bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒09‒13
fifty-one papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Aging Cell. 2020 Sep 11. e13188
    Fielder E, Tweedy C, Wilson C, Oakley F, LeBeau FEN, Passos JF, Mann DA, von Zglinicki T, Jurk D.
      Chronic inflammation is a common feature of many age-related conditions including neurodegenerative diseases such as Alzheimer's disease. Cellular senescence is a state of irreversible cell-cycle arrest, thought to contribute to neurodegenerative diseases partially via induction of a chronic pro-inflammatory phenotype. In this study, we used a mouse model of genetically enhanced NF-κB activity (nfκb1-/- ), characterized by low-grade chronic inflammation and premature aging, to investigate the impact of inflammaging on cognitive decline. We found that during aging, nfkb1-/- mice show an early onset of memory loss, combined with enhanced neuroinflammation and increased frequency of senescent cells in the hippocampus and cerebellum. Electrophysiological measurements in the hippocampus of nfkb1-/- mice in vitro revealed deficits in gamma frequency oscillations, which could explain the decline in memory capacity. Importantly, treatment with the nonsteroidal anti-inflammatory drug (NASID) ibuprofen reduced neuroinflammation and senescent cell burden resulting in significant improvements in cognitive function and gamma frequency oscillations. These data support the hypothesis that chronic inflammation is a causal factor in the cognitive decline observed during aging.
    Keywords:  aging; cognitive decline; hippocampus; memory; neuroinflammation; senescence
  2. Exp Gerontol. 2020 Sep 05. pii: S0531-5565(20)30425-3. [Epub ahead of print] 111077
    Shin HE, Kwak SE, Zhang DD, Lee J, Yoon KJ, Cho HS, Moon HY, Song W.
      Tight junction protein is representative regulator of gut permeability. Also, it has been noted for controlling inflammatory responses through tight junction. Therefore, in this study, we examined that whether tight junction protein is changed in aged mice, and to further, confirmed the effect of treadmill exercise on the tight junction protein. In in vitro study, doxorubicin that induces cell senescence was treated to Caco2 cells (colon cell) to mimic aging effect. After that, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), exercise mimic chemical that stimulates AMPK level, was also administered to Caco2 cells. In animal study, 2 months and 21 months C57BL/6 J mouse were treated with treadmill exercise for 4 weeks (YE = 5, OE = 5). Then, the tight junction protein expression level was examined by western blot. Also, serum lipopolysaccharide (LPS) and zonulin level were analyzed to identify gut permeability. In vitro studies showed that doxorubicin downregulates tight junction protein expression levels in Caco2 cell, and also AICAR treatment upregulates tight junction protein expression levels. In animal study, 4 weeks treadmill exercise upregulated claudin-1 (p < 0.05) and occludin (p < 0.01) protein expression level in 21 months old mice. Also, zonula occluden-1 (ZO-1) protein expression level was not significant difference among all mice group. In addition, old mice group had higher level of serum LPS compared to young mice group, but the level was downregulated in both 2 months and 21 months mice group after four weeks of treadmill exercise. Zonulin, which is known as degrading tight junction protein, is not significantly changed by both age and exercise. This study compared that tight junction protein expression level in old mice compared to its level in young mice, and also clarified that the effect of treadmill exercise on tight junction protein in both young and old mice.
    Keywords:  Intestinal barrier; Intestinal tight junction proteins; Lipopolysaccharide; Treadmill exercise; Zonulin
  3. J Cachexia Sarcopenia Muscle. 2020 Sep 12.
    Brown JL, Lawrence MM, Ahn B, Kneis P, Piekarz KM, Qaisar R, Ranjit R, Bian J, Pharaoh G, Brown C, Peelor FF, Kinter MT, Miller BF, Richardson A, Van Remmen H.
      BACKGROUND: Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia.METHODS: Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data were analysed by two-way ANOVA with Tukey-Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM.
    RESULTS: Muscle mass and cross-sectional area were significantly reduced, in tumour-bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour-bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour-bearing mice compared with saline-injected wild-type mice. Mitochondrial protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.0204 ± 0.00159; wild-type LLC, 0.167 ± 0.00157) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2 ± 0.861; wild-type LLC, 28.8 ± 0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation.
    CONCLUSIONS: Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.
    Keywords:  CuZn superoxide dismutase knockout mice (Sod1KO); Lewis lung carcinoma cells (LLC); Lung cancer; Oxidative stress; Reactive oxygen species (ROS)
  4. Cell Signal. 2020 Sep 04. pii: S0898-6568(20)30248-5. [Epub ahead of print] 109771
    Salminen A, Kaarniranta K, Kauppinen A.
      Exosomes represent an evolutionarily conserved signaling pathway which can act as an alarming mechanism in responses to diverse stresses, e.g. chronic inflammation activates the budding of exosomal vesicles in both immune and non-immune cells. Exosomes can contain both pro- and anti-inflammatory cargos but in chronic inflammation, exosomes mostly carry immunosuppressive cargos, e.g. enzymes and miRNAs. The aging process is associated with chronic low-grade inflammation and the accumulation of pro-inflammatory senescent cells into tissues. There is clear evidence that aging increases the number of exosomes in both the circulation and tissues. Especially, the secretion of immunosuppressive exosomes robustly increases from senescent cells. There are observations that the exosomes from senescent cells are involved in the expansion of senescence into neighbouring cells. Interestingly, the age-related exosomes contain immune suppressive cargos which enhance the immunosuppression within recipient immune cells, i.e. tissue-resident and recruited immune cells including M2 macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). It seems that increased immunosuppression with aging impairs the clearance of senescent cells and their accumulation within tissues augments the aging process.
    Keywords:  Aging; Extracellular vesicles; Immune evasion; Immunometabolism; Inflammaging; SASP
  5. Nat Commun. 2020 Sep 11. 11(1): 4571
    Flores J, Noël A, Foveau B, Beauchet O, LeBlanc AC.
      Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.
  6. Int J Mol Sci. 2020 Sep 09. pii: E6579. [Epub ahead of print]21(18):
    Okuno K, Cicalese S, Elliott KJ, Kawai T, Hashimoto T, Eguchi S.
      Cardiovascular disease (CVD) is a prevalent issue in the global aging population. Premature vascular aging such as elevated arterial stiffness appears to be a major risk factor for CVD. Vascular smooth muscle cells (VSMCs) are one of the essential parts of arterial pathology and prone to stress-induced senescence. The pervasiveness of senescent VSMCs in the vasculature increases with age and can be further expedited by various stressing events such as oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, and chronic inflammation. Angiotensin II (AngII) can induce many of these responses in VSMCs and is thus considered a key regulator of VSMC senescence associated with CVD. Understanding the precise mechanisms and consequences of senescent cell accumulation may uncover a new generation of therapies including senolytic and senomorphic compounds against CVD. Accordingly, in this review article, we discuss potential molecular mechanisms of VSMC senescence such as those induced by AngII and the therapeutic manipulations of senescence to control age-related CVD and associated conditions such as by senolytic.
    Keywords:  aging; angiotensin II; senolytic; vascular smooth muscle cells
  7. Ageing Res Rev. 2020 Sep 04. pii: S1568-1637(20)30303-2. [Epub ahead of print] 101168
    Chiang JL, Shukla P, Pagidas K, Ahmed N, Karri S, Gunn D, Hurd W, Singh KK.
      Mitochondrial dysfunction is one of the hallmarks of aging. Consistently mitochondrial DNA (mtDNA) copy number and function decline with age in various tissues. There is increasing evidence to support that mitochondrial dysfunction drives ovarian aging. A decreased mtDNA copy number is also reported during ovarian aging. However, the mitochondrial mechanisms contributing to ovarian aging and infertility are not fully understood. Additionally, investigations into mitochondrial therapies to rejuvenate oocyte quality, select viable embryos and improve mitochondrial function may help enhance fertility or extend reproductive longevity in the future. These therapies include the use of mitochondrial replacement techniques, quantification of mtDNA copy number, and various pharmacologic and lifestyle measures. This review aims to describe the key evidence and current knowledge of the role of mitochondria in ovarian aging and identify the emerging potential options for therapy to extend reproductive longevity and improve fertility.
    Keywords:  Infertility; Mitochondrial DNA; Mitochondrial Dysfunction; Mitochondrial therapies; Ovarian aging; Reproductive longevity
  8. Aging Cell. 2020 Sep 12. e13234
    Frisch SM, MacFawn IP.
      This review article addresses the largely unanticipated convergence of two landmark discoveries. The first is the discovery of interferons, critical signaling molecules for all aspects of both innate and adaptive immunity, discovered originally by Isaacs and Lindenmann at the National Institute for Medical Research, London, in 1957 (Proceedings of the Royal Society of London. Series B: Biological Sciences, 1957, 147, 258). The second, formerly unrelated discovery, by Leonard Hayflick and Paul Moorhead (Wistar Institute, Philadelphia) is that cultured cells undergo an irreversible but viable growth arrest, termed senescence, after a finite and predictable number of cell divisions (Experimental Cell Research, 1961, 25, 585). This phenomenon was suspected to relate to organismal aging, which was confirmed subsequently (Nature, 2011, 479, 232). Cell senescence has broad-ranging implications for normal homeostasis, including immunity, and for diverse disease states, including cancer progression and response to therapy (Nature Medicine, 2015, 21, 1424; Cell, 2019, 179, 813; Cell, 2017, 169, 1000; Trends in Cell Biology, 2018, 28, 436; Journal of Cell Biology, 2018, 217, 65). Here, we critically address the bidirectional interplay between interferons (focusing on type I) and cell senescence, with important implications for health and healthspan.
    Keywords:  DNA damage; cellular immunology; cellular senescence; inflammation; longevity; senescence
  9. Nat Commun. 2020 Sep 08. 11(1): 4496
    Shi D, Xia X, Cui A, Xiong Z, Yan Y, Luo J, Chen G, Zeng Y, Cai D, Hou L, McDermott J, Li Y, Zhang H, Han JJ.
      Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P2. MI and PI(4,5)P2 are precursors of PI(3,4,5)P3, which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator PTEN induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.
  10. Aging Cell. 2020 Aug;19(8): e13200
    Yao H, Chen X, Kashif M, Wang T, Ibrahim MX, Tüksammel E, Revêchon G, Eriksson M, Wiel C, Bergo MO.
      Several progeroid disorders are caused by deficiency in the endoprotease ZMPSTE24 which leads to accumulation of prelamin A at the nuclear envelope. ZMPSTE24 cleaves prelamin A twice: at the third carboxyl-terminal amino acid following farnesylation of a -CSIM motif; and 15 residues upstream to produce mature lamin A. The carboxyl-terminal cleavage can also be performed by RAS-converting enzyme 1 (RCE1) but little is known about the importance of this cleavage for the ability of prelamin A to cause disease. Here, we found that knockout of RCE1 delayed senescence and increased proliferation of ZMPSTE24-deficient fibroblasts from a patient with non-classical Hutchinson-Gilford progeria syndrome (HGPS), but did not influence proliferation of classical LMNA-mutant HGPS cells. Knockout of Rce1 in Zmpste24-deficient mice at postnatal week 4-5 increased body weight and doubled the median survival time. The absence of Rce1 in Zmpste24-deficient fibroblasts did not influence nuclear shape but reduced an interaction between prelamin A and AKT which activated AKT-mTOR signaling and was required for the increased proliferation. Prelamin A levels increased in Rce1-deficient cells due to a slower turnover rate but its localization at the nuclear rim was unaffected. These results strengthen the idea that the presence of misshapen nuclei does not prevent phenotype improvement and suggest that targeting RCE1 might be useful for treating the rare progeroid disorders associated with ZMPSTE24 deficiency.
    Keywords:  RCE1; ZMPSTE24; mouse models; prelamin A; progeria
  11. Appl Immunohistochem Mol Morphol. 2020 Sep;28(8): 579-592
    Cho MJ, Kim DH, Ha S, Bang E, Jung HJ, Moon HR, Chung HY.
      Chronic inflammation is a major risk factor underlying aging and age-associated diseases. It impairs normal lipid accumulation, adipose tissue function, and mitochondrial function, which eventually lead to insulin resistance. Peroxisome proliferator-activated receptors (PPARs) critically regulate gluconeogenesis, lipid metabolism, and the lipid absorption and breakdown process, and PPAR activity decreases in the liver during aging. In the present study, we investigated the ability of 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), synthesized PPARα/PPARβ/PPARγ pan agonist, to suppress the inflammatory response and attenuate insulin resistance in aged rat liver. Six- and 20-month-old rats were divided into 4 groups: young and old rats fed ad libitum; and old rats fed ad libitum supplemented with MHY2013 (1 mg and 5 mg/kg/d for 4 wk). We found that MHY2013 supplementation efficiently downregulated the activity of nuclear factor-κB through JNK/ERK/p38 mitogen-activated protein kinase signaling in the liver of aged rats. In addition, MHY2013 treatment increased hepatic insulin signaling, and the downstream signaling activity of FOXO1, which is negatively regulated by Akt. Downregulation of Akt increases expression of FOXO1, which acts as a transcription factor and increases transcription of interleukin-1β, leading to hepatic inflammation. The major finding of this study is that MHY2013 acts as a therapeutic agent against age-related inflammation associated with insulin resistance by activating PPARα, PPARβ, and PPARγ. Thus, the study provides evidence for the anti-inflammatory properties of MHY2013, and the role it plays in the regulation of age-related alterations in signal transduction pathways.
  12. Exp Gerontol. 2020 Sep 07. pii: S0531-5565(20)30429-0. [Epub ahead of print] 111081
    Matsui M, Kosaki K, Tanahashi K, Akazawa N, Osuka Y, Tanaka K, Kuro-O M, Maeda S.
      OBJECTIVE: Circulating levels of fibroblast growth factor 21 (FGF21) increase with advancing age and may lead to the development of cardiometabolic diseases via impaired lipid and glucose metabolism. While physical activity can reduce these risks of cardiometabolic dysfunction, it remains obscure whether circulation FGF21 levels are influenced by physical activity. The purpose of this study was to investigate the relations between daily physical activities and circulating FGF21 levels in middle-aged and older adults.METHODS: In this cross-sectional study with 110 middle-aged and 102 older adults, circulating (serum) FGF21 levels were evaluated by enzyme-linked immunosorbent assay, and the time spent in light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA) was assessed using a uniaxial accelerometer.
    RESULTS: Serum FGF21 levels in the older group (158 pg/mL) were significantly higher than those in the middle-aged group (117 pg/mL). When we examined the joint association of age (middle-aged or older) and MVPA (lower or higher than the median) groups, serum FGF21 levels in the older and higher MVPA group (116 pg/mL) were significantly lower than those in the older and lower MVPA group (176 pg/mL). However, there was no difference in serum FGF21 levels between the lower and higher MVPA groups in the middle-aged group. In multivariable liner regression analysis, serum FGF21 levels were independently determined by MVPA time after adjusting for potential covariates in older adults (β = -0.209).
    CONCLUSIONS: These cross-sectional study findings indicate that the time spent in MVPA is an independent determinant of circulating FGF21 levels, and that an age-related increase in serum FGF21 levels may be attenuated by habitually performing MVPA. (250/250 words).
    Keywords:  Accelerometer; Activity intensity; Aging; FGF21; Physical activity
  13. Geroscience. 2020 Sep 10.
    Kim SJ, Miller B, Kumagai H, Silverstein AR, Flores M, Yen K.
      A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Here, we review the evidence that a decline in the levels of mitochondrial-derived peptides contributes to aging and age-related diseases. In particular, we discuss how mitochondrial-derived peptides, humanin and MOTS-c, contribute to specific aspects of the aging process, including cellular senescence, chronic inflammation, and cognitive decline. Genetic variations in the coding region of humanin and MOTS-c that are associated with age-related diseases are also reviewed, with particular emphasis placed on how mitochondrial variants might, in turn, regulate MDP expression and age-related phenotypes. Taken together, these observations suggest that mitochondrial-derived peptides influence or regulate a number of key aspects of aging and that strategies directed at increasing mitochondrial-derived peptide levels might have broad beneficial effects.
    Keywords:  Age-related diseases; Aging; Humanin; MOTS-c; Mitochondria; Mitochondrial-derived peptides
  14. Proc Natl Acad Sci U S A. 2020 Sep 08. pii: 202011243. [Epub ahead of print]
    Brandão BB, Madsen S, Rabiee A, Oliverio M, Ruiz GP, Ferrucci DL, Branquinho JL, Razolli D, Pinto S, Nielsen TS, Festuccia WT, Martins AS, Guerra BA, Knittel TL, Søgaard D, Larsen S, Helge JW, Brandauer J, Velloso LA, Emanuelli B, Kornfeld JW, Kahn CR, Vienberg SG, Zierath JR, Treebak JT, Mori MA.
      DICER is a key enzyme in microRNA (miRNA) biogenesis. Here we show that aerobic exercise training up-regulates DICER in adipose tissue of mice and humans. This can be mimicked by infusion of serum from exercised mice into sedentary mice and depends on AMPK-mediated signaling in both muscle and adipocytes. Adipocyte DICER is required for whole-body metabolic adaptations to aerobic exercise training, in part, by allowing controlled substrate utilization in adipose tissue, which, in turn, supports skeletal muscle function. Exercise training increases overall miRNA expression in adipose tissue, and up-regulation of miR-203-3p limits glycolysis in adipose under conditions of metabolic stress. We propose that exercise training-induced DICER-miR-203-3p up-regulation in adipocytes is a key adaptive response that coordinates signals from working muscle to promote whole-body metabolic adaptations.
    Keywords:  adipose tissue; cross-talk; exercise; metabolic flexibility; microRNA
  15. Cell Rep. 2020 Sep 08. pii: S2211-1247(20)31114-1. [Epub ahead of print]32(10): 108125
    Burkewitz K, Feng G, Dutta S, Kelley CA, Steinbaugh M, Cram EJ, Mair WB.
      Individually, dysfunction of both the endoplasmic reticulum (ER) and mitochondria has been linked to aging, but how communication between these organelles might be targeted to promote longevity is unclear. Here, we provide evidence that, in Caenorhabditis elegans, inhibition of the conserved unfolded protein response (UPRER) mediator, activating transcription factor (atf)-6, increases lifespan by modulating calcium homeostasis and signaling to mitochondria. Atf-6 loss confers longevity via downregulation of the ER calcium buffer, calreticulin. ER calcium release via the inositol triphosphate receptor (IP3R/itr-1) is required for longevity, while IP3R/itr-1 gain of function is sufficient to extend lifespan. Highlighting coordination between organelles, the mitochondrial calcium import channel mcu-1 is also required for atf-6 longevity. IP3R inhibition leads to impaired mitochondrial bioenergetics and hyperfusion, which is sufficient to suppress long life in atf-6 mutants. This study reveals the importance of organellar calcium handling as a critical output for the UPRER in determining the quality of aging.
    Keywords:  InsP3R; UPR; aging; calreticulin; interorganelle communication; longevity
  16. Cell Res. 2020 Sep 10.
    Ma S, Sun S, Li J, Fan Y, Qu J, Sun L, Wang S, Zhang Y, Yang S, Liu Z, Wu Z, Zhang S, Wang Q, Zheng A, Duo S, Yu Y, Belmonte JCI, Chan P, Zhou Q, Song M, Zhang W, Liu GH.
      Aging is a major risk factor for many diseases, especially in highly prevalent cardiopulmonary comorbidities and infectious diseases including Coronavirus Disease 2019 (COVID-19). Resolving cellular and molecular mechanisms associated with aging in higher mammals is therefore urgently needed. Here, we created young and old non-human primate single-nucleus/cell transcriptomic atlases of lung, heart and artery, the top tissues targeted by SARS-CoV-2. Analysis of cell type-specific aging-associated transcriptional changes revealed increased systemic inflammation and compromised virus defense as a hallmark of cardiopulmonary aging. With age, expression of the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) was increased in the pulmonary alveolar epithelial barrier, cardiomyocytes, and vascular endothelial cells. We found that interleukin 7 (IL7) accumulated in aged cardiopulmonary tissues and induced ACE2 expression in human vascular endothelial cells in an NF-κB-dependent manner. Furthermore, treatment with vitamin C blocked IL7-induced ACE2 expression. Altogether, our findings depict the first transcriptomic atlas of the aged primate cardiopulmonary system and provide vital insights into age-linked susceptibility to SARS-CoV-2, suggesting that geroprotective strategies may reduce COVID-19 severity in the elderly.
  17. Nat Commun. 2020 Sep 09. 11(1): 4510
    Ham DJ, Börsch A, Lin S, Thürkauf M, Weihrauch M, Reinhard JR, Delezie J, Battilana F, Wang X, Kaiser MS, Guridi M, Sinnreich M, Rich MM, Mittal N, Tintignac LA, Handschin C, Zavolan M, Rüegg MA.
      With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (, as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.
  18. Adv Exp Med Biol. 2020 Sep 11.
    De D, Karmakar P, Bhattacharya D.
      Stem cells are a promising source for regenerative medicine to cure a plethora of diseases that are currently treated based on either palliative or symptomatic relief or by preventing their onset and progression. Aging-associated degenerative changes in stem cells, stem cell niches, and signaling pathways bring a step by step decline in the regenerative and functional potential of tissues. Clinical studies and experiments on model organisms have pointed out checkpoints that aging will inevitably impose on stem cell aiming for transplantation and hence questions are raised about the age of the donor. In the following discourse, we review the fundamental molecular pathways that are implicated in stem cell aging and the current progress in tissue engineering and transplantation of each type of stem cells in regenerative medicine. We further focus on the consequences of stem cell aging on their clinical uses and the development of novel strategies to bypass those pitfalls and improve tissue replenishment.
    Keywords:  Aging; Regeneration; Regenerative medicine; Senescence; Stem cells
  19. Ageing Res Rev. 2020 Sep 05. pii: S1568-1637(20)30300-7. [Epub ahead of print] 101165
    Li PH, Zhang R, Cheng LQ, Liu JJ, Chen HZ.
      The process of ageing includes molecular changes within cells and interactions between cells, eventually resulting in age-related diseases. Although various cells (immune cells, parenchymal cells, fibroblasts and endothelial cells) in tissues secrete proinflammatory signals in age-related diseases, immune cells are the major contributors to inflammation. Many studies have emphasized the role of metabolic dysregulation in parenchymal cells in age-related inflammatory diseases. However, few studies have discussed metabolic modifications in immune cells during ageing. In this review, we introduce the metabolic dysregulation of major nutrients (glucose, lipids, and amino acids) within immune cells during ageing, which leads to dysfunctional NAD + metabolism that increases immune cell senescence and leads to the acquisition of the corresponding senescence-associated secretory phenotype (SASP). We then focus on senescent immune cell interactions with parenchymal cells and the extracellular matrix and their involvement in angiogenesis, which lead to proinflammatory microenvironments in tissues and inflammatory diseases at the systemic level. Elucidating the roles of metabolic modifications in immune cells during ageing will provide new insights into the mechanisms of ageing and therapeutic directions for age-related inflammatory diseases.
    Keywords:  ageing; immune cell; inflammatory disease; metabolism; senescence-associated secretory phenotype (SASP)
  20. Mol Cell Biochem. 2020 Sep 11.
    Yuan H, Xu Y, Luo Y, Wang NX, Xiao JH.
      Nuclear factor-E2-related factor 2 (Nrf2) is a key transcription factor known to be involved in maintaining cell redox balance and signal transduction and plays central role in reducing intracellular oxidative stress damage, delaying cell senescence and preventing age-related diseases. However, it has been shown that the level of Nrf2 decreases with age and that the silencing of the Nrf2 gene is associated with the induction of premature senescence. Therefore, a plethora of researchers have focused on elucidating the regulatory mechanism of Nrf2 in the prevention of cell senescence. This complex regulatory mechanism of Nrf2 in the cell senescence process involves coordinated regulation of multiple signaling molecules. After summarizing the function of Nrf2 and its relationship with cell senescence pathway, this review focuses on the recent advances and progress made in elucidating the regulatory mechanism of Nrf2 in the cell senescence process. Additionally, the information collected here may provide insights for further research on Nrf2, in particular, on its regulatory mechanism in the cell senescence process.
    Keywords:  Aging; Cell senescence; Nuclear factor-E2-related factor 2; Oxidative stress; Regulatory mechanism
  21. Mol Cell Biochem. 2020 Sep 12.
    Makino N, Maeda T.
      The aims of this study were to investigate the impact of caloric restriction (CR) on cardiac senescence in an animal model of diabetes and examine the signal transduction mechanisms for changes in cell survival as well as cardiac function. Male 8-week-old Otsuka Long-Evans Tokushima fatty (OLETF) diabetic rats were divided into 2 groups: a group fed ad libitum (AL), and a group fed with CR (30% energy reduction). Long-Evans Tokushima Otsuka (LETO) non-diabetic rats were used as controls. LETO rats were divided into 3 groups: a high fat diet (HFD) group with a 22% increase in caloric intake, a CR group, and a group fed AL. At 40 weeks of age, the telomere length was significantly shorter in the heart tissue of HFD rats but was not altered by CR in experimental rats with or without CR, however, telomerase activity in both strains of CR rats was significantly elevated. Protein expression of IGF-1, Sirt 1 and phospho-FoxO1 was increased in both CR groups. Echocardiography showed that CR preserved LV diastolic function with a significantly shorter E-wave deceleration time and a greater E/A ratio compared with the AL groups. These findings suggest that CR protocol increased telomerase activity without changing of telomere length, enhanced autophagy and improved LV diastolic function in animal model of diabetes rats. It is finally suggested that those impacts may be important for the maintenance of normal cardiac function and for delayed cardiac aging.
    Keywords:  Autophagy; Calorie restriction; Diabetes; Diastolic function; Signal transduction; Telomere
  22. Diabetologia. 2020 Oct;63(10): 2022-2029
    Aguayo-Mazzucato C.
      Insulin secretion from beta cells is crucial for maintaining euglycaemia and preventing type 2 diabetes, a disease correlated with ageing. Therefore, understanding the functional changes that beta cell function undergoes with age can reveal new therapeutic targets and strategies to delay or revert the disease. Herein, a systematic review of the literature agrees that, as humans age, their beta cell function declines, independently of peripheral insulin resistance, BMI and waist circumference. Rodent studies reveal that, with age, basal insulin secretion increases with either no change or an increase in stimulated insulin secretion, but the biological significance of this is unclear. The accumulation of senescent beta cells could explain some of these functional changes: transcriptional analysis of senescent and aged beta cells revealed parallel downregulation of several steps along the pathway linking glucose stimulation and insulin secretion. Moreover, specific deletion of senescent cells (senolysis) improved residual beta cell function, gene expression profile and blood glucose levels. In conclusion, cellular senescence could underlie the functional decline of beta cells during ageing and could represent a novel and promising approach for recovering insulin secretion. Graphical abstract.
    Keywords:  Ageing; Beta cells; Function; Human; Insulin secretion; Review; Rodents; Senescence; Senolysis; Type 2 diabetes
  23. Elife. 2020 Sep 08. pii: e54383. [Epub ahead of print]9
    Bersini S, Schulte R, Huang L, Tsai H, Hetzer MW.
      Vascular dysfunctions are a common feature of multiple age-related diseases. However, modeling healthy and pathological aging of the human vasculature represents an unresolved experimental challenge. Here, we generated induced vascular endothelial cells (iVECs) and smooth muscle cells (iSMCs) by direct reprogramming of healthy human fibroblasts from donors of different ages and Hutchinson-Gilford Progeria Syndrome (HGPS) patients. iVECs induced from old donors revealed upregulation of GSTM1 and PALD1, genes linked to oxidative stress, inflammation and endothelial junction stability, as vascular aging markers. A functional assay performed on PALD1 KD VECs demonstrated a recovery in vascular permeability. We found that iSMCs from HGPS donors overexpressed bone morphogenetic protein (BMP)-4, which plays a key role in both vascular calcification and endothelial barrier damage observed in HGPS. Strikingly, BMP4 concentrations are higher in serum from HGPS vs. age-matched mice. Furthermore, targeting BMP4 with blocking antibody recovered the functionality of the vascular barrier in vitro, hence representing a potential future therapeutic strategy to limit cardiovascular dysfunction in HGPS. These results show that iVECs and iSMCs retain disease-related signatures, allowing modeling of vascular aging and HGPS in vitro.
    Keywords:  aging; direct reprogramming; endothelial cell; human; hutchinson-gilford progeria syndrome; medicine; mouse; smooth muscle cell; vascular barrier
  24. Microb Cell. 2020 Jun 22. 7(9): 222-233
    Pellegrino-Coppola D.
      Aging is an evolutionarily conserved process and is tightly connected to mitochondria. To uncover the aging molecular mechanisms related to mitochondria, different organisms have been extensively used as model systems. Among these, the budding yeast Saccharomyces cerevisiae has been reported multiple times as a model of choice when studying cellular aging. In particular, yeast provides a quick and trustworthy system to identify shared aging genes and pathway patterns. In this viewpoint on aging and mitochondria, I will focus on the mitochondrial permeability transition pore (mPTP), which has been reported and proposed as a main player in cellular aging. I will make several parallelisms with yeast to highlight how this unicellular organism can be used as a guidance system to understand conserved cellular and molecular events in multicellular organisms such as humans. Overall, a thread connecting the preservation of mitochondrial functionality with the activity of the mPTP emerges in the regulation of cell survival and cell death, which in turn could potentially affect aging and aging-related diseases.
    Keywords:  adenine nucleotide translocator; aging; cell death; mPTP; mitochondria; yeast
  25. Front Pharmacol. 2020 ;11 1150
    Li Y, Liu M, Song X, Zheng X, Yi J, Liu D, Wang S, Chu C, Yang J.
      Stress aging of myocardial cells participates in the mechanism of myocardial fibrosis (MF). Previous studies have shown that hydrogen sulfide (H2S) can improve MF, however the specific internal mechanism remains still unclear. Therefore, this study aims to explore whether H2S can improve myocardial cell aging induced by high glucose and myocardial fibrosis in diabetic rats by activating autophagy through SIRT6/AMPK. We observed that HG (high glucose, 33 mM) induced down-regulation of endogenous H2S-producing enzyme CSE protein expression, increased cell senescence, down-regulation of autophagy-related proteins Beclin1, Atg5, Atg12, Atg16L1, and inhibition of SIRT6/AMPK signaling pathway in H9c2 cardiomyocytes. H2S (NaHS: 400 μM) could up-regulate CSE protein expression, inhibit cell senescence, activate autophagy and SIRT6/AMPK signaling pathway. On the contrary, no above phenomena was achieved upon addition of CSE inhibitor PAG (dl-propargylglycine: mmol/L). In order to further elucidate the relationship between H2S and SIRT6/AMPK signaling pathway, dorsomorphin dihydrochloride (Dor), an inhibitor of AMPK signaling pathway, was added to observe the reversal of H2S's inhibitory effect on myocardial cell aging. At the same, streptozotocin (STZ; 40 mg/kg) was injected intraperitoneally to build an animal model of diabetic SD rats. The results showed that myocardial collagen fibers were significantly deposited, myocardial tissue senescent cells were significantly increased and the expression of CSE protein was down-regulated, while SIRT6/AMPK signaling pathway and cell autophagy were significantly inhibited. H2S-treated (NaHS; 56 μmol/kg) could significantly reverse the above phenomenon. In conclusion, these findings suggest that exogenous H2S can inhibit myocardial cell senescence and improve diabetic myocardial fibrosis by activating CSE and autophagy through SIRT6/AMPK signaling pathway.
    Keywords:  Sirt6/AMPK pathway; autophagy; cell aging; hydrogen sulfide; myocardial fibrosis
  26. Aging (Albany NY). 2020 Sep 09. 12
    Yakhine-Diop SMS, Morales-García JA, Niso-Santano M, González-Polo RA, Uribe-Carretero E, Martinez-Chacon G, Durand S, Maiuri MC, Aiastui A, Zulaica M, Ruíz-Martínez J, López de Munain A, Pérez-Tur J, Pérez-Castillo A, Kroemer G, Bravo-San Pedro JM, Fuentes JM.
      The research of new biomarkers for Parkinson's disease is essential for accurate and precocious diagnosis, as well as for the discovery of new potential disease mechanisms and drug targets. The main objective of this work was to identify metabolic changes that might serve as biomarkers for the diagnosis of this neurodegenerative disorder. For this, we profiled the plasma metabolome from mice with neurotoxin-induced Parkinson's disease as well as from patients with familial or sporadic Parkinson's disease. By using mass spectrometry technology, we analyzed the complete metabolome from healthy volunteers compared to patients with idiopathic or familial (carrying the G2019S or R1441G mutations in the LRRK2 gene) Parkinson's disease, as well as, from mice treated with 6-hydroxydopamine to induce Parkinson disease. Both human and murine Parkinson was accompanied by an increase in plasma levels of unconjugated bile acids (cholic acid, deoxycholic acid and lithocholic acid) and purine base intermediary metabolites, in particular hypoxanthine. The comprehensive metabolomic analysis of plasma from Parkinsonian patients underscores the importance of bile acids and purine metabolism in the pathophysiology of this disease. Therefore, plasma measurements of certain metabolites related to these pathways might contribute to the diagnosis of Parkinson's Disease.
    Keywords:  Parkinson’s disease; bile acids; biomarkers; metabolism; purines
  27. Aging (Albany NY). 2020 Sep 09. 12
    Chen Y, Zhang P, Lin X, Zhang H, Miao J, Zhou Y, Chen G.
      Postoperative cognitive dysfunction (POCD) is frequently observed in elderly patients following anesthesia, but its pathophysiological mechanisms have not been fully elucidated. Sevoflurane was reported to repress autophagy in aged rat neurons; however, the role of mitophagy, which is crucial for the control of mitochondrial quality and neuronal health, in sevoflurane-induced POCD in aged rats remains undetermined. Therefore, this study investigated whether mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction. We found sevoflurane treatment inhibited mitochondrial respiration and mitophagic flux, changes in mitochondria morphology, impaired lysosomal acidification, and increased Tomm20 and deceased LAMP1 accumulation were observed in H4 cell and aged rat models. Rapamycin counteracted ROS induced by sevoflurane, restored mitophagy and improved mitochondrial function. Furthermore, rapamycin ameliorated the cognitive deficits observed in aged rats given sevoflurane anesthesia as determined by the Morris water maze test; this improvement was associated with an increased number of dendritic spines and pyramidal neurons. Overexpression of PARK2, but not mutant PARK2 lacking enzyme activity, in H4 cells decreased ROS and Tomm20 accumulation and reversed mitophagy dysfunction after sevoflurane treatment. These findings suggest that mitophagy dysfunction could be a mechanism underlying sevoflurane-induced POCD and that activating mitophagy may provide a new strategy to rescue cognitive deficits.
    Keywords:  aged rat; mitophagy; postoperative cognitive dysfunction; rapamycin; sevoflurane
  28. Immun Ageing. 2020 ;17 24
    Ratliff ML, Garton J, James JA, Webb CF.
      Background: Immunologic aging leads to immune dysfunction, significantly reducing the quality of life of the elderly. Aged-related defects in early hematopoiesis result in reduced lymphoid cell development, functionally defective mature immune cells, and poor protective responses to vaccines and pathogens. Despite considerable progress understanding the underlying causes of decreased immunity in the elderly, the mechanisms by which these occur are still poorly understood. The DNA-binding protein ARID3a is expressed in a subset of human hematopoietic progenitors. Inhibition of ARID3a in bulk human cord blood CD34+ hematopoietic progenitors led to developmental skewing toward myeloid lineage at the expense of lymphoid lineage cells in vitro. Effects of ARID3a expression in adult-derived hematopoietic stem cells (HSCs) have not been analyzed, nor has ARID3a expression been assessed in relationship to age. We hypothesized that decreases in ARID3a could explain some of the defects observed in aging.Results: Our data reveal decreased frequencies of ARID3a-expressing peripheral blood HSCs from aged healthy individuals compared with young donor HSCs. Inhibition of ARID3a in young donor-derived HSCs limits B lineage potential, suggesting a role for ARID3a in B lymphopoiesis in bone marrow-derived HSCs. Increasing ARID3a levels of HSCs from aged donors in vitro alters B lineage development and maturation. Finally, single cell analyses of ARID3a-expressing HSCs from young versus aged donors identify a number of differentially expressed genes in aged ARID3A-expressing cells versus young ARID3A-expressing HSCs, as well as between ARID3A-expressing and non-expressing cells in both young and aged donor HSCs.
    Conclusions: These data suggest that ARID3a-expressing HSCs from aged individuals differ at both molecular and functional levels compared to ARID3a-expressing HSCs from young individuals.
    Keywords:  ARID3a; Hematopoiesis; Hematopoietic stem cells; Human immunity; Immunoaging
  29. Environ Toxicol. 2020 Sep 12.
    Romualdo GR, Da Silva TC, de Albuquerque Landi MF, Morais JÁ, Barbisan LF, Vinken M, Oliveira CP, Cogliati B.
      Non-alcoholic fatty liver disease (NAFLD) affects around 25% of the worldwide population. Non-alcoholic steatohepatitis (NASH), the more progressive variant of NAFLD, is characterized by steatosis, cellular ballooning, lobular inflammation, and may culminate on hepatic stellate cell (HSC) activation, thus increasing the risk for fibrosis, cirrhosis, and HCC development. Conversely, the antifibrotic effects of sorafenib, an FDA-approved drug for HCC treatment, have been demonstrated in 2D cell cultures and animal models, but its mechanisms in a NAFLD-related microenvironment in vitro requires further investigation. Thus, a human 3D co-culture model of fatty hepatocytes and HSC was established by culturing hepatoma C3A cells, pre-treated with 1.32 mM oleic acid, with HSC LX-2 cells. The fatty C3A/LX-2 spheroids showed morphological and molecular hallmarks of altered lipid metabolism and steatosis-induced fibrogenesis, similarly to the human disease. Sorafenib (15 μM) for 72 hours reduced fatty spheroid viability, and upregulated the expression of lipid oxidation- and hydrolysis-related genes, CPT1 and LIPC, respectively. Sorafenib also inhibited steatosis-induced fibrogenesis by downregulating COL1A1, TGFB1, PDGF, and TIMP1 and by decreasing protein levels of IL-6, TGF-β1, and TNF-α in fatty spheroids. The demonstration of the antifibrotic properties of sorafenib on steatosis-induced fibrogenesis in a 3D in vitro model of NAFLD supports its clinical use as a therapeutic agent for the treatment of NAFLD/NASH patients.
    Keywords:  antifibrotic therapy; fatty hepatocytes; hepatic stellate cells; non-alcoholic steatohepatitis; tridimensional cell culture
  30. Science. 2020 Sep 10. pii: eabd0237. [Epub ahead of print]
    Kujirai T, Zierhut C, Takizawa Y, Kim R, Negishi L, Uruma N, Hirai S, Funabiki H, Kurumizaka H.
      The cyclic GMP-AMP synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-EM structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of H2A-H2B and nucleosomal DNA. In this configuration, all three known cGAS DNA-binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA.
  31. Geroscience. 2020 Sep 09.
    Justice JN, Gubbi S, Kulkarni AS, Bartley JM, Kuchel GA, Barzilai N.
      We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.
    Keywords:  Aging; COVID-19; Geroscience; Immunity; Metformin
  32. Cell Metab. 2020 Sep 03. pii: S1550-4131(20)30425-3. [Epub ahead of print]
    Chevalier C, Kieser S, Çolakoğlu M, Hadadi N, Brun J, Rigo D, Suárez-Zamorano N, Spiljar M, Fabbiano S, Busse B, Ivanišević J, Macpherson A, Bonnet N, Trajkovski M.
      Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects. Both warmth and warm microbiota transplantation revert the ovariectomy-induced transcriptomics changes of the tibia and increase periosteal bone formation. Combinatorial metagenomics/metabolomics analysis shows that warmth enhances bacterial polyamine biosynthesis, resulting in higher total polyamine levels in vivo. Spermine and spermidine supplementation increases bone strength, while inhibiting polyamine biosynthesis in vivo limits the beneficial warmth effects on the bone. Our data suggest warmth exposure as a potential treatment option for osteoporosis while providing a mechanistic framework for its benefits in bone disease.
    Keywords:  bone; metabolomics; metadata; metagenomics; microbiota; osteoporosis; ovariectomy; polyamines; post-menopause; warm
  33. Oxid Med Cell Longev. 2020 ;2020 2647807
    Feng H, Mou SQ, Li WJ, Zhang N, Zhou ZY, Ding W, Bian ZY, Liao HH.
      Aims: The aim of this study was to investigate whether resveratrol (RSV) could ameliorate ischemia- and hypoxia-associated cardiomyocyte apoptosis and injury via inhibiting senescence signaling and inflammasome activation.Materials and Methods: Mice were treated with RSV by gastric tube (320 mg/kg/day) or vehicle one week before left coronary artery ligation or sham surgery until the end of the experiments. After pressure-volume loop analysis, mouse hearts were harvested for histopathological (including PSR, TTC, TUNEL staining, immunohistochemistry, and immunofluorescence) and molecular analysis by western blotting and RT-PCR. In addition, neonatal rat cardiomyocytes (NRCMs), cardiac fibroblasts (CFs), and macrophages were isolated for in vitro experiments. Key Findings. RSV treatment decreased mortality and improved cardiac hemodynamics. RSV inhibited the expression of senescence markers (p53, p16, and p19), inflammasome markers (NLRP3 and Cas1 p20), and nuclear translocation of NF-κB, hence alleviating infarction area, fibrosis, and cell apoptosis. RSV also inhibited expression of interleukin- (IL-) 1β, IL-6, tumor necrosis factor-α, and IL-18 in vivo. In in vitro experiment, RSV prevented hypoxia-induced NRCM senescence and apoptosis. After inhibition of sirtuin 1 (Sirt1) by EX27, RSV failed to inhibit p53 acetylation and expression. Moreover, RSV could inhibit expression of NLRP3 and caspase 1 p20 in NRCMs, CFs, and macrophages, respectively, in in vitro experiments. Significance. Our findings revealed that RSV protected against ischemia-induced mouse heart injury in vivo and hypoxia-induced NRCM injury in vitro via regulating Sirt1/p53-mediated cell senescence and inhibiting NLRP3-mediated inflammasome activation.
  34. Brain Res Bull. 2020 Sep 04. pii: S0361-9230(20)30606-7. [Epub ahead of print]
    Wen J, Ding Y, Wang L, Xiao Y.
      BACKGROUND: Increased permeability of blood-brain barrier (BBB) is a major pathophysiological mechanism of postoperative cognitive dysfunction (POCD) in the elderly. The reduced beneficial gut microbiome due to aging results in a decline in the production of sodium butyrate (NaB), which might enhance the BBB permeability. The present study investigated whether gut microbiome or NaB could improve the postoperative cognitive function in aged and gut dysbiosis mouse model.METHODS: A total of 210 male C57BL/6 J mice were randomly and equally divided into 7 groups (young control, young anesthesia/surgery, young anesthesia/surgery + antibiotic, aged control, aged anesthesia/surgery, aged anesthesia/surgery + Lactobacillus, aged anesthesia/surgery + NaB). Lactobacillus mix and antibiotic mix were administered by oral gavage to establish the gut dysbiosis and microbiome restoration model. Splenectomy was performed under sevoflurane anesthesia. Spatial memory learning ability was measured by Y maze. BBB permeability was detected by FITC-dextran imaging and brain tissue dextran spectrum. Tight junction (TJ) protein of hippocampus brain tissue was quantitated by Western blot.
    RESULT: Aging and antibiotic mix decreased the expression of the TJ, increased the BBB permeability and induced POCD, which could be reversed by the application of Lactobacillus and NaB.
    CONCLUSION: Lactobacillus and NaB increased the expression of TJ protein between endothelial cells (ECs), reduced the BBB permeability, and consequently protected the postoperative cognitive functions of the aged and gut dysbiosis mice.
    Keywords:  blood-brain barrier; gut microbiome; postoperative cognitive dysfunction; sodium butyrate
  35. Mech Ageing Dev. 2020 Sep 07. pii: S0047-6374(20)30147-0. [Epub ahead of print] 111351
    Panwar A, Jhun M, Rentsendorj A, Mardiros A, Cordner R, Birch K, Yeager N, Duvall G, Golchian D, Koronyo-Hamaoui M, Cohen R, Ley E, Black K, Wheeler C.
      Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Injecting T cells into athymic mice induces rapid homeostatic expansion, but its relevance to aging remains uncertain. We hypothesized that homeostatic expansion of T cells injected into T-deficient hosts models physiologically relevant CD8 T cell aging in young mice, and aimed to analyze age-related T cell phenotype and tissue pathology in such animals. Indeed, we found that such injection conferred uniform age-related phenotype, genotype, and function to mouse CD8 T cells, heightened age-associated tissue pathology in young athymic hosts, and humanized amyloidosis after brain injury in secondary wild-type recipients. This validates a model conferring a human-specific aging feature to mice that identifies targetable drivers of tissue pathology. Similar examination of independent aging features should promote systematic understanding of aging and identify additional targets to mitigate its effects on human health.
    Keywords:  CD8 T cell; Cellular immunity; Homeostatic expansion; Immune aging; Neurodegeneration; Resident memory T cell
  36. Curr Opin Cell Biol. 2020 Sep 07. pii: S0955-0674(20)30098-3. [Epub ahead of print]67 56-63
    Mizi A, Zhang S, Papantonis A.
      The spatial conformation of chromatin within the confines of eukaryotic cell nuclei is now acknowledged as a decisive epigenetic mechanism for the modulation of such cellular functions as gene expression regulation, DNA replication or DNA damage repair. Of course, these processes are tightly regulated during organismal development and markedly affected by cellular ageing. Thus, the question that arises is to what extent does folding or refolding of the genome in three-dimensional space underlie the progression of development or ageing? Herein, we discuss recent experimental and modelling evidence to address this question and revisit how these seemingly different processed might represent two sides of the same coin.
    Keywords:  Chromatin hub; Chromatin loop; Conformation capture; Epigenetic; Reprogramming; Senescence
  37. Life (Basel). 2020 Sep 05. pii: E178. [Epub ahead of print]10(9):
    No MH, Choi Y, Cho J, Heo JW, Cho EJ, Park DH, Kang JH, Kim CJ, Seo DY, Han J, Kwak HB.
      Aging represents a major risk for developing cardiac disease, including heart failure. The gradual deterioration of cell quality control with aging leads to cell death, a phenomenon associated with mitochondrial dysfunction in the heart. Apoptosis is an important quality control process and a necessary phenomenon for maintaining homeostasis and normal function of the heart. However, the mechanism of mitochondria-mediated apoptosis in aged hearts remains poorly understood. Here, we used male Fischer 344 rats of various ages, representing very young (1 month), young (4 months), middle-aged (12 months), and old (20 months) rats, to determine whether mitochondria-mediated apoptotic signals and apoptosis in the left ventricle of the heart are altered notably with aging. As the rats aged, the extramyocyte space and myocyte cross-sectional area in their left ventricle muscle increased, while the number of myocytes decreased. Additionally, mitochondrion-mediated apoptotic signals and apoptosis increased remarkably during aging. Therefore, our results demonstrate that aging promotes remarkable morphological changes and increases the degree of mitochondrion-mediated apoptosis in the left ventricle of rat hearts.
    Keywords:  Bcl-2 family; aging heart; mitochondria; programmed cell death
  38. Liver Int. 2020 Sep 05.
    Karakousis ND, Papatheodoridi A, Chatzigeorgiou A, Papatheodoridis G.
      Chronic hepatitis B is mainly responsible for the morbidity and mortality from hepatitis B virus (HBV) related complications, including hepatocellular carcinoma and decompensated cirrhosis. Hepatocellular carcinoma remains the main challenge in the management of not only undiagnosed and/or untreated but also diagnosed and treated patients with chronic HBV infection, as its incidence decreases but is not eliminated even after many years of effective anti-HBV therapy. The exact mechanisms used by HBV to cause malignant transformation remain uncertain, although much of the available data are in favor of a pathogenetic role of HBx protein. Senescence is a cellular state, in which cells lose their ability to proliferate. This biological mechanism may function in a dual mode, namely being both cancer-protective due to reduced cellular proliferation, but also cancer-enhancing due to modulation of the tissular microenvironment by immune cells during persistent accumulation of senescent cells. Protein X of HBV protein exhibits many similarities in terms of the implemented mechanisms of action and pathways related to the biological process of cellular senescence. Concurrently, insufficient clearance of both senescent and pre-cancerous hepatocytes combined with inadequate immune surveillance due to immunosenescence caused by chronic HBV infection may lead to hepatocarcinogenesis. Thus, the effect of HBV seems to be critical as a connecting link between cellular senescence and development of hepatocellular carcinoma. An ongoing research is underway towards identifying and validating markers of hepatocyte senescence, which could improve the landscape for evaluation of chronic liver disease, thereby providing valuable information in terms of HBV related carcinogenesis.
    Keywords:  hepatitis B virus; hepatocellular carcinoma; hepatocyte senescence; immunosenescence; protein X
  39. Mech Ageing Dev. 2020 Sep 06. pii: S0047-6374(20)30146-9. [Epub ahead of print] 111350
    Zajda A, Huttunen KM, Sikora J, Podsiedlik M, Markowicz-Piasecka M.
      Nowadays we observe a growing scientific interest and need to develop novel research approach that target ageing. Metformin, apart from its proven efectiveness as a glucose-lowering agent, was found to exert multidirecional effects because of its cardioprotective, anti-inflammatory and anti-cancer activity. Recently, metformin has become a subject of interest of many researchers as a promising drug with anti-aging properties; however, its impact on clinical ageing features is still hypothetical. Nevertheless, results of cellular experiments and animal studies confirm that metformin has advantageous effects on ageing. Additionally, a number of clinical trials prove positive effects of metformin on the prevalence of age-related diseases (ADR), including cardiovascular disease or carcinoma. We have observed a significant advancement in human research since a few randomised clinical trials evaluating the impact of metformin on aging were launched. Here, we present an investigation on anti-ageing properties of metformin, and provide the explanation of mechanisms and pathways implicated in this function. We also analyse available clinical evidence on healthspan extension, all-cause mortality and ADR. Finally, we discuss currently conducted randiomized clinical trials which aim to explore metformin potential as an anti-ageing drug in humans.
    Keywords:  ageing; biguanides; geroprotector; metformin; senescence
  40. Front Cell Dev Biol. 2020 ;8 784
    Zhang T, Li H, Wang K, Xu B, Chen ZN, Bian H.
      Cluster of differentiation 147 (CD147) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. CD147 overexpression has been reported to facilitate the development of hepatocellular carcinoma (HCC) and influence immunologic disorders. Although increased expression of CD147 was reported in non-alcoholic steatohepatitis (NASH), functions of CD147 in NASH have not been evaluated. Firstly, we confirmed that CD147 expression was increased in the liver tissues from methionine-choline-deficient (MCD) diet-induced NASH model mice and NASH patients. Mice with hepatocyte-specific CD147 deletion exhibited attenuated NASH phenotypes, including reduced steatosis, liver injury, hepatocyte apoptosis and inflammatory cytokines IL-1β/IL-18 secretion. Following the administration of the MCD diet, NLRP3 expression was increased gradually along with CD147 expression. Furthermore, CD147 deletion inhibited the NF-κB/NLRP3 signaling pathway in both MCD diet-induced mice and primary hepatocytes. Finally, CypA inhibitor TMN355 attenuated liver steatosis and injury and inhibited NF-κB/NLRP3 signaling pathway. Therefore, our results suggest that CD147 played a vital role in NASH pathogenesis by regulating the inflammatory response, and CypA/CD147 could be attractive therapeutic targets for NASH treatment.
    Keywords:  CD147; CypA; NASH; NLRP3; inflammation
  41. Nat Rev Cardiol. 2020 Sep 11.
    Tyrrell DJ, Goldstein DR.
      The number of old people is rising worldwide, and advancing age is a major risk factor for atherosclerotic cardiovascular disease. However, the mechanisms underlying this phenomenon remain unclear. In this Review, we discuss vascular intrinsic and extrinsic mechanisms of how ageing influences the pathology of atherosclerosis. First, we focus on factors that are extrinsic to the vasculature. We discuss how ageing affects the development of myeloid cells leading to the expansion of certain myeloid cell clones and induces changes in myeloid cell functions that promote atherosclerosis via inflammation, including a potential role for IL-6. Next, we describe vascular intrinsic factors by which ageing promotes atherogenesis - in particular, the effects on mitochondrial function. Studies in mice and humans have shown that ageing leads to a decline in vascular mitochondrial function and impaired mitophagy. In mice, ageing is associated with an elevation in the levels of the inflammatory cytokine IL-6 in the aorta, which participates in a positive feedback loop with the impaired vascular mitochondrial function to accelerate atherogenesis. We speculate that vascular and myeloid cell ageing synergize, via IL-6 signalling, to accelerate atherosclerosis. Finally, we propose future avenues of clinical investigation and potential therapeutic approaches to reduce the burden of atherosclerosis in old people.
  42. Biochem Biophys Res Commun. 2020 Sep 08. pii: S0006-291X(20)31705-8. [Epub ahead of print]
    Liu R, Peters M, Urban N, Knowlton J, Napierala T, Gabrysiak J.
      Extracellular signal-regulated kinase 1 and 2 (ERK1/2) have been implicated as important regulators of metabolic homeostasis. Here we generated a new mouse model with genetic deletion of two ERK1/2 phosphatases, dual specificity phosphatase (DUSP) 6 and 8, to further define the role of ERK1/2 in obesity development. Dusp6/8 double-null mice demonstrated elevated ERK1/2 phosphorylation in multiple tissues, without any change of phosphorylation of p38 and c-Jun N-terminal kinases (JNKs). Elevated ERK1/2 activity in Dusp6/8 double-null mice was associated with larger hearts and other organs, consistent with greater rate of cell proliferation in these mice. However, ERK1/2 activation was not sufficient to protect the mouse hearts from pathological hypertrophy and interstitial fibrosis following angiotensin II and phenylephrine stimulation. Interestingly, mice lacking DUSP6/8 were resistant to high-fat diet-induced obesity. Serum triglyceride, lipid content in the liver and visceral adipose tissues was also dramatically reduced in Dusp6/8 double-null mice. Furthermore, Dusp6/8 double-null mice had improved glucose tolerance. Mechanistically, we found out that elevated ERK1/2 activity increased the expression levels of genes involved in lipid metabolism and glucose homeostasis. Together, our data suggest that ERK1/2 play an essential role for the management of metabolic homeostasis.
    Keywords:  Cell proliferation; Dual specificity phosphatase; ERK1/2; Glucose tolerance; Obesity
  43. Arch Physiol Biochem. 2020 Sep 10. 1-9
    Binayi F, Moslemi M, Khodagholi F, Hedayati M, Zardooz H.
      This study investigated the effect of long-term high-fat diet (HFD) on plasma lipid profile and probability of inflammation in adult rats. After weaning, male offspring were divided into six groups based on diet type and medication. After 20 weeks of dietary intake, 4-PBA (endoplasmic reticulum (ER) stress inhibitor) was injected for three days. Then, blood samples were taken to measure plasma concentrations of low-density lipoprotein (LDL), triglyceride (TG), high-density lipoprotein (HDL), cholesterol, leptin and interleukin 1-β (IL 1-β). The HFD increased body weight and food intake and intra-abdominal fat and thymus weights, which were associated with elevated plasma leptin level. Moreover, HFD increased plasma concentrations of TG, LDL, cholesterol and IL 1-β and decreased HDL level. Injection of 4-PBA reversed the plasma parameters changes caused by HFD. It seems that long-term HFD feeding through inducing the ER stress, disrupted the lipid metabolism and resulted in inflammation.
    Keywords:  High-fat diet; endoplasmic reticulum stress; inflammation; lipid metabolism
  44. J Cell Mol Med. 2020 Sep 11.
    Zhu MJ, Liu BY, Shi L, Wang X, Wang Y.
      It is growingly concerned about methamphetamine (MA)-induced lung toxicity. IMP1 is identified as a key molecule for cell life processes, but the role of IMP1 in MA-induced senescence remains unclear. The purpose of this study was to investigate whether chronic exposure to MA can cause autophagy and senescence of the lungs, whether there are interactions between Mammalian target of rapamycin (mTOR) and IMP1 and whether IMP1 is involved in pulmonary senescence promoted by mTOR-autophagy. The rats were randomly divided into control group and MA group, following by H&E staining, immunohistochemistry staining and Western blot. The alveolar epithelial cells were proceeded by ß-galactosidase staining, cell cycle detection, transfection and co-immunoprecipitation. Long-term exposure to MA led to the thickening of alveolar septum and more compact lungs. MA promoted the conversion of LC3-I to LC3-II and inhibited the activation of mTOR to induce autophagy. Bioinformatics and co-immunoprecipitation results presented the interactions between IMP1 and mTOR. MA induced cell senescence by decreasing IMP1, up-regulating p21 and p53, arresting cell cycle and increasing SA-β-gal. Overexpression of IMP1 reduced p21 and SA-β-gal to inhibit the senescence of alveolar epithelial cells. These results demonstrated that mTOR-autophagy promotes pulmonary senescence through IMP1 in chronic toxicity of methamphetamine.
    Keywords:  IMP1; autophagy; mTOR; methamphetamine; pulmonary; senescence
  45. Nature. 2020 Sep 10.
    Pathare GR, Decout A, Glück S, Cavadini S, Makasheva K, Hovius R, Kempf G, Weiss J, Kozicka Z, Guey B, Melenec P, Fierz B, Thomä NH, Ablasser A.
      The DNA sensor cGAS initiates innate immune responses following microbial infection, cellular stress, and cancer1. Upon activation by double-stranded DNA, cytosolic cGAS produces 2'3' cyclic GMP-AMP and triggers inflammatory cytokine and type I interferon (IFN) induction2-7. cGAS is also present inside the cell nucleus replete with genomic DNA8, where chromatin has been implicated in restricting its enzymatic activity9. However, the structural basis for cGAS inhibition by chromatin has remained unknown. Here we present the cryo-electron microscopy structure of human cGAS bound to nucleosomes at 3.1 Å resolution. cGAS makes extensive contacts with both the acidic patch of the histone H2A-H2B heterodimer and nucleosomal DNA. The structural and complementary biochemical analysis also finds cGAS engaged to a second nucleosome in trans. Mechanistically, nucleosome binding locks cGAS in a monomeric state, in which steric hindrance suppresses spurious activation by genomic DNA. We find that mutations to the cGAS-acidic patch interface are necessary and sufficient to abolish the inhibitory effect of nucleosomes in vitro and to unleash cGAS activity on genomic DNA in living cells. Our work uncovers the structural basis of cGAS interaction with chromatin and defines a compelling mechanism that permits self-nonself discrimination of genomic DNA by cGAS.
  46. Animals (Basel). 2020 Sep 08. pii: E1596. [Epub ahead of print]10(9):
    Magalhães-Sant'Ana M, Peleteiro MC, Stilwell G.
      Promoting animal welfare is one of the basic tenets of the veterinary profession and, in doing so, veterinarians are expected to abide to the highest legal and professional standards. However, the Portuguese veterinary code of conduct, established in 1994, largely overlooks animal welfare and fails to address issues such as the euthanasia or humane killing of animals. As part of a wider research aiming to revise the Portuguese veterinary code of conduct, a Policy Delphi study was conducted in late 2018, using a pre-validated three-round structure and vignette methodology, to explore the range of opinions and the level of agreement on end-of-life dilemmas and animal welfare rules of conduct of a purposeful sample of forty-one (out of seventy) Portuguese veterinarians. When faced with ethical vignettes involving end-of-life dilemmas, veterinarians were shown to privilege personal moral agency over legal obligations in order to defend the interests of stakeholders, namely of the animals. Most participants agreed that the suggested animal welfare rules of conduct reflected their own views on the subject (88%), in addition to representing a significant improvement in terms of regulatory standards (93%). We expect that this study will support regulation and policy-making by the Portuguese Veterinary Order and by veterinary representative bodies elsewhere.
    Keywords:  Policy Delphi; animal law; animal welfare; code of conduct; emergency slaughter; euthanasia; fitness for transport; moral agency; veterinary ethics; vignettes
  47. J Cardiovasc Pharmacol. 2020 Sep;76(3): 296-304
    Guo X, Yan F, Li J, Zhang C, Su H, Bu P.
      Obesity and the associated complications are a major public health issue as obesity incidence increases yearly, worldwide. Effects of obesity on heart failure have been reported previously. Obesity-related cardiac remodeling includes structural and functional dysfunctions, in which cardiac inflammation and fibrosis play a key role. The main mitochondrial deacetylase, SIRT3 participates in numerous cellular processes; however, its role in obesity-related cardiac remodeling remains unclear. In our study, high-fat diet (HFD) feeding induced downregulation of SIRT3 protein level in mice. SIRT3-KO mice fed on HFD exhibited higher cardiac dysfunction and cardiac remodeling compared with the wild-type controls. Further study revealed increases in collagen accumulation and inflammatory cytokine expression including MCP-1, IL-6, TGF-β, TNF-α in mice fed on HFD compared with chow diet, with higher levels observed in SIRT3-KO mice. Furthermore, significantly high levels of cardiac MCP-1 expression and macrophage infiltration, and ROS generation and activated NF-κB were observed in HFD-fed SIRT3-KO mice. We presumed that SIRT3 ablation-mediated MCP-1 upregulation is attributed to ROS-NF-κB activation. Thus, we concluded that SIRT3 prevents obesity-related cardiac remodeling by attenuating cardiac inflammation and fibrosis, through modulation of ROS-NF-κB-MCP-1 pathway.
  48. Curr Opin Immunol. 2020 Sep 05. pii: S0952-7915(20)30081-9. [Epub ahead of print]68 21-27
    Chawla M, Roy P, Basak S.
      The canonical NF-κB pathway instructs the expression of inflammatory genes by the RelA:p50 transcription factor in response to diverse cell-activating stimuli. However, this mainstay RelA:p50 transcriptional output must also be curated so as to provide for stimulus-type-specific and cell-type-specific inflammatory responses adapted to the local tissue-microenvironment. Here, we summarize the fundamental mechanisms regulating RelA:p50-mediated gene expressions and discuss how the NF-κB system imparts specificity in the inflammatory gene program. We put forward a conceptual framework where the dynamical attributes and the composition of the nuclear NF-κB complexes cumulatively instruct context-specific inflammatory gene patterns. We propose that integrating mechanistic knowledge and systems-level analyses may offer further insights on NF-κB-mediated inflammatory gene control in the future.
  49. Mech Ageing Dev. 2020 Sep 03. pii: S0047-6374(20)30141-X. [Epub ahead of print] 111345
    Daskalaki I, Tavernarakis N.
      Mitochondrial biogenesis is indispensable for organismal homeostasis. The semi-autonomous nature of mitochondria makes their biogenesis rather complex, as it requires the contribution of the nucleus, the cytoplasm and the organelle itself. Recently, several transcription regulators, RNA binding proteins and outer mitochondrial membrane (OMM) components have been implicated in the regulation of the process. Both the expression and the abundance of several of these factors are altered during ageing, and their impairment can have diverse, yet principally detrimental, effects on lifespan. These findings converge on the notion that mitochondrial biogenesis is an age-modulated process that, when perturbed, compromises survival. Notably, core brain functions are dependent on mitochondrial metabolite availability. Indeed, emerging evidence indicates that mitochondrial biogenesis regulators play important roles in the onset and progression of severe neurodegenerative syndromes such as AD, PD and HD. These devastating human pathologies remain incurable to date. A better understanding of the mechanisms that govern mitochondrial biogenesis could facilitate the development of effective pharmaceutical interventions against these diseases.
    Keywords:  Ageing; Mitochondrial biogenesis; Neurodegeneration; Organismal Senescence; Transcription factor; mRNA translation
  50. EMBO Rep. 2020 Sep 07. e50636
    van Schaik T, Vos M, Peric-Hupkes D, Hn Celie P, van Steensel B.
      In mammalian interphase nuclei, more than one thousand large genomic regions are positioned at the nuclear lamina (NL). These lamina-associated domains (LADs) are involved in gene regulation and may provide a backbone for the folding of interphase chromosomes. Little is known about the dynamics of LADs during interphase, in particular at the onset of G1 phase and during DNA replication. We developed an antibody-based variant of the DamID technology (named pA-DamID) that allows us to map and visualize genome-NL interactions with high temporal resolution. Application of pA-DamID combined with synchronization and cell sorting experiments reveals that LAD-NL contacts are generally rapidly established early in G1 phase. However, LADs on the distal ~25 Mb of most chromosomes tend to contact the NL first and then gradually detach, while centromere-proximal LADs accumulate gradually at the NL. Furthermore, our data indicate that S-phase chromatin shows transiently increased lamin interactions. These findings highlight a dynamic choreography of LAD-NL contacts during interphase progression and illustrate the usefulness of pA-DamID to study the dynamics of genome compartmentalization.
    Keywords:  DamID; cell cycle; genome organization; nuclear lamina; telomeres
  51. Aging (Albany NY). 2020 Sep 10. 12
    Zhong X, Ke C, Cai Z, Wu H, Ye Y, Liang X, Yu L, Jiang S, Shen J, Wang L, Xie M, Wang G, Zhao X.
      In recent years, LNK, an adapter protein, has been found to be associated with metabolic diseases, including hypertension and diabetes. We found that the expression of LNK in human adipose tissue was positively correlated with serum glucose and insulin in obese people. We examined the role of LNK in insulin resistance and systemic energy metabolism using LNK-deficient mice (LNK-/-). With consumption of a high-fat diet, wild type (WT) mice accumulated more intrahepatic triglyceride, higher serum triglyceride (TG), free fatty acid (FFA) and high sensitivity C-reactive protein (hsCRP) compared with LNK-/- mice. However, there was no significant difference between LNK-/- and WT mice under normal chow diet. Meanwhile, glucose transporter 4 (GLUT4) expression in adipose tissue and insulin-stimulated glucose uptake in adipocytes were increased in LNK-/- mice. LNK-/- adipose tissue showed activated reactivity for IRS1/PI3K/Akt/AS160 signaling, and administration of a PI3K inhibitor impaired glucose uptake. In conclusion, LNK plays a pivotal role in adipose glucose transport by regulating insulin-mediated IRS1/PI3K/Akt/AS160 signaling.
    Keywords:  LNK; glucose translocation; insulin resistance; obesity