scholarly journals 15-PGDH as a Negative Regulator of Age-Related Organ Fitness

2020 ◽  
Author(s):  
Won Jin Ho ◽  
Julianne N.P. Smith ◽  
Young Soo Park ◽  
Matthew Hadiono ◽  
Kelsey Christo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tissue Injury ◽  
Peripheral Blood Cell ◽  
Multiple Organ ◽  
Negative Regulator ◽  
Post Transplantation ◽  
Aged Mice ◽  
Cell Counts ◽  
Age Related ◽  
Organ Systems

ABSTRACTEmerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cell regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness.ARTICLE SUMMARY15-PGDH as a Driver of Age-Related Tissue Dysfunction

scholarly journals Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Miwa Nahata ◽  
Sachiko Mogami ◽  
Hitomi Sekine ◽  
Seiichi Iizuka ◽  
Naoto Okubo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Energy Homeostasis ◽  
Mitochondrial Dynamics ◽  
Negative Regulator ◽  
Aged Mice ◽  
Glucose Levels ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Daily Food ◽  
Young Mice

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

Evaluation of Congenital Neutropenic Disorders by in Vitro Bone Marrow Culture

PEDIATRICS ◽  
1977 ◽  
Vol 59 (5) ◽  
pp. 739-748
Author(s):  
Peter M. Falk ◽  
Kenneth Rich ◽  
Stephen Feig ◽  
E. Richard Stiehm ◽  
David W. Golde ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Severe Disease ◽  
Stem Cell Differentiation ◽  
Peripheral Blood Cell ◽  
Clinical Expression ◽  
Essentially Normal ◽  
Cell Counts

The congenital neutropenias are a heterogeneous group of diseases whose etiology and pathogenesis are largely unknown. We studied nine neutropenic patients from seven families. Evaluation included peripheral blood cell and differential cell counts, epinephrine and typhoid vaccine stimulation studies, Rebuck skin windows, and bone marrow aspirations for morphological assessment and for in vitro culture in liquid suspension and in agar plates. Parallel cultures were set up with and without colony-stimulating activity (CSA), and peripheral leukocytes were assayed for cellular production of CSA. Patients were initially classified on the basis of their clinical course: benign, mild, moderately severe, or severe disease. One patient in the moderately severe group had an immunoglobulin disorder. Morphologically normal mature granulocytes were seen in bone marrow aspirates of two patients, and maturational defects of varying degree were seen in the remaining seven. Colony formation in agar was markedly reduced below normal in three of seven, moderately reduced in two of seven, and greater than normal in two patients. Colonies in six of seven patients consisted exclusively of macrophages. Marrow from all but one of the nine patients demonstrated poor neutrophil development in suspension culture, and addition of CSA did not result in augmented granulocytic proliferation or maturation. A scheme of normal neutrophil maturation is proposed, and the nine patients were categorized according to this scheme. Four patterns of congenital neutropenia emerged: type 1 was the most benign form of disease with essentially normal clinical and in vitro parameters, and a defect considered to be due to a small committed stem cell pool, abnormal release, or excessive utilization peripherally; type 2 had mild disease with presumed defective committed stem cell differentiation along the granulocyte line; type 3 included benign to severe clinical expression with an apparent defect at the level of the committed granulocyte precursor more severe than in type 2; type 4 disease had varied clinical expression but evidence for a defect at the level of the pluripotent stem cell.

scholarly journals Association Between Elevated suPAR, a New Biomarker of Inflammation, and Accelerated Aging

2020 ◽  
Author(s):  
Line Jee Hartmann Rasmussen ◽  
Avshalom Caspi ◽  
Antony Ambler ◽  
Andrea Danese ◽  
Maxwell Elliott ◽  
...  
Keyword(s):  
Chronic Inflammation ◽  
Functional Decline ◽  
Accelerated Aging ◽  
Multiple Organ ◽  
Biological Aging ◽  
Blood Levels ◽  
Urokinase Plasminogen Activator Receptor ◽  
Reactive Protein ◽  
Age Related ◽  
Organ Systems

Abstract Background To understand and measure the association between chronic inflammation, aging, and age-related diseases, broadly applicable standard biomarkers of systemic chronic inflammation are needed. We tested whether elevated blood levels of the emerging chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR) were associated with accelerated aging, lower functional capacity, and cognitive decline. Methods We used data from the Dunedin Study, a population-representative 1972–1973 New Zealand birth cohort (n = 1037) that has observed participants to age 45 years. Plasma suPAR levels were analyzed at ages 38 and 45 years. We performed regression analyses adjusted for sex, smoking, C-reactive protein, and current health conditions. Results Of 997 still-living participants, 875 (88%) had plasma suPAR measured at age 45. Elevated suPAR was associated with accelerated pace of biological aging across multiple organ systems, older facial appearance, and with structural signs of older brain age. Moreover, participants with higher suPAR levels had greater decline in physical function and cognitive function from childhood to adulthood compared to those with lower suPAR levels. Finally, improvements in health habits between ages 38 and 45 (smoking cessation or increased physical activity) were associated with less steep increases in suPAR levels over those years. Conclusions Our findings provide initial support for the utility of suPAR in studying the role of chronic inflammation in accelerated aging and functional decline.

Latexin: A Potential Tumor Suppressor.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1805-1805
Author(s):  
Ying Liang ◽  
Gary Van Zant
Keyword(s):  
Cell Proliferation ◽  
Stem Cell ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Negative Regulator ◽  
Stem Cell Population ◽  
Western Blots ◽  
Hematopoietic Stem ◽  
Cell Counts

Abstract We recently found that latexin is a negative regulator of the size of the hematopoietic stem cell population in mice. It acts by increasing apoptosis and decreasing cell proliferation. This 29 kD protein bears a strong structural resemblance to tazarotene-induced gene 1 (TIG1), a tumor suppressor down-regulated in a variety of cancers. The structural similarity and close genetic linkage led us to hypothesize that latexin also may have tumor suppressor properties. We found that latexin was down-regulated in a variety of human leukemias and lymphomas as determined by a survey of malignant cell lines and by analysis of CD34+ cells isolated from the blood and marrow of patients diagnosed with these malignancies and presenting with very high white cell counts. Bisulfite sequencing revealed that methylation of CpG dinucleotides in the latexin promoter at least partially accounted for latexin down-regulation. 5-aza-deoxycytidine treatment reinitiated or significantly increased latexin expression in K562, Molt4, CRF-CEM, Jurkat, U937, HL60, KG-1, and Sup B15 cell lines. To test the hypothesis that ectopic latexin expression in tumor cells would inhibit their growth, we developed a retrovirus-based expression vector with which we infected the murine lymphoma cell lines, WEHI231 and A20, neither of which contained significant latexin levels by Western blot. A vector containing GFP, but not latexin, was used to infect control cells. In triplicate experiments, the growth of both cell lines in vitro was inhibited an average 48% by infection with the latexin vector. Western blots revealed that latexin was durably expressed throughout the 2-week culture period at 2- to 4-fold the level expressed in normal T and B cells. As we found in our normal stem cell studies, latexin caused growth inhibition of lymphoma cells by significantly increasing apoptosis by 6-fold, and by suppressing cell proliferation by 2-fold. To test whether tumor inhibition extended to lymphomas in vivo, we injected either control or latexin vector-infected A20 cells subcutaneously in the flanks of BALB/c mice. Three weeks following adoptive transfer of identical numbers of cells, in duplicate experiments the latexin-expressing cells developed tumors only half the volume of those caused by the control cells. These results are consistent with a tumor suppressor role for latexin and suggest that latexin, or molecular mimics thereof, may have clinical efficacy in the treatment of malignancies.

Decreased oxygen exposure during transportation of newborns

2017 ◽  
Vol 103 (3) ◽  
pp. 269-271 ◽  
Author(s):  
Chayatat Ruangkit ◽  
Sasivimon Soonsawad ◽  
Thavatchai Tutchamnong ◽  
Buranee Swatesutipun
Keyword(s):  
Tissue Injury ◽  
Multiple Organ ◽  
Antioxidant Defences ◽  
Oxygen Exposure ◽  
Species Formation ◽  
Organ Systems ◽  
Improvement Programme ◽  
Excessive Oxygen

Oxygen is the most common treatment for newborns in need of respiratory support. However, oxygen can cause tissue injury through reactive oxygen species formation, especially in premature infants with reduced antioxidant defences, and may result in short-term and long-term toxic effects in multiple organ systems. Although most hospitals have the capability to tightly control oxygen delivery to hospitalised neonates, in many circumstances, the need is overlooked during infant transport. Lack of awareness of harm or appropriate medical equipment invariably results in excessive oxygen exposure. We developed a quality improvement programme to decrease oxygen exposure to newborns during their transportation, thus improving patient safety and quality of care.

scholarly journals THE GUT MICROBIOME AND AGING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S833-S833
Author(s):  
Christy S Carter ◽  
Michal Masternak ◽  
Thomas W Buford
Keyword(s):  
Gut Microbiome ◽  
Multiple Organ ◽  
Model Systems ◽  
Multiple Model ◽  
Gut Dysbiosis ◽  
Critical Areas ◽  
Age Related ◽  
Organ Systems ◽  
Health And Disease ◽  
Gut Microorganisms

Abstract The human intestinal tract (i.e., “gut”) is inhabited by over 100 trillion microorganisms; including over 1000 species of known bacteria. These organisms have co-evolved with humans over millennia to live together for mutual benefit. Though long overlooked in considerations of human health and disease treatment, gut microorganisms are highly involved in numerous metabolic reactions which influence normal host physiology. A variety of biologic, medical, and lifestyle factors appear to contribute to gut dysbiosis in late-life, and interventions specifically designed to target these factors may be useful in restoring microbial balance. Evidence from both clinical and preclinical studies suggests that gut dysbiosis is related to age-related inflammation as well as age-related conditions including frailty, Alzheimer’s disease, and perhaps even longevity. Crosstalk between the gut and multiple organ systems (brain, heart, muscle etc.) may lead to the development of age-related diseases and loss of physiological function, although the signals are not well understood. In this symposium we address the broad topic of the Gut Microbiome and Aging by presenting evidence from multiple model systems (mice, rats and monkeys) and provide a forum to discuss critical areas of research for moving forward.

Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction

2005 ◽  
Vol 33 (6) ◽  
pp. 650-674 ◽  
Author(s):  
Kevin P. Keenan ◽  
Chao-Min Hoe ◽  
Lori Mixson ◽  
Carol L. Mccoy ◽  
John B. Coleman ◽  
...  
Keyword(s):  
Body Fat ◽  
Dietary Restriction ◽  
Reproductive Organs ◽  
Multiple Organ ◽  
Sprague Dawley ◽  
Sd Rats ◽  
Age Related ◽  
Organ Systems ◽  
Estrous Cyclicity ◽  
Ad Libitum

This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on the pathogenesis of a metabolic syndrome of diabesity comprised of age-related degenerative diseases and obesity in a outbred stock of Sprague–Dawley (SD) rats [Crl:CD (SD) IGS BR]. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72–79% of AL (group 2), DR at 68–72% of AL (group 3) or DR at 47–48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Body weights, organ weights, carcass analysis, in-life data including estrous cyclicity, and histopathology were determined. At 6–7 weeks of age SD rats had 6% body fat. AL-feeding resulted in hypertriglyceridemia, hypercholesterolemia, and dietary-induced obesity (DIO) by study week 14, with 25% body fat that progressed to 36–42% body fat by 106 weeks. As early as 14 weeks, key biomarkers developed for spontaneous nephropathy, cardiomyopathy, and degenerative changes in multiple organ systems. Early endocrine disruption was indicated by changes in metabolic and endocrine profiles and the early development and progression of lesions in the pituitary, pancreatic islets, adrenals, thyroids, parathyroids, liver, kidneys, and other tissues. Reproductive senescence was seen by 9 months with declines in estrous cyclicity and pathological changes in the reproductive organs of both sexes fed AL or moderate DR, but not marked DR. The diabesity syndrome in AL-fed, DIO SD rats was readily modulated or prevented by moderate to marked DR. Moderate DR of balanced diets resulted in a better toxicology model by significantly improving survival, controlling adult body weight and obesity, reducing the onset, severity, and morbidity of age-related renal, endocrine, metabolic, and cardiac diseases. Moderate DR feeding reduces study-to-study variability, increases treatment exposure time, and increases the ability to distinguish true treatment effects from spontaneous aging. The structural and metabolic differences between the phenotypes of DIO and DR SD rats indicated changes of polygenic expression over time in this outbred stock. AL-overfeeding of SD rats produces a needed model of DIO and diabesity that needs further study of its patterns of polygenic expression and phenotype.

scholarly journals Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span

Science ◽  
2021 ◽  
Vol 373 (6554) ◽  
pp. eabc8479
Author(s):  
M. Grunewald ◽  
S. Kumar ◽  
H. Sharife ◽  
E. Volinsky ◽  
A. Gileles-Hillel ◽  
...  
Keyword(s):  
Life Span ◽  
Healthy Aging ◽  
Vascular Diseases ◽  
Tumor Burden ◽  
Multiple Organ ◽  
Vegf Signaling ◽  
Established Risk Factor ◽  
Age Related ◽  
Organ Systems ◽  
And Function

Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, “inflammaging” (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.

scholarly journals Interventional Strategies to Delay Aging-Related Dysfunctions of the Musculoskeletal System

2021 ◽  
Author(s):  
Naomasa Fukase ◽  
Ingrid K. Stake ◽  
Yoichi Murata ◽  
William S. Hambright ◽  
Sudheer Ravuri ◽  
...  
Keyword(s):  
Stem Cell ◽  
Musculoskeletal System ◽  
Healthy Aging ◽  
Mtor Inhibitors ◽  
Negative Regulator ◽  
Musculoskeletal Tissue ◽  
Musculoskeletal Tissues ◽  
Age Related ◽  
Secretory Phenotype ◽  
Novel Approaches

Aging affects bones, cartilage, muscles, and other connective tissue in the musculoskeletal system, leading to numerous age-related pathologies including osteoporosis, osteoarthritis, and sarcopenia. Understanding healthy aging may therefore open new therapeutic targets, thereby leading to the development of novel approaches to prevent several age-related orthopaedic diseases. It is well recognized that aging-related stem cell depletion and dysfunction leads to reduced regenerative capacity in various musculoskeletal tissues. However, more recent evidence suggests that dysregulated autophagy and cellular senescence might be fundamental mechanisms associated with aging-related musculoskeletal decline. The mammalian/mechanical target of Rapamycin (mTOR) is known to be an essential negative regulator of autophagy, and its inhibition has been demonstrated to promote longevity in numerous species. Besides, several reports demonstrate that selective elimination of senescent cells and their cognate Senescence-Associated Secretory Phenotype (SASP) can mitigate musculoskeletal tissue decline. Therefore, senolytic drugs/agents that can specifically target senescent cells, may offer a novel therapeutic strategy to treat a litany of age-related orthopaedic conditions. This chapter focuses on osteoarthritis and osteoporosis, very common debilitating orthopaedic conditions, and reviews current concepts highlighting new therapeutic strategies, including the mTOR inhibitors, senolytic agents, and mesenchymal stem cell (MSC)-based therapies.

scholarly journals Quantification of biological aging in young adults

2015 ◽  
Vol 112 (30) ◽  
pp. E4104-E4110 ◽  
Author(s):  
Daniel W. Belsky ◽  
Avshalom Caspi ◽  
Renate Houts ◽  
Harvey J. Cohen ◽  
David L. Corcoran ◽  
...  
Keyword(s):  
Young Adults ◽  
Brain Aging ◽  
Multiple Organ ◽  
Biological Aging ◽  
Research Translation ◽  
Human Aging ◽  
Aging Research ◽  
Cross Sectional ◽  
Age Related ◽  
Organ Systems

Antiaging therapies show promise in model organism research. Translation to humans is needed to address the challenges of an aging global population. Interventions to slow human aging will need to be applied to still-young individuals. However, most human aging research examines older adults, many with chronic disease. As a result, little is known about aging in young humans. We studied aging in 954 young humans, the Dunedin Study birth cohort, tracking multiple biomarkers across three time points spanning their third and fourth decades of life. We developed and validated two methods by which aging can be measured in young adults, one cross-sectional and one longitudinal. Our longitudinal measure allows quantification of the pace of coordinated physiological deterioration across multiple organ systems (e.g., pulmonary, periodontal, cardiovascular, renal, hepatic, and immune function). We applied these methods to assess biological aging in young humans who had not yet developed age-related diseases. Young individuals of the same chronological age varied in their “biological aging” (declining integrity of multiple organ systems). Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older. Measured biological aging in young adults can be used to identify causes of aging and evaluate rejuvenation therapies.

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