bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒01‒17
thirty-two papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Science. 2021 01 15. 371(6526): 265-270
      Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (GLS1) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.
  2. Aging Cell. 2021 Jan 15. e13291
      The fecundity reduction with aging is referred as the reproductive aging which comes earlier than that of chronological aging. Since humans have postponed their childbearing age, to prolong the reproductive age becomes urgent agenda for reproductive biologists. In the current study, we examined the potential associations of α-ketoglutarate (α-KG) and reproductive aging in mammals including mice, swine, and humans. There is a clear tendency of reduced α-KG level with aging in the follicle fluids of human. To explore the mechanisms, mice were selected as the convenient animal model. It is observed that a long term of α-KG administration preserves the ovarian function, the quality and quantity of oocytes as well as the telomere maintaining system in mice. α-KG suppresses ATP synthase and alterations of the energy metabolism trigger the nutritional sensors to down-regulate mTOR pathway. These events not only benefit the general aging process but also maintain ovarian function and delay the reproductive decline. Considering the safety of the α-KG as a naturally occurring molecule in energy metabolism, its utility in reproduction of large mammals including humans deserves further investigation.
    Keywords:  mTOR; ovarian aging; reproduction; telomere; α-KG
  3. Nat Commun. 2021 01 11. 12(1): 257
      Advances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.
  4. J Immunol. 2021 Jan 13. pii: ji2001022. [Epub ahead of print]
      Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1-/- mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD+, this leading to increased hepatic NAD+ and elevated activity of the NAD+-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease.
  5. Mech Ageing Dev. 2021 Jan 07. pii: S0047-6374(21)00004-X. [Epub ahead of print] 111432
      Cellular senescence is a state of stable and irreversible cell cycle arrest with active metabolism, that normal cells undergo after a finite number of divisions (Hayflick limit). Senescence can be triggered by intrinsic and/or extrinsic stimuli including telomere shortening at the end of a cell's lifespan (telomere-initiated senescence) and in response to oxidative, genotoxic or oncogenic stresses (stress-induced premature senescence). Several effector mechanisms have been proposed to explain senescence programmes in diploid cells, including the induction of DNA damage responses, a senescence-associated secretory phenotype and epigenetic changes. Senescent cells display senescence-associated-β-galactosidase activity and undergo chromatin remodeling resulting in heterochromatinisation. Senescence is established by the pRb and p53 tumour suppressor networks. Senescence has been detected in in vitro cellular settings and in premalignant, but not malignant lesions in mice and humans expressing mutant oncogenes. Despite oncogene-induced senescence, which is believed to be a cancer initiating barrier and other tumour suppressive mechanisms, benign cancers may still develop into malignancies by bypassing senescence. Here, we summarise the functional genetic screens that have identified genes, uncovered pathways and characterised mechanisms involved in senescence evasion. These include cell cycle regulators and tumour suppressor pathways, DNA damage response pathways, epigenetic regulators, SASP components and noncoding RNAs.
    Keywords:  Cell cycle regulators and Tumour suppressors; Chromatin modifiers; Noncoding RNAs; Oncogenic signalling; Transcription factors and SASP
  6. Exp Cell Res. 2021 Jan 09. pii: S0014-4827(21)00005-7. [Epub ahead of print] 112474
      The aging proteostasis decline manifests in a failure of aging cells and organisms to properly respond to proteotoxic challenges. This proteostasis collapse has long been considered a hallmark of aging in nematodes, and has recently been shown to occur also in human cells upon entry to senescence, opening the way to exploring the phenomenon in the broader context of human aging. Cellular senescence is part of the normal human physiology of aging, with senescent cell accumulation as a prominent feature of aged tissues. Being highly resistant to cell death, senescent cells, as they accumulate, become pro-inflammatory and promote disease. Here we discuss the causes of human senescence proteostasis decline, in view of the current literature on nematodes, on the one hand, and senescence, on the other hand. We review two major aspects of the phenomenon: (1) the decline in transcriptional activation of stress-response pathways, and (2) impairments in proteasome function. We further outline potential underlying mechanisms of transcriptional proteostasis decline, focusing on reduced chromatin dynamics and compromised nuclear integrity. Finally, we discuss potential strategies for reinforcing proteostasis as a means to improve organismal health and address the relationship to senolytics.
    Keywords:  ATF6; HSF1; HSR; Protein homeostasis; UPR; aging; heat shock response; proteostasis; senescence
  7. Ageing Res Rev. 2021 Jan 09. pii: S1568-1637(21)00003-9. [Epub ahead of print] 101256
      Population aging is one of the most significant social changes of the twenty-first century. This increase in longevity is associated with a higher prevalence of chronic diseases, further rising healthcare costs. At the molecular level, cellular senescence has been identified as a major process in age-associated diseases, as accumulation of senescent cells with aging leads to progressive organ dysfunction. Of particular importance, mitochondrial oxidative stress and consequent organelle alterations have been pointed out as key players in the aging process, by both inducing and maintaining cellular senescence. Monoamine oxidases (MAOs), a class of enzymes that catalyze the degradation of catecholamines and biogenic amines, have been increasingly recognized as major producers of mitochondrial ROS. Although well-known in the brain, evidence showing that MAOs are also expressed in a variety of peripheral organs stimulated a growing interest in the extra-cerebral roles of these enzymes. Besides, the fact that MAO-A and/or MAO-B are frequently upregulated in aged or dysfunctional organs has uncovered new perspectives on their roles in pathological aging. In this review, we will give an overview of the major results on the regulation and function of MAOs in aging and age-related diseases, paying a special attention to the mechanisms linked to the increased degradation of MAO substrates or related to MAO-dependent ROS formation.
    Keywords:  ROS; age-associated chronic diseases; autophagy; mitochondria; monoamine oxidases; senescence
  8. Cell Immunol. 2020 Dec 31. pii: S0008-8749(20)30438-X. [Epub ahead of print]361 104278
      Organs and tissues contain a large number of tissue-resident macrophages (MΦ-Ts), which are essential for regulating homeostasis and ensuring a rapid response to injury. However, the environmental signals shaping MΦ-Ts phenotypes and the contribution of MΦ-Ts to pathological processes are just starting to be identified. MΦ-Ts isolated from aged animals or patients show alterations in morphology and distribution, defects in phagocytosis and autophagy, and loss of tissue-repair capacity. These variations are closely associated with age-associated disorders, such as inflammaging, which is characterized by cell senescence and a senescence-associated secretory phenotype (SASP) and is frequently observed in patients afflicted with chronic diseases. It seems that the role of these resident populations cannot be avoided in the treatment of aging-related diseases. This review will describe the mechanism by which MΦ-Ts support immune homeostasis and will then discuss how MΦ-Ts facilitate inflammaging and age-related diseases, which will be helpful in the development of new interventions and treatments for chronic diseases of the elderly.
    Keywords:  Age-related disease; Aging; Homeostasis dysregulation; Inflammaging; Tissue-resident macrophages
  9. Cell. 2021 Jan 07. pii: S0092-8674(20)31750-5. [Epub ahead of print]
      The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.
  10. Int J Mol Sci. 2021 Jan 08. pii: E590. [Epub ahead of print]22(2):
      Cells can become senescent in response to stress. Senescence is a process characterised by a stable proliferative arrest. Sometimes it can be beneficial-for example, it can suppress tumour development or take part in tissue repair. On the other hand, studies show that it is also involved in the ageing process. DNA damage response (DDR) is triggered by DNA damage or telomere shortening during cell division. When left unresolved, it may lead to the activation of senescence. Senescent cells secrete certain proteins in larger quantities. This phenomenon is referred to as senescence-associated secretory phenotype (SASP). SASP can induce senescence in other cells; evidence suggests that overabundance of senescent cells contributes to ageing. SASP proteins include proinflammatory cytokines and metalloproteinases, which degrade the extracellular matrix. Shortening of telomeres is another feature associated with organismal ageing. Older organisms have shorter telomeres. Restoring telomerase activity in mice not only slowed but also partially reversed the symptoms of ageing. Changes in chromatin structure during senescence include heterochromatin formation or decondensation and loss of H1 histones. During organismal ageing, cells can experience heterochromatin loss, DNA demethylation and global histone loss. Cellular and organismal ageing are both complex processes with many aspects that are often related. The purpose of this review is to bring some of these aspects forward and provide details regarding them.
    Keywords:  DNA damage response; SASP; ageing; chromatin; inflammation; senescence; telomeres
  11. Exp Gerontol. 2021 Jan 11. pii: S0531-5565(21)00001-2. [Epub ahead of print] 111226
      One of the causes for aging is free radical damage. Resveratrol (RSV), a polyphenolic compound has been shown to act as an antioxidant and anti-inflammatory. The objective this study was to verify in an oxidative stress environment in Human Mononuclear cells from Middle aged and Elderly donors, the existence of a change in the SIRT1 and AMPK signaling pattern by RSV. In both age groups there was a reduction in reactive oxygen species (ROS) in cells stimulated with RSV. It was observed that in the Elderly group there was a higher production of ROS and that the reduction from RSV was smaller compared to the other group. There was an increased activity of Superoxide Dismutase in cells exposed to RSV in the elderly group. It was observed that for the Middle Aged group, SIRT 1 and AMPK are antioxidant pathways and RSV acts via SIRT1. In the elderly, the SIRT1 remains antioxidant and RSV ceases its operation via SIRT1. RSV has an antioxidant action in both age groups, and that in aging there was a change in the cellular context characterized by the silencing of the AMPK pathway antioxidant character.
    Keywords:  AMPK; Aging; Oxidative stress; Resveratrol; SIRT1
  12. Int J Mol Sci. 2021 Jan 12. pii: E697. [Epub ahead of print]22(2):
      Cellular senescence contributes to aging and age-related disorders. High glucose (HG) induces mesenchymal stromal/stem cell (MSC) senescence, which hampers cell expansion and impairs MSC function. Intracellular HG triggers metabolic shift from aerobic glycolysis to oxidative phosphorylation, resulting in reactive oxygen species (ROS) overproduction. It causes mitochondrial dysfunction and morphological changes. Tryptophan metabolites such as 5-methoxytryptophan (5-MTP) and melatonin attenuate HG-induced MSC senescence by protecting mitochondrial integrity and function and reducing ROS generation. They upregulate the expression of antioxidant enzymes. Both metabolites inhibit stress-induced MSC senescence by blocking p38 MAPK signaling pathway, NF-κB, and p300 histone acetyltransferase activity. Furthermore, melatonin upregulates SIRT-1, which reduces NF-κB activity by de-acetylation of NF-κB subunits. Melatonin and 5-MTP are a new class of metabolites protecting MSCs against replicative and stress-induced cellular senescence. They provide new strategies to improve the efficiency of MSC-based therapy for diverse human diseases.
    Keywords:  5-methoxytryptophan; antioxidant enzymes; cellular senescence mitochondrial dysfunction; hyperglycemia; melatonin; mesenchymal stromal/stem cells; reactive oxygen species; type 2 diabetes
  13. Cell Mol Life Sci. 2021 Jan 13.
      In recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called 'zombie cells' are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies.
    Keywords:  Ageing; Cancer; Resolution of inflammation; Senescence; Senolytics; Tissue repair
  14. Immun Ageing. 2021 Jan 13. 18(1): 4
      Older age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6. However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role. In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases/co-morbidities where macrophages are known to play a key role, focussed on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.
    Keywords:  Age‐related diseases; Cancer; Inflammation; Injury repair; Macrophages
  15. Aging Cell. 2021 Jan 14. e13304
      Stem cell transplantation has been generally considered as promising therapeutics in preserving or recovering functions of lost, damaged, or aging tissues. Transplantation of primordial germ cells (PGCs) or oogonia stem cells (OSCs) can reconstitute ovarian functions that yet sustain for only short period of time, limiting potential application of stem cells in preservation of fertility and endocrine function. Here, we show that mTOR inhibition by INK128 extends the follicular and endocrine functions of the reconstituted ovaries in aging and premature aging mice following transplantation of PGCs/OSCs. Follicular development and endocrine functions of the reconstituted ovaries by transplanting PGCs into kidney capsule of the recipient mice were maintained by INK128 treatment for more than 12 weeks, in contrast to the controls for only about 4 weeks without receiving the mTOR inhibitors. Comparatively, rapamycin also can prolong the ovarian functions but for limited time. Furthermore, our data reveal that INK128 promotes mitochondrial function in addition to its known function in suppression of immune response and inflammation. Taken together, germline stem cell transplantation in combination with mTOR inhibition by INK128 improves and extends the reconstituted ovarian and endocrine functions in reproductive aging and premature aging mice.
    Keywords:  Hormone; INK128; aging; primordial germ cells; rapamycin; reconstituted ovary; stem cell transplantation
  16. Aging Cell. 2021 Jan 14. e13277
      Metformin, a drug widely used for treating diabetes, can prolong the lifespan in several species. Metformin also has the promise to slow down age-related cognitive impairment. However, metformin's therapeutic use as an anti-aging drug is yet to be accepted because of conflicting animal and human studies results. We examined the effects of metformin treatment in late middle age on cognitive function in old age. Eighteen-month-old male C57BL6/J mice received metformin or no treatment for 10 weeks. A series of behavioral tests revealed improved cognitive function in animals that received metformin. Such findings were evident from a better ability for pattern separation, object location, and recognition memory function. Quantification of microglia revealed that metformin treatment reduced the incidence of pathological microglial clusters with alternative activation of microglia into an M2 phenotype, displaying highly ramified processes in the hippocampus. Metformin treatment also seemed to reduce astrocyte hypertrophy. Additional analysis demonstrated that metformin treatment in late middle age increased adenosine monophosphate-activated protein kinase activation, reduced proinflammatory cytokine levels, and the mammalian target of rapamycin signaling, and enhanced autophagy in the hippocampus. However, metformin treatment did not alter neurogenesis or synapses in the hippocampus, implying that improved cognitive function with metformin did not involve enhanced neurogenesis or neosynaptogenesis. The results provide new evidence that metformin treatment commencing in late middle age has promise for improving cognitive function in old age. Modulation of microglia, proinflammatory cytokines, and autophagy appear to be the mechanisms by which metformin facilitated functional benefits in the aged brain.
    Keywords:  activated microglia; cognitive function; metformin; neurogenesis; neuroinflammation
  17. Neurobiol Aging. 2021 Jan 06. pii: S0197-4580(20)30412-7. [Epub ahead of print]99 19-27
      Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were performed for total microglia, 2 microglia morphologies (hypertrophic and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared with controls, the number of dystrophic microglia was greater in cases with either Alzheimer's disease, dementia with Lewy bodies, or limbic-predominant age-related TDP-43 encephalopathy. These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease.
    Keywords:  Aging; Microglia morphology; Neurodegeneration; Neuroinflammation; Neuropathology; Senescence
  18. Mol Cell. 2021 Jan 13. pii: S1097-2765(20)30955-2. [Epub ahead of print]
      In addition to its role as an electron transporter, mitochondrial nicotinamide adenine dinucleotide (NAD+) is an important co-factor for enzymatic reactions, including ADP-ribosylation. Although mitochondria harbor the most intra-cellular NAD+, mitochondrial ADP-ribosylation remains poorly understood. Here we provide evidence for mitochondrial ADP-ribosylation, which was identified using various methodologies including immunofluorescence, western blot, and mass spectrometry. We show that mitochondrial ADP-ribosylation reversibly increases in response to respiratory chain inhibition. Conversely, H2O2-induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation. Elevated mitochondrial ADP-ribosylation, in turn, dampens H2O2-triggered nuclear ADP-ribosylation and increases MMS-induced ARTD1 chromatin retention. Interestingly, co-treatment of cells with the mitochondrial uncoupler FCCP decreases PARP inhibitor efficacy. Together, our results suggest that mitochondrial ADP-ribosylation is a dynamic cellular process that impacts nuclear ADP-ribosylation and provide evidence for a NAD+-mediated mitochondrial-nuclear crosstalk.
    Keywords:  ADP-ribosylation; ARTD1; DNA damage; NAD; PARP inhibitors; PARP-inhibitor; PARP1; mito-nuclear crosstalk; mitochondria; mitochondrial ADP-ribosylation
  19. Cell Biochem Biophys. 2021 Jan 11.
      Chloride intracellular channel 1 (CLIC1) is a sensor of oxidative stress in endothelial cells (EC). However, the mechanism by which CLIC1 mediate the regulation of endothelial dysfunction has not been established. In this study, overexpressed CLIC1 impaired the ability of the vascular cells to resist oxidative damage and promoted cellular senescence. Besides, suppressed CLIC1 protected against cellular senescence and dysfunction in Human Umbilical Vein Endothelial Cells (HUVECs) through the Nrf2/HO-1 pathway. We also found that ROS-activated CLIC1-induced oxidative stress in HUVECs. Nrf2 nuclear translocation was inhibited by CLIC1 overexpression, but was enhanced by IAA94 (CLICs inhibitor) treatment or knockdown of CLIC1. The Nrf2/HO-1 pathway plays a critical role in the anti-oxidative effect of suppressing CLIC1. And inhibition of CLIC1 decreases oxidative stress injury by downregulating the levels of ROS, MDA, and the expression of EC effectors (ICAM1 and VCAM1) protein expression and promotes the activity of superoxide dismutase (SOD). The AMPK-mediated signaling pathway activates Nrf2 through Nrf2 phosphorylation and nuclear translocation, which is also regulated by CLIC1. Moreover, the activation of CLIC1 contributes to H2O2-induced mitochondrial dysfunction and activation of mitochondrial fission. Therefore, elucidation of the mechanisms by which CLIC1 is involved in these pivotal pathways may uncover its therapeutic potential in alleviating ECs oxidative stress and age-related cardiovascular disease development.
    Keywords:  CLIC1; Endothelial dysfunction; HUVECs; Nrf2; Oxidative stress
  20. FASEB J. 2021 Feb;35(2): e21319
      The tumor suppressor p53 is known as a critical mediator of many cellular processes, including cellular senescence, but its role in mitochondrial dynamics is not fully understood. We have previously shown that p53 regulates mitochondrial dynamics via the PKA-Drp1 pathway to induce cellular senescence. In this study, to further understand the role of p53-dependent regulation of mitochondrial dynamics, the effect of p53 expression on mitochondrial morphology was examined in various cancer cell lines and normal human cells. We found that p53 induced remarkable mitochondrial elongation and cellular senescence in various cancer cells regardless of their p53 status. p53 also induced mitochondrial elongation in various human primary normal cells, suggesting that p53-mediated mitochondrial elongation is a general phenomenon. Moreover, we found that p53 plays an essential role in mitochondrial elongation in H-Ras-induced cellular senescence and in the replicative senescence of normal human cells. Treatment with the MDM-2 antagonist Nutlin-3a also induced mitochondrial elongation through the PKA-Drp1 pathway in IMR90 normal human cells. Furthermore, the inhibition of PKA activity in late-passage normal cells significantly reduced both mitochondrial elongation and cellular senescence, suggesting that the p53-PKA pathway is essential for maintaining the senescence phenotype in normal cells. Together, these results further confirm the direct regulation of mitochondrial dynamics by p53 and the important role of p53-mediated mitochondrial elongation in cellular senescence.
    Keywords:  Drp1; PKA; cellular senescence; mitochondrial dynamics; p53
  21. Semin Cell Dev Biol. 2021 Jan 06. pii: S1084-9521(20)30203-2. [Epub ahead of print]
      Even healthy older adults experience gastrointestinal (GI) and neurological changes. In fact, the aging process of these two systems are interrelated due the extensive, multifaceted communication network connecting them, termed the gut-brain axis. Age-related modification of the GI environment can influence the bacterial species that survive and thrive there. Additionally, the lifestyle common to older adults in the West, including sedentariness, polypharmacy, and a poor diet, can compound the effect of aging on the GI tract, gut microbiota, and nervous system. Emerging animal and human findings suggest that GI organisms play a major role in gut-brain communication, ultimately shaping neurological aging trajectories by either helping to maintain nervous system function into late life or promoting pathology. Aging and age-related behaviors help to define the gut microbiota's composition and function, but, conversely, the gut microbiota may help to determine late-life functionality and may be harnessed to limit the prevalence of steep neurological decline and diseases. Focusing primarily on clinical research, this review first defines the gut-brain axis, then details age-related GI and nervous system changes, and discusses the impact of age-related lifestyle factors on the GI and nervous systems. The remainder of this review describes cutting-edge research that positions the gut microbiota as an arbiter of age-related neurological decline.
    Keywords:  Aging; Gastrointestinal; Gut microbiota; Gut-brain axis; Health behaviors; Nervous system; Neurological
  22. Behav Brain Res. 2021 Jan 07. pii: S0166-4328(21)00012-7. [Epub ahead of print] 113125
      Age-related cognitive decline is associated with chronic low grade neuroinflammation that may result from a complex interplay among many factors, such as bidirectional communication between the central nervous system (CNS) and gut microbiota. The present study used 2-month-old (young group) and 15-month-old (aged group) male C57BL/6 mice to explore the potential association between age-related cognitive decline and the microbiota-gut-brain axis disorder. We observed that aged mice exhibited significant deficits in learning and memory, neuronal loss, and synaptic damage compared with young mice. Aged mice also exhibited significant dysbiosis of the gut microbiota. Disruptions of the intestinal barrier and blood-brain barrier were also observed, including increases in intestinal, low-grade systemic and cerebral inflammation. Furthermore, plasma and brain levels of lipopolysaccharide (LPS) were significantly higher in aged mice compared with young mice, with increases in the expression of Toll-like receptor 4 (TLR4) and myeloid differential protein-88 (MyD88) and the nuclear translocation of nuclear factor κB (NF-κB) in intestinal and brain tissues. These findings showed that microbiota-gut-brain axis dysfunction that occurs through LPS-induced activation of the TLR4/NF-κB signaling pathway is implicated in age-related neuroinflammation and cognitive decline.
    Keywords:  LPS/TLR4; aging; cognitive decline; inflammation; microbiota-gut-brain axis
  23. Mol Cancer Res. 2020 Dec 22. pii: molcanres.1181.2019. [Epub ahead of print]
      Though frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine Oncostatin M (OSM) activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and requires cooperation between STAT3 and the TGF-β effector SMAD3. Importantly, as cells escape CIS, they retain the mesenchymal/SC program and are thereby bestowed with a set of cancer SC (CSC) traits. Of therapeutic importance, cells that escape CIS can be induced back into senescence by CDK4/6 inhibition, confirming that the mechanisms allowing cells to escape senescence are targetable and reversible. Moreover, by combining CDK4/6 inhibition with a senolytic therapy, mesenchymal/CSC can be efficiently killed. Our studies provide insight into how the CIS barriers that prevent tumorigenesis can be exploited as potential therapies for highly aggressive cancers. Implications: These studies reveal how a normal cell's arduous escape from senescence can bestow aggressive features early in the transformation process, and how this persistent mesenchymal/stem-cell program can create a novel potential targetability following tumor development.
  24. Aging Cell. 2021 Jan 15. e13306
      Osteoarthritis (OA) is a heterogeneous disease that is extremely hard to cure owing to its complex regulation network of pathogenesis, especially cartilage degeneration. FBXO21 is a subunit of ubiquitin E3 ligases that degrades P-glycoprotein and EID1 by ubiquitination and activates the JNK and p38 pathways; however, its role in OA remains unknown. Here, the main objective of this study was to evaluate the potential effects and mechanism of FBXO21 in OA degeneration, we revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate-induced OA rats, and chondrocytes treated with interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide. Moreover, the in vivo and in vitro knockdown of FBXO21 suppressed OA-related cartilage degeneration, as evidenced by activated autophagy, upregulated anabolism, alleviated apoptosis, and downregulated catabolism. In contrast, its overexpression promoted OA-related cartilage degeneration. In addition, using mass spectrometry and co-immunoprecipitation assay, we demonstrated that the downstream mechanism of FBXO21 inhibits autophagy by interacting with and phosphorylating ERK. Furthermore, FBXO21 alleviated anabolism and enhanced apoptosis and catabolism by inhibiting autophagy in rat chondrocytes. Interestingly, for its upstream mechanism, JUNB promoted FBXO21 expression by directly targeting the FBXO21 promoter, thus further accelerating cartilage degeneration in SW1353 cells and rat chondrocytes. Overall, our findings reveal that the JUNB-FBXO21-ERK axis regulates OA apoptosis and cartilage matrix metabolism by inhibiting autophagy. Therefore, FBXO21 is an attractive target for regulating OA pathogenesis, and its knockdown may provide a novel targeted therapy for OA.
    Keywords:  ERK; FBXO21; JUNB; autophagy; cartilage degeneration; metabolism; osteoarthritis; rats
  25. Antiviral Res. 2021 Jan 11. pii: S0166-3542(21)00005-X. [Epub ahead of print] 105015
      The newly emerged severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) coronavirus initiated a pneumonia outbreak (COVID-19) that rapidly spread worldwide and quickly became a public health emergency of international concern; However to date, except Remdesivir, there are no clinically approved specific or effective medicines to prevent or treat COVID-19. Therefore, the development of novel treatments against coronavirus infections caused by the current SARS-CoV-2 virus, as well as other highly pathogenic human coronaviruses, represents an urgent unmet need. Stimulator of interferon genes (STING) plays a central role in host defense mechanisms against microbial infections. STING activation leads to the induction of both type I interferon and autophagy responses, which elicit strong inhibitory effect against the infections caused by a broad range of microbial pathogens. However, whether STING activation can impact infections from SARS-CoV-2 or other coronaviruses remains largely unknown. In this study, we investigated the anti-coronavirus activity triggered by STING activation. We discovered that dimeric amidobenzimidazole (diABZI), a synthetic small molecule STING receptor agonist, showed potent anti-coronavirus activity against both the common cold human coronavirus 229E (HCoV-229E) and SARS-CoV-2 in cell culture systems. In addition, we demonstrated that the antiviral activity of diABZI was dependent on the interferon pathway in HCoV-229E infected normal human fibroblast lung cells (MRC-5) and reconstituted primary human airway air-liquid interface (ALI) cultures. Furthermore, low-dose of diABZI treatment at 0.1 μM effectively reduced the SARS-CoV-2 viral load at the epithelial apical surface and prevented epithelial damage in the reconstituted primary human bronchial airway epithelial ALI system. Our findings have thus revealed the therapeutic potential of STING agonists, such as diABZI, as treatments for SARS-CoV-2 and other human coronavirus infections.
    Keywords:  Coronavirus; HCoV-229E; SARS-CoV-2; STING agonist; diABZI
  26. Aging (Albany NY). 2021 Jan 11. 13
      Telomeres are subject to age related shortening which can be accelerated by oxidative stress and inflammation. Many studies have reported an inverse correlation between telomere length and survival, but such inverse correlation has not been always confirmed in different populations. We analyzed the trend of Leukocyte Telomere Length (LTL) as a function of age in a cohort of 516 subjects aged 65-106 years from Southern Italy. The trend of LTL obtained was quite similar to demographic survival curves reported with data of western societies. We observed a decrease of LTL after 70 years of age and then an increase after 92 years, in agreement with the sharp decrease of survival after 70 years of age and its increase after 90 years, due to the deceleration of mortality at old ages. Our data suggest that a generalized LTL attrition after 70 years of age, associated to organismal decline, affects most of the population. Such generalized attrition may exacerbate senescence in these subjects, predisposing them to high mortality risk. Conversely, the subjects with better physical conditions, experience a lower attrition and, consequently, a delayed senescence, contributing to the deceleration of mortality which has been observed among very old subjects in modern societies.
    Keywords:  aging; lifespan; mortality deceleration; telomere
  27. Aging (Albany NY). 2021 Jan 11. 12
      The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.
    Keywords:  COVID-19; SARS-CoV-2; aging; telomeres
  28. Life Sci Alliance. 2021 Mar;pii: e202000809. [Epub ahead of print]4(3):
      Accumulation of senescent cells is an important contributor to chronic inflammation upon aging. The inflammatory phenotype of senescent cells was previously shown to be driven by cytoplasmic DNA. Here, we propose that cytoplasmic double-stranded RNA has a similar effect. We find that several cell types driven into senescence by different routes share an accumulation of long promoter RNAs and 3' gene extensions rich in retrotransposon sequences. Accordingly, these cells display increased expression of genes involved in response to double stranded RNA of viral origin downstream of the interferon pathway. The RNA accumulation is associated with evidence of reduced RNA turnover, including in some cases, reduced expression of RNA exosome subunits. Reciprocally, depletion of RNA exosome subunit EXOSC3 accelerated expression of multiple senescence markers. A senescence-like RNA accumulation was also observed in cells exposed to oxidative stress, an important trigger of cellular senescence. Altogether, we propose that in a subset of senescent cells, repeat-containing transcripts stabilized by oxidative stress or reduced RNA exosome activity participate in driving and maintaining the permanent inflammatory state characterizing cellular senescence.
  29. Nature. 2021 Jan 13.
      The activation of mostly quiescent haematopoietic stem cells (HSCs) is a prerequisite for life-long production of blood cells1. This process requires major molecular adaptations to allow HSCs to meet the regulatory and metabolic requirements for cell division2-4. The mechanisms that govern cellular reprograming upon stem-cell activation, and the subsequent return of stem cells to quiescence, have not been fully characterized. Here we show that chaperone-mediated autophagy (CMA)5, a selective form of lysosomal protein degradation, is involved in sustaining HSC function in adult mice. CMA is required for protein quality control in stem cells and for the upregulation of fatty acid metabolism upon HSC activation. We find that CMA activity in HSCs decreases with age and show that genetic or pharmacological activation of CMA can restore the functionality of old mouse and human HSCs. Together, our findings provide mechanistic insights into a role for CMA in sustaining quality control, appropriate energetics and overall long-term HSC function. Our work suggests that CMA may be a promising therapeutic target for enhancing HSC function in conditions such as ageing or stem-cell transplantation.
  30. Neurosci Lett. 2021 Jan 10. pii: S0304-3940(21)00005-7. [Epub ahead of print] 135627
      The review article briefly discusses a hypothesis based on the potential participation of iron dyshomeostasis and iron-mediated cell death (ferroptosis) in the pathogenesis of some neurodegenerative diseases. Iron dyshomeostasis (especially cellular iron overload) is considered to be a critical condition of neurodegeneration. The etiopathogenesis of many neurodegenerative diseases including Alzheimer's and Parkinson's diseases, Multiple sclerosis, and others, is different. However, there are several identical cellular processes, such as iron dyshomeostasis (an excessive iron deposition), iron-induced oxidative stress, the accumulation of lipid-generated reactive oxygen species, and ferroptosis that accompany these diseases. Based on the existing theoretical and experimental evidence, the article provides current insight into iron dyshomeostasis and ferroptosis as a contributing factor to the pathogenesis of neurodegeneration. In addition, special attention is addressed to the possible relationship between cellular iron overload and key pathological features of selected neurodegenerative diseases, such as β-amyloid and tau proteins, α-synuclein, and demyelination. The mechanism by which ferroptosis may be involved in the pathogenesis of various neurodegenerative diseases is not fully elucidated. Further experimental and clinical studies are needed to clarify the hypothesis on the potential role of ferroptosis in the pathogenesis of neurodegenerative diseases.
    Keywords:  demyelination; ferroptosis; iron dyshomeostasis; lipid peroxidation; neurodegeneration