bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒09‒20
37 papers selected by
Maria Grazia Vizioli
Mayo Clinic


  1. Mech Ageing Dev. 2020 Sep 14. pii: S0047-6374(20)30151-2. [Epub ahead of print] 111355
    Lim JS, Lee DY, Kim HS, Park SC, Oh WK, Cho KA.
      Senescent cells are deeply involved in the induction of tissue damage and aging-related diseases. The identification of factors that eliminate senescent cells or inhibit the senescence-associated secretory phenotype (SASP) in these cells is necessary. Here, we report an avenanthramice C (Avn C) extracted from oat as a new SASP modulator. Treatment with Avn C led to a significant reduction in the levels of markers of senescent cells, with no toxicity observed. The SASP was also inhibited by Avn C treatment, similar to non-senescent cells, and the suppression of cell division by autocrine signals associated with SASP was restored. To investigate the mechanism underlying SASP inhibition by Avn C, we analyzed the effect of Avn C in lipopolysaccharide (LPS)-induced inflammation in non-senescent cells. Avn C inhibited nuclear factor κB (NF-κB) activity and the secretion of inflammatory cytokines before or after LPS treatment. Although the activity of MAP kinases, which are NF-κB upstream signals, was inhibited by Avn C in LPS-induced inflammation, only p38 activity was specifically inhibited in senescent cells. Interestingly, the inhibition of p38 in senescent cells was observed through Avn C-induced 5'-adenosine monophosphate-activated protein kinase (AMPK) activity. Avn C-induced inhibition of the SASP is triggered by senescence-related stress.
    Keywords:  Avenanthramide C; Senescence-associated secretory phenotype (SASP); Senescent cells; Senomorphic
    DOI:  https://doi.org/10.1016/j.mad.2020.111355
  2. Aging Cell. 2020 Sep 15. e13229
    Liu Z, Leung D, Thrush K, Zhao W, Ratliff S, Tanaka T, Schmitz LL, Smith JA, Ferrucci L, Levine ME.
      Epigenetic clocks, developed using DNA methylation data, have been widely used to quantify biological aging in multiple tissues/cells. However, many existing epigenetic clocks are weakly correlated with each other, suggesting they may capture different biological processes. We utilize multi-omics data from diverse human tissue/cells to identify shared features across eleven existing epigenetic clocks. Despite the striking lack of overlap in CpGs, multi-omics analysis suggested five clocks (Horvath1, Horvath2, Levine, Hannum, and Lin) share transcriptional associations conserved across purified CD14+ monocytes and dorsolateral prefrontal cortex. The pathways enriched in the shared transcriptional association suggested links between epigenetic aging and metabolism, immunity, and autophagy. Results from in vitro experiments showed that two clocks (Levine and Lin) were accelerated in accordance with two hallmarks of aging-cellular senescence and mitochondrial dysfunction. Finally, using multi-tissue data to deconstruct the epigenetic clock signals, we developed a meta-clock that demonstrated improved prediction for mortality and robustly related to hallmarks of aging in vitro than single clocks.
    Keywords:  DNA methylation; biological aging; cellular senescence; epigenetic clock; mitochondria
    DOI:  https://doi.org/10.1111/acel.13229
  3. Oxid Med Cell Longev. 2020 ;2020 9503562
    Zhang Y, Yang B, Wang J, Cheng F, Shi K, Ying L, Wang C, Xia K, Huang X, Gong Z, Yu C, Li F, Liang C, Chen Q.
      The intervertebral disc degeneration (IDD) with increasing aging mainly manifests as low back pain (LBP) accompanied with a loss of physical ability. These pathological processes can be preliminarily interpreted as a series of changes at cellular level. In addition to cell death, disc cells enter into the stagnation with dysfunction and deteriorate tissue microenvironment in degenerative discs, which is recognized as cell senescence. During aging, many intrinsic and extrinsic factors have been proved to have strong connections with these cellular senescence phenomena. Growing evidences of these connections require us to gather up critical cues from potential risk factors to pathogenesis and relative interventions for retarding cell senescence and attenuating degenerative changes. In this paper, we try to clarify another important cell state apart from cell death in IDD and discuss senescence-associated changes in cells and extracellular microenvironment. Then, we emphasize the role of oxidative stress and epigenomic perturbations in linking risk factors to cell senescence in the onset of IDD. Further, we summarize the current interventions targeting senescent cells that may exert the benefits of antidegeneration in IDD.
    DOI:  https://doi.org/10.1155/2020/9503562
  4. Aging (Albany NY). 2020 Sep 14. 12
    Pan XH, Lin QK, Yao X, Li ZA, Cai XM, Pang RQ, Ruan GP.
      BACKGROUND: To study the effect of allogeneic umbilical cord mesenchymal stem cell transplantation on the structure and function of the thymus in aged C57 mice and provide a new method for the treatment of senile thymic atrophy.RESULTS: The changes in the thymus cortex and medulla volume and the lymphocyte ratio were analyzed by immunofluorescence. For thymus tissue sections, immunohistochemical staining was performed to detect p16, p53, SOD, becline1, LC3b, p62, sirt1, and sirt3. Changes in CK5, CK8, CD4 and CD8 expression were observed. Treatment with mUCMSCs could promote hair regeneration in aging mice and regenerate the thymus structure.
    CONCLUSIONS: mUCMSCs inhibited senescence of the thymus and promoted structural and functional thymus regeneration by downregulating the senescence genes p53 and p16 and upregulating the SOD, Sirt1 and Sirt3 genes, but the mechanism requires further research.
    METHODS: C57 mice were obtained and met the requirements of thymic aging. mUCMSCs were infused via the tail vein at a dose of 1×107 cells/kg twice per week for 3 weeks. Six weeks after the last transplantation, the thymus was weighed, and the thymus-to-body weight ratio was calculated. The thymus tissue was stained with HE.
    Keywords:  aged; senescence; thymus; transplantation; umbilical cord mesenchymal stem cells
    DOI:  https://doi.org/10.18632/aging.103594
  5. DNA Repair (Amst). 2020 Sep 01. pii: S1568-7864(20)30205-6. [Epub ahead of print]95 102956
    Pańczyszyn A, Boniewska-Bernacka E, Goc A.
      Senescence is a process related to the stopping of divisions and changes leading the cell to the SASP phenotype. Permanent senescence of many SASP cells contributes to faster aging of the body and development of age-related diseases due to the release of pro-inflammatory factors. Both mitotically active and non-dividing cells can undergo senescence as a result of activation of different molecular pathways. Telomeres, referred to as the molecular clock, direct the dividing cell into the aging pathway when reaching a critical length. In turn, the senescence of postmitotic cells depends not on the length of telomeres, but their functionality. Dysfunctional telomeres are responsible for triggering the signaling of DNA damage response (DDR). Telomerase subunits in post-mitotic cells translocate between the nucleus, cytoplasm and mitochondria, participating in the regulation of their activity. Among other things, they contribute to the reduction of reactive oxygen species generation, which leads to telomere dysfunction and, consequently, senescence. Some proteins of the shelterin complex also play a protective role by inhibiting senescence-initiating kinases and limiting ROS production by mitochondria.
    Keywords:  Senescence; Telomerase; Telomeres
    DOI:  https://doi.org/10.1016/j.dnarep.2020.102956
  6. Invest Ophthalmol Vis Sci. 2020 Sep 01. 61(11): 21
    Shimizu H, Yamada K, Suzumura A, Kataoka K, Takayama K, Sugimoto M, Terasaki H, Kaneko H.
      Purpose: To determine whether caveolin-1 (i) prevents epithelial-mesenchymal transition in the RPE and laser-induced subretinal fibrosis and (ii) promotes or inhibits cellular senescence in the RPE.Methods: We examined laser-induced subretinal fibrosis and RPE cell contraction in wild-type and Caveolin-1 knockout (Cav-1-/-) mice treated with or without cavtratin, a cell-permeable peptide of caveolin-1. The senescence marker p16INK4a was measured in RPE tissues from patients with geographic atrophy and aged mice, laser-induced subretinal fibrosis, and primary human RPE cells. Human RPE was examined by TUNEL staining, reactive oxygen species generation, cell viability, and senescence-associated β-galactosidase staining.
    Results: The volume of subretinal fibrosis was significantly smaller in cavtratin-injected eyes from wild-type mice than in control eyes from wild-type, P = 0.0062, and Cav-1-/- mice, P = 0.0095. Cavtratin treatment produced significant improvements in primary RPE cell contraction in wild-type, P = 0.04, and Cav-1-/- mice, P = 0.01. p16INK4a expression in the RPE was higher in patients with than without geographic atrophy. p16INK4a was expressed in 18-month-old but not 2-month-old wild-type mouse eyes. p16INK4a and collagen type I antibodies showed co-localization in subretinal fibrosis. Cavtratin did not affect RPE cell apoptosis or reactive oxygen species generation, but decreased cell viability and increased senescence-associated β-galactosidase-positive cells.
    Conclusions: Enhanced expression of caveolin-1 successfully blocked epithelial-mesenchymal transition of RPE and the reduction of subretinal fibrosis in mice. Nevertheless, in exchange for blocking subretinal fibrosis, caveolin-1 promotes RPE cellular senescence and might affect the progression of geographic atrophy in AMD.
    DOI:  https://doi.org/10.1167/iovs.61.11.21
  7. Vasc Biol. 2019 ;1(1): H75-H81
    Colpani O, Spinetti G.
      During organism aging, the process of cellular senescence is triggered by critical stressors such as DNA damage, oncogenes, oxidative stress, and telomere erosion, and vascular cells are not exempted. Senescent cells stop proliferating but remain metabolically active producing pro-inflammatory signals in the environment collectively named senescence-associated secretory phenotype (SASP) that contribute to the amplification of the response to the neighbor and distant cells. Although the shift toward senescence is protective against tumors and needed during wound healing, the accumulation of senescent cells during aging due to an impairment of the immune system deputed to their clearance, can predispose to diseases of the cardiovascular system such as atherosclerosis. In this short review, we describe the main features of senescence of endothelial and smooth muscle cells and focus on the role non-coding RNAs of the microRNAs class in controlling this process. Finally, we discuss the potential of new strategies based on senescence removal in counteracting vascular disease burden.
    Keywords:  atherosclerosis; microRNAs; senescence; senolytics
    DOI:  https://doi.org/10.1530/VB-19-0017
  8. Nat Commun. 2020 09 15. 11(1): 4618
    Schultz MB, Kane AE, Mitchell SJ, MacArthur MR, Warner E, Vogel DS, Mitchell JR, Howlett SE, Bonkowski MS, Sinclair DA.
      The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.
    DOI:  https://doi.org/10.1038/s41467-020-18446-0
  9. Mech Ageing Dev. 2020 Sep 09. pii: S0047-6374(20)30132-9. [Epub ahead of print] 111336
    Harraz OF, Jensen LJ.
      Calcium signaling in vascular smooth muscle is crucial for arterial tone regulation and vascular function. Several proteins, including Ca2+ channels, function in an orchestrated fashion so that blood vessels can sense and respond to physiological stimuli such as changes in intravascular pressure. Activation of the voltage-dependent Ca2+ channel, Cav1.2, leads to Ca2+ influx and consequently arterial tone development and vasoconstriction. Unique among Ca2+ channels, the vascular Cav3.2 T-type channel mediates feedback inhibition of arterial tone-and therefore causes vasodilation-of resistance arteries by virtue of functional association with hyperpolarizing ion channels. During aging, several signaling modalities are altered along with vascular remodeling. There is a growing appreciation of how calcium channel signaling alters with aging and how this may affect vascular function. Here, we discuss key determinants of arterial tone development and the crucial involvement of Ca2+ channels. We next provide an updated view of key changes in Ca2+ channel expression and function during aging and how these affect vascular function. Further, this article synthesizes new questions in light of recent developments. We hope that these questions will outline a roadmap for new research, which, undoubtedly, will unravel a more comprehensive picture of arterial tone dysfunction during aging.
    Keywords:  Aging; T-type; calcium channel; myogenic tone; vascular smooth muscle
    DOI:  https://doi.org/10.1016/j.mad.2020.111336
  10. Am J Chin Med. 2020 Sep 13. 1-15
    Ke SY, Liu DH, Wu L, Yu XG, Wang M, Shi GY, Wen RH, Zhou B, Hao BS, Liu Y, Zhu JM, Qian XX.
      Age-related myocardial dysfunction is a very large healthcare burden. Here, we aimed to investigate whether ginsenoside Rb1 (Rb1) improves age-related myocardial dysfunction and to identify the relevant molecular mechanism. Young mice and aged mice were injected with Rb1 or vehicle for 3 months. Then, their cardiac function was inspected by transthoracic echocardiography. Serum and myocardium tissue were collected from all mice for histological or molecular expression analyses, including aging-related proteins, markers relevant to fibrosis and inflammation, and markers indicating the activation of the nuclear factor-kappa B (NF-[Formula: see text]B) pathway. Compared with the control condition, Rb1 treatment significantly increased the ejection fraction percentage and significantly decreased the internal diameter and volume of the left ventricle at the end-systolic and end-diastolic phases in aged mice. Rb1 treatment reduced collagen deposition and collagen I, collagen III, and transforming growth factor-[Formula: see text]1 protein expression levels in aged hearts. Rb1 also decreased the aging-induced myocardial inflammatory response, as measured by serum or myocardial interleukin-6 and tumor necrosis factor-[Formula: see text] levels. Furthermore, Rb1 treatment in aged mice increased cytoplasmic NF-[Formula: see text]B but decreased nuclear NF-[Formula: see text]B, which indicated the suppression of the NF-[Formula: see text]B signaling pathway by regulating the translocation of NF-[Formula: see text]B. Rb1 could alleviate aging-related myocardial dysfunction by suppressing fibrosis and inflammation, which is potentially associated with regulation of the NF-[Formula: see text]B signaling pathway.
    Keywords:  Aged Mice; Cardiac Fibrosis; Ginsenoside Rb1; Inflammation; NF-[Formula: see text]B Signaling Pathway
    DOI:  https://doi.org/10.1142/S0192415X20500676
  11. Mol Cell Oncol. 2020 ;7(4): 1754723
    Cassidy LD, Narita M.
      Reduced autophagy has been implicated in aging, yet whether its loss can promote aging phenotypes and pathologies in mammals, and how reversible this process is, has never been fully explored. Using inducible short hairpin RNA (shRNA) mouse models, we have recently shown that autophagy inhibition accelerates aging, and that even a temporary block in autophagy can create irreversible damage that increases a cancer risk.
    Keywords:  Autophagy; aging; cancer; senescence
    DOI:  https://doi.org/10.1080/23723556.2020.1754723
  12. EMBO J. 2020 Sep 16. e103420
    Sun C, Wang K, Stock AJ, Gong Y, Demarest TG, Yang B, Giri N, Harrington L, Alter BP, Savage SA, Bohr VA, Liu Y.
      Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
    Keywords:  CD38 NADase; NAD metabolism; mitochondrial impairment; replicative senescence; telomere biology disorders
    DOI:  https://doi.org/10.15252/embj.2019103420
  13. Genome Biol. 2020 Sep 17. 21(1): 248
    Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC.
      BACKGROUND: Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease.RESULTS: To decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns.
    CONCLUSIONS: These patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.
    DOI:  https://doi.org/10.1186/s13059-020-02138-5
  14. Aging Cell. 2020 Sep 15. e13241
    Tao S, Wang Y, Wu J, Zeng T, Cui H, Tao Z, Lei L, Yu L, Liu A, Wang H, Zhang L, Tang D.
      Currently, the world's aging population is expanding rapidly, leading to a rise in aged hematopoietic cell transplantation (HCT) recipients and aged donors. However, the age of donors is negatively related to the prognosis after transplantation due to functional decline in hematopoietic stem cells (HSCs) during aging. Previously, we showed that an early-onset dietary restriction (DR) significantly retards early aging of HSCs. However, the effects of a mid-onset DR on HSCs remain unknown. In the current study, we performed 30% DR in 15- to 18-month-old mice (equivalent to 50-60 human years) for short-term (4 months) and long-term (9 months). We show that DR reduces and rectifies the imbalance of the HSC pool in aged mice. Short-term DR improves hematopoietic reconstitution in purified HSC transplantations, but not in bone marrow transplantations. Intriguingly, long-term mid-onset DR improves the hematopoietic regeneration of aging HSCs with a particular enhancement of lymphoid outputs even in total bone marrow transplantation settings. Mechanistically, long-term DR rejuvenates the aberrantly regulated mitochondrial pathways in aging HSCs and is accompanied by increased quiescence and reduced DNA damage signaling in HSCs. Short-term DR showed a similar trend of rescuing these aging hallmarks but to a much lesser extent. Together, the current study suggests that mid-onset DR ameliorates the function of aging HSCs and long-term DR even improved hematopoietic reconstitution in bone marrow transplantation, which could potentially have considerable implications in HCT of humans when only old donors are available.
    Keywords:  aging; bone marrow transplantation; dietary restriction; hematopoietic stem cells
    DOI:  https://doi.org/10.1111/acel.13241
  15. Aging Cell. 2020 Sep 16. e13238
    Wan J, Wu X, Chen H, Xia X, Song X, Chen S, Lu X, Jin J, Su Q, Cai D, Liu B, Li B.
      Non-alcoholic fatty liver disease (NAFLD), characterized by an increase in hepatic triglyceride (TG) content, is the most common liver disease worldwide. Aging has been shown to increase susceptibility to NAFLD; however, the underlying molecular mechanism remains poorly understood. In the present study, we examined hepatic TG content and gene expression profiles in body weight-matched young (3 months old), middle-aged (10 months old), and old (20 months old) C57BL/6 mice and found that TGs were markedly accumulated while mitochondrial β-oxidation-related genes, including PPARα, were downregulated in the liver of old mice. In addition, advanced glycation end product receptor (RAGE), a key regulator of glucose metabolism, was upregulated in the old mice. Mechanistically, suppression of RAGE upregulated PPARα and its downstream target genes, which in turn led to reduced TG retention. Finally, we found that hepatic RAGE expression was increased in aging patients, a finding that correlated with decreased PPARα levels. Taken together, our findings demonstrate that the upregulation of RAGE may play a critical role in aging-associated liver steatosis.
    Keywords:  PPARα; RAGE; aging; hepatic steatosis; mitochondria
    DOI:  https://doi.org/10.1111/acel.13238
  16. Eur Respir Rev. 2020 Sep 30. pii: 200087. [Epub ahead of print]29(157):
    Gea J, Ausín P, Martínez-Llorens JM, Barreiro E.
      Ageing is a progressive condition that usually leads to the loss of physiological properties. This process is also present in respiratory muscles, which are affected by both senescent changes occurring in the whole organism and those that are more specific for muscles. The mechanisms of the latter changes include oxidative stress, decrease in neurotrophic factors and DNA abnormalities. Ageing normally coexists with comorbidities, including respiratory diseases, which further deteriorate the structure and function of respiratory muscles. In this context, changes intrinsic to ageing become enhanced by more specific factors such as the impairment in lung mechanics and gas exchange, exacerbations and hypoxia. Hypoxia in particular has a direct effect on muscles, mainly through the expression of inducible factors (hypoxic-inducible factor), and can result in oxidative stress and changes in DNA, decrease in mitochondrial biogenesis and defects in the tissue repair mechanisms. Intense exercise can also cause damage in respiratory muscles of elderly respiratory patients, but this can be followed by tissue repair and remodelling. However, ageing interferes with muscle repair by tampering with the function of satellite cells, mainly due to oxidative stress, DNA damage and epigenetic mechanisms. In addition to the normal process of ageing, stress-induced premature senescence can also occur, involving changes in the expression of multiple genes but without modifications in telomere length.
    DOI:  https://doi.org/10.1183/16000617.0087-2020
  17. Biomedicines. 2020 Sep 14. pii: E350. [Epub ahead of print]8(9):
    Hsu MJ, Karkossa I, Schäfer I, Christ M, Kühne H, Schubert K, Rolle-Kampczyk UE, Kalkhof S, Nickel S, Seibel P, von Bergen M, Christ B.
      Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were analyzed one week thereafter. Combined metabolomic and proteomic data were applied to weighted gene correlation network analysis (WGCNA) and subsequent identification of key drivers. Livers were analyzed histologically and biochemically. The mechanisms of MSC action on hepatocyte lipid accumulation were studied in co-cultures of hepatocytes and MSCs by quantitative image analysis and immunocytochemistry. WGCNA and key driver analysis revealed that NASH caused the impairment of central carbon; amino acid; and lipid metabolism associated with mitochondrial and peroxisomal dysfunction; which was reversed by MSC treatment. MSC improved hepatic lipid metabolism and tissue homeostasis. In co-cultures of hepatocytes and MSCs; the decrease of lipid load was associated with the transfer of mitochondria from the MSCs to the hepatocytes via tunneling nanotubes (TNTs). Hence; MSCs may ameliorate lipid load and tissue perturbance by the donation of mitochondria to the hepatocytes. Thereby; they may provide oxidative capacity for lipid breakdown and thus promote recovery from NASH-induced metabolic impairment and tissue injury.
    Keywords:  mesenchymal stromal cells; non-alcoholic steatohepatitis (NASH); organelle transfer; primary hepatocytes; tunneling nanotubes (TNTs)
    DOI:  https://doi.org/10.3390/biomedicines8090350
  18. Nat Commun. 2020 09 15. 11(1): 4639
    Shao LW, Peng Q, Dong M, Gao K, Li Y, Li Y, Li CY, Liu Y.
      The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.
    DOI:  https://doi.org/10.1038/s41467-020-18501-w
  19. Adipocyte. 2020 Dec;9(1): 535-541
    Wueest S, Lucchini FC, Haim Y, Rudich A, Konrad D.
      Increasing energy expenditure via induction of browning in white adipose tissue has emerged as a potential strategy to treat obesity and associated metabolic complications. We previously reported that ASK1 inhibition in adipocytes protected from high-fat diet (HFD) or lipopolysaccharide (LPS)-mediated downregulation of UCP1 both in vitro and in vivo. Conversely, adipocyte-specific ASK1 overexpression attenuated cold-induction of UCP-1 in inguinal fat. Herein, we provide evidence that both TNFα-mediated and HFD-induced activation of p38 MAPK in white adipocytes are ASK1-dependent. Moreover, expression of senescence markers was reduced in HFD-fed adipocyte-specific ASK1 knockout mice. Similarly, LPS-induced upregulation of senescence markers was blunted in ASK1-depleted adipocytes. Thus, our study identifies a previously unknown role for ASK1 in the induction of stress-induced senescence.
    Keywords:  Obesity; adipose tissue; browning; diabetes; lipopolysaccharide; p38 MAPK; subcutaneous
    DOI:  https://doi.org/10.1080/21623945.2020.1815977
  20. J Extracell Vesicles. 2020 Aug 10. 9(1): 1800971
    Gong L, Chen B, Zhang J, Sun Y, Yuan J, Niu X, Hu G, Chen Y, Xie Z, Deng Z, Li Q, Wang Y.
      Tissue-resident stem cell senescence leads to stem cell exhaustion, which is a major cause of physiological and pathological ageing. Stem cell-derived extracellular vesicles (SC-EVs) have been reported in preclinical studies to possess therapeutic potential for diverse diseases. However, whether SC-EVs can rejuvenate senescent tissue stem cells to prevent age-related disorders still remains unknown. Here, we show that chronic application of human embryonic stem cell-derived small extracellular vesicles (hESC-sEVs) rescues the function of senescent bone marrow mesenchymal stem cells (BM-MSCs) and prevents age-related bone loss in ageing mice. Transcriptome analysis revealed that hESC-sEVs treatment upregulated the expression of genes involved in antiaging, stem cell proliferation and osteogenic differentiation in BM-MSCs. Furthermore, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified 4122 proteins encapsulated in hESC-sEVs. Bioinformatics analysis predicted that the protein components in the hESCs-sEVs function in a synergistic way to induce the activation of several canonical signalling pathways, including Wnt, Sirtuin, AMPK, PTEN signalling, which results in the upregulation of antiaging genes in BM-MSCs and then the recovery of senescent BM-MSCs function. Collectively, our findings reveal the effect of hESC-sEVs in reversing BM-MSCs senescence and age-related osteogenic dysfunction, thereby preventing age-related bone loss. Because hESC-sEVs could alleviate senescence of tissue-resident stem cells, they might be promising therapeutic candidates for age-related diseases.
    Keywords:  Extracellular vesicle; bone loss; bone marrow MSCs; cellular senescence; embryonic stem cells
    DOI:  https://doi.org/10.1080/20013078.2020.1800971
  21. iScience. 2020 Sep 01. pii: S2589-0042(20)30712-4. [Epub ahead of print]23(9): 101520
    Tsukamoto H, Kouwaki T, Oshiumi H.
      Aging-associated changes in the immune system often lead to immune dysfunction; however, the mechanisms that underlie this phenomenon have yet to be fully elucidated. This study found that the microRNA-192 (miR-192) is an aging-associated immune regulatory microRNA whose concentration was significantly increased in aged extracellular vesicles (EVs) due to the hyperinflammatory state of aged mice. Interestingly, EV miR-192 exhibited anti-inflammatory effects on macrophages. In our aged mouse model, aging was associated with prolonged inflammation in the lung upon stimulation with inactivated influenza whole virus particles (WVP), whereas EV miR-192 alleviated the prolonged inflammation associated with aging. The hyperinflammatory state of aged mice resulted in reduced production of specific antibodies and efficacy of vaccination with WVP; however, EV miR-192 attenuated this hyperinflammatory state and improved vaccination efficacy in aged mice. Our data indicate that aged EVs constitute a negative feedback loop that alleviates aging-associated immune dysfunction.
    Keywords:  Human Physiology; Immunology; Molecular Biology; Molecular Physiology
    DOI:  https://doi.org/10.1016/j.isci.2020.101520
  22. Curr Med Chem. 2020 Sep 17.
    Gasmi A, Chirumbolo S, Peana M, Mujawdiya PK, Dadar M, Menzel A, Bjørklund G.
      Human life expectancy is increasing significantly over time thanks to the improved possibility of taking care of themselves and the higher availability of food, drugs, hygiene, services, and assistance. The increase in the average age of the population worldwide is, however, becoming a real concern, since aging is associated with the rapid increase in chronic inflammatory pathologies and degenerative diseases, very frequently dependent on senescent phenomena that occur alongside with senescence. Therefore, the search for reliable biomarkers that can diagnose the possible onset or predict the risk of developing a disease associated with aging is a crucial target of current medicine. In this review, we construct a synopsis of the main addressable biomarkers to study the development of aging and the associated ailments.
    Keywords:  aging; ailments. ; biomarkers; inflammation; neurodegeneration; senescence
    DOI:  https://doi.org/10.2174/0929867327999200917150652
  23. Diabetes. 2020 Sep 18. pii: db191176. [Epub ahead of print]
    Zang H, Wu W, Qi L, Tan W, Nagarkatti P, Nagarkatti M, Wang X, Cui T.
      Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) may either ameliorate or worsen diabetic cardiomyopathy. However, the underlying mechanisms are poorly understood. Herein we report a novel mechanism of Nrf2-mediated myocardial damage in type 1 diabetes (T1D). Global Nrf2 knockout (Nrf2KO) hardly affected the onset of cardiac dysfunction induced by T1D but slowed down its progression in mice independent of sex. In addition, Nrf2KO inhibited cardiac pathological remodeling, apoptosis and oxidative stress associated with both onset and advancement of cardiac dysfunction in T1D. Such Nrf2-mediated progression of diabetic cardiomyopathy was confirmed by cardiomyocyte-restricted (CR) Nrf2 transgenic (Tg) approach in mice. Moreover, cardiac autophagy inhibition via CR KO of autophagy related 5 gene (CR-Atg5KO) led to early onset and accelerated development of cardiomyopathy in T1D, and CR-Atg5KO-induced adverse phenotypes were rescued by additional Nrf2KO. Mechanistically, chronic T1D leads to glucolipotoxicity inhibiting autolysosome efflux, which in turn intensifies Nrf2-driven transcription to fuel lipid peroxidation while inactivating Nrf2-mediated antioxidant defense and impairing Nrf2-coordinated iron metabolism, thereby leading to ferroptosis in cardiomyocytes. These results demonstrate that diabetes over time causes autophagy deficiency, which turns off Nrf2-mediated defense while switching on Nrf2-operated pathological program toward ferroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy.
    DOI:  https://doi.org/10.2337/db19-1176
  24. Semin Immunopathol. 2020 Sep 15.
    Fulop T, Larbi A, Hirokawa K, Cohen AA, Witkowski JM.
      Alterations in the immune system with aging are considered to underlie many age-related diseases. However, many elderly individuals remain healthy until even a very advanced age. There is also an increase in numbers of centenarians and their apparent fitness. We should therefore change our unilaterally detrimental consideration of age-related immune changes. Recent data taking into consideration the immunobiography concept may allow for meaningful distinctions among various aging trajectories. This implies that the aging immune system has a homeodynamic characteristic balanced between adaptive and maladaptive aspects. The survival and health of an individual depends from the equilibrium of this balance. In this article, we highlight which parts of the aging of the immune system may be considered adaptive in contrast to those that may be maladaptive.
    Keywords:  Adaptation; Centenarians; Immunosenescence; Immunosuppressive mechanisms; Inflammaging; Maladaptation; Trained immunity
    DOI:  https://doi.org/10.1007/s00281-020-00818-9
  25. Cell. 2020 Sep 05. pii: S0092-8674(20)31000-X. [Epub ahead of print]
    Zhao Q, Liu J, Deng H, Ma R, Liao JY, Liang H, Hu J, Li J, Guo Z, Cai J, Xu X, Gao Z, Su S.
      Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet-induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.
    DOI:  https://doi.org/10.1016/j.cell.2020.08.009
  26. Science. 2020 Sep 18. pii: eaas8995. [Epub ahead of print]369(6510):
    Magupalli VG, Negro R, Tian Y, Hauenstein AV, Di Caprio G, Skillern W, Deng Q, Orning P, Alam HB, Maliga Z, Sharif H, Hu JJ, Evavold CL, Kagan JC, Schmidt FI, Fitzgerald KA, Kirchhausen T, Li Y, Wu H.
      Inflammasomes are supramolecular complexes that play key roles in immune surveillance. This is accomplished by the activation of inflammatory caspases, which leads to the proteolytic maturation of interleukin 1β (IL-1β) and pyroptosis. Here, we show that nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3)- and pyrin-mediated inflammasome assembly, caspase activation, and IL-1β conversion occur at the microtubule-organizing center (MTOC). Furthermore, the dynein adapter histone deacetylase 6 (HDAC6) is indispensable for the microtubule transport and assembly of these inflammasomes both in vitro and in mice. Because HDAC6 can transport ubiquitinated pathological aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for the down-regulation of these inflammasomes by autophagy. This work suggests an unexpected parallel between the formation of physiological and pathological aggregates.
    DOI:  https://doi.org/10.1126/science.aas8995
  27. Int J Mol Sci. 2020 Sep 11. pii: E6670. [Epub ahead of print]21(18):
    Anaya JM, Bollag WB, Hamrick MW, Isales CM.
      Although aging is considered a normal process, there are cellular and molecular changes that occur with aging that may be detrimental to health. Osteoporosis is one of the most common age-related degenerative diseases, and its progression correlates with aging and decreased capacity for stem cell differentiation and proliferation in both men and women. Tryptophan metabolism through the kynurenine pathway appears to be a key factor in promoting bone-aging phenotypes, promoting bone breakdown and interfering with stem cell function and osteogenesis; however, little data is available on the impact of tryptophan metabolites downstream of kynurenine. Here we review available data on the impact of these tryptophan breakdown products on the body in general and, when available, the existing evidence of their impact on bone. A number of tryptophan metabolites (e.g., 3-hydroxykynurenine (3HKYN), kynurenic acid (KYNA) and anthranilic acid (AA)) have a detrimental effect on bone, decreasing bone mineral density (BMD) and increasing fracture risk. Other metabolites (e.g., 3-hydroxyAA, xanthurenic acid (XA), picolinic acid (PIA), quinolinic acid (QA), and NAD+) promote an increase in bone mineral density and are associated with lower fracture risk. Furthermore, the effects of other tryptophan breakdown products (e.g., serotonin) are complex, with either anabolic or catabolic actions on bone depending on their source. The mechanisms involved in the cellular actions of these tryptophan metabolites on bone are not yet fully known and will require further research as they are potential therapeutic targets. The current review is meant as a brief overview of existing English language literature on tryptophan and its metabolites and their effects on stem cells and musculoskeletal systems. The search terms used for a Medline database search were: kynurenine, mesenchymal stem cells, bone loss, tryptophan metabolism, aging, and oxidative stress.
    Keywords:  kynurenine; stem cells; tryptophan metabolites
    DOI:  https://doi.org/10.3390/ijms21186670
  28. Sci Rep. 2020 Sep 17. 10(1): 15301
    Singh A, Thakur M, Singh SK, Sharma LK, Chandra K.
      YPEL3 that induces cellular senescence in both normal and tumour cells of humans may show altered expression under the influence of incidental mutations. In this study, we proposed the first structure of Native YPEL3 protein and its five possible deleterious mutants-V40M, C61Y, G98R, G108S, and A131T and predicted their deleterious effects to alter stability, flexibility and conformational changes in the protein. The MD simulation (RMSD, RMSF, Rg, h-bond and SASA) analysis revealed that the variants V40M, G98R and G108S increased the flexibility in protein, and variant V40M imparted more compactness to the protein.. In general, variants attributed changes in the native conformation and structure of the YPEL3 protein which might affect the native function of cellular senescence. The study provides opportunities for health professionals and practitioners in formulating précised medicines to effectively cure various cancers. We propose in-vitro or in-vivo studies should consider these reported nsSNPs while examining any malfunction in the YPEL3 protein.
    DOI:  https://doi.org/10.1038/s41598-020-72333-8
  29. Oxid Med Cell Longev. 2020 ;2020 4898217
    Schneider AM, Özsoy M, Zimmermann FA, Feichtinger RG, Mayr JA, Kofler B, Sperl W, Weghuber D, Mörwald K.
      Aging is an important and inevitable biological process in human life, associated with the onset of chronic disease and death. The mechanisms behind aging remain unclear. However, changes in mitochondrial function and structure, including reduced activity of the mitochondrial respiratory chain and increased production of reactive oxygen species-thus oxidative damage-are believed to play a major role. Mitochondria are the main source of cellular energy, producing adenosine triphosphate (ATP) via oxidative phosphorylation. Accumulation of damaged cellular components reduces a body's capacity to preserve tissue homeostasis and affects biological aging and all age-related chronic conditions. This includes the onset and progression of classic degenerative diseases such as cardiovascular disease, kidney failure, neurodegenerative diseases, and cancer. Clinical manifestations of intestinal disorders, such as mucosal barrier dysfunction, intestinal dysmotility, and chronic obstipation, are highly prevalent in the elderly population and have been shown to be associated with an age-dependent decline of mitochondrial function. This review summarizes our current understanding of the role of mitochondrial dysfunction in intestinal aging.
    DOI:  https://doi.org/10.1155/2020/4898217
  30. Cell Death Dis. 2020 Sep 17. 11(9): 775
    Ye G, Xie Z, Zeng H, Wang P, Li J, Zheng G, Wang S, Cao Q, Li M, Liu W, Cen S, Li Z, Wu Y, Ye Z, Shen H.
      Ankylosing spondylitis (AS) is a chronic inflammatory disease possessing a morbid serum microenvironment with enhanced oxidative stress. Long-term exposure to an oxidative environment usually results in cellular senescence alone with cellular dysfunction. Mesenchymal stem cells (MSCs) are a kind of stem cell possessing strong capabilities for immunoregulation, and senescent MSCs may increase inflammation and participate in AS pathogenesis. The objective of this study was to explore whether and how the oxidative serum environment of AS induces MSC senescence. Here, we found that AS serum facilitated senescence of MSCs in vitro, and articular tissues from AS patients exhibited higher expression levels of the cell cycle arrest-related proteins p53, p21 and p16. Importantly, the levels of advanced oxidative protein products (AOPPs), markers of oxidative stress, were increased in AS serum and positively correlated with the extent of MSC senescence induced by AS serum. Furthermore, MSCs cultured with AS serum showed decreased mitochondrial membrane potential and ATP production together with a reduced oxygen consumption rate. Finally, we discovered that AS serum-induced mitochondrial dysfunction resulted in elevated reactive oxygen species (ROS) in MSCs, and ROS inhibition successfully rescued MSCs from senescence. In conclusion, our data demonstrated that the oxidative serum environment of AS facilitated MSC senescence through inducing mitochondrial dysfunction and excessive ROS production. These results may help elucidate the pathogenesis of AS and provide potential targets for AS treatment.
    DOI:  https://doi.org/10.1038/s41419-020-02993-x
  31. J Bioenerg Biomembr. 2020 Sep 17.
    Liang J, Ke X, Yang R, Wang X, Du Z, Hu C.
      Hyperlipidemia is an important factor in the induction of cardiovascular diseases. However, the molecular mechanisms underlying the vascular injury involved in hyperlipidemia remains unclear. This study aimed to investigate the Notch pathway of endothelial progenitor cells (EPCs) in reendothelialization after vascular injury and to explore the involvement of Notch pathway in the senescence of EPCs. Our results demonstrated that high-fat diet (HFD) treatment inhibited reendothelialization after vascular injury in the mice model. In vitro studies showed that 7-ketocholesterol (7-keto) stimulation induced senescence in the isolated EPCs from mice. In addition, 7-keto markedly upregulated the protein expression of Notch1 and Delta-like ligand 4 and induced the transport of notch intracellular domain (NICD) to the nucleus. Mechanistically, treatment with NICD inhibitor reduced the senescence of the EPCs stimulated by cholesterol. In summary, our results showed that HFD treatment caused the disruption of reendothelialization after vascular injury in the mouse model. In vitro studies indicated that 7-keto-induced senescence of EPCs was at least via the activation of the Notch1 pathway. Mechanistic data suggested that 7-keto may activate the Notch1 pathway by regulating the generation and transport of NICD to the nucleus. Future investigations are warranted to confirm the role of Notch1 in the dysfunction of EPCs during obesity.
    Keywords:  Cholesterol; Endothelial progenitor cells; High-fat diet; Notch pathway; Senescence
    DOI:  https://doi.org/10.1007/s10863-020-09853-5
  32. Sci Adv. 2020 Aug;6(35): eaba8271
    Motori E, Atanassov I, Kochan SMV, Folz-Donahue K, Sakthivelu V, Giavalisco P, Toni N, Puyal J, Larsson NG.
      Neurodegeneration in mitochondrial disorders is considered irreversible because of limited metabolic plasticity in neurons, yet the cell-autonomous implications of mitochondrial dysfunction for neuronal metabolism in vivo are poorly understood. Here, we profiled the cell-specific proteome of Purkinje neurons undergoing progressive OXPHOS deficiency caused by disrupted mitochondrial fusion dynamics. We found that mitochondrial dysfunction triggers a profound rewiring of the proteomic landscape, culminating in the sequential activation of precise metabolic programs preceding cell death. Unexpectedly, we identified a marked induction of pyruvate carboxylase (PCx) and other anaplerotic enzymes involved in replenishing tricarboxylic acid cycle intermediates. Suppression of PCx aggravated oxidative stress and neurodegeneration, showing that anaplerosis is protective in OXPHOS-deficient neurons. Restoration of mitochondrial fusion in end-stage degenerating neurons fully reversed these metabolic hallmarks, thereby preventing cell death. Our findings identify a previously unappreciated pathway conferring resilience to mitochondrial dysfunction and show that neurodegeneration can be reversed even at advanced disease stages.
    DOI:  https://doi.org/10.1126/sciadv.aba8271
  33. Oncoimmunology. 2020 Aug 30. 9(1): 1808424
    Funck F, Pahl J, Kyjacova L, Freund L, Oehrl S, Gräbe G, Pezer S, Hassel JC, Sleeman J, Cerwenka A, Schäkel K.
      Mononuclear phagocytes and NK cells constitute the first line of innate immune defense. How these cells interact and join forces against cancer is incompletely understood. Here, we observed an early accumulation of slan+ (6-sulfo LacNAc) non-classical monocytes (slanMo) in stage I melanoma, which was followed by an increase in NK cell numbers in stage III. Accordingly, culture supernatants of slanMo induced migration of primary human NK cells in vitro via the chemotactic cytokine IL-8 (CXCL8), suggesting a role for slanMo in NK cell recruitment into cancer tissues. High levels of TNF-α and IFN-γ were produced in co-cultures of TLR-ligand stimulated slanMo and NK cells, whereas much lower levels were contained in cultures of slanMo and NK cells alone. Moreover, TNF-α and IFN-γ concentrations in slanMo/NK cell co-cultures exceeded those in CD14+ monocyte/NK cell and slanMo/T cell co-cultures. Importantly, TNF-α and IFN-γ that was produced in TLR-ligand stimulated slanMo/NK cell co-cultures induced senescence in different melanoma cell lines, as indicated by reduced melanoma cell proliferation, increased senescence-associated β-galactosidase expression, p21 upregulation, and induction of a senescence-associated secretory phenotype (SASP). Taken together, we identified a role for slanMo and NK cells in a collaborative innate immune defense against melanoma by generating a tumor senescence-inducing microenvironment. We conclude that enhancing the synergistic innate immune crosstalk of slanMo and NK cells could improve current immunotherapeutic approaches in melanoma.
    Keywords:  NK cell; cytokines; melanoma; senescence; slanMo
    DOI:  https://doi.org/10.1080/2162402X.2020.1808424
  34. Cell Mol Life Sci. 2020 Sep 16.
    Rattanavirotkul N, Kirschner K, Chandra T.
      Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. In addition, single-cell studies described differences between primary and secondary senescent end-points, which have thus far not been considered functionally distinct. Here we discuss emerging concepts in senescence transmission and heterogeneity in primary and secondary senescence on a cellular and organ level.
    Keywords:  Juxtacrine senescence; Notch signalling; Oncogene-induced senescence; Secondary senescence
    DOI:  https://doi.org/10.1007/s00018-020-03638-0
  35. J Invest Dermatol. 2020 Sep 12. pii: S0022-202X(20)32062-5. [Epub ahead of print]
    Tinaburri L, Valente C, Teson M, Minafò YA, Cordisco S, Guerra L, Dellambra E.
      Age-related changes in the dermis can play a primary role in tumor initiation promoting the unrestrained proliferation of precancerous keratinocytes through cytokines and growth factor secretion. We found that a high percentage of epithelial-mesenchymal transition (EMT)-like colonies raised in primary human keratinocyte cultures from old subjects after treatment with aged fibroblast supernatants (SPN). Continuous extracellular signals were required for maintaining these changes. Conversely, the secretome did not induce EMT-like colonies in keratinocytes from youngs. SPN-treated aged keratinocytes displayed the activation of pathways involved in the disjunction of cell-cell adhesion, ECM remodeling, manifestation of mesenchymal phenotype and dedifferentiation programs. Moreover, they recovered proliferation and clonogenic ability, and showed enhanced migration. We identified an age-related increase of the BDNF secretion from fibroblasts as well as of the expression of its receptor TrkB in keratinocytes. BDNF-treatment of aged keratinocytes induces TrkB phosphorylation and recapitulated modifications promoted by aged fibroblast SPN. Furthermore, the treatment with a specific antibody against BDNF or a TrkB antagonist inhibited the paracrine signaling preventing SPN-mediated morphological and molecular changes. Finally, BDNF induced signs of matrix invasion in a 3D organotypic model. Therefore, we demonstrate that aged fibroblast SPN promotes phenotypic plasticity in keratinocytes from the elderly through BDNF-TrkB axis.
    Keywords:  EMT; aging; primary fibroblasts; primary keratinocytes; secretome; skin
    DOI:  https://doi.org/10.1016/j.jid.2020.08.019
  36. J Theor Biol. 2020 Sep 14. pii: S0022-5193(20)30328-3. [Epub ahead of print] 110473
    Jones E, Sheng J, Carlson J, Wang S.
      The adaptive and innate branches of the vertebrate immune system work in close collaboration to protect organisms from harmful pathogens. As an organism ages its immune system undergoes immunosenescence, characterized by declined performance or malfunction in either immune branch, which can lead to disease and death. In this study we develop a mathematical framework of coupled innate and adaptive immune responses, namely the integrated immune branch (IIB) model. This model describes dynamics of immune components in both branches, uses a shape-space representation to encode pathogen-specific immune memory, and exhibits three steady states- health, septic death, and chronic inflammation- qualitatively similar to clinically-observed immune outcomes. In this model, the immune system (initialized in the health state) is subjected to a sequence of pathogen encounters, and we use the number of prior pathogen encounters as a proxy for the "age" of the immune system. We find that repeated pathogen encounters may trigger a fragility in which any encounter with a novel pathogen will cause the system to irreversibly switch from health to chronic inflammation. This transition is consistent with the onset of "inflammaging", a condition observed in aged individuals who experience chronic low-grade inflammation even in the absence of pathogens. The IIB model predicts that the onset of chronic inflammation strongly depends on the history of encountered pathogens; the timing of onset differs drastically when the same set of infections occurs in a different order. Lastly, the coupling between the innate and adaptive immune branches generates a trade-off between rapid pathogen clearance and a delayed onset of immunosenescence. Overall, by considering the complex feedback between immune compartments, our work suggests potential mechanisms for immunosenescence and provides a theoretical framework at the system level and on the scale of an organism's lifetime to account for clinical observations.
    Keywords:  Computational and systems biology; Immunosenescence; Innate and adaptive immune responses; Mathematical modeling
    DOI:  https://doi.org/10.1016/j.jtbi.2020.110473
  37. ACS Chem Neurosci. 2020 Sep 18.
    Lv R, Du L, Zhou F, Yuan X, Liu X, Zhang L.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder mainly occurring in the elderly. MicroRNA-155-5p (miR-155-5p) plays a vital role in neurodegenerative disease and has been reported to be regulated by rosmarinic acid (RA). In our previous study, it was found that RA could improve motor function and alleviate inflammatory responses in a mice model of PD. This study aimed to investigate the role of miR-155-5p in RA-treated PD mice. The PD mice model was established by injecting mice with N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) and treated with RA or/and miR-155-5p agomir. The effects of miR-155-5p agomir on motor function, microglial activation, inflammation, apoptosis, and oxidative stress were analyzed by performing behavioral test, ionized calcium-binding adapter molecule 1 staining, quantitative real-time PCR, western blot, enzyme-linked immunosorbent assay, tyrosine hydroxylase (TH)-Terminal dUTP nick end labeling double staining, TH-cleaved-caspase 3 double staining, and assessment of anti-oxidative parameters in RA-treated PD mice. The interaction between miR-155-5p and suppressor of cytokine signaling 1/nuclear factor erythroid 2-related factor 2 was validated using dual-luciferase reporter assay. MiR-155-5p up-regulation inhibited the alleviation of motor deficits caused by RA in PD mice, as evidence by increasing descending time, decreasing limb movement score, increasing the time crossing the beam, and decreasing the times of front limb use. MiR-155-5p up-regulation could elevate microglial activation, inflammation, apoptosis and oxidative stress in RA-treated PD mice. In conclusion, RA was able to alleviate PD by regulating miR-155-5p, suggesting that miR-155-5p could be used as a therapeutic target for PD treatment.
    DOI:  https://doi.org/10.1021/acschemneuro.0c00375