation induced by repeated injections of low doses of heat-killed Brucella abortus (HKBA), and determined the effects of T administration on erythropoiesis in this model. Female C57BL/6NCrl mice were injected weekly with HKBA for 10 wk. Weekly injections of T or vehicle oil were started 4 wk later. Control mice were injected with saline and vehicle oil in parallel. HKBA-injected mice had significantly lower hemoglobin, hematocrit, mean corpuscular volume, reticulocyte hemoglobin, transferrin saturation (TSAT), and tissue nonheme iron in liver and spleen, enlarged spleen, and up-regulated hepatic expression of inflammatory markers, serum amyloid A1, and TNFα, but down-regulated IL-6, bone morphogenic protein 6, and hepcidin compared with saline controls. HKBA also reduced serum hepcidin and increased serum erythropoietin. Bone marrow erythroid precursors were substantially reduced in HKBA-injected mice. Cotreatment with T increased the percentage of late-stage erythroid precursors in the bone marrow relative to HKBA-injected and saline controls and reversed HKBA-induced suppression of hemoglobin and hematocrit. T also normalized serum erythropoietin, TSAT, and reticulocyte hemoglobin without correcting the expression of the hepatic inflammation markers. Conclusions are that low-dose HKBA induces moderate anemia characterized by chronic inflammation, decreased iron stores, and suppression of erythroid precursors in the bone marrow. T administration reverses HKBA-induced anemia by stimulating erythropoiesis, which is associated with a shift toward accelerated maturation of erythroid precursors in the bone marrow.
Collapse
Affiliation(s)
- Wen Guo
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center (W.G., S.B.), and Department of Pathology (P.J.S., M.D.F.), Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Paul J Schmidt
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center (W.G., S.B.), and Department of Pathology (P.J.S., M.D.F.), Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Mark D Fleming
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center (W.G., S.B.), and Department of Pathology (P.J.S., M.D.F.), Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Shalender Bhasin
- Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center (W.G., S.B.), and Department of Pathology (P.J.S., M.D.F.), Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| |
Collapse
|
|
28
|
Gonzales GF, Chaupis D. Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean Highlanders: a review. Andrologia 2014; 47:729-43. [PMID: 25277225 DOI: 10.1111/and.12359] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/12/2014] [Indexed: 01/12/2023] Open
Abstract
Populations living at high altitudes (HA), particularly in the Peruvian Central Andes, are characterised by presenting subjects with erythrocytosis and others with excessive erythrocytosis (EE)(Hb>21 g dl(-1) ). EE is associated with chronic mountain sickness (CMS), or lack of adaptation to HA. Testosterone is an erythropoietic hormone and it may play a role on EE at HA. The objective of the present review was to summarise findings on role of serum T levels on adaptation at HA and genes acting on this process. Men at HA without EE have higher androstenedione levels and low ratio androstenedione/testosterone than men with EE, suggesting low activity of 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and this could be a mechanism of adaptation to HA. Higher conversion of dehydroepiandrosterone to testosterone in men with EE suggests nigher 17beta-HSD activity. Men with CMS at Peruvian Central Andes have two genes SENP1, and ANP32D with higher transcriptional response to hypoxia relative to those without. SUMO-specific protease 1 (SENP1) is an erythropoiesis regulator, which is essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1α) under hypoxia. SENP1 reverses the hormone-augmented SUMOylation of androgen receptor (AR) increasing the transcription activity of AR.In conclusion, increased androgen activity is related with CMS.
Collapse
Affiliation(s)
- G F Gonzales
- Laboratory of Endocrinology and Reproduction, High Altitude Research Institute and Department of Biological and Physiological Sciences, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - D Chaupis
- Laboratory of Endocrinology and Reproduction, High Altitude Research Institute and Department of Biological and Physiological Sciences, Faculty of Sciences and Philosophy, Universidad Peruana Cayetano Heredia, Lima, Peru
| |
Collapse
|
|
29
|
Bachman E, Travison TG, Basaria S, Davda MN, Guo W, Li M, Connor Westfall J, Bae H, Gordeuk V, Bhasin S. Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J Gerontol A Biol Sci Med Sci 2013; 69:725-35. [PMID: 24158761 DOI: 10.1093/gerona/glt154] [Citation(s) in RCA: 254] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear. METHODS We assessed the hormonal and hematologic responses to testosterone administration in a clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months. RESULTS The 7%-10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range. CONCLUSIONS Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.
Collapse
Affiliation(s)
- Eric Bachman
- Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies, Boston Medical Center, Massachusetts.
| | - Thomas G Travison
- Section of Hematology/Oncology Sickle Cell Center, MC 712, University of Illinois at Chicago
| | - Shehzad Basaria
- Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies, Boston Medical Center, Massachusetts
| | - Maithili N Davda
- Section of Hematology/Oncology Sickle Cell Center, MC 712, University of Illinois at Chicago
| | - Wen Guo
- Section of Hematology/Oncology Sickle Cell Center, MC 712, University of Illinois at Chicago
| | - Michelle Li
- Section of Hematology/Oncology Sickle Cell Center, MC 712, University of Illinois at Chicago
| | - John Connor Westfall
- Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies, Boston Medical Center, Massachusetts
| | - Harold Bae
- Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston Claude D. Pepper Older Americans Independence Center for Function Promoting Therapies, Boston Medical Center, Massachusetts
| | - Victor Gordeuk
- Section of Hematology/Oncology Sickle Cell Center, MC 712, University of Illinois at Chicago
| | - Shalender Bhasin
- Brigham and Women's Hospital, Department of Medicine, Section on Men's Health, Aging and Metabolism, Boston, Massachusetts
| |
Collapse
|