ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy

Abstract Background: Sepsis is a critical challenge for the elderly population as the immune function is less responsive by aging. Although cell numbers seem preserved in the elderly, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues.Methods: We treated the aged (12-16 months) and young (4-6 months) C57BL/6 mouse with ABT-263, then gave the animals cecal slurry injection to induce sepsis to observe the effect of senolytic compound ABT-263 on the survival rate of sepsis. Additionally, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. RT-PCR and Western Blot were used to detect autophagy related gene and protein changes in sepsis. EGFP-expressing E. Coli was used as a marker to evaluate the phagocytic ability of macrophages. Results: The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy, while blocking the autophagy can eliminate this effect. It is revealed that ABT-263 enhanced the phagocytic ability of the peritoneal macrophages by increasing the Trem-2 receptor. Additionally, ABT-263 blocked the binding of Bcl-2 to Beclin-1, thus induced Beclin-1-dependent autophagy. Conclusion: ABT-263 enhanced the macrophage function in aged mouse by increasing the Trem-2 receptors and inducing a beclin-1-dependent autophagy, consequently, protected the aged mouse from sepsis.

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ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy

BMC Geriatrics ◽

10.1186/s12877-021-02173-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yu Zhang ◽

Li-hua Tang ◽

Jia Lu ◽

Li-ming Xu ◽

Bao-li Cheng ◽

...

Keyword(s):

Older Adults ◽

Survival Rate ◽

Cell Function ◽

Peritoneal Macrophages ◽

Beclin 1 ◽

Aged Mouse ◽

Phagocytic Ability ◽

Age Related ◽

Slurry Injection

Abstract Background Sepsis is a critical challenge for the older adults as the immune function is less responsive by aging. Although cell numbers seem preserved in the older adults, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues. Methods We treated the aged (12–16 months) and young (4–6 months) C57BL/6 mouse with ABT-263, then gave the animals cecal slurry injection to induce sepsis to observe the effect of senolytic compound ABT-263 on the survival rate of sepsis. Additionally, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. RT-PCR and Western Blot were used to detect autophagy related gene and protein changes in sepsis. EGFP-expressing E. coli was used as a marker to evaluate the phagocytic ability of macrophages. Results The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy, while blocking the autophagy can eliminate this effect. It is revealed that ABT-263 enhanced the phagocytic ability of the peritoneal macrophages by increasing the Trem-2 receptor. Additionally, ABT-263 blocked the binding of Bcl-2 to Beclin-1, thus induced Beclin-1-dependent autophagy. Conclusion ABT-263 enhanced the macrophage function in aged mouse by increasing the Trem-2 receptors and inducing a beclin-1-dependent autophagy, consequently, protected the aged mouse from sepsis.

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Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

10.21203/rs.3.rs-19857/v1 ◽

2020 ◽

Author(s):

Yu Zhang ◽

Li-hua Tang ◽

Jia Lu ◽

Li-ming Xu ◽

Bao-li Cheng ◽

...

Keyword(s):

Survival Rate ◽

Cell Function ◽

The Elderly ◽

Peritoneal Macrophages ◽

Aged Mouse ◽

Phagocytic Ability ◽

Age Related ◽

Apoptotic Protein ◽

Slurry Injection

Abstract Sepsis is a critical challenge for the elderly population as the immune function is less responsive by aging. Although cell numbers seem preserved in the elderly, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues. Therefore, we treated the aged mouse with ABT-263 and used cecal slurry injection to induce sepsis to observe its effect on the survival rate of sepsis. Besides, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. EGFP-expressing E. Coli was used as a marker to evaluate the phagocytic ability of macrophages. The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy. Additionally, It is revealed that ABT-263 induced autophagy and enhanced the phagocytic ability of the peritoneal macrophages. However, blocking the autophagy can eliminate this effect. In conclusion, ABT-263 enhanced the macrophage function by inducing autophagy, consequently, protected the aged mouse from sepsis.

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Aging and immune response to exercise

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y98-043 ◽

1998 ◽

Vol 76 (5) ◽

pp. 562-572 ◽

Cited By ~ 22

Author(s):

Shoji Shinkai ◽

Masamitsu Konishi ◽

Roy J Shephard

Keyword(s):

Cellular Immunity ◽

Acute Exercise ◽

Cell Function ◽

Nk Cell ◽

Cell Activity ◽

The Elderly ◽

Strenuous Exercise ◽

Elderly Subjects ◽

Older Individuals ◽

Age Related

Human immune function undergoes adverse changes with aging. The T cells, which have a central role in cellular immunity, show the largest age-related differences in distribution and function, with thymus involution as the apparent underlying cause. The immune responses to acute exercise and training have not been studied extensively in the elderly. The natural killer (NK) cell response to a single exercise challenge is normal in older individuals, but immediately after exercise the elderly subjects manifest less suppression of phytohemagglutinin (PHA)-induced lymphocyte proliferation than younger individuals. In contrast, a strenuous exercise seems to induce a more sustained postexercise suppression of cellular immunity in older individuals than in their young peers. A few cross-sectional comparisons of immune status between physically fit elderly individuals and young sedentary controls suggest that habitual physical activity may enhance NK cell activity, checking certain aspects of the age-related decline in T cell function, such as reduced mitogenesis in response to plant lectins and decreases in the production of certain types of cytokine. The clinical implications, however, remain to be clarified by future study.Key words: immune senescence, innate immunity, adaptive immunity.

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Arrhythmia susceptibility in senescent rat hearts

Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale ◽

10.4081/jbr.2014.2143 ◽

2014 ◽

Vol 87 (1) ◽

Author(s):

Stefano Rossi ◽

Silvana Baruffi ◽

Domenico Corradi ◽

Sergio Callegari ◽

Ezio Musso ◽

...

Keyword(s):

Cardiac Electrophysiology ◽

The Elderly ◽

Detailed Knowledge ◽

Activation Patterns ◽

Electrophysiological Properties ◽

Age Related ◽

Rat Hearts ◽

Arrhythmogenic Substrate ◽

Ventricular Activation

Cardiovascular disease increases with age as well as alterations of cardiac electrophysiological properties, but a detailed knowledge about changes in cardiac electrophysiology relevant to arrhythmogenesis in the elderly is relatively lacking. The aim of this study was to determine specific age-related changes in electrophysiological properties of the ventricles which can be related to a structural-functional arrhythmogenic substrate. Multiple epicardial electrograms were recorded on the ventricular surface of in vivo control and aged rats, while arrhythmia vulnerability was investigated by premature stimulation protocols. Single or multiple ectopic beats and sustained ventricular arrhythmias were frequently induced in aged but not in control hearts. Abnormal ventricular activation patterns during sinus rhythm and unchanged conduction velocity during point stimulation in aged hearts suggest the occurrence of impaired impulse conduction through the distal Purkinje system that might create a potential reentry substrate.

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Aging and dietary modulation of elastase and interleukin-1 beta secretion

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.268.1.r208 ◽

1995 ◽

Vol 268 (1) ◽

pp. R208-R213 ◽

Cited By ~ 3

Author(s):

J. G. Cannon ◽

M. A. Fiatarone ◽

M. Meydani ◽

J. Gong ◽

L. Scott ◽

...

Keyword(s):

Arachidonic Acid ◽

Cell Function ◽

Interleukin 1 ◽

Lipid Peroxide ◽

Arachidonic Acid Metabolism ◽

Interleukin 1 Beta ◽

Tension Development ◽

Age Related

Aging is associated with diminished immune function that may stem from alterations in arachidonic acid metabolism and lipid peroxidation. This study sought to determine if dietary modification of fatty acids influenced neutrophil and monocyte secretion after an in vivo inflammatory stress in older human subjects. Volunteers participated in protocols that forced their quadriceps muscles to lengthen during tension development (eccentric stress). These protocols can cause inflammatory foci in the muscle as well as alterations in circulating leukocyte function. In this study, in vivo neutrophil degranulation was assessed by plasma elastase concentrations, and mononuclear cell function was assessed by interleukin-1 beta (IL-1 beta) secretion in vitro. In response to eccentric stress, older subjects (> 60 yr old) taking a placebo had no apparent elastase response, whereas those taking fish oil supplements responded with a 142% increase in plasma elastase (P = 0.011), similar to responses of younger reference subjects (< 33 yr old) taking no supplement. Overall, elastase responses correlated with individual plasma arachidonic acid-to-eicosapentaenoic acid ratios (r = -0.881, P = 0.004). Thus apparent age-related differences in elastase release were reconciled by individual differences in fatty acid nutriture. No significant temporal changes in urinary lipid peroxide excretion or IL-1 beta secretion were observed; however, age-associated differences were found.

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Arginine behaviour after arginine or citrulline administration in older subjects

British Journal Of Nutrition ◽

10.1017/s0007114515004638 ◽

2015 ◽

Vol 115 (3) ◽

pp. 399-404 ◽

Cited By ~ 20

Author(s):

C. Moinard ◽

J. Maccario ◽

S. Walrand ◽

V. Lasserre ◽

J. Marc ◽

...

Keyword(s):

Plasma Concentrations ◽

The Elderly ◽

Volume Of Distribution ◽

Elderly Subjects ◽

Healthy Elderly ◽

Age Related ◽

Loading Tests ◽

Kinetics Of ◽

Healthy Elderly Subjects

AbstractArginine (ARG) and its precursor citrulline (CIT) are popular dietary supplements, especially for the elderly. However, age-related reductions in lean body mass and alterations in organ functions could change their bioavailability. Pharmacokinetics and tolerance to amino acid (AA) loads are poorly documented in elderly subjects. The objective here was to characterise the plasma kinetics of CIT and ARG in a single-dosing study design. Eight fasting elderly men underwent two separate isomolar oral loading tests (10 g of CIT or 9·94 g of ARG). Blood was withdrawn over an 8-h period to measure plasma AA concentrations. Only CIT, ornithine and ARG plasma concentrations were changed. Volume of distribution was not dependent on AA administered. Conversely, parameters related to ARG kinetics were strongly dependent on AA administered: after ARG load, elimination was higher (ARG>CIT; P=0·041) and admission period+time at peak concentration was lower (ARG<CIT; P=0·033), and the combination of both phenomena results in a marked increase in ARG availability when CIT was administered (ARG<CIT; P=0·033) compared with ARG administration itself. In conclusion, a single CIT administration in the elderly is safe and well tolerated, and CIT proves to be a better in vivo ARG precursor than ARG itself in healthy elderly subjects.

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The role of high cholesterol in age-related COVID19 lethality

10.1101/2020.05.09.086249 ◽

2020 ◽

Cited By ~ 14

Author(s):

Hao Wang ◽

Zixuan Yuan ◽

Mahmud Arif Pavel ◽

Robert Hobson ◽

Scott B. Hansen

Keyword(s):

Viral Entry ◽

Super Resolution ◽

The Elderly ◽

High Cholesterol ◽

Entry Site ◽

Age Related ◽

Entry Points ◽

Resolution Imaging ◽

Tissue Cholesterol

ABSTRACTCoronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan, China in 2019. The disease is notably severe in elderly and those with underlying chronic conditions. A molecular mechanism that explains why the elderly are vulnerable and why children are resistant is largely unknown. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the entry of pseudotyped SARS-CoV-2 and the infectivity of the virion. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol shows almost twice the total number of endocytic entry points. Cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the endocytic entry site where SARS-CoV-2 presumably docks to efficiently exploit entry into the cell. Furthermore, in cells producing virus, cholesterol optimally positions furin for priming SARS-CoV-2, producing a more infectious virion with improved binding to the ACE2 receptor. In vivo, age and high fat diet induces cholesterol loading by up to 40% and trafficking of ACE2 to endocytic entry sites in lung tissue from mice. We propose a component of COVID19 severity based on tissue cholesterol level and the sensitivity of ACE2 and furin to cholesterol. Molecules that reduce cholesterol or disrupt ACE2 localization with viral entry points or furin localization in the producer cells, may reduce the severity of COVID19 in obese patients.

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Impact of endoplasmic reticulum stress on oocyte aging mechanisms

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa040 ◽

2020 ◽

Vol 26 (8) ◽

pp. 567-575

Author(s):

Isao Takehara ◽

Hideki Igarashi ◽

Jun Kawagoe ◽

Koki Matsuo ◽

Kyoko Takahashi ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Embryo Development ◽

Oocyte Quality ◽

Initiation Factor ◽

Aged Mouse ◽

Age Related ◽

Initiation Factor 2 ◽

Aging Mechanisms

Abstract Endoplasmic reticulum (ER) stress is associated with several aging-related diseases; however, the mechanism underlying age-related deterioration of oocyte quality is unclear. Here, we used post-ovulatory, in vivo aged mouse oocytes as a model. Super-ovulated oocytes harvested from the oviduct at 14 h and 20 h post-hCG injection were designated as ‘fresh’ and ‘aged’, respectively. Embryo development following IVF was compared between fresh, aged and ER stress-induced oocytes. Expression of the ER stress marker GRP78 was examined at each stage. To evaluate the effect of salubrinal, an ER stress suppressor, on embryo development following IVF, expression levels of GRP78 and phospho-eukaryotic initiation factor 2 alpha were compared between aged and salubrinal-treated aged oocytes. Embryo transfer of salubrinal-treated aged oocytes was performed to examine the safety of salubrinal. Similar to aged oocytes, ER stress-induced oocytes showed lower fertilization rates and poor embryo development. Following IVF, expression of GRP78 decreased with embryo development. GRP78 expression was significantly higher in aged oocytes than in fresh oocytes. Salubrinal lowered GRP78 levels and improved embryo development. No adverse effect of salubrinal treatment was found on the birth weight of pups or on organogenesis in mice. The limitation of this study was that protein kinase-like ER kinase was the only ER stress pathway examined; the role of IRE1 and ATF6 pathways was not considered. Nevertheless, salubrinal can significantly improve embryo development in in vivo aged oocytes undergoing ER stress. Hence, regulation of ER stress might represent a promising therapeutic strategy to overcome poor oocyte quality.

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IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production

Blood ◽

10.1182/blood-2009-07-230631 ◽

2010 ◽

Vol 115 (23) ◽

pp. 4699-4706 ◽

Cited By ~ 49

Author(s):

Kenichiro Maeda ◽

Harshini Mehta ◽

Douglas A. Drevets ◽

K. Mark Coggeshall

Keyword(s):

B Cell ◽

Peritoneal Macrophages ◽

Direct Result ◽

Feed Forward ◽

Splenic Macrophages ◽

Age Related ◽

Show Evidence ◽

Igg Receptors ◽

Src Homology 2 Domain

Abstract Src homology 2 domain-containing inositol 5-phosphatase (SHIP−/−) animals display an age-related increase in interleukin-6 (IL-6), a decrease in B lymphopoiesis, and an elevation in myelopoiesis. We investigated the origin of the IL-6 production and show that it is largely produced by peritoneal and splenic macrophages. IL-6 production by these macrophages is not a direct result of the loss of SHIP: IL-6 production is not spontaneous, is absent from bone marrow-derived macrophages, declines with prolonged culture of macrophages, and requires a stimulus present in vivo. The IL-6–rich peritoneal cavity of SHIP−/− mice shows more than 700-fold more immunoglobulin G (IgG) than wild-type, approximately 20% of which is aggregated or in an immune complex and contains B220+ cells that secrete IgG. The SHIP-deficient peritoneal macrophages show evidence of IgG receptor stimulation. Animals lacking both the signal-transducing γ-chain of IgG receptors and SHIP or Ig and SHIP produce less IL-6. The data indicate a feed-forward process in which peripheral macrophages, responding through IgG receptors to secreted IgG, produce IL-6, to support further B-cell production of IgG. Because of the proinflammatory phenotype of SHIP−/− animals, these findings emphasize the importance of IL-6–neutralizing strategies in autoimmune and proinflammatory diseases.

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