bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒12‒06
thirty papers selected by
Maria Grazia Vizioli
Mayo Clinic


  1. Genes Dev. 2020 Dec 01. 34(23-24): 1565-1576
    Birch J, Gil J.
      Cellular senescence is a stress response that elicits a permanent cell cycle arrest and triggers profound phenotypic changes such as the production of a bioactive secretome, referred to as the senescence-associated secretory phenotype (SASP). Acute senescence induction protects against cancer and limits fibrosis, but lingering senescent cells drive age-related disorders. Thus, targeting senescent cells to delay aging and limit dysfunction, known as "senotherapy," is gaining momentum. While drugs that selectively kill senescent cells, termed "senolytics" are a major focus, SASP-centered approaches are emerging as alternatives to target senescence-associated diseases. Here, we summarize the regulation and functions of the SASP and highlight the therapeutic potential of SASP modulation as complimentary or an alternative to current senolytic approaches.
    Keywords:  SASP; aging; cancer; disease; inflammation; senescence; senolytics; senomorphics; therapeutics
    DOI:  https://doi.org/10.1101/gad.343129.120
  2. Nature. 2020 Dec;588(7836): 124-129
    Lu Y, Brommer B, Tian X, Krishnan A, Meer M, Wang C, Vera DL, Zeng Q, Yu D, Bonkowski MS, Yang JH, Zhou S, Hoffmann EM, Karg MM, Schultz MB, Kane AE, Davidsohn N, Korobkina E, Chwalek K, Rajman LA, Church GM, Hochedlinger K, Gladyshev VN, Horvath S, Levine ME, Gregory-Ksander MS, Ksander BR, He Z, Sinclair DA.
      Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1-3. Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity5-7. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.
    DOI:  https://doi.org/10.1038/s41586-020-2975-4
  3. Ageing Res Rev. 2020 Nov 25. pii: S1568-1637(20)30366-4. [Epub ahead of print] 101231
    Elyahu Y, Monsonego A.
      Aging is generally characterized as a gradual increase in tissue damage, which is associated with senescence and chronic systemic inflammation and is evident in a variety of age-related diseases. The extent to which such tissue damage is a result of a gradual decline in immune regulation, which consequently compromises the capacity of the body to repair damages, has not been fully explored. Whereas CD4 T lymphocytes play a critical role in the orchestration of immunity, thymus involution initiates gradual changes in the CD4 T-cell landscape, which may significantly compromise tissue repair. In this review, we describe the lifespan accumulation of specific dysregulated CD4 T-cell subsets and their coevolution with systemic inflammation in the process of declined immunity and tissue repair capacity with age. Then, we discuss the process of thymus involution-which appears to be most pronounced around puberty-as a possible driver of the aging T-cell landscape. Finally, we identify individualized T cell-based early diagnostic biomarkers and therapeutic strategies for age-related diseases.
    Keywords:  Aging; Chronic systemic inflammation; Dysregulated CD4 T cells; Immune-mediated repair; Thymus
    DOI:  https://doi.org/10.1016/j.arr.2020.101231
  4. Proc Natl Acad Sci U S A. 2020 Nov 30. pii: 202018138. [Epub ahead of print]
    Sabath N, Levy-Adam F, Younis A, Rozales K, Meller A, Hadar S, Soueid-Baumgarten S, Shalgi R.
      Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.
    Keywords:  UPR; chaperones; heat shock response; protein homeostasis; senescence
    DOI:  https://doi.org/10.1073/pnas.2018138117
  5. Aging Cell. 2020 Dec 04. e13276
    Yao J, Ding D, Li X, Shen T, Fu H, Zhong H, Wei G, Ni T.
      Intron retention (IR) is the least well-understood alternative splicing type in animals, and its prevalence and function in physiological and pathological processes have long been underestimated. Cellular senescence contributes to individual aging and age-related diseases and can also serve as an important cancer prevention mechanism. Dynamic IR events have been observed in senescence models and aged tissues; however, whether and how IR impacts senescence remain unclear. Through analyzing polyA+ RNA-seq data from human replicative senescence models, we found IR was prevalent and dynamically regulated during senescence and IR changes negatively correlated with expression alteration of corresponding genes. We discovered that knocking down (KD) splicing factor U2AF1, which showed higher binding density to retained introns and decreased expression during senescence, led to senescence-associated phenotypes and global IR changes. Intriguingly, U2AF1-KD-induced IR changes also negatively correlated with gene expression. Furthermore, we demonstrated that U2AF1-mediated IR of specific gene (CPNE1 as an example) contributed to cellular senescence. Decreased expression of U2AF1, higher IR of CPNE1, and reduced expression of CPNE1 were also discovered in dermal fibroblasts with age. We discovered prevalent IR could fine-tune gene expression and contribute to senescence-associated phenotypes, largely extending the biological significance of IR.
    Keywords:  CPNE1; U2AF1; intron retention; senescence; splicing factor
    DOI:  https://doi.org/10.1111/acel.13276
  6. Mech Ageing Dev. 2020 Nov 26. pii: S0047-6374(20)30205-0. [Epub ahead of print] 111409
    Georgakopoulou EA, Valsamidi C, Veroutis D, Havaki S.
      The number of senescent cells in the skin is increasing with age. Numerous studies have attempted to elucidate the role of these cells in normal aging of the skin as well as in age-related skin conditions. In recent years, attempts have also been made to find treatments that aim either to cleanse the skin tissues of senescent cells or to neutralize their effects (referred to as senolytics and senomorphics respectively) and thus prevent the consequences, particularly on the skin's appearance in advanced age. Through this review, we have tried to gather data on the role of senescent cells in the skin, in treatments aimed at removing them, and we are asking a reasonable question as to whether anti-senescence treatments may contribute to the protection against age-related skin pathologies, including skin cancer, such as non-melanoma skin cancer, in addition to their involvement in skin rejuvenation.
    Keywords:  Skin aging; cellular senescence; senolytics
    DOI:  https://doi.org/10.1016/j.mad.2020.111409
  7. Aging Cell. 2020 Dec 03. e13279
    Lee GH, Hoang TH, Jung ES, Jung SJ, Han SK, Chung MJ, Chae SW, Chae HJ.
      Endothelial dysfunction is one of the main age-related arterial phenotypes responsible for cardiovascular disease (CVD) in older adults. This endothelial dysfunction results from decreased bioavailability of nitric oxide (NO) arising downstream of endothelial oxidative stress. In this study, we investigated the protective effect of anthocyanins and the underlying mechanism in rat thoracic aorta and human vascular endothelial cells in aging models. In vitro, cyanidin-3-rutinoside (C-3-R) and cyanidin-3-glucoside (C-3-G) inhibited the d-galactose (d-gal)-induced senescence in human endothelial cells, as indicated by reduced senescence-associated-β-galactosidase activity, p21, and p16INK4a . Anthocyanins blocked d-gal-induced reactive oxygen species (ROS) formation and NADPH oxidase activity. Anthocyanins reversed d-gal-mediated inhibition of endothelial nitric oxide synthase (eNOS) serine phosphorylation and SIRT1 expression, recovering NO level in endothelial cells. Also, SIRT1-mediated eNOS deacetylation was shown to be involved in anthocyanin-enhanced eNOS activity. In vivo, anthocyanin-rich mulberry extract was administered to aging rats for 8 weeks. In vivo, mulberry extract alleviated endothelial senescence and oxidative stress in the aorta of aging rats. Consistently, mulberry extract also raised serum NO levels, increased phosphorylation of eNOS, increased SIRT1 expression, and reduced nitrotyrosine in aortas. The eNOS acetylation was higher in the aging group and was restored by mulberry extract treatment. Similarly, SIRT1 level associated with eNOS decreased in the aging group and was restored in aging plus mulberry group. These findings indicate that anthocyanins protect against endothelial senescence through enhanced NO bioavailability by regulating ROS formation and reducing eNOS uncoupling.
    Keywords:  NO; SIRT1; anthocyanins; eNOS deacetylation; senescence
    DOI:  https://doi.org/10.1111/acel.13279
  8. Pharmacol Ther. 2020 Dec 01. pii: S0163-7258(20)30282-5. [Epub ahead of print] 107751
    Abdelgawad IY, Sadak KT, Lone DW, Dabour MS, Niedernhofer LJ, Zordoky BN.
      Cancer treatment has been associated with accelerated aging that can lead to early-onset health complications typically experienced by older populations. In particular, cancer survivors have an increased risk of developing premature cardiovascular complications. In the last two decades, cellular senescence has been proposed as an important mechanism of premature cardiovascular diseases. Cancer treatments, specifically anthracyclines and radiation, have been shown to induce senescence in different types of cardiovascular cells. Additionally, clinical studies identified increased systemic markers of senescence in cancer survivors. Preclinical research has demonstrated the potential of several approaches to mitigate cancer therapy-induced senescence. However, strategies to prevent and/or treat therapy-induced cardiovascular senescence have not yet been translated to the clinic. In this review, we will discuss how therapy-induced senescence can contribute to cardiovascular complications. Thereafter, we will summarize the current in vitro, in vivo, and clinical evidence regarding cancer therapy-induced cardiovascular senescence. Then, we will discuss interventional strategies that have the potential to protect against therapy-induced cardiovascular senescence. To conclude, we will highlight challenges and future research directions to mitigate therapy-induced cardiovascular senescence in cancer survivors.
    Keywords:  Senescence; cancer therapy; cardio-oncology; cardiotoxicity; cardiovascular diseases; doxorubicin; radiation
    DOI:  https://doi.org/10.1016/j.pharmthera.2020.107751
  9. Nat Neurosci. 2020 Nov 30.
    Jin WN, Shi K, He W, Sun JH, Van Kaer L, Shi FD, Liu Q.
      Normal aging is accompanied by escalating systemic inflammation. Yet the potential impact of immune homeostasis on neurogenesis and cognitive decline during brain aging have not been previously addressed. Here we report that natural killer (NK) cells of the innate immune system reside in the dentate gyrus neurogenic niche of aged brains in humans and mice. In situ expansion of these cells contributes to their abundance, which dramatically exceeds that of other immune subsets. Neuroblasts within the aged dentate gyrus display a senescence-associated secretory phenotype and reinforce NK cell activities and surveillance functions, which result in NK cell elimination of aged neuroblasts. Genetic or antibody-mediated depletion of NK cells leads to sustained improvements in neurogenesis and cognitive function during normal aging. These results demonstrate that NK cell accumulation in the aging brain impairs neurogenesis, which may serve as a therapeutic target to improve cognition in the aged population.
    DOI:  https://doi.org/10.1038/s41593-020-00745-w
  10. Exp Gerontol. 2020 Nov 27. pii: S0531-5565(20)30510-6. [Epub ahead of print] 111162
    Zamboni M, Nori N, Brunelli A, Zoico E.
      Across aging, white adipose tissue (WAT) undergoes significant changes in quantity and distribution, with an increase in visceral adipose tissue, ectopic fat deposition and a decline in gluteofemoral subcutaneous depot. In particular, WAT becomes dysfunctional with an increase in production of inflammatory peptides and a decline of those with anti-inflammatory activity and infiltration of inflammatory cells. Moreover, dysfunction of WAT is characterized by preadipocyte differentiation decline, increased oxidative stress and mitochondrial dysfunction, reduction in vascularization and hypoxia, increased fibrosis and senescent cell accumulation. WAT changes represent an important hallmark of the aging process and may be responsible for the systemic pro-inflammatory state ("inflammageing") typical of aging itself, leading to age-related metabolic alterations. This review focuses on mechanisms linking age-related WAT changes to inflammageing.
    Keywords:  Adipose tissue; Ectopic fat; Inflammageing; Senescent cells; Subcutaneous adipose tissue; Visceral adipose tissue
    DOI:  https://doi.org/10.1016/j.exger.2020.111162
  11. Int J Mol Sci. 2020 Nov 30. pii: E9130. [Epub ahead of print]21(23):
    Isermann A, Mann C, Rübe CE.
      Irreparable double-strand breaks (DSBs) in response to ionizing radiation (IR) trigger prolonged DNA damage response (DDR) and induce premature senescence. Profound chromatin reorganization with formation of senescence-associated heterochromatin foci (SAHF) is an essential epigenetic mechanism for controlling the senescence-associated secretory phenotype (SASP). To decipher molecular mechanisms provoking continuous DDR leading to premature senescence, radiation-induced DSBs (53BP1-foci) and dynamics of histone variant H2A.J incorporation were analyzed together with chromatin re-modeling in human fibroblasts after IR exposure. High-resolution imaging by transmission electron microscopy revealed that persisting 53BP1-foci developed into DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS), consistently located at the periphery of SAHFs. Quantitative immunogold-analysis by electron microscopy revealed that H2A.J, steadily co-localizing with 53BP1, is increasingly incorporated into DNA-SCARS during senescence progression. Strikingly, shRNA-mediated H2A.J depletion in fibroblasts modified senescence-associated chromatin re-structuring and abolished SASP, thereby shutting down the production of inflammatory mediators. These findings provide mechanistic insights into biological phenomena of SASP and suggest that H2A.J inhibition could ablate SASP, without affecting the senescence-associated growth arrest.
    Keywords:  DNA-SCARS; histone variant H2A.J; radiation-induced senescence; senescence-associated heterochromatin foci (SAHF); senescence-associated secretory phenotype (SASP); transmission electron microscopy (TEM)
    DOI:  https://doi.org/10.3390/ijms21239130
  12. Aging Dis. 2020 Dec;11(6): 1640-1653
    Wu Q, Chen X, Li J, Sun S.
      As one of the nonessential amino acids (NEAAs), serine is involved in the anabolism of multiple macromolecular substances by participating in one-carbon unit metabolism. Thus, rapidly proliferating cells such as tumor cells and activated immune cells are highly dependent on serine. Serine supports the proliferation of various immune cells through multiple pathways to enhance the antitumor immune response. Moreover, serine influences aging specificity in an epigenetic and metabolic manner. In this review, we focus on recent advances in the relationship between serine metabolism, antitumor immunity, and senescence. The metabolic regulation of serine seems to be a key point of intervention in antitumor immunity and aging-related disease, providing an opportunity for several novel therapeutics.
    Keywords:  Serine; antitumor immunity and senescence; metabolism
    DOI:  https://doi.org/10.14336/AD.2020.0314
  13. Aging Dis. 2020 Dec;11(6): 1363-1373
    Moskalev A, Stambler I, Caruso C.
      The interrelation of the processes of immunity and senescence now receives an unprecedented emphasis during the COVID-19 pandemic, which brings to the fore the critical need to combat immunosenescence and improve the immune function and resilience of older persons. Here we review the historical origins and the current state of the science of innate and adaptive immunity in aging and longevity. From the modern point of view, innate and adaptive immunity are not only affected by aging but also are important parts of its underlying mechanisms. Excessive levels or activity of antimicrobial peptides, C-reactive protein, complement system, TLR/NF-κB, cGAS/STING/IFN 1,3 and AGEs/RAGE pathways, myeloid cells and NLRP3 inflammasome, declined levels of NK cells in innate immunity, thymus involution and decreased amount of naive T-cells in adaptive immunity, are biomarkers of aging and predisposition factors for cellular senescence and aging-related pathologies. Long-living species, human centenarians, and women are characterized by less inflamm-aging and decelerated immunosenescence. Despite recent progress in understanding, the harmonious theory of immunosenescence is still developing. Geroprotectors targeting these mechanisms are just emerging and are comprehensively discussed in this article.
    Keywords:  adaptive immunity; aging; innate immunity; longevity; resilience
    DOI:  https://doi.org/10.14336/AD.2020.0603
  14. Stem Cells. 2020 Nov 30.
    Jiao H, Walczak BE, Lee MS, Lemieux ME, Li WJ.
      Cellular reprogramming forcing the expression of pluripotency markers can reverse aging of cells but how molecular mechanisms through which reprogrammed cells alter aging-related cellular activities still remain largely unclear. In this study, we reprogrammed human synovial fluid-derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs) using six reprogramming factors and reverted the iPSCs back to MSCs, as an approach to cell rejuvenation. Using the parental and reprogrammed MSCs as control nonrejuvenated and rejuvenated cells, respectively, for comparative analysis, we found that aging-related activities were greatly reduced in reprogrammed MSCs compared with those in their parental lines, indicating reversal of cell aging. Global transcriptome analysis revealed differences in activities of regulatory networks associated with inflammation and proliferation. Mechanistically, we demonstrated that, compared with control cells, the expression of GATA binding protein 6 (GATA6) in reprogrammed cells was attenuated, resulting in an increase in the activity of sonic hedgehog signaling and the expression level of downstream forkhead box P1 (FOXP1), in turn ameliorating cellular hallmarks of aging. Lower levels of GATA6 expression were also found in cells harvested from younger mice or lower passage cultures. Our findings suggest that GATA6 is a critical regulator increased in aged MSCs that controls the downstream sonic hedgehog signaling and FOXP1 pathway to modulate cellular senescence and aging-related activities.
    Keywords:  aging; cell signaling; mesenchymal stem cells; reprogramming; transcription factors
    DOI:  https://doi.org/10.1002/stem.3297
  15. Thorax. 2020 Dec 03. pii: thoraxjnl-2020-215114. [Epub ahead of print]
    Woldhuis RR, Heijink IH, van den Berge M, Timens W, Oliver BGG, de Vries M, Brandsma CA.
      COPD-derived fibroblasts have increased cellular senescence. Senescent cell accumulation can induce tissue dysfunction by their senescence-associated secretory phenotype (SASP). We aimed to determine the SASP of senescent fibroblasts and COPD-derived lung fibroblasts, including severe, early-onset (SEO)-COPD. SASP protein secretion was measured after paraquat-induced senescence in lung fibroblasts using Olink Proteomics and compared between (SEO-)COPD-derived and control-derived fibroblasts. We identified 124 SASP proteins of senescent lung fibroblasts, of which 42 were secreted at higher levels by COPD-derived fibroblasts and 35 by SEO-COPD-derived fibroblasts compared with controls. Interestingly, the (SEO-)COPD-associated SASP included proteins involved in chronic inflammation, which may contribute to (SEO-)COPD pathogenesis.
    Keywords:  COPD mechanisms; COPD pathology
    DOI:  https://doi.org/10.1136/thoraxjnl-2020-215114
  16. Aging Dis. 2020 Dec;11(6): 1471-1480
    Cao M, Ruan L, Huang Y, Wang J, Yan J, Sang Y, Li S, Wang G, Wu X.
      Acquired immune responses mediated by CD4+ T cells contribute to the initiation and progression of acute coronary syndrome (ACS). ACS patients show acquired immune system abnormalities that resemble the characteristics of autoimmune dysfunction described in the elderly. This study aimed to investigate the role of premature CD4+ T cells senescence in ACS and the underlying mechanism. We compared the immunological status of 25 ACS patients, 15 young healthy individuals (C1), and 20 elderly individuals with absence of ACS (C2). The percentages of CD4+ T lymphocyte subsets (including naïve, regulatory, memory and effector T cells) in peripheral blood were analyzed. In ACS patients, a significant expansion of CD4+CD28null effector T cells and a decline of CD4+CD25+CD62L+Treg cells were observed. In addition, patients with ACS showed an accelerated loss of CD4+CD45RA+CD62L+ naïve T cells and a compensatory increase in the number of CD4+CD45RO+ memory T cells. ACS patients demonstrated no significant difference in frequency of T cell receptor excision circles (TRECs) compared to age-matched healthy volunteers. The expression of p16Ink4a was increased while CD62L was decreased in CD4+CD28null T cells of ACS patients. Compared to healthy donors, ACS patients demonstrated the lowest telomerase activity in both CD4+CD28+and CD4+CD28null T cells. The serum levels of C-reactive protein, Cytomegalovirus IgG, Helicobactor pylori IgG and Chlamydia pneumonia IgG were significantly higher in ACS patients. The results suggested that the percentage of CD4+ T cell subpopulations correlated with chronic infection, which contributes to immunosenescence. In conclusion, chronic infection induced senescence of premature CD4+T cells, which may be responsible for the development of ACS.
    Keywords:  CD28null T cells; CD4+ T cells; acute coronary syndrome; immunosenescence; infection
    DOI:  https://doi.org/10.14336/AD.2020.0203
  17. FEBS Open Bio. 2020 Nov 28.
    Cao X, Liu L, Zhang Y, Yang Y.
      Age-associated decline of the immune system is referred to as immunosenescence. The E3 ligase RING finger 10 (RNF10) has long been associated with the innate immune response, but a potential role in immunosenescence has not previously been reported. In the present study, we identified that RNF10 expression is lower in aged mouse macrophages than in young cells. After lipopolysaccharide (LPS) stimulation, RNF10 expression remained at a basal low level in aged mouse cells, but declined sharply in young mouse cells. Knockdown of RNF10 enhanced both the nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways and thus enhanced proinflammatory cytokines and type I interferons (IFN-I) in macrophages, promoting clearance of L. monocytigenes. These findings indicate that dysregulated expression of RNF10 is associated with age-associated immune dysfunction, and RNF10 may thus be a potential target for the treatment of age-related inflammatory diseases.
    Keywords:  E3 ubiquitin ligase; RNF10; immunosenescence; inflammation; macrophages
    DOI:  https://doi.org/10.1002/2211-5463.13049
  18. Reproduction. 2020 Dec 01. pii: REP-20-0489.R1. [Epub ahead of print]
    Foley KG, Pritchard MT, Duncan FE.
      Inflammaging is a state of chronic, low grade inflammation associated with biological aging which contributes to age-related diseases. Recently, an age-associated increase in inflammation has been documented in the mammalian ovary, which is accompanied by a shift in the immune cell profile. In this Point of View article, we consider a unique population of macrophage-derived multinucleated giant cells, found in all reproductively old mouse ovaries, as potential markers or functional drivers of inflammation in ovarian aging.
    DOI:  https://doi.org/10.1530/REP-20-0489
  19. J Nat Prod. 2020 Dec 01.
    Cho HM, Lee YR, Lee BW, Zhang M, Ryu B, Nghiem DT, Pham HT, Oh WK.
      With the advent of senolytic agents capable of selectively removing senescent cells in old tissues, the perception of age-associated diseases has been changing from being an inevitable to a preventable phenomenon of human life. In the search for materials with senolytic activity from natural products, six new flavonostilbenes (1-6), three new phenylethylchromanones (7-9), three new phenylethylchromones (10-12), and four known compounds (13-16) were isolated from the roots of Rhamnoneuron balansae. The chemical structures of these isolated compounds were determined based on the interpretation of spectroscopic data, including 1D and 2D NMR, ECD, and HRMS. The absolute configuration of compound 1 was also determined by a Mosher ester analysis and ECD calculations. Compounds 6-8 were shown to selectively destroy senescent cells, and the promoter activity of p16INK4A, a representative senescence marker, was reduced significantly by compound 6. The present results suggest the potential activity of flavonostilbene and phenylethylchromanone skeletons from R. balansae as new senolytics.
    DOI:  https://doi.org/10.1021/acs.jnatprod.0c00885
  20. Cells. 2020 Nov 25. pii: E2540. [Epub ahead of print]9(12):
    Mittermeier C, Konopa A, Muehlich S.
      Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer-related death and is the most common type of liver cancer. Due to the current paucity of drugs for HCC therapy there is a pressing need to develop new therapeutic concepts. In recent years, the role of Serum Response Factor (SRF) and its coactivators, Myocardin-Related Transcription Factors A and B (MRTF-A and -B), in HCC formation and progression has received considerable attention. Targeting MRTFs results in HCC growth arrest provoked by oncogene-induced senescence. The induction of senescence acts as a tumor-suppressive mechanism and therefore gains consideration for pharmacological interventions in cancer therapy. In this article, we describe the key features and the functional role of senescence in light of the development of novel drug targets for HCC therapy with a focus on MRTFs.
    Keywords:  DLC1; HCC; MRTF; SRF; senescence; senolytics
    DOI:  https://doi.org/10.3390/cells9122540
  21. Antioxidants (Basel). 2020 Nov 27. pii: E1187. [Epub ahead of print]9(12):
    Fernández-Ortiz M, Sayed RKA, Fernández-Martínez J, Cionfrini A, Aranda-Martínez P, Escames G, de Haro T, Acuña-Castroviejo D.
      Aging is a major risk for cardiovascular diseases (CVD). Age-related disorders include oxidative stress, mitochondria dysfunction, and exacerbation of the NF-κB/NLRP3 innate immune response pathways. Some of the molecular mechanisms underlying these processes, however, remain unclear. This study tested the hypothesis that NLRP3 inflammasome plays a role in cardiac aging and melatonin is able to counteract its effects. With the aim of investigating the impact of NLRP3 inflammasome and the actions and target of melatonin in aged myocardium, we analyzed the expression of proteins implied in mitochondria dynamics, autophagy, apoptosis, Nrf2-dependent antioxidant response and mitochondria ultrastructure in heart of wild-type and NLRP3-knockout mice of 3, 12, and 24 months-old, with and without melatonin treatment. Our results showed that the absence of NLRP3 prevented age-related mitochondrial dynamic alterations in cardiac muscle with minimal effects in cardiac autophagy during aging. The deficiency of the inflammasome affected Bax/Bcl2 ratio, but not p53 or caspase 9. The Nrf2-antioxidant pathway was also unaffected by the absence of NLRP3. Furthermore, NLRP3-deficiency prevented the drop in autophagy and mice showed less mitochondrial damage than wild-type animals. Interestingly, melatonin treatment recovered mitochondrial dynamics altered by aging and had few effects on cardiac autophagy. Melatonin supplementation also had an anti-apoptotic action in addition to restoring Nrf2-antioxidant capacity and improving mitochondria ultrastructure altered by aging.
    Keywords:  NLRP3 inflammasome; Nrf2; apoptosis; heart ultrastructure; melatonin; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/antiox9121187
  22. Biomed Pharmacother. 2020 Nov 27. pii: S0753-3322(20)31164-1. [Epub ahead of print]133 110972
    Du H, Xu T, Cui M.
      Recent studies have shown that the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway may play an important role in antitumor immunity. Additionally, the cGAS-STING pathway promotes the senescence of cancer cells, induces apoptosis of cancer cells, and increases the protective effect of cytotoxic T cells and natural killer cell-mediated cytotoxicity. We believe that the combination of the cGAS-STING signaling pathway with other therapeutic methods provides a new perspective from which to overcome obstacles in the application of this review. Further, we highlight the antitumor mechanism of the cGAS-STING signaling pathway and the latest advances in monotherapy and combination therapy with related agonists.
    Keywords:  Antitumor; Cancer immunity; Cancer therapy; cGAS-STING signaling
    DOI:  https://doi.org/10.1016/j.biopha.2020.110972
  23. Nat Commun. 2020 11 30. 11(1): 6129
    Olah M, Menon V, Habib N, Taga MF, Ma Y, Yung CJ, Cimpean M, Khairallah A, Coronas-Samano G, Sankowski R, Grün D, Kroshilina AA, Dionne D, Sarkis RA, Cosgrove GR, Helgager J, Golden JA, Pennell PB, Prinz M, Vonsattel JPG, Teich AF, Schneider JA, Bennett DA, Regev A, Elyaman W, Bradshaw EM, De Jager PL.
      The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.
    DOI:  https://doi.org/10.1038/s41467-020-19737-2
  24. Aging (Albany NY). 2020 Nov 26. 12
    Sciorati C, Gamberale R, Monno A, Citterio L, Lanzani C, De Lorenzo R, Ramirez GA, Esposito A, Manunta P, Manfredi AA, Rovere-Querini P.
      Sarcopenia is a hallmark of aging. Inflammation due to increased generation of cytokines such as TNFα, IL-1β and IL-6 has been implicated in the pathogenesis of sarcopenia. In skeletal muscle of C57BL/6 mice from 12 until 28 months of age, we observed a progressive reduction of myofiber cross sectional area, loss of type II fibers and infiltration by inflammatory cells. Muscle strength decreased in parallel. Pharmacological TNFα blockade by weekly subcutaneous injection of Etanercept from 16 to 28 months of age prevented atrophy and loss of type II fibers, with significant improvements in muscle function and mice lifespan. The effects on leukocyte recruitment were limited. These results provide a proof of principle that endogenous TNFα is sufficient to cause sarcopenia and to reduce animal survival, and open a novel perspective on novel potential pharmacological treatment strategies based on TNFα blockade to prevent the noxious events associated with aging.
    Keywords:  TNF alpha; aging; inflammation; pharmacological intervention; sarcopenia
    DOI:  https://doi.org/10.18632/aging.202200
  25. Elife. 2020 Dec 01. pii: e62048. [Epub ahead of print]9
    Krukowski K, Nolan A, Frias ES, Boone M, Ureta G, Grue K, Paladini MS, Elizarraras E, Delgado L, Bernales S, Walter P, Rosi S.
      With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.
    Keywords:  mouse; neuroscience
    DOI:  https://doi.org/10.7554/eLife.62048
  26. Aging (Albany NY). 2020 Dec 03. 12
    Yusipov I, Bacalini MG, Kalyakulina A, Krivonosov M, Pirazzini C, Gensous N, Ravaioli F, Milazzo M, Giuliani C, Vedunova M, Fiorito G, Gagliardi A, Polidoro S, Garagnani P, Ivanchenko M, Franceschi C.
      The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a meta-analysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the age-associated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.
    Keywords:  meta-analysis; methylation; sex; variability; whole blood
    DOI:  https://doi.org/10.18632/aging.
  27. Nature. 2020 Dec 02.
    Ledford H.
      
    Keywords:  Ageing; Cell biology; Diseases; Epigenetics
    DOI:  https://doi.org/10.1038/d41586-020-03403-0
  28. Mech Ageing Dev. 2020 Nov 26. pii: S0047-6374(20)30206-2. [Epub ahead of print] 111410
    Huidobro C, Martín-Vicente P, López-Martínez C, Alonso-López I, Amado-Rodríguez L, Crespo I, Albaiceta GM.
      A wide range of insults can trigger acute injury in the lungs, which eventually may lead to respiratory failure and death of patients. Current treatment relies mainly on supportive measures and mechanical ventilation. Even so, survivors frequently develop important sequels that compromise quality of life. In the search for new approaches to prevent and treat acute lung injury, many investigations have focused on molecular and cellular pathways which could exert a pathogenic role in this disease. Herein, we review recent findings in the literature suggesting that cellular senescence could be involved in lung injury and discuss the potential use of senotherapies to prevent disease progression.
    Keywords:  acute lung injury; acute respiratory distress syndrome; senescence
    DOI:  https://doi.org/10.1016/j.mad.2020.111410
  29. Nat Commun. 2020 12 03. 11(1): 6182
    Sun X, Liu T, Zhao J, Xia H, Xie J, Guo Y, Zhong L, Li M, Yang Q, Peng C, Rouvet I, Belot A, Shu HB, Feng P, Zhang J.
      Upon sensing cytosolic DNA, the enzyme cGAS induces innate immune responses that underpin anti-microbial defenses and certain autoimmune diseases. Missense mutations of PRKDC encoding the DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs) are associated with autoimmune diseases, yet how DNA-PK deficiency leads to increased immune responses remains poorly understood. In this study, we report that DNA-PK phosphorylates cGAS and suppresses its enzymatic activity. DNA-PK deficiency reduces cGAS phosphorylation and promotes antiviral innate immune responses, thereby potently restricting viral replication. Moreover, cells isolated from DNA-PKcs-deficient mice or patients carrying PRKDC missense mutations exhibit an inflammatory gene expression signature. This study provides a rational explanation for the autoimmunity of patients with missense mutations of PRKDC, and suggests that cGAS-mediated immune signaling is a potential target for therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41467-020-19941-0
  30. Aging Dis. 2020 Dec;11(6): 1585-1593
    Pan YH, Wu WP, Xiong XD.
      Aging is a complex biological process closely linked with the occurrence and development of age-related diseases. Despite recent advances in lifestyle management and drug therapy, the late diagnosis of these diseases causes severe complications, usually resulting in death and consequently impacting social economies. Therefore, the identification of reliable biomarkers and the creation of effective treatment alternatives for age-related diseases are needed. Circular RNAs (circRNAs) are a novel class of RNA molecules that form covalently closed loops capable of regulating gene expression at multiple levels. Several studies have reported the emerging functional roles of circRNAs in various conditions, providing new perspectives regarding cellular physiology and disease pathology. Notably, accumulating evidence demonstrates the involvement of circRNAs in the regulation of age-related pathologies, including cardio-cerebrovascular disease, neurodegenerative disease, cancer, diabetes, rheumatoid arthritis, and osteoporosis. Therefore, the association of circRNAs with these age-related pathologies highlights their potential as diagnostic biomarkers and therapeutic targets for better disease management. Here, we review the biogenesis and function of circRNAs, with a special focus on their regulatory roles in aging-related pathologies, as well as discuss their potential as biological biomarkers and therapeutic targets for these diseases.
    Keywords:  age-related diseases; aging; biomarker; circRNAs
    DOI:  https://doi.org/10.14336/AD.2020.0309