bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒10‒04
thirty papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Aging Cell. 2020 Sep 29. e13249
      A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study, we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS-based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia-reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro-inflammatory, profibrotic, and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-β3, interleukin-11, interleukin-16, and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time-point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.
    Keywords:  cardiac; ischemia-reperfusion; remodeling; senescence; senolytic
  2. Annu Rev Pharmacol Toxicol. 2020 Sep 30.
      Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 7, 2021. Please see for revised estimates.
  3. J Biochem. 2020 Oct 01. pii: mvaa109. [Epub ahead of print]
      Cellular senescence is an important tumor suppression mechanism that inhibits the proliferation of damaged cells. In senescent cells, irreparable DNA damage causes accumulation of genomic DNA fragments in the cytoplasm, which are recognized by the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, resulting in secretion of numerous inflammatory proteins. This phenomenon is called senescence-associated secretory phenotype (SASP), and results in multiple physiological or pathological processes in the body. In addition, DNA damage also increases small extracellular vesicle (EV) release from senescent cells. This review presents recent insights into the molecular mechanisms and biological functions of senescence-associated extracellular vesicle (SA-EV) release that is associated with age-related diseases, particularly cancer.
    Keywords:  Cellular senescence; DNA damage; cGAS-STING; extracellular vesicle; senescence-associated secretory phenotype
  4. PLoS One. 2020 ;15(9): e0239976
      Cellular senescence is associated with inflammation and the senescence-associated secretory phenotype (SASP) of secreted proteins. Vascular smooth muscle cell (VSMC) expressing the SASP contributes to chronic vascular inflammation, loss of vascular function, and the developments of age-related diseases. Although VSMC senescence is well recognized, the mechanism of VSMC senescence and inflammation has not been established. In this study, we aimed to determine whether prednisolone (PD) attenuates adriamycin (ADR)-induced VSMC senescence and inflammation through the SIRT1-AMPK signaling pathway. We found that PD inhibited ADR-induced VSMC senescence and inflammation response by decreasing p-NF-κB expression through the SIRT1-AMPK signaling pathway. In addition, Western blotting revealed PD not only increased SIRT1 expression but also increased the phosphorylation of AMPK at Ser485 in ADR-treated VSMC. Furthermore, siRNA-mediated downregulation or pharmacological inhibitions of SIRT1 or AMPK significantly augmented ADR-induced inflammatory response and senescence in VSMC despite PD treatment. In contrast, the overexpression of SIRT1 or constitutively active AMPKα (CA-AMPKα) attenuated cellular senescence and p-NF-κB expression. Taken together, the inhibition of p-NF-κB by PD through the SIRT1 and p-AMPK (Ser485) pathway suppressed VSMC senescence and inflammation. Collectively, our results suggest that anti-aging effects of PD are caused by reduced VSMC senescence and inflammation due to reciprocal regulation of the SIRT1/p-AMPK (Ser485) signaling pathway.
  5. Aging Cell. 2020 Sep 29. e13248
      Alterations in metabolism in skin are accelerated by environmental stressors such as solar radiation, leading to premature aging. The impact of aging on mitochondria is of interest given their critical role for metabolic output and the finding that environmental stressors cause lowered energy output, particularly in fibroblasts where damage accumulates. To better understand these metabolic changes with aging, we performed an in-depth profiling of the expression patterns of dermal genes in face, forearm, and buttock biopsies from females of 20-70 years of age that encode for all subunits comprising complexes I-V of the mitochondrial electron transport chain. This complements previous preliminary analyses of these changes. "Oxidative phosphorylation" was the top canonical pathway associated with aging in the face, and genes encoding for numerous subunits had decreased expression patterns with age. Investigations on fibroblasts from older aged donors also showed decreased gene expression of numerous subunits from complexes I-V, oxidative phosphorylation rates, spare respiratory capacity, and mitochondrial number and membrane potential compared to younger cells. Treatment of older fibroblasts with nicotinamide (Nam) restored these measures to younger cell levels. Nam increased complexes I, IV, and V activity and gene expression of representative subunits. Elevated mt-Keima staining suggests a possible mechanism of action for these restorative effects via mitophagy. Nam also improved mitochondrial number and membrane potential in younger fibroblasts. These findings show there are significant changes in mitochondrial functionality with aging and that Nam treatment can restore bioenergetic efficiency and capacity in older fibroblasts with an amplifying effect in younger cells.
  6. Int J Mol Med. 2020 Nov;46(5): 1603-1610
      Cell senescence is caused by the activation of cell cycle inhibition pathways induced by an accumulation of cellular damage, where cells permanently leave the cell cycle. Senescent cells undergo changes in cell morphology, transcription, protein homeostasis, metabolism and other characteristic alterations. At the same time, senescent cells are able to resist apoptosis and accumulate in multiple organs and tissues in vivo. Senescent cells are capable of activating inflammatory factor secretion pathways, generating local, non‑infectious inflammatory microenvironments within tissues, leading to organ degeneration and the development of aging‑associated diseases. A large number of recently published studies have demonstrated that removing senescent cells from the body delays the occurrence of various aging‑associated diseases. Therefore, the targeted killing of senescent cells potentially has important clinical applications in the treatment of various aging‑associated diseases, aiming to improve the life span of patients. The present review summarizes recent progress that has been made in the field of senescent cell clearance and various anti‑aging strategies. The history of cell senescence research is briefly reviewed, along with the association between cell senescence and tumor therapy. Furthermore, the potential of senescent cells to be used as therapeutic targets in various senescence‑associated diseases is primarily discussed, and the limitations, as well as the future prospects of this line of research, are reviewed.
  7. Aging (Albany NY). 2020 Sep 29. 12
      Treatment of glioblastoma using radiotherapy and chemotherapy has various outcomes, key among them being cellular senescence. However, the molecular mechanisms of this process remain unclear. In the present study, we tested the ability of D-galactose (D-gal), a reducing sugar, to induce senescence in glioblastoma cells. Following pretreatment with D-gal, glioblastoma cell lines (C6 and U87MG) showed typical characteristics of senescence. These included the reduced cell proliferation, hypertrophic morphology, increased senescence-associated β-galactosidase activity, downregulation of Lamin B1, and upregulation of several senescence-associated genes such as p16, p53, and NF-κB. Furthermore, our results showed that D-gal was more suitable than etoposide (a DNA-damage drug) in inducing senescence of glioblastoma cells. Mechanistically, D-gal inactivated the YAP-CDK6 signaling pathway, while overexpression of YAP or CDK6 could restore D-gal-induced senescence of C6 cells. Finally, metformin, an anti-aging agent, activated the YAP-CDK6 pathway and suppressed D-gal-induced senescence of C6 cells. Taken together, these findings established a new model for analyzing senescence in glioblastoma cells, which occurred through the YAP-CDK6 pathway. This is expected to provide a basis for development of novel therapies for the treatment of glioblastoma.
    Keywords:  CDK6; D-galatose; YAP; cellular senescence; glioblastoma
  8. Cytokine. 2020 Sep 28. pii: S1043-4666(20)30330-6. [Epub ahead of print]137 155314
      Senescent thymic stromal cells (TSCs) producing senescence-associated secretory phenotype (SASP) may play a role at later phases of thymic involution. However, the etiology and mechanisms responsible for TSC senescence remain to be elucidated. In the present study, the effects of oxidative stress on TSCs and role of miRNA-146a-5p in stress-induced premature senescence (SIPS) were identified. D-galactose (D-gal) induced oxidative stress in primary TSCs and a limited cumulative oxidative stress induced premature senescence but not apoptosis of TSCs. miRNA-146a-5p overexpression can mitigate the SIPS by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6) instead of increasing autophagy clearance. Furthermore, exogenous miRNA-146a-5p reversed the upregulation of chemokines including Cxcl5, pro-inflammatory cytokines, and antimicrobial peptides in TSCs with SIPS. In conclusion, the accumulated oxidative stress may be partially responsible for senescence in TSCs and modulation of miRNA-146a-5p may attenuate this process.
    Keywords:  D-galactose; Oxidative stress; Premature senescence; TSCs; miRNA-146a-5p
  9. Antioxidants (Basel). 2020 Sep 29. pii: E932. [Epub ahead of print]9(10):
      Recently, nutritional interventions have received attention as promising approaches to promote human health during a lifespan. The Mediterranean and Okinawan diets have been associated with longevity and decreasing risk for age-related diseases in contrast to the Western diet. The effect might be due to several antioxidative bioactive compounds highly consumed in both diets, namely, resveratrol, hydroxytyrosol, oleuropein, curcumin, and spermidine. This review aims to address the underlying mechanisms of these compounds to enhance mental fitness throughout life with a focus on brain mitophagy. Mitophagy is the autophagic clearance of dysfunctional, redundant, and aged mitochondria. In aging and neurodegenerative disorders, mitophagy is crucial to preserve the autophagy mechanism of the whole cell, especially during oxidative stress. Growing evidence indicates that curcumin, astaxanthin, resveratrol, hydroxytyrosol, oleuropein, and spermidine might exert protective functions via antioxidative properties and as well the enhanced induction of mitophagy mediators. The compounds seem to upregulate mitophagy and thereby alleviate the clearance of dysfunctional and aged mitochondria as well as mitogenesis. Thus, the Mediterranean or Okinawan diet could represent a feasible nutritional approach to reduce the risk of developing age-related cognitive impairment and corresponding disorders via the stimulation of mitophagy and thereby ensure a balanced redox state of brain cells.
    Keywords:  antioxidants; astaxanthin; brain aging; curcumin; diet; hydroxytyrosol; mitophagy; oleuropein; resveratrol; spermidine
  10. Am J Respir Crit Care Med. 2020 Sep 29.
      RATIONALE: Idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Accelerated aging, loss of epithelial progenitor cell function and/or numbers and cellular senescence are implicated in the pathogenies of IPF.OBJECTIVES: We sought to investigate the role of alveolar type 2 (AT2) cells cellular senescence in initiation and/or progression of pulmonary fibrosis and therapeutic potential of targeting senescence related pathways and senescent cells.
    METHODS: Epithelial cells of 9 control donor proximal and distal lung tissues and 11 IPF fibrotic lung tissues were profiled by single cell RNAseq to assesses the contribution of epithelial cells to the senescent cell fraction for IPF. A novel mouse model of conditional AT2 cell senescence was generated to study role of cellular senescence in pulmonary fibrosis.
    MEASUREMENTS AND MAIN RESULTS: We show that alveolar type 2 (AT2) cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation or senescence block fibrogenesis.
    CONCLUSIONS: Senescence of AT2 cells is sufficient to drive progressive pulmonary fibrosis. Early attenuation of senescence-related pathways and elimination of senescent cells are promising therapeutic approachs to prevent pulmonary fibrosis.
    Keywords:  Cellular Senescence; IPF; Sin3a; alveolar type 2 cell
  11. Exp Dermatol. 2020 Oct 03.
      Recently, increasing attention has been paid to senescence-associated secretory phenotype (SASP), a phenomenon that senescent cells secrete molecules such as inflammatory cytokines and matrix metalloproteinases (MMPs), due to its noxious effects on the surrounding tissue. Senescent cells in the blood and liver are known to be properly depleted by macrophages. In the dermis, accumulation of senescent cells has been reported and is thought to be involved with skin aging. In this study, to elucidate the clearance mechanism of senescent cells in the dermis, we focused on macrophage functions. Our co-culture experiments of senescent fibroblasts and macrophages revealed a two-step clearance mechanism; first, TNF-α secreted from macrophages induces apoptosis in senescent fibroblasts, and then dead cells are phagocytosed by macrophages. Furthermore, it was suggested that SASP factors suppress both of the two steps of the senescent cell clearance by macrophages. From these findings, normally senescent cells in the dermis are thought to be removed by macrophages, but when senescent cells are excessively accumulated owing to oxidative stress, ultraviolet (UV) ray or other reasons, SASP was suggested to suppress the macrophage-dependent clearance functions and thereby cause further accumulation of senescent cells.
    Keywords:  SASP; apoptosis; homeostasis; phagocytosis; skin
  12. Biochim Biophys Acta Mol Basis Dis. 2020 Sep 28. pii: S0925-4439(20)30331-8. [Epub ahead of print] 165983
      Senescent cells accumulate in numerous tissues in several chronic conditions such as aging, obesity, and diabetes. These cells are in a state of irreversible cell-cycle arrest and secrete inflammatory cytokines, chemokines and other immune modulators that have paracrine effects on nearby tissues. Adipose tissue, in particular, harbors senescent cells, which have been linked with numerous chronic conditions and age-related comorbidities. Here we performed a series of in vitro experiments to determine the influence of senescent preadipocytes on key cell types found in vessel walls, including vascular smooth muscle cells (VSMCs), endothelial cells (ECs), macrophages (MQs), and adipose-derived stromal/stem cells (ASCs). Primary human preadipocytes were irradiated to trigger a senescence-like phenotype. VSMCs, ECs, MQs, and ASCs were exposed to conditioned media collected from irradiated preadipocytes or control preadipocytes. Additional experiments were performed where VSMCs, ECs, MQs, and ASCs were co-cultured with irradiated or control preadipocytes. The secretome of irradiated cells induced an inflammatory phenotype, decreased cell viability, disrupted proliferation and migration, and impaired metabolic function of these cell types in vitro. These maladaptive changes in response to senescent cell exposure provide early evidence in support of a hypothesis that senescent preadipocytes trigger phenotypic and functional changes in key cellular components of blood vessels that may contribute to vascular disease.
    Keywords:  Senescence; endothelial cells; inflammation; macrophages; smooth muscle; stem cells
  13. Mech Ageing Dev. 2020 Sep 26. pii: S0047-6374(20)30162-7. [Epub ahead of print] 111366
      Remyelination is a physiological response to demyelinating events aiming to restore saltatory conduction and preserve axonal integrity. Resident oligodendrocyte precursor cells (OPC) of the CNS tissue under appropriate conditions are mobilized to proliferate, migrate, and differentiate, in order to produce new myelin sheaths in the demyelinated lesion. In multiple sclerosis (MS), the most common immune-mediated demyelinating disease, remyelination efficiency declines with increasing age and disease duration. As myelin regeneration attempts in clinical trials so far are scarce, and have been met with limited success, the need to explore new remyelinating strategies is more compelling. Recently, ageing and cellular senescence have been implicated to the pathophysiology of a number of neurodegenerative diseases, including multiple sclerosis. Evidence on OPC senescence brings forward the possibility of exploiting cellular senescence as a possible target for promoting the endogenous remyelinating capacity of the CNS. Here we discuss the data indicating how cellular senescence affects remyelination, and the putative benefits to be drawn through the use of senolytic or senomorphic therapies targeting senescent cell populations in MS.
    Keywords:  cellular senescence; multiple sclerosis; oligodendrocyte; oligodendrocyte progenitor; remyelination
  14. Aging (Albany NY). 2020 Sep 29. 12
      Cellular senescence is considered a stress response imposing a stable cell cycle arrest to restrict the growth of damaged cells. More recently however, cellular senescence was identified during mouse embryo development at particular structures during specific periods of time. This programmed cell senescence has been proposed to serve developmental and morphogenetic functions and to potentially represent an evolutionary origin of senescence. Cellular senescence has also been described to take place during bird (chick and quail) and amphibian (xenopus and axoltl) development. Fish however, have been described to show a very narrow and restricted pattern of developmental cell senescence. Here we carried out a detailed characterization of senescence during zebrafish development and found it to be conserved and widespread. Apart from yolk and cloaca, previously described structures, we also identified senescence in the developing central nervous system, intestine, liver, pronephric ducts, and crystalline. Interestingly, senescence at these developing structures disappeared upon treatment with senolytic compound ABT-263, supporting their senescent identity and opening the possibility of studying the contribution of this process to development. In summary, our findings extend the description of developmentally-programmed cell senescence to lower vertebrates contributing to the notion of the relevance of this process for embryo development.
    Keywords:  cellular senescence; development; zebrafish
  15. Mol Oncol. 2020 Sep 27.
      Senescence refers to a cellular state featuring a stable cell-cycle arrest triggered in response to stress. This response also involves other distinct morphological and intracellular changes including alterations in gene expression and epigenetic modifications, elevated macromolecular damage, metabolism deregulation, and a complex proinflammatory secretory phenotype. The initial demonstration of oncogene-induced senescence in vitro established senescence as an important tumour suppressive mechanism, in addition to apoptosis. Senescence not only halts the proliferation of premalignant cells but also facilitates the clearance of affected cells through immunosurveillance. Failure to clear senescent cells owing to deficient immunosurveillance may, however, lead to a state of chronic inflammation that nurtures a pro-tumorigenic microenvironment favouring cancer initiation, migration, and metastasis. In addition, senescence is a response to post-therapy genotoxic stress. Therefore, tracking the emergence of senescent cells becomes pivotal to detect potential pro-tumorigenic events. Current protocols for the in vivo detection of senescence require the analysis of fixed or deep-frozen tissues, despite a significant clinical need for real-time bioimaging methods. Accuracy and efficiency of senescence detection is further hampered by a lack of universal and more specific senescence biomarkers. Recently, in an attempt to overcome these hurdles, an assortment of detection tools have been developed. These strategies all have significant potential for clinical utilization, and include flow cytometry combined with histo- or cytochemical approaches, nanoparticle-based targeted delivery of imaging contrast agents, OFF-ON fluorescent senoprobes, positron emission tomography (PET) senoprobes, and analysis of circulating SASP factors, extracellular vesicles, and cell-free nucleic acids isolated from plasma. Here we highlight the occurrence of senescence in neoplasia and advanced tumours, assess the impact of senescence on tumorigenesis, and discuss how the ongoing development of senescence detection tools might improve early detection of multiple cancers and response to therapy in the near future.
    Keywords:  Cellular senescence; cancer; detection; senoprobes; tumour microenvironment
  16. Aging (Albany NY). 2020 Sep 29. 12
      Pneumonia outbreak in the city of Wuhan, China, prompted the finding of a novel strain of severe acute respiratory syndrome virus (SARS-CoV-2). Here, we discuss potential long-term consequences of SARS-CoV-2 infection, and its possibility to cause permanent damage to the immune system and the central nervous system. Advanced chronological age is one of the main risk factors for the adverse outcomes of COVID-19, presumably due to immunosenescence and chronic low-grade inflammation, both characteristic of the elderly. The combination of viral infection and chronic inflammation in advanced chronological age might cause multiple detrimental unforeseen consequences for the predisposition and severity of neurodegenerative diseases and needs to be considered so that we can be prepared to deal with future outcomes of the ongoing pandemic.
    Keywords:  COVID-19; SARS-CoV-2; aging; immunosenescence; inflammaging; neuroinflammation
  17. Aging (Albany NY). 2020 Oct 01. 12
      The liver gradually loses its regenerative capabilities with aging. However, it remains unknown whether aging affects drug-induced liver injury. Here, we used acetaminophen induced acute liver injury model to compare tissue injury and regeneration of aged mice (>80 weeks old) with young ones (8-10 weeks old). The mortality of aged mice after acetaminophen injury was higher than that of young mice. Transient increase of serum GOT and decrease of reduced glutathione (GSH) were not returned to original levels in aged mice even at 48 hours. In addition, Foxm1b and its targets Ccnd1 and Cdk1 were upregulated in young but not in aged mice after 48 hours. Moreover, an apoptosis-related gene, Cidea, was upregulated specifically in aged livers, which was consistent with increased number of TUNEL+ hepatocytes. Unexpectedly, damaged hepatocytes were retained in aged liver tissue, which may be caused by impaired recruitment of macrophages to the damaged area, without increases in Ccl2 after acetaminophen injury. Collectively, prolonged oxidative stress due to delayed recovery of GSH and the retention of damaged hepatocytes may suppress tissue repair and hepatocyte proliferation, resulting in exacerbation of acetaminophen injury in aged mice. Thus, aging is a risk factor conferring susceptibility against drug-induced liver injury.
    Keywords:  acetaminophen; aging; drug-induced liver injury; necrosis; oxidative stress
  18. Front Immunol. 2020 ;11 2060
      Obesity, similar to aging, is associated with chronic low-grade systemic inflammation, known as inflammaging, and represents a significantly higher risk for developing chronic diseases typical of old age. Immune cells are recruited to the obese adipose tissue (AT) by chemotactic molecules secreted by non-immune and immune cells in the AT, both contributing to the release of several pro-inflammatory mediators that fuel local and systemic inflammation, to the refractory response of immune cells to further in vivo and in vitro stimulation and to the induction of autoimmune B cells with potentially pathogenic repertoires. In terms of molecular mechanisms involved, leptin, an adipokine secreted primarily by adipocytes, has been proposed to be involved in the reduced generation of protective antibodies, and in the increased generation of autoimmune antibodies, further supporting the concept that obesity accelerates age defects. Leptin has also been shown to induce intrinsic B cell inflammation and B cell immunosenescence. The results presented in this review highlight the importance of weight reduction programs to improve immunity and reduce the risk for developing chronic diseases in obese and older individuals.
    Keywords:  B cells; aging; antibody responses; inflammation; obesity
  19. Transl Med Aging. 2020 ;4 73-75
    Keywords:  Aging; Chromatin; Epigenetics; Histone; Senescence
  20. Int J Mol Sci. 2020 Sep 28. pii: E7174. [Epub ahead of print]21(19):
      With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; autophagy; melatonin; neurodegenerative diseases; organophosphate-induced delayed neuropathy
  21. Aging (Albany NY). 2020 Sep 29. 12
      DNA methylation (DNAm) age estimators are widely used to study aging-related conditions. It is not yet known whether DNAm age is associated with the accumulation of stochastic epigenetic mutations (SEMs), which reflect dysfunctions of the epigenetic maintenance system. Here, we defined epigenetic mutation load (EML) as the total number of SEMs per individual. We assessed associations between EML and DNAm age acceleration estimators using biweight midcorrelations in four population-based studies (total n = 6,388). EML was not only positively associated with chronological age (meta r = 0.171), but also with four measures of epigenetic age acceleration: the Horvath pan tissue clock, intrinsic epigenetic age acceleration, the Hannum clock, and the GrimAge clock (meta-analysis correlation ranging from r = 0.109 to 0.179). We further conducted pathway enrichment analyses for each participant's SEMs. The enrichment result demonstrated the stochasticity of epigenetic mutations, meanwhile implicated several pathways: signaling, neurogenesis, neurotransmitter, glucocorticoid, and circadian rhythm pathways may contribute to faster DNAm age acceleration. Finally, investigating genomic-region specific EML, we found that EMLs located within regions of transcriptional repression (TSS1500, TSS200, and 1stExon) were associated with faster age acceleration. Overall, our findings suggest a role for the accumulation of epigenetic mutations in the aging process.
    Keywords:  DNA methylation; aging; epigenetic clock; epigenetic mutation load; stochastic epigenetic mutation
  22. Cancers (Basel). 2020 Sep 30. pii: E2828. [Epub ahead of print]12(10):
      The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8+ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence.
    Keywords:  CD8+ T cells; immunotherapy; metabolism; senescence
  23. Aging Cell. 2020 Oct 01. e13230
      COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is known to preferentially target older subjects and those with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in all countries tested, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to antiviral approaches, by approaches that target the aging process.
    Keywords:  COVID-19; age-related diseases; gene expression; lifespan; pneumonia; viral infection
  24. Mol Cell Biochem. 2020 Oct 01.
      Telomeres are protective structures that are shortened during the lifetime, resulting in aging and degenerative diseases. Subjects experiencing aging and degenerative disorders present smaller telomeres than young and healthy ones. The size of these structures can be stabilized by telomerase, an enzyme which is inactive in adult tissues but functional in fetal and newborn tissues and adult testes and ovaries. The aim of this study was to perform a systematic review to evaluate the effect of telomerase activation in the treatment of degenerative and aging disorders. We accomplished the search using the Pubmed interface for papers published from September 1985 to April 16th, 2020. We found twenty one studies that matched our eligibility criteria. I concluded that telomerase is probably a potential and safe treatment for aging and degenerative diseases, demonstrating neither side effects nor risk of cancer in the selected studies. Further studies in humans are needed to confirm safety and efficiency of this treatment.
    Keywords:  Aging; Biological therapy; Enzyme activation; Systematic review; Telomerase; Telomere
  25. Transl Med Aging. 2020 ;4 96-98
      Circulating factors are well known to influence aging and age-related disease. As part of the Aging Science Talks: Science for the Community series, data was presented on two types of circulating functional biomarkers: extracellular RNA (exRNA) and extracellular vesicles (EVs). EVs in the context of type 2 diabetes mellitus was also discussed, as this is an area of interest due to the growing global epidemic of this age-related disease.
    Keywords:  Biomarker; EV; Exosome; Microparticle; Microvesicle; Type 2 diabetes mellitus; exRNA; microRNA
  26. Semin Immunopathol. 2020 Sep 30.
      During the course of evolution, bacteria have developed an intimate relationship with humans colonizing specific body sites at the interface with the body exterior and invaginations such as nose, mouth, lung, gut, vagina, genito-urinary tract, and skin and thus constituting an integrated meta-organism. The final result has been a mutual adaptation and functional integration which confers significant advantages to humans and bacteria. The immune system of the host co-evolved with the microbiota to develop complex mechanisms to recognize and destroy invading microbes, while preserving its own bacteria. Composition and diversity of the microbiota change according to development and aging and contribute to humans' health and fitness by modulating the immune system response and inflammaging and vice versa. In the last decades, we experienced an explosion of studies on the role of gut microbiota in aging, age-related diseases, and longevity; however, less reports are present on the role of the microbiota at different body sites. In this review, we describe the key steps of the co-evolution between Homo sapiens and microbiome and how this adaptation can impact on immunosenescence and inflammaging. We briefly summarized the role of gut microbiota in aging and longevity while bringing out the involvement of the other microbiota.
    Keywords:  Aging; Evolution; Immunosenescence; Inflammaging; Microbiota
  27. Cell Biol Int. 2020 Sep 29.
      Imbalance of sexual steroids milieu and oxidative stress are often observed during aging and correlated to prostate disorders. Likewise, high-fat intake has been related to prostate damage and tumor development. Melatonin (MLT) is an antioxidant whose secretion decreases in elderly and is also suggested to protect the gland. This study evaluated the impact of a long-term high-fat diet during aging on prostate morphology and antioxidant system of rats and tested the effects of MLT supplementation under these conditions. Male rats were assigned into four groups: control, treated with MLT, high-fat diet and high-fat diet treated with MLT. The high-fat diet was provided from the 24th week of age, MLT from the 48th (100μg/kg/day) and rats were euthanized at the 62th week. The high-fat diet increased body weight, retroperitoneal fatness, glycaemia and circulating estrogen levels. It aggravated the aging effects, leading to epithelial atrophy (~32% reduction of epithelial height) and collagen fibers increase (83%). MLT alone did not alter biometric and physiological parameters, except for the prostate weight decrease, whereas it alleviated biometric as well as ameliorated acinar atrophy induced by high-lipid intake. Systemic oxidative stress increased, and prostatic GPx activity decreased 5-fold with the high-fat diet despite of the indole. Regardless of the diet, MLT triggered epithelial desquamation, reduced AR-positive cells, increased smooth muscle layer thickness (12%), decreased at least 50% corpora amylacea formation and stimulated prostatic GST activity. In conclusion, MLT partially recovered prostate damage induced by aging and the long-term high-fat diet and ameliorated degenerative prostate alterations. This article is protected by copyright. All rights reserved.
    Keywords:  GST; aging; high-fat; melatonin; oxidative stress; prostate
  28. Nat Cell Biol. 2020 Oct;22(10): 1159-1161
  29. Nat Cell Biol. 2020 Oct;22(10): 1170-1179
      SIRT1 (Sir2) is an NAD+-dependent deacetylase that plays critical roles in a broad range of biological events, including metabolism, the immune response and ageing1-5. Although there is strong interest in stimulating SIRT1 catalytic activity, the homeostasis of SIRT1 at the protein level is poorly understood. Here we report that macroautophagy (hereafter referred to as autophagy), a catabolic membrane trafficking pathway that degrades cellular components through autophagosomes and lysosomes, mediates the downregulation of mammalian SIRT1 protein during senescence and in vivo ageing. In senescence, nuclear SIRT1 is recognized as an autophagy substrate and is subjected to cytoplasmic autophagosome-lysosome degradation, via the autophagy protein LC3. Importantly, the autophagy-lysosome pathway contributes to the loss of SIRT1 during ageing of several tissues related to the immune and haematopoietic system in mice, including the spleen, thymus, and haematopoietic stem and progenitor cells, as well as in CD8+CD28- T cells from aged human donors. Our study reveals a mechanism in the regulation of the protein homeostasis of SIRT1 and suggests a potential strategy to stabilize SIRT1 to promote productive ageing.
  30. Nat Genet. 2020 Oct;52(10): 1024-1035
      Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.