bims-senagi Biomed News
on Senescence and aging
Issue of 2021–09–19
forty-two papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3.
  2. REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons.
  3. Nutrition and cellular senescence in obesity-related disorders.
  4. Deferoxamine accelerates endothelial progenitor cell senescence and compromises angiogenesis.
  5. Riboflavin transporter SLC52A1, a target of p53, suppresses cellular senescence by activating mitochondrial complex II.
  6. A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: A potential drug target in IPF.
  7. The balance between NAD+ biosynthesis and consumption in ageing.
  8. RAS induced senescence of skin keratinocytes is mediated through Rho-associated protein kinase (ROCK).
  9. Radiation-induced liver injury and hepatocyte senescence.
  10. Oxidative stress in retinal pigment epithelium impairs stem cells: a vicious cycle in age-related macular degeneration.
  11. DNA methylation-based biomarkers of aging were slowed down in a two-year diet and physical activity intervention trial: the DAMA study.
  12. Virus-induced senescence is driver and therapeutic target in COVID-19.
  13. The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages.
  14. Necroptosis increases with age in the brain and contributes to age-related neuroinflammation.
  15. Cellular senescence promotes cancer metastasis by enhancing soluble E-cadherin production.
  16. Transcriptional features of biological age maintained in human cultured cardiac interstitial cells.
  17. H2S-mediated blockage of protein acetylation and oxidative stress attenuates lipid overload-induced cardiac senescence.
  18. Immunology of Aging: the Birth of Inflammaging.
  19. IL-1 Mediates Microbiome-Induced Inflamm-Ageing of Hematopoietic Stem Cells in Mice.
  20. Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.
  21. Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing.
  22. Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS.
  23. S3QELs protect against diet-induced intestinal barrier dysfunction.
  24. Multi-omic profiling of primary mouse neutrophils predicts a pattern of sex and age-related functional regulation.
  25. Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27KIP1.
  26. Exogenous melatonin prevents type 1 diabetes mellitus-induced bone loss, probably by inhibiting senescence.
  27. Astrocyte-Derived Extracellular Vesicles (ADEVs): Deciphering their Influences in Aging.
  28. Chronic inflammation-induced senescence impairs immunomodulatory properties of synovial fluid mesenchymal stem cells in rheumatoid arthritis.
  29. Molecular mechanisms of dietary restriction promoting health and longevity.
  30. Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.
  31. Protective effect of MitoQ on oxidative stress-mediated senescence of canine bone marrow mesenchymal stem cells via activation of the Nrf2/ARE pathway.
  32. Classical HDACs in the regulation of neuroinflammation.
  33. Environmental enrichment mitigates age-related metabolic decline and Lewis lung carcinoma growth in aged female mice.
  34. Effect of different exercise training intensities on age-related cardiac damage in male mice.
  35. A high fat, sugar, and salt Western diet induces motor-muscular and sensory dysfunctions and neurodegeneration in mice during aging: Ameliorative action of metformin.
  36. p38 MAPK-mediated loss of nuclear RNase III enzyme Drosha underlies amyloid beta-induced neuronal stress in Alzheimer's disease.
  37. Reversal of brain aging by targeting telomerase: A nutraceutical approach.
  38. Emerging roles of kisspeptin/galanin in age-related metabolic disease.
  39. Environmental enrichment modulates silent information regulator 1 (SIRT1) activity to attenuate central presbycusis in a rat model of normal aging.
  40. Lithium can mildly increase health during ageing but not lifespan in mice.
  41. The Evolution of the Hallmarks of Aging.
  42. N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice.
  1. Aging (Albany NY). 2021 Sep 16. 12(undefined):
    SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3.
    Utkarsh Tripathi, Rayhane Nchioua, Larissa G P Langhi Prata, Yi Zhu, Erin O Wissler Gerdes, Nino Giorgadze, Tamar Pirtskhalava, Erik Parker, Ailing Xue, Jair Machado Espindola-Netto, Steffen Stenger, Paul D Robbins, Laura J Niedernhofer, Stephanie L Dickinson, David B Allison, Frank Kirchhoff, Konstantin Maria Johannes Sparrer, Tamar Tchkonia, James L Kirkland.
      Senescent cells, which arise due to damage-associated signals, are apoptosis-resistant and can express a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). We recently reported that a component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface protein, S1, can amplify the SASP of senescent cultured human cells and that a related mouse β-coronavirus, mouse hepatitis virus (MHV), increases SASP factors and senescent cell burden in infected mice. Here, we show that SARS-CoV-2 induces senescence in human non-senescent cells and exacerbates the SASP in human senescent cells through Toll-like receptor-3 (TLR-3). TLR-3, which senses viral RNA, was increased in human senescent compared to non-senescent cells. Notably, genetically or pharmacologically inhibiting TLR-3 prevented senescence induction and SASP amplification by SARS-CoV-2 or Spike pseudotyped virus. While an artificial TLR-3 agonist alone was not sufficient to induce senescence, it amplified the SASP in senescent human cells. Consistent with these findings, lung p16INK4a+ senescent cell burden was higher in patients who died from acute SARS-CoV-2 infection than other causes. Our results suggest that induction of cellular senescence and SASP amplification through TLR-3 contribute to SARS-CoV-2 morbidity, indicating that clinical trials of senolytics and/or SASP/TLR-3 inhibitors for alleviating acute and long-term SARS-CoV-2 sequelae are warranted.
    Keywords:  COVID-19; SARS-COV-2; senescence; toll like receptor 3
    DOI:  https://doi.org/10.18632/aging.203560
  2. Aging Cell. 2021 Sep 14. e13471
    REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons.
    Anna Rocchi, Emanuele Carminati, Antonio De Fusco, Jagoda Aleksandra Kowalska, Thomas Floss, Fabio Benfenati.
      During aging, brain performances decline. Cellular senescence is one of the aging drivers and a key feature of a variety of human age-related disorders. The transcriptional repressor RE1-silencing transcription factor (REST) has been associated with aging and higher risk of neurodegenerative disorders. However, how REST contributes to the senescence program and functional impairment remains largely unknown. Here, we report that REST is essential to prevent the senescence phenotype in primary mouse neurons. REST deficiency causes failure of autophagy and loss of proteostasis, increased oxidative stress, and higher rate of cell death. Re-establishment of autophagy reverses the main hallmarks of senescence. Our data indicate that REST has a protective role in physiological aging by regulating the autophagic flux and the senescence program in neurons, with implications for neurological disorders associated with aging.
    Keywords:  REST/NRSF; autophagy; mitochondria; neurons; oxidative stress; rapamycin; senescence; trehalose
    DOI:  https://doi.org/10.1111/acel.13471
  3. J Nutr Biochem. 2021 Sep 10. pii: S0955-2863(21)00281-3. [Epub ahead of print] 108861
    Nutrition and cellular senescence in obesity-related disorders.
    Teresa Rubio-Tomás, Ascensión Rueda-Robles, Julio Plaza-Díaz, Ana I Álvarez-Mercado.
      Adequate nutrition is vital for immune homeostasis. However, the incidence of obesity is increasing worldwide due to the adoption of the Western diet and a sedentary lifestyle. Obesity is associated with chronic inflammation which alters the function of adipose tissue, liver, pancreas, and the nervous system. Inflammation is related to cellular senescence, distinguished by irreversible cell cycle arrest. Senescent cells secrete the senescence-associated secretory phenotype (SASP) which contains pro-inflammatory factors. Targeting processes in senescence might have a salutary approach to obesity. The present review highlights the impact of an unhealthy diet on tissues affected by obesity, and the mechanisms that promote the consequent inflammation and senescence.
    Keywords:  aging; diet; inflammation; microbiota obesity; senescence
    DOI:  https://doi.org/10.1016/j.jnutbio.2021.108861
  4. Aging (Albany NY). 2021 Sep 11. 13(undefined):
    Deferoxamine accelerates endothelial progenitor cell senescence and compromises angiogenesis.
    Yi-Nan Lee, Hsueh-Hsiao Wang, Cheng-Huang Su, Hsin-I Lee, Yen-Hung Chou, Chin-Ling Hsieh, Wen-Ting Liu, Kuo-Tung Shu, Kai-Ting Chang, Hung-I Yeh, Yih-Jer Wu.
      Senescence reduces the circulating number and angiogenic activity of endothelial progenitor cells (EPCs), and is associated with aging-related vascular diseases. However, it is very time-consuming to obtain aged cells (~1 month of repeated replication) or animals (~2 years) for senescence studies. Here, we established an accelerated senescence model by treating EPCs with deferoxamine (DFO), an FDA-approved iron chelator. Four days of low-dose (3 μM) DFO induced senescent phenotypes in EPCs, including a senescent pattern of protein expression, impaired mitochondrial bioenergetics, altered mitochondrial protein levels and compromised angiogenic activity. DFO-treated early EPCs from young and old donors (< 35 vs. > 70 years old) displayed similar senescent phenotypes, including elevated senescence-associated β-galactosidase activity and reduced relative telomere lengths, colony-forming units and adenosine triphosphate levels. To validate this accelerated senescence model in vivo, we intraperitoneally injected Sprague-Dawley rats with DFO for 4 weeks. Early EPCs from DFO-treated rats displayed profoundly senescent phenotypes compared to those from control rats. Additionally, in hind-limb ischemic mice, DFO pretreatment compromised EPC angiogenesis by reducing both blood perfusion and capillary density. DFO thus accelerates EPC senescence and appears to hasten model development for cellular senescence studies.
    Keywords:  angiogenesis; deferoxamine; endothelial progenitor cell; senescence
    DOI:  https://doi.org/10.18632/aging.203469
  5. Mol Biol Cell. 2021 Sep 15. mbcE21050262
    Riboflavin transporter SLC52A1, a target of p53, suppresses cellular senescence by activating mitochondrial complex II.
    Taiki Nagano, Yuto Awai, Shione Kuwaba, Taiichi Osumi, Kentaro Mio, Tetsushi Iwasaki, Shinji Kamada.
      Cellular senescence is a state of permanent proliferative arrest induced by a variety of stresses, such as DNA damage. The transcriptional activity of p53 has been known to be essential for senescence induction. It remains unknown, however, whether among the downstream genes of p53, there is a gene that has anti-senescence function. Our recent studies have indicated that the expression of SLC52A1 (also known as GPR172B/RFVT1), a riboflavin transporter, is upregulated specifically in senescent cells depending on p53, but the relationship between senescence and SLC52A1 or riboflavin has not been described. Here, we examined the role of SLC52A1 in senescence. We found that knockdown of SLC52A1 promoted senescence phenotypes induced by DNA damage in tumor and normal cells. The senescence suppressive-action of SLC52A1 was dependent on its riboflavin transport activity. Furthermore, elevation of intracellular riboflavin led to activation of mitochondrial membrane potential (MMP) mediated by the mitochondrial electron transport chain complex II. Finally, the SLC52A1-dependent activation of MMP inhibited the AMPK-p53 pathway, a central mediator of mitochondria dysfunction-related senescence. These results suggest that SLC52A1 contributes to suppress senescence through the uptake of riboflavin and acts downstream of p53 as a negative feedback mechanism to limit aberrant senescence induction.
    DOI:  https://doi.org/10.1091/mbc.E21-05-0262
  6. Am J Physiol Lung Cell Mol Physiol. 2021 Sep 15.
    A cGAS-dependent response links DNA damage and senescence in alveolar epithelial cells: A potential drug target in IPF.
    Michael Schuliga, Amama Kanwal, Jane Read, Kaj Erik Cornelis Blokland, Janette K Burgess, Cecilia M Prêle, Steven E Mutsaers, Christopher Grainge, Claire Thomson, Allen James, Nathan W Bartlett, Darryl A Knight.
      Alveolar epithelial cell (AEC) senescence is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Mitochondrial dysfunction including release of mitochondrial DNA (mtDNA) is a feature of senescence, which led us to investigate the role of the DNA-sensing GMP-AMP synthase (cGAS) in IPF, with a focus on AEC senescence. cGAS expression in fibrotic tissue from lungs of IPF patients was detected within cells immunoreactive for epithelial cell adhesion molecule (EpCAM) and p21, epithelial and senescence markers respectively. Submerged primary cultures of AECs isolated from lung tissue of IPF patients (IPF-AECs, n=5) exhibited higher baseline senescence than AECs from control donors (Ctrl-AECs, n=5-7), as assessed by increased nuclear histone 2AXγ phosphorylation, p21 mRNA and expression of senescence-associated secretory phenotype (SASP) cytokines. Pharmacological cGAS inhibition using RU.521 diminished IPF-AEC senescence in culture and attenuated induction of Ctrl-AEC senescence following etoposide-induced DNA damage. Short interfering RNA (siRNA) knockdown of cGAS also attenuated etoposide-induced senescence of the AEC line, A549. Higher levels of mtDNA were detected in the cytosol and culture supernatants of primary IPF- and etoposide-treated Ctrl-AECs when compared to Ctrl-AECs at baseline. Furthermore, ectopic mtDNA augmented cGAS-dependent senescence of Ctrl-AECs, whereas DNAse I treatment diminished IPF-AEC senescence. This study provides evidence that a self-DNA driven, cGAS-dependent response augments AEC senescence, identifying cGAS as a potential therapeutic target for IPF.
    Keywords:  Alveolar epithelium; Idiopathic pulmonary fibrosis; Mitochondrial DNA; Senescence; cGAS
    DOI:  https://doi.org/10.1152/ajplung.00574.2020
  7. Mech Ageing Dev. 2021 Sep 09. pii: S0047-6374(21)00141-X. [Epub ahead of print] 111569
    The balance between NAD+ biosynthesis and consumption in ageing.
    Øyvind Strømland, Joseph Diab, Eugenio Ferrario, Lars J Sverkeli, Mathias Ziegler.
      Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme in redox reactions. NAD+ is also important in cellular signalling as it is consumed by PARPs, SARM1, sirtuins and CD38. Cellular NAD+ levels regulate several essential processes including DNA repair, immune cell function, senescence, and chromatin remodelling. Maintenance of these cellular processes is important for healthy ageing and lifespan. Interestingly, the levels of NAD+ decline during ageing in several organisms, including humans. Declining NAD+ levels have been linked to several age-related diseases including various metabolic diseases and cognitive decline. Decreasing tissue NAD+ concentrations have been ascribed to an imbalance between biosynthesis and consumption of the dinucleotide, resulting from, for instance, reduced levels of the rate limiting enzyme NAMPT along with an increased activation state of the NAD+-consuming enzymes PARPs and CD38. The progression of some age-related diseases can be halted or reversed by therapeutic augmentation of NAD+ levels. NAD+ metabolism has therefore emerged as a potential target to ameliorate age-related diseases. The present review explores how ageing affects NAD+ metabolism and current approaches to reverse the age-dependent decline of NAD+.
    Keywords:  NAD biosynthesis; NAD metabolism; PARP; Sirtuins; ageing
    DOI:  https://doi.org/10.1016/j.mad.2021.111569
  8. Mol Carcinog. 2021 Sep 17.
    RAS induced senescence of skin keratinocytes is mediated through Rho-associated protein kinase (ROCK).
    Alex J Lee, Elise Fraser, Brittany Flowers, Jee Kim, Kenneth Wong, Christophe Cataisson, Huaitian Liu, Howard Yang, Maxwell P Lee, Stuart H Yuspa, Luowei Li.
      Cellular senescence is a well-documented response to oncogene activation in many tissues. Multiple pathways are invoked to achieve senescence indicating its importance to counteract the transforming activities of oncogenic stimulation. We now report that the Rho-associated protein kinase (ROCK) signaling pathway is a critical regulator of oncogene-induced senescence in skin carcinogenesis. Transformation of mouse keratinocytes with oncogenic RAS upregulates ROCK activity and initiates a senescence response characterized by cell enlargement, growth inhibition, upregulation of senescence associated β-galactosidase (SAβgal) expression, and release of multiple pro-inflammatory factors comprising the senescence-associated secretory phenotype (SASP). The addition of the ROCK inhibitor Y-27632 and others prevents these senescence responses and maintains proliferating confluent RAS transformed keratinocyte cultures indefinitely. Mechanistically, oncogenic RAS transformation is associated with upregulation of cell cycle inhibitors p15Ink4b , p16Ink4a , and p19Arf and downregulation of p-AKT, all of which are reversed by Y-27632. RNA-seq analysis of Y-27632 treated RAS-transformed keratinocytes indicated that the inhibitor reduced growth-inhibitory gene expression profiles and maintained expression of proliferative pathways. Y-27632 also reduced the expression of NF-κB effector genes and the expression of IκBζ downstream mediators. The senescence inhibition from Y-27632 was reversible, and upon its removal, senescence reoccurred in vitro with rapid upregulation of cell cycle inhibitors, SASP expression, and cell detachment. Y-27632 treated cultured RAS-keratinocytes formed tumors in the absence of the inhibitor when placed in skin orthografts suggesting that factors in the tumor microenvironment can overcome the drive to senescence imparted by overactive ROCK activity.
    Keywords:  RAS; ROCK; keratinocytes; oncogene; senescence
    DOI:  https://doi.org/10.1002/mc.23351
  9. Cell Death Discov. 2021 Sep 16. 7(1): 244
    Radiation-induced liver injury and hepatocyte senescence.
    Wei Zhu, Xiaofen Zhang, Mengli Yu, Bingru Lin, Chaohui Yu.
      Radiation-induced liver injury (RILI) is a major complication of radiotherapy during treatment for liver cancer and other upper abdominal malignant tumors that has poor pharmacological therapeutic options. A series of pathological changes can be induced by radiation. However, the underlying mechanism of RILI remains unclear. Radiation can induce cell damage via direct energy deposition or reactive free radical generation. Cellular senescence can be observed due to the DNA damage response (DDR) caused by radiation. The senescence-associated secretory phenotype (SASP) secreted from senescent cells can cause chronic inflammation and aggravate liver dysfunction for a long time. Oxidative stress further activates the signaling pathway of the inflammatory response and affects cellular metabolism. miRNAs clearly have differential expression after radiation treatment and take part in RILI development. This review aims to systematically profile the overall mechanism of RILI and the effects of radiation on hepatocyte senescence, laying foundations for the development of new therapies.
    DOI:  https://doi.org/10.1038/s41420-021-00634-6
  10. Mol Cell Biochem. 2021 Sep 17.
    Oxidative stress in retinal pigment epithelium impairs stem cells: a vicious cycle in age-related macular degeneration.
    Raffaella Lazzarini, Michele Nicolai, Guendalina Lucarini, Vittorio Pirani, Cesare Mariotti, Massimo Bracci, Monica Mattioli-Belmonte.
      Aging, chronic oxidative stress, and inflammation are major pathogenic factors in the development and progression of age-related macular degeneration (AMD) with the loss of retinal pigment epithelium (RPE). The human RPE contains a subpopulation of progenitors (i.e., RPE stem cells-RPESCs) whose role in the RPE homeostasis is under investigation. We evaluated the paracrine effects of mature RPE cells exposed to oxidative stress (H2O2) on RPESCs behavior through co-cultural, morphofunctional, and bioinformatic approaches. RPESCs showed a decline in proliferation, an increase of the senescence-associated β-galactosidase activity, the acquisition of a senescent-like secretory phenotype (SASP), and the reduction of their stemness and differentiation competencies. IL-6 and Superoxide Dismutase 2 (SOD2) seem to be key molecules in RPESCs response to oxidative stress. Our results get insight into stress-induced senescent-associated molecular mechanisms implicated in AMD pathogenesis. The presence of chronic oxidative stress in the microenvironment reduces the RPESCs abilities, inducing and/or maintaining a pro-inflammatory retinal milieu that in turn could affect AMD onset and progression.
    Keywords:  Age-related macular degeneration (AMD); Inflammation; Oxidative stress; Retinal pigment epithelium; Senescence-associated secretory phenotype (SASP); Stem cells
    DOI:  https://doi.org/10.1007/s11010-021-04258-3
  11. Aging Cell. 2021 Sep 18. e13439
    DNA methylation-based biomarkers of aging were slowed down in a two-year diet and physical activity intervention trial: the DAMA study.
    Giovanni Fiorito, Saverio Caini, Domenico Palli, Benedetta Bendinelli, Calogero Saieva, Ilaria Ermini, Virginia Valentini, Melania Assedi, Piera Rizzolo, Daniela Ambrogetti, Laura Ottini, Giovanna Masala.
      Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed "next-generation clock" DNAmGrimAge outperforms "first-generation clocks" in predicting longevity and the onset of many age-related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm-based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the "Diet, Physical Activity, and Mammography" (DAMA) study: a 24-month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer-related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging-related epigenetic mechanisms.
    Keywords:  DNA methylation; dietary habits; epigenetic clock; epigenetic mutation load; physical activity; postmenopausal women; primary prevention trial
    DOI:  https://doi.org/10.1111/acel.13439
  12. Nature. 2021 Sep 13.
    Virus-induced senescence is driver and therapeutic target in COVID-19.
    Soyoung Lee, Yong Yu, Jakob Trimpert, Fahad Benthani, Mario Mairhofer, Paulina Richter-Pechanska, Emanuel Wyler, Dimitri Belenki, Sabine Kaltenbrunner, Maria Pammer, Lea Kausche, Theresa C Firsching, Kristina Dietert, Michael Schotsaert, Carles Martínez-Romero, Gagandeep Singh, Séverine Kunz, Daniela Niemeyer, Riad Ghanem, Helmut J F Salzer, Christian Paar, Michael Mülleder, Melissa Uccellini, Edward G Michaelis, Amjad Khan, Andrea Lau, Martin Schönlein, Anna Habringer, Josef Tomasits, Julia M Adler, Susanne Kimeswenger, Achim D Gruber, Wolfram Hoetzenecker, Herta Steinkellner, Bettina Purfürst, Reinhard Motz, Francesco Di Pierro, Bernd Lamprecht, Nikolaus Osterrieder, Markus Landthaler, Christian Drosten, Adolfo García-Sastre, Rupert Langer, Markus Ralser, Roland Eils, Maurice Reimann, Dorothy N Y Fan, Clemens A Schmitt.
      Derailed cytokine and immune cell networks account for organ damage and clinical severity of COVID-191-4. Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and accompanied by a senescence-associated secretory phenotype (SASP), composed of pro-inflammatory cytokines, extracellular matrix-active factors and pro-coagulatory mediators5-7. COVID-19 patients displayed markers of senescence in their airway mucosa in situ and elevated serum levels of SASP factors. Mirroring COVID-19 hallmark features such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9, in vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, neutrophil extracellular trap (NET) formation as well as activation of platelets and the clotting cascade in response to supernatant of VIS cells, including SARS-CoV-2-induced senescence. Senolytics such as Navitoclax and Dasatinib/Quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-driven hamster and mouse models. Our findings mark VIS as pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest senolytic targeting of virus-infected cells as a novel treatment option against SARS-CoV-2 and perhaps other viral infections.
    DOI:  https://doi.org/10.1038/s41586-021-03995-1
  13. Cell Biosci. 2021 Sep 16. 11(1): 173
    The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages.
    Yihua Huang, Xue Yang, Yan Meng, Changchun Shao, Jianping Liao, Fengwei Li, Rong Li, Yingying Jing, Aimin Huang.
       BACKGROUND: Liver cancer is one of the most common malignancies in the world with a poor prognosis. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80-90% of cases. The initiation and progression of HCC are closely associated with chronic liver inflammation. In addition, HCC is often accompanied by cell senescence. Senescent hepatocytes can secrete various inflammatory factors, collectively called the senescence-associated secretory phenotype (SASP). The SASP has been confirmed to promote the occurrence of liver cancer by affecting the inflammatory microenvironment. However, its role and the underlying mechanism of hepatic SASP in hepatocarcinogenesis are not clearly understood. Therefore, a better understanding of the pathogenic mechanisms of the effect of the hepatic SASP on the occurrence of HCC is still needed.
    METHODS: The study aims to explore the role of SASP factors and the underlying mechanism in tumorigenesis and the progression of HCC in vivo. We used diethylnitrosamine (DEN) combined with carbon tetrachloride (CCl4) (DEN-CCl4) to establish liver cancer model in wild-type (WT) mice and Bcl3 knockout (Bcl3-/-) mice. β-galactosidase (β-gal) staining was performed to evaluate the degree of cellular senescence. Immunohistochemistry (IHC) were used to detect the degree of cellular senescence and the activation of macrophage. PCR chip and clinical tissue chip assays were used to estimate the RNA levels of SASP factors and NF-κB related genes, and their protein levels were examined by Western blot assays.
    RESULTS: DEN-CCl4 induced cellular senescence in mouse hepatocytes. In addition, senescent hepatocytes might release a variety of inflammatory factors that further activate macrophages, thereby changing the microenvironmental state and promoting the occurrence of HCC. Mechanistically, the NF-κB pathway is important because it regulates the SASP. Therefore, we used a PCR chip to detect the expression of NF-κB-related genes in senescent liver tissue. Our results showed that the expression of Bcl3 was increased in senescent hepatocytes, and knocking out Bcl3 significantly inhibited the secretion of hepatocyte SASP factors and the activation of macrophages, thereby inhibiting hepatocarcinogenesis. Finally, in clinical tissues adjacent to HCC tissues in patients, the expression of Bcl3 and IL-8 correlated with poor prognosis in HCC patients.
    CONCLUSION: The hepatic SASP can further induce the activation of macrophages during hepatocarcinogenesis, thereby promoting the occurrence of HCC, and that this process is closely related to the expression of Bcl3 in hepatocytes.
    Keywords:  Bcl3; Hepatic senescence-associated secretory phenotype; Liver cancer; Macrophage
    DOI:  https://doi.org/10.1186/s13578-021-00683-5
  14. Geroscience. 2021 Sep 13.
    Necroptosis increases with age in the brain and contributes to age-related neuroinflammation.
    Nidheesh Thadathil, Evan H Nicklas, Sabira Mohammed, Tommy L Lewis, Arlan Richardson, Sathyaseelan S Deepa.
      Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which cause membrane binding and permeabilization, were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl-/- mice reduced markers of neuroinflammation (Iba-1 and GFAP) in the brains of old mice, and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice.
    Keywords:  Aging; Brain; Necroptosis; Necrostatin-1s; Neuroinflammation
    DOI:  https://doi.org/10.1007/s11357-021-00448-5
  15. iScience. 2021 Sep 24. 24(9): 103022
    Cellular senescence promotes cancer metastasis by enhancing soluble E-cadherin production.
    Koichiro Kawaguchi, Kaori Komoda, Ryuta Mikawa, Azusa Asai, Masataka Sugimoto.
      Cellular senescence acts as a potent tumor-suppression mechanism in mammals; however, it also promotes tumor progression in a non-cell-autonomous manner. We provided insights into the mechanism underlying senescence-dependent metastatic cancer development. The elimination of senescent cells suppressed the lung metastasis of melanoma cells. Using an antibody array screening of humoral factor(s) that depend on cellular senescence, we identified soluble E-cadherin (seCad) as a potential mediator of the senescence-induced melanoma metastasis. seCad enhanced the invasive activity of melanoma cells both in vitro and in vivo, and gene expression profiling revealed that seCad induced genes associated with poor prognosis in patients with melanoma. An analysis of sera from patients revealed that serum seCad is associated with distant metastasis. Our data suggest that senescent cells promote metastatic lung cancer through seCad, and that seCad may be a potential diagnostic marker as well as a therapeutic target for metastatic lung cancer.
    Keywords:  cancer; cell biology
    DOI:  https://doi.org/10.1016/j.isci.2021.103022
  16. Genomics. 2021 Sep 09. pii: S0888-7543(21)00344-X. [Epub ahead of print]
    Transcriptional features of biological age maintained in human cultured cardiac interstitial cells.
    Oscar Echeagaray, Taeyong Kim, Alex Casillas, Megan Monsanto, Mark Sussman.
      Ex vivo expansion of cells is necessary in regenerative medicine to generate large populations for therapeutic use. Adaptation to culture conditions prompt an increase in transcriptome diversity and decreased population heterogeneity in cKit+ cardiac interstitial cells (cCICs). The "transcriptional memory" influenced by cellular origin remained unexplored and is likely to differ between neonatal versus senescent input cells undergoing culture expansion. Transcriptional profiles derived from single cell RNASEQ platforms characterized human cCIC derived from neonatal and adult source tissue. Bioinformatic analysis revealed contrasting imprint of age influencing targets of 1) cell cycle, 2) senescence associated secretory phenotype (SASP), 3) RNA transport, and 4) ECM-receptor/fibrosis. A small subset of cCICs exist in a transcriptional continuum between "youthful" phenotype and the damaged microenvironment of LVAD tissue in which they were embedded. The connate transcriptional phenotypes offer fundamental biological insight and highlights cellular input as a consideration in culture expansion and adoptive transfer protocols.
    Keywords:  Biological age; Culture adaptation; In vitro expansion; Senescence; Single cell RNASEQ; Transcriptional memory
    DOI:  https://doi.org/10.1016/j.ygeno.2021.09.004
  17. Arch Physiol Biochem. 2021 Sep 11. 1-14
    H2S-mediated blockage of protein acetylation and oxidative stress attenuates lipid overload-induced cardiac senescence.
    Ruihuan Yu, Yuehong Wang, Jiechun Zhu, Guangdong Yang.
      Hydrogen sulphide (H2S), a newly identified gasotransmitter, can be endogenously produced by cystathionine gamma-lyase (CSE) in the cardiovascular system. This study investigated the role of the CSE/H2S system on lipid overload-induced lipotoxicity and cardiac senescence. Lipid overload in rat cardiomyocyte cells (H9C2) promoted intracellular accumulation of lipid, oxidative stress, mitochondrial dysfunctions, lipid peroxidation and inhibited cell viability, all of which could be reversed by exogenously applied H2S. Further data revealed that H2S protected H9C2 cells from lipid overload-induced senescence by altering the expressions of lipid metabolism-related genes and inhibiting cellular acetyl-CoA and global protein acetylation. Enhancement of protein acetylation abolished the protective role of H2S on cardiac senescence. In vivo, knockout of the CSE gene strengthened cardiac lipid accumulation, protein acetylation, and cellular ageing in high fat diet-fed mice. Taken together, the CSE/H2S system is capable of maintaining lipid homeostasis and cellular senescence in heart cells under lipid overload.
    Keywords:  H2S; cystathionine gamma-lyase; lipotoxicity; protein acetylation; senescence
    DOI:  https://doi.org/10.1080/13813455.2021.1976209
  18. Clin Rev Allergy Immunol. 2021 Sep 18.
    Immunology of Aging: the Birth of Inflammaging.
    T Fulop, A Larbi, G Pawelec, A Khalil, A A Cohen, K Hirokawa, J M Witkowski, C Franceschi.
      The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.
    Keywords:  Cytokines; Free radicals; Immunobiography; Immunosenescence; Inflammaging; Macrophages; Microbiome; Mitochondria; SASP; Signaling; Trained immunity
    DOI:  https://doi.org/10.1007/s12016-021-08899-6
  19. Blood. 2021 Sep 15. pii: blood.2021011570. [Epub ahead of print]
    IL-1 Mediates Microbiome-Induced Inflamm-Ageing of Hematopoietic Stem Cells in Mice.
    Larisa Vladimirovna Kovtonyuk, Francisco Caiado, Santiago Garcia-Martin, Eva-Maria Manz, Patrick Michael Helbling, Hitoshi Takizawa, Steffen Boettcher, Fatima Al-Shahrour, Cesar Nombela-Arrieta, Emma Slack, Markus G Manz.
      Ageing is associated with impaired hematopoietic and immune function. This is caused in part by decreased hematopoietic stem cell (HSC) population fitness and an increased myeloid differentiation bias. The reasons for this aging-associated HSC impairment are incompletely understood. We here demonstrate that aged specific pathogen free (SPF) wild-type mice in contrast to young SPF mice produce more IL-1a/b in steady-state bone marrow (BM), with most of IL-1a/b being derived from myeloid BM cells. Further, blood of steady-state aged SPF wild-type mice contains higher levels of microbe associated molecular patterns (MAMPs), specifically TLR4 and TLR8 ligands. Also, BM myeloid cells from aged mice produce more IL-1b in vitro, and aged mice show higher and more durable IL-1a/b responses upon LPS stimulation in vivo. To test if HSC ageing is driven via IL-1a/b, we evaluated HSCs from IL-1 receptor 1 (IL-1R1) knock-out mice. Indeed, aged HSCs from IL-1R1 knock-out mice show significantly mitigated ageing-associated inflammatory signatures. Moreover, HSCs from aged IL-1R1KO and also from germ-free mice maintain unbiased lympho-myeloid hematopoietic differentiation upon transplantation, thus resembling this functionality of young HSCs. Importantly, in vivo antibiotic suppression of microbiota or pharmacologic blockade of IL-1 signaling in aged wild-type mice was similarly sufficient to reverse myeloid biased output of their HSC populations. Collectively, our data defines the microbiome-IL-1/IL-1R1 axis as a key, self-sustaining, but also therapeutically partially reversible driver of HSC inflamm-ageing.
    DOI:  https://doi.org/10.1182/blood.2021011570
  20. Nat Commun. 2021 Sep 13. 12(1): 5402
    Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.
    Mathieu F Bakhoum, Jasmine H Francis, Albert Agustinus, Ethan M Earlie, Melody Di Bona, David H Abramson, Mercedes Duran, Ignas Masilionis, Elsa Molina, Alexander N Shoushtari, Michael H Goldbaum, Paul S Mischel, Samuel F Bakhoum, Ashley M Laughney.
      Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-021-25529-z
  21. Mech Ageing Dev. 2021 Sep 10. pii: S0047-6374(21)00139-1. [Epub ahead of print] 111567
    Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing.
    Ole Kristian Reiten, Martin Andreas Wilvang, Sarah J Mitchell, Zeping Hu, Evandro F Fang.
      NAD+ is a fundamental molecule in human life and health as it participates in energy metabolism, cell signalling, mitochondrial homeostasis, and in dictating cell survival or death. Emerging evidence from preclinical and human studies indicates an age-dependent reduction of cellular NAD+, possibly due to reduced synthesis and increased consumption. In preclinical models, NAD+ repletion extends healthspan and / or lifespan and mitigates several conditions, such as premature ageing diseases and neurodegenerative diseases. These findings suggest that NAD+ replenishment through NAD+ precursors has great potential as a therapeutic target for ageing and age-predisposed diseases, such as Alzheimer's disease. Here, we provide an updated review on the biological activity, safety, and possible side effects of NAD+ precursors in preclinical and clinical studies. Major NAD+ precursors focused on by this review are nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and the new discovered dihydronicotinamide riboside (NRH). In summary, NAD+ precursors have an exciting therapeutic potential for ageing, metabolic and neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; NAD(+); ageing; healthspan
    DOI:  https://doi.org/10.1016/j.mad.2021.111567
  22. J Immunol. 2021 Sep 15. pii: ji2100392. [Epub ahead of print]
    Leaked Mitochondrial C1QBP Inhibits Activation of the DNA Sensor cGAS.
    Kun Song, Yakun Wu, Bishi Fu, Lingyan Wang, Wenzhuo Hao, Fang Hua, Yiwen Sun, Martin E Dorf, Shitao Li.
      Cytosolic DNA from pathogens activates the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) that produces the second messenger, cGAMP. cGAMP triggers a signal cascade leading to type I IFN expression. Host DNA is normally restricted in the cellular compartments of the nucleus and mitochondria. Recent studies have shown that DNA virus infection triggers mitochondrial stress, leading to the release of mitochondrial DNA to the cytosol and activation of cGAS; however, the regulatory mechanism of mitochondrial DNA-mediated cGAS activation is not well elucidated. In this study, we analyzed cGAS protein interactome in mouse RAW264.7 macrophages and found that cGAS interacted with C1QBP. C1QBP predominantly localized in the mitochondria and leaked into the cytosol during DNA virus infection. The leaked C1QBP bound the NTase domain of cGAS and inhibited cGAS enzymatic activity in cells and in vitro. Overexpression of the cytosolic form of C1QBP inhibited cytosolic DNA-elicited innate immune responses and promoted HSV-1 infection. By contrast, deficiency of C1QBP led to the elevated innate immune responses and impaired HSV-1 infection. Taken together, our study suggests that C1QBP is a novel cGAS inhibitor hidden in the mitochondria.
    DOI:  https://doi.org/10.4049/jimmunol.2100392
  23. Aging Cell. 2021 Sep 14. e13476
    S3QELs protect against diet-induced intestinal barrier dysfunction.
    Mark A Watson, Blaine Pattavina, Tyler A U Hilsabeck, Jose Lopez-Dominguez, Pankaj Kapahi, Martin D Brand.
      The underlying causes of aging remain elusive, but may include decreased intestinal homeostasis followed by disruption of the intestinal barrier, which can be mimicked by nutrient-rich diets. S3QELs are small-molecule suppressors of site IIIQo electron leak; they suppress superoxide generation at complex III of the mitochondrial electron transport chain without inhibiting oxidative phosphorylation. Here we show that feeding different S3QELs to Drosophila on a high-nutrient diet protects against greater intestinal permeability, greater enterocyte apoptotic cell number, and shorter median lifespan. Hif-1α knockdown in enterocytes also protects, and blunts any further protection by S3QELs. Feeding S3QELs to mice on a high-fat diet also protects against the diet-induced increase in intestinal permeability. Our results demonstrate by inference of S3QEL use that superoxide produced by complex III in enterocytes contributes to diet-induced intestinal barrier disruption in both flies and mice.
    Keywords:  aging; complex III; diet; drosophila; intestinal permeability; intestine; leaky gut; metabolism; mitochondria; oxidative stress; superoxide
    DOI:  https://doi.org/10.1111/acel.13476
  24. Nat Aging. 2021 Aug;1(8): 715-733
    Multi-omic profiling of primary mouse neutrophils predicts a pattern of sex and age-related functional regulation.
    Ryan J Lu, Shalina Taylor, Kévin Contrepois, Minhoo Kim, Juan I Bravo, Mathew Ellenberger, Nirmal K Sampathkumar, Bérénice A Benayoun.
      Neutrophils are the most abundant human white blood cell and constitute a first line of defense in the innate immune response. Neutrophils are short-lived cells, and thus the impact of organismal aging on neutrophil biology, especially as a function of biological sex, remains poorly understood. Here, we describe a multi-omic resource of mouse primary bone marrow neutrophils from young and old female and male mice, at the transcriptomic, metabolomic and lipidomic levels. We identify widespread regulation of neutrophil 'omics' landscapes with organismal aging and biological sex. In addition, we leverage our resource to predict functional differences, including changes in neutrophil responses to activation signals. To date, this dataset represents the largest multi-omics resource for neutrophils across sex and ages. This resource identifies neutrophil characteristics which could be targeted to improve immune responses as a function of sex and/or age.
    DOI:  https://doi.org/10.1038/s43587-021-00086-8
  25. Biol Cell. 2021 Sep 14.
    Decreased proliferation of aged rat beta cells corresponds with enhanced expression of the cell cycle inhibitor p27KIP1.
    Talon J Aitken, Jacqueline E Crabtree, Daelin M Jensen, Kavan H Hess, Brennan R Leininger, Jeffery S Tessem.
       BACKGROUND: Over 400 million people are diabetic. Type 1 and type 2 diabetes are characterized by decreased functional β-cell mass and, consequently, decreased glucose-stimulated insulin secretion. A potential intervention is transplantation of β-cell containing islets from cadaveric donors. A major impediment to greater application of this treatment is the scarcity of transplant-ready β-cells. Therefore, inducing β-cell proliferation ex vivo could be used to expand functional β-cell mass prior to transplantation. Various molecular pathways are sufficient to induce proliferation of young β-cells, however aged β-cells are refractory to these proliferative signals. Given that the majority of cadaveric donors fit an aged demographic, defining the mechanisms that impede aged β-cell proliferation is imperative.
    RESULTS: We demonstrate that aged rat (5-month-old) β-cells are refractory to mitogenic stimuli that otherwise induce young rat (5-week-old) β-cell proliferation. We hypothesized that this change in proliferative capacity could be due to differences in cyclin-dependent kinase inhibitor expression. We measured levels of p16INK4a , p15INK4b , p18INK4c , p19INK4d , p21CIP1 , p27KIP1 and p57KIP2 by immunofluorescence analysis. Our data demonstrates an age-dependent increase of p27KIP1 in rat β-cells by immunofluorescence and was validated by increased p27KIP1 protein levels by western blot analysis. Interestingly, HDAC1, which modulates the p27KIP1 promoter acetylation state, is downregulated in aged rat islets. These data demonstrate increased p27KIP1 protein levels at 5 months of age, which may be due to decreased HDAC1 mediated repression of p27KIP1 expression.
    SIGNIFICANCE: As the majority of transplant-ready β-cells come from aged donors, it is imperative that we understand why aged β-cells are refractory to mitogenic stimuli. Our findings demonstrate that increased p27KIP1 expression occurs early in β-cell aging, which corresponds with impaired β-cell proliferation. Furthermore, the correlation between HDAC1 and p27 levels suggests that pathways that activate HDAC1 in aged β-cells could be leveraged to decrease p27KIP1 levels and enhance β-cell proliferation. This article is protected by copyright. All rights reserved.
    Keywords:  HDAC1; aging; diabetes; p27KIP1; β-cell
    DOI:  https://doi.org/10.1111/boc.202100035
  26. Osteoporos Int. 2021 Sep 14.
    Exogenous melatonin prevents type 1 diabetes mellitus-induced bone loss, probably by inhibiting senescence.
    Z Gong, W Da, Y Tian, R Zhao, S Qiu, Q Wu, K Wen, L Shen, R Zhou, L Tao, Y Zhu.
      Exogenous melatonin inhibited the senescence of preosteoblast cells in type 1 diabetic (T1D) mice and those cultured in high glucose (HG) by multiple regulations. Exogenous melatonin had a protective effect on diabetic osteoporosis, which may depend on the inhibition of senescence.
    INTRODUCTION: Senescence is thought to play an important role in the pathophysiological mechanisms underlying diabetic bone loss. Increasing evidence has shown that melatonin exerts anti-senescence effects. In this study, we investigated whether melatonin can inhibit senescence and prevent diabetic bone loss.
    METHODS: C57BL/6 mice received a single intraperitoneal injection of 160 mg/kg streptozotocin, followed by the oral administration of melatonin or vehicle for 2 months. Then, tissues were harvested and subsequently examined. MC3T3-E1 cells were cultured under HG conditions for 7 days and then treated with melatonin or not for 24 h. Sirt1-specific siRNAs and MT1- or MT2-specific shRNA plasmids were transfected into MC3T3-E1 cells for mechanistic study.
    RESULTS: The total protein extracted from mouse femurs revealed that melatonin prevented senescence in T1D mice. The micro-CT results indicated that melatonin prevented bone loss in T1D mice. Cellular experiments indicated that melatonin administration prevented HG-induced senescence, whereas knockdown of the melatonin receptors MT1 or MT2 abolished these effects. Sirt1 expression was upregulated by melatonin administration but significantly reduced after MT1 or MT2 was knocked down. Knockdown of Sirt1 blocked the anti-senescence effects of melatonin. Additionally, melatonin promoted the expression of CDK2, CDK4, and CyclinD1, while knockdown of MT1 or MT2 abolished these effects. Furthermore, melatonin increased the expression of the polycomb repressive complex (PRC), but knockdown of MT1 or MT2 abolished these effects. Furthermore, melatonin increased the protein levels of Sirt1, PRC1/2 complex-, and cell cycle-related proteins.
    CONCLUSION: This work shows that melatonin protects against T1D-induced bone loss, probably by inhibiting senescence. Targeting senescence in the investigation of diabetic osteoporosis may lead to novel discoveries.
    Keywords:  High glucose; Melatonin; Osteoporosis; Senescence; Type 1 diabetes
    DOI:  https://doi.org/10.1007/s00198-021-06061-8
  27. Aging Dis. 2021 Sep;12(6): 1462-1475
    Astrocyte-Derived Extracellular Vesicles (ADEVs): Deciphering their Influences in Aging.
    Megan E Rouillard, Pearl A Sutter, Olivia R Durham, Cory M Willis, Stephen J Crocker.
      Astrocytes are an abundant and dynamic glial cell exclusive to the central nervous system (CNS). In the context of injury, inflammation, and/or diseases of the nervous system, astrocyte responses, termed reactive astrogliosis, are a recognized pathological feature across a range of conditions and diseases. However, the impact of reactive astrogliosis is not uniform and varies by context and duration (time). In recent years, extracellular communication between glial cells via extracellular vesicles (EVs) has garnered interest as a process connected with reactive astrogliosis. In this review, we relate recent findings on astrocyte-derived extracellular vesicles (ADEVs) with a focus on factors that can influence the effects of ADEVs and identified age related changes in the function of ADEVs. Additionally, we will discuss the current limitations of existing experimental approaches and identify questions that highlight areas for growth in this field, which will continue to enhance our understanding of ADEVs in age-associated processes.
    Keywords:  aging; exosome; extracellular matrix; myelin; neurodegeneration; p16; regeneration
    DOI:  https://doi.org/10.14336/AD.2021.0608
  28. Stem Cell Res Ther. 2021 Sep 14. 12(1): 502
    Chronic inflammation-induced senescence impairs immunomodulatory properties of synovial fluid mesenchymal stem cells in rheumatoid arthritis.
    Hyeon-Jeong Lee, Won-Jae Lee, Sun-Chul Hwang, Yongho Choe, Saetbyul Kim, Eunyeong Bok, Sangyeob Lee, Seung-Joon Kim, Hyun-Ok Kim, Sun-A Ock, Hae-Sook Noh, Gyu-Jin Rho, Sang-Il Lee, Sung-Lim Lee.
       BACKGROUND: Although the immunomodulatory properties of mesenchymal stem cells (MSCs) have been highlighted as a new therapy for autoimmune diseases, including rheumatoid arthritis (RA), the disease-specific characteristics of MSCs derived from elderly RA patients are not well understood.
    METHODS: We established MSCs derived from synovial fluid (SF) from age-matched early (average duration of the disease: 1.7 years) and long-standing (average duration of the disease: 13.8 years) RA patients (E-/L-SF-MSCs) and then analyzed the MSC characteristics such as stemness, proliferation, cellular senescence, in vitro differentiation, and in vivo immunomodulatory properties.
    RESULTS: The presence of MSC populations in the SF from RA patients was identified. We found that L-SF-MSCs exhibited impaired proliferation, intensified cellular senescence, reduced immunomodulatory properties, and attenuated anti-arthritic capacity in an RA animal model. In particular, E-SF-MSCs demonstrated cellular senescence progression and attenuated immunomodulatory properties similar to those of L-SF-MSC in an RA joint-mimetic milieu due to hypoxia and pro-inflammatory cytokine exposure. Due to a long-term exposure to the chronic inflammatory milieu, cellular senescence, attenuated immunomodulatory properties, and the loss of anti-arthritic potentials were more often identified in SF-MSCs in a long-term RA than early RA.
    CONCLUSION: We conclude that a chronic RA inflammatory milieu affects the MSC potential. Therefore, this work addresses the importance of understanding MSC characteristics during disease states prior to their application in patients.
    Keywords:  Cellular senescence; Duration of inflammatory disease; Immunomodulation; Mesenchymal stem cell-derived from the patient; Rheumatoid arthritis
    DOI:  https://doi.org/10.1186/s13287-021-02453-z
  29. Nat Rev Mol Cell Biol. 2021 Sep 13.
    Molecular mechanisms of dietary restriction promoting health and longevity.
    Cara L Green, Dudley W Lamming, Luigi Fontana.
      Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD+), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.
    DOI:  https://doi.org/10.1038/s41580-021-00411-4
  30. Am J Physiol Heart Circ Physiol. 2021 Sep 17.
    Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.
    Keita Horitani, Masayoshi Iwasaki, Hiroshi Kishimoto, Kensaku Wada, Miyuki Nakano, Haengnam Park, Yasushi Adachi, Daisuke Motooka, Daisuke Okuzaki, Ichiro Shiojima.
      Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction.Repetitive glucose+lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.
    Keywords:  endothelial progenitor cells; glucose; histone demethylase; triglyceride
    DOI:  https://doi.org/10.1152/ajpheart.00261.2021
  31. In Vitro Cell Dev Biol Anim. 2021 Sep 13.
    Protective effect of MitoQ on oxidative stress-mediated senescence of canine bone marrow mesenchymal stem cells via activation of the Nrf2/ARE pathway.
    Lijun Zhong, Jiaqiang Deng, Congwei Gu, Liuhong Shen, Zhihua Ren, Xiaoping Ma, Qigui Yan, Junliang Deng, Zhicai Zuo, Ya Wang, Suizhong Cao, Shumin Yu.
      The destruction of biological activity such as senescence and apoptosis caused by oxidative stress could play a pivotal role in the poor therapeutic efficiency of bone marrow mesenchymal stem cells (BMSCs) transplantation. Mitoquinone (MitoQ) has a highly effective mitochondrial antioxidant effect, and has been widely used in many oxidative damage models. This study aimed to investigate the protective effect of MitoQ on the oxidative stress-mediated senescence of canine BMSCs and the underlying mechanism. The senescence of BMSCs was determined by senescence-associated β-galactosidase staining and quantitative real-time PCR. The expression of p-Nrf2 protein was detected by Western blotting. The results demonstrated that, as BMSCs were expanded in vitro, the senescent phenotype appeared. And the senescence of BMSCs may be caused by oxidative stress, manifested by increasing the level of ROS and decreasing the activity of antioxidant enzymes. Treatment of MitoQ down-regulated the mRNA levels of senescence-related and apoptosis-related genes, but up-regulated the mRNA levels of proliferation-related genes. Meanwhile, ROS generation and senescent activity were reduced in MitoQ-treated BMSCs. Further mechanism studies showed that MitoQ obviously promoted Nrf2 phosphorylation, and also facilitated the translocation of Nrf2 into the nucleus. Moreover, treatment of MitoQ increased the mRNA levels of downstream antioxidant genes and enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase. Thus, our study revealed that MitoQ, via the Nrf2/ARE signaling pathway, exerts an antioxidant effect as well as potentially delays OS-mediated senescence during BMSCs that were expanded in vitro, which may serve as a novel strategy to optimize the clinical application of BMSCs.
    Keywords:  Apoptosis; Mitoquinone; Oxidative stress; Senescence; Stem cells
    DOI:  https://doi.org/10.1007/s11626-021-00605-2
  32. Neurochem Int. 2021 Sep 09. pii: S0197-0186(21)00228-X. [Epub ahead of print] 105182
    Classical HDACs in the regulation of neuroinflammation.
    Yunjian Dai, Taofeng Wei, Zexu Shen, Yun Bei, Haoran Lin, Haibin Dai.
      Neuroinflammation is a key factor of the pathology of various neurological diseases (brain injury, depression, neurodegenerative diseases). It is a complex and orderly process that relies on various types of glial cells and peripheral immune cells. Inhibition of neuroinflammation can reduce the severity of neurological diseases. The initiation, progression, and termination of inflammation require gene activation, epigenetic modification, transcriptional translation, and post-translational regulation, all of which are tightly regulated by different enzymes. Epigenetics refers to the regulation of epigenetic gene expression by epigenetic changes (DNA methylation, histone modification, and non-coding RNAs such as miRNA) that are not dependent on changes in gene sequence and are heritable. Histone deacetylases (HDACs) are a group of important enzymes that regulate epigenetics. They can remove the acetyl group on the lysine ɛ-amino group of the target protein, thereby affecting gene transcription or altering protein activity. HDACs are involved in the regulation of immunity and inflammation. HDAC inhibitor (HDACi) has also become a new hotspot in the research of anti-inflammatory drugs. Therefore, the aim of the current review is to discuss and summarize the role and mechanism of different HDACs in neuroinflammation and the corresponding role of HDACi in neurological diseases, and to providing new ideas for future research on neuroinflammation-related diseases and drug development.
    Keywords:  Histone deacetylases; Histone deacetylases inhibitor; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuint.2021.105182
  33. Cancer Prev Res (Phila). 2021 Sep 17. pii: canprevres.0085.2021. [Epub ahead of print]
    Environmental enrichment mitigates age-related metabolic decline and Lewis lung carcinoma growth in aged female mice.
    Nicholas J Queen, Hong Deng, Wei Huang, Xiaokui Mo, Ryan K Wilkins, Tao Zhu, Xiaoyu Wu, Lei Cao.
      Aging is a complex physiological process that leads to the progressive decline of metabolic and immune function, among other biological mechanisms. As global life expectancy increases, it is important to understand determinants of healthy aging-including environmental and genetic factors-and thus slow the onset or progression of age-related disease. Environmental enrichment (EE) is a housing environment wherein laboratory animals engage with complex physical and social stimulation. EE is a prime model to understand environmental influences on aging dynamics, as it confers an anti-obesity and anti-cancer phenotype that has been implicated in healthy aging and health span extension. While EE is frequently used to study malignancies in young mice, fewer studies characterize EE-cancer outcomes in older mice. Here, we used young (3-month-old) and aged (14-month-old) female C57BL/6 mice to determine whether EE would be able to mitigate age-related deficiencies in metabolic function and thus alter Lewis lung carcinoma (LLC) growth. Overall, EE improved metabolic function, resulting in reduced fat mass, increased lean mass, and improved glycemic processing; many of these effects were stronger in the aged cohort than in the young cohort, indicating an age-driven effect on metabolic responses. In the aged-EE cohort, subcutaneously-implanted LLC tumor growth was inhibited and tumors exhibited alterations in various markers of apoptosis, proliferation, angiogenesis, inflammation, and malignancy. These results validate EE as an anti-cancer model in aged mice and underscore the importance of understanding environmental influences on cancer malignancy in aged populations.
    DOI:  https://doi.org/10.1158/1940-6207.CAPR-21-0085
  34. Aging (Albany NY). 2021 Sep 14. 13(undefined):
    Effect of different exercise training intensities on age-related cardiac damage in male mice.
    Zuowei Pei, Chenguang Yang, Ying Guo, Min Dong, Fang Wang.
      Aging is the most important risk factor for cardiovascular diseases. Although exercise is known to be beneficial for the health of aging heart, the optimal exercise training intensity to prevent natural aging-induced cardiac damage has not been defined. In this study, we used 32-week-old male mice and randomly divided them into three groups, namely, untrained (UNT) mice, moderate-intensity exercise training (MET) mice, and high-intensity interval training (HIIT) mice. Mice in the two exercise training groups were subjected to exercise 5 days per week for 24 consecutive weeks. Metabolic characteristics, cardiac function and morphology, myocardial remodeling, myocardial fibrosis (collagen III, α-SMA, and TGF-β), oxidative stress (NRF2, HO-1, SOD, and NOX4), and apoptosis (BAX, Bak, Bcl-2, and Bcl-XL) were analyzed 24 weeks after the different treatments. MET improved cardiac function and reduced myocardial remodeling, myocardial fibrosis, and oxidative stress in the aging heart. MET treatment exerted an anti-apoptotic effect in the heart of the aging mice. Importantly, HIIT did not protect against cardiac damage during the natural aging process. These findings suggest that MET may be one of the main methods to prevent cardiac damage induced by natural aging.
    Keywords:  aging; cardiac damage; mice; myocardial remodeling; oxidative stress
    DOI:  https://doi.org/10.18632/aging.203513
  35. CNS Neurosci Ther. 2021 Sep 12.
    A high fat, sugar, and salt Western diet induces motor-muscular and sensory dysfunctions and neurodegeneration in mice during aging: Ameliorative action of metformin.
    Song Hong, Aarti Nagayach, Yan Lu, Hongying Peng, Quoc-Viet A Duong, Nicholas B Pham, Christopher A Vuong, Nicolas G Bazan.
       AIMS: To explore the novel linkage between a Western diet combining high saturated fat, sugar, and salt (HFSS) and neurological dysfunctions during aging as well as Metformin intervention, we assessed cerebral cortex abnormalities associated with sensory and motor dysfunctions and cellular and molecular insights in brains using HFSS-fed mice during aging. We also explored the effect of Metformin treatment on these mice.
    METHODS: C57BL/6 mice were fed with HFSS and treated with metformin from 20 to 22 months of age, resembling human aging from 56 to 68 years of age (an entry phase of the aged portion of lifespan).
    RESULTS: The motor and sensory cortexes in mice during aging after HFSS diet showed: (A) decreased motor-muscular and sensory functions; (B) reduced inflammation-resolving Arg-1+ microglia; (C) increased inflammatory iNOs+ microglia and TNFα levels; (D) enhanced abundance of amyloid-β peptide and of phosphorylated Tau. Metformin attenuated these changes.
    CONCLUSION: A HFSS-combined diet caused motor-muscular and sensory dysfunctions, neuroinflammation, and neurodegeneration, whereas metformin counteracted these effects. Our findings show neuroinflammatory consequences of a HFSS diet in aging. Metformin curbs the HFSS-related neuroinflammation eliciting neuroprotection.
    Keywords:  Western diet combing high saturated fat, sugar and salt; amyloid beta and phosphorylated tau in Alzheimer's disease; metformin; microglia in neuroinflammation; neurodegeneration in motor and sensory cortexes
    DOI:  https://doi.org/10.1111/cns.13726
  36. Aging Cell. 2021 Sep 16. e13434
    p38 MAPK-mediated loss of nuclear RNase III enzyme Drosha underlies amyloid beta-induced neuronal stress in Alzheimer's disease.
    Haidong Xu, Xiaolei Liu, Wenming Li, Ye Xi, Peng Su, Bo Meng, Xiaoyun Shao, Beisha Tang, Qian Yang, Zixu Mao.
      MicroRNAs (miRNAs) are small noncoding RNAs ubiquitously expressed in the brain and regulate gene expression at the post-transcriptional level. The nuclear RNase III enzyme Drosha initiates the maturation process of miRNAs in the nucleus. Strong evidence suggests that dysregulation of miRNAs is involved in many neurological disorders including Alzheimer's disease (AD). Dysfunction of miRNA biogenesis components may be involved in the processes of those diseases. However, the role of Drosha in AD remains unknown. By using immunohistochemistry, biochemistry, and subcellular fractionation methods, we show here that the level of Drosha protein was significantly lower in the postmortem brain of human AD patients as well as in the transgenic rat model of AD. Interestingly, Drosha level was specifically reduced in neurons of the cortex and hippocampus but not in the cerebellum in the AD brain samples. In primary cortical neurons, amyloid-beta (Aβ) oligomers caused a p38 MAPK-dependent phosphorylation of Drosha, leading to its redistribution from the nucleus to the cytoplasm and a decrease in its level. This loss of Drosha function preceded Aβ-induced neuronal death. Importantly, inhibition of p38 MAPK activity or overexpression of Drosha protected neurons from Aβ oligomers-induced apoptosis. Taken together, these results establish a role for p38 MAPK-Drosha pathway in modulating neuronal viability under Aβ oligomers stress condition and implicate loss of Drosha as a key molecular change in the pathogenesis of AD.
    Keywords:  Alzheimer's disease; Drosha; amyloid beta (Aβ); neuronal death; p38 MAPK
    DOI:  https://doi.org/10.1111/acel.13434
  37. Int J Mol Med. 2021 Nov;pii: 199. [Epub ahead of print]48(5):
    Reversal of brain aging by targeting telomerase: A nutraceutical approach.
    Dimitris Tsoukalas, Ana Maria Buga, Anca Oana Docea, Evangelia Sarandi, Radu Mitrut, Elisavet Renieri, Demetrios A Spandidos, Ion Rogoveanu, Liliana Cercelaru, Mihaela Niculescu, Aristidis Tsatsakis, Daniela Calina.
      Telomeres, the protective caps of chromosomes, shorten with age, as telomerase, the enzyme responsible for the compensation of telomere erosion, is inactive in the majority of cells. Telomere shortening and subsequent cell senescence lead to tissue aging and age‑related diseases. Neurodegenerative disorders, characterized by the progressive loss of neurons among other hallmarks of aged tissue, and poor cognitive function, have been associated with a short telomere length. Thus, telomerase activity has emerged as a therapeutic target, with novel agents being under investigation. The present study aimed to examine the effects of a novel natural telomerase activator, 'Reverse™', containing Centella asiatica extract, vitamin C, zinc and vitamin D3 on the brains of 18‑month‑old rats. The administration of the 'Reverse™' supplement for 3 months restored telomerase reverse transcriptase (TERT) expression in the brains of rats, as revealed by ELISA and immunohistochemistry. In addition, the findings from PCR‑ELISA demonstrated an enhanced telomerase activity in the cerebellum and cortex cells in the brains of rats treated with the 'Reverse™' supplement. The histopathological findings confirmed a structural reversibility effect close to the differentiation observed in the young control group of rats treated with two capsules/kg body weight of the 'Reverse™' supplement. On the whole, the findings of the present study provide a strong indication that an increased telomerase activity and TERT expression may be achieved not only in the postnatal or embryonic period, but also in the brains of middle‑aged rats through nutraceutical supplementation. The use of the 'Reverse™' supplement may thus contribute to the potential alleviation of a number of central nervous system diseases.
    Keywords:  Centella asiatica; aging; telomerase activators; telomerase reverse transcriptase; vitamin D; vitamin C; zinc
    DOI:  https://doi.org/10.3892/ijmm.2021.5032
  38. Mech Ageing Dev. 2021 Sep 10. pii: S0047-6374(21)00143-3. [Epub ahead of print] 111571
    Emerging roles of kisspeptin/galanin in age-related metabolic disease.
    Penghua Fang, Yuqing She, Juan Zhao, Jing Yan, Xizhong Yu, Yu Jin, Qingbo Wei, Zhenwen Zhang, Wenbin Shang.
      Age is a major risk factor for developing metabolic diseases such as obesity and diabetes. There is an unprecedented rise in obesity and type 2 diabetes in recent decades. A convincing majority of brain-gut peptides are associated with a higher risk to develop metabolic disorders, and may contribute to the pathophysiology of age-related metabolic diseases. Accumulating basic studies revealed an intriguing role of kisspeptin and galanin involved in the amelioration of insulin resistance in different ways. In patients suffered from obesity and diabetes a significant, sex-related changes in the plasma kisspeptin and galanin levels occurred. Kisspeptin is anorexigenic to prevent obesity, its level is negatively correlative with obesity and insulin resistance. While galanin is appetitive to stimulate food intake and body weight, its level is positively correlative with obesity, HOMA-IR and glucose/triglyceride concentration. In turn, kisspeptin and galanin also distinctly increase glucose uptake and utilization as well as energy expenditure. This article reviews recent evidence dealing with the role of kisspeptin and galanin in the pathophysiology of age-related metabolic diseases. It should be therefore taken into account that the targeted modulation of those peptidergic signaling may be potentially helpful in the future treatment of age-related metabolic diseases.
    Keywords:  Age; Kisspeptin; Metabolic diseases; galanin
    DOI:  https://doi.org/10.1016/j.mad.2021.111571
  39. Exp Gerontol. 2021 Sep 13. pii: S0531-5565(21)00334-X. [Epub ahead of print] 111552
    Environmental enrichment modulates silent information regulator 1 (SIRT1) activity to attenuate central presbycusis in a rat model of normal aging.
    Min Kyung Song, Yoon Ju Kim, Sang Hoon Kim, Seung Geun Yeo, Youn-Jung Kim.
      Age-related hearing loss (ARHL) is sensory impairment in the elderly. This study aimed to identify a critical molecular mechanism that can maintain young phenotypes. We focused on the effect of exposure to environmental enrichment (EE) for 12 weeks in the central auditory pathway and limbic system of aged rats. The effects of EE were compared with the effects of dexamethasone administration. We found that in 74-week-old rats hearing function was significantly reduced and the number of neuronal specific nuclear protein (NeuN)-positive cells was decreased by 10-15% in the auditory cortex, amygdala, and hippocampus. EE exposure did not significantly affect the number of neurons, but DX administration significantly decreased their numbers in the amygdala compared with untreated aged rats. Both treatments reduced inducible nitric oxide synthase (iNOS) expression in the auditory pathway and limbic system. Exposure to EE significantly increased silent information regulator 1 (SIRT1) expression and activity, and nicotinamide phosphoribosyltransferase (NAMPT) concentration. In this study, the exposure to EE resulted in attenuated age-related hearing loss accompanied by reduction of iNOS expression and increase SIRT1 activity and NAMPT level. These data showed that EE may be a potential therapeutic to prevent ARHL.
    Keywords:  Age-related hearing loss; Central auditory pathway; Environmental enrichment; Limbic system; SIRT1 activity
    DOI:  https://doi.org/10.1016/j.exger.2021.111552
  40. Aging Cell. 2021 Sep 17. e13479
    Lithium can mildly increase health during ageing but not lifespan in mice.
    Tobias Nespital, Brit Neuhaus, Andrea Mesaros, André Pahl, Linda Partridge.
      Lithium is a nutritional trace element, used clinically as an anti-depressant. Preclinically, lithium has neuroprotective effects in invertebrates and mice, and it can also extend lifespan in fission yeast, C. elegans and Drosophila. An inverse correlation of human mortality with the concentration of lithium in tap water suggests a possible, evolutionarily conserved mechanism mediating longevity. Here, we assessed the effects of lithium treatment on lifespan and ageing parameters in mice. Lithium has a narrow therapeutic dose range, and overdosing can severely affect organ health. Within the tolerable dosing range, we saw some mildly positive effects of lithium on health span but not on lifespan.
    Keywords:  ageing; healthspan; lifespan; lithium
    DOI:  https://doi.org/10.1111/acel.13479
  41. Front Genet. 2021 ;12 693071
    The Evolution of the Hallmarks of Aging.
    Maël Lemoine.
      The evolutionary theory of aging has set the foundations for a comprehensive understanding of aging. The biology of aging has listed and described the "hallmarks of aging," i.e., cellular and molecular mechanisms involved in human aging. The present paper is the first to infer the order of appearance of the hallmarks of bilaterian and thereby human aging throughout evolution from their presence in progressively narrower clades. Its first result is that all organisms, even non-senescent, have to deal with at least one mechanism of aging - the progressive accumulation of misfolded or unstable proteins. Due to their cumulation, these mechanisms are called "layers of aging." A difference should be made between the first four layers of unicellular aging, present in some unicellular organisms and in all multicellular opisthokonts, that stem and strike "from the inside" of individual cells and span from increasingly abnormal protein folding to deregulated nutrient sensing, and the last four layers of metacellular aging, progressively appearing in metazoans, that strike the cells of a multicellular organism "from the outside," i.e., because of other cells, and span from transcriptional alterations to the disruption of intercellular communication. The evolution of metazoans and eumetazoans probably solved the problem of aging along with the problem of unicellular aging. However, metacellular aging originates in the mechanisms by which the effects of unicellular aging are kept under control - e.g., the exhaustion of stem cells that contribute to replace damaged somatic cells. In bilaterians, additional functions have taken a toll on generally useless potentially limited lifespan to increase the fitness of organisms at the price of a progressively less efficient containment of the damage of unicellular aging. In the end, this picture suggests that geroscience should be more efficient in targeting conditions of metacellular aging rather than unicellular aging itself.
    Keywords:  aging; bilaterians; evolution; geroscience; metacellular aging; unicellular aging
    DOI:  https://doi.org/10.3389/fgene.2021.693071
  42. Redox Rep. 2021 Dec;26(1): 170-175
    N-acetyl cysteine ameliorates aortic fibrosis by promoting M2 macrophage polarization in aging mice.
    Qing-Yi Zhu, Shi Tai, Liang Tang, Yi-Chao Xiao, Jian-Jun Tang, Ya-Qin Chen, Li Shen, Jia He, Ming-Qi Ouyang, Sheng-Hua Zhou.
      Background: Vascular fibrosis is a universal phenomenon associated with aging, and oxidative stress plays an important role in the genesis of vascular damage in line with the aging process. However, whether antioxidants can ameliorate vascular fibrosis remains unclear.Objectives: The present study was to determine antioxidant N-acetylcysteine (NAC) could ameliorates aortic fibrosis in aging wild-type C57BL/6 mice.Methods: The aortas were harvested from both 12-week and 60-week wild-type mice. The 60-week mice were treated with and without the NAC for 12 weeks starting at the age of 48 weeks. Hematoxylin and eosin (H&E) staining and Masson's trichrome staining of aortic samples were performed, and the levels of reactive oxygen species (ROS), RNA expression of GAPDH, TNF-α, MCP-1, IL-6, IL-10, IL-4, SIRT-1, SIRT-3, FOXO-1, and macrophage polarization were determined.Results: There is a positive relationship between collagen deposition and the M1/M2 macrophage ratio in the aortic wall of aged wild-type C57BL/6 mice. The higher collagen area percentage in the aortas of 60-week-old mice than in 12-week-old mice was reversed by NAC. NAC could not impact the total number of macrophages, but partly promoted M2 macrophage polarization. By performing qRT-PCR using aortic samples from these mice, we identified that SIRT-1, SIRT-3, FOXO-1 could be somehow responsible for aging-related fibrosis.Conclusions: NAC ameliorates aortic fibrosis in aging wild type mice partly by promoting M2 macrophage polarization.
    Keywords:  M1; M2; NAC; Vascular fibrosis; inflammaging; macrophage polarization; oxidative stress; vascular aging
    DOI:  https://doi.org/10.1080/13510002.2021.1976568
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