bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒01‒31
38 papers selected by
Maria Grazia Vizioli
Mayo Clinic


  1. Elife. 2021 Jan 29. pii: e63728. [Epub ahead of print]10
    Miller KN, Dasgupta N, Liu T, Adams PD, Vizioli MG.
      Senescent cells, damaged cells that permanently exit the cell cycle, play important roles in development, tissue homeostasis, and tumorigenesis. Although many of these roles are beneficial in acute responses to stress and damage, the persistent accumulation of senescent cells is associated with many chronic diseases through their proinflammatory senescence-associated secretory phenotype (SASP). SASP expression is linked to DNA damage; however, the mechanisms that control the SASP are incompletely understood. More recently, it has been shown that senescent cells shed fragments of nuclear chromatin into the cytoplasm, so called cytoplasmic chromatin fragments (CCF). Here, we provide an overview of the current evidence linking DNA damage to the SASP through the formation of CCF. We describe mechanisms of CCF generation and their functional role in senescent cells, with emphasis on therapeutic potential.
    Keywords:  aging; cell biology; chromosomes; cytoplasmic chromatin fragments; epigenetics; gene expression; mitochondria; senescence
    DOI:  https://doi.org/10.7554/eLife.63728
  2. Aging Cell. 2021 Jan 26. e13299
    Nian Y, Iske J, Maenosono R, Minami K, Heinbokel T, Quante M, Liu Y, Azuma H, Yang J, Abdi R, Zhou H, Elkhal A, Tullius SG.
      Age impacts alloimmunity. Effects of aging on T-cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4+ and CD8+ T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4+ T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age-independent source of mitochondria for activated CD4+ T cells, old but not young CD4+ T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4+ T cells with 6-diazo-5-oxo-l-norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN-γ production and compromised proliferative capacities specifically of old CD4+ T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1- and Th17-driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4+ T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2-deoxy-d-glucose, 2-DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4+ T cells as adoptively transferred young CD4+ T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8+ T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age-specific metabolic reprogramming of CD4+ T cells. Targeting those pathways offers novel and age-specific approaches for immunosuppression.
    Keywords:  T cell; aging; cellular immunology; cellular senescence; interleukin 2; metabolic rate; mitochondria; respiratory chains
    DOI:  https://doi.org/10.1111/acel.13299
  3. Biogerontology. 2021 Jan 27.
    Li Z, Zhang Z, Ren Y, Wang Y, Fang J, Yue H, Ma S, Guan F.
      Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.
    Keywords:  Age‐related diseases; Aging; Anti‐aging drugs; Hallmarks of aging
    DOI:  https://doi.org/10.1007/s10522-021-09910-5
  4. Aging Cell. 2021 Jan 29. e13290
    Sebastiani P, Federico A, Morris M, Gurinovich A, Tanaka T, Chandler KB, Andersen SL, Denis G, Costello K, Ferrucci L, Jennings L, Glass DJ, Monti S, Perls TT.
      Using samples from the New England Centenarian Study (NECS), we sought to characterize the serum proteome of 77 centenarians, 82 centenarians' offspring, and 65 age-matched controls of the offspring (mean ages: 105, 80, and 79 years). We identified 1312 proteins that significantly differ between centenarians and their offspring and controls (FDR < 1%), and two different protein signatures that predict longer survival in centenarians and in younger people. By comparing the centenarian signature with 2 independent proteomic studies of aging, we replicated the association of 484 proteins of aging and we identified two serum protein signatures that are specific of extreme old age. The data suggest that centenarians acquire similar aging signatures as seen in younger cohorts that have short survival periods, suggesting that they do not escape normal aging markers, but rather acquire them much later than usual. For example, centenarian signatures are significantly enriched for senescence-associated secretory phenotypes, consistent with those seen with younger aged individuals, and from this finding, we provide a new list of serum proteins that can be used to measure cellular senescence. Protein co-expression network analysis suggests that a small number of biological drivers may regulate aging and extreme longevity, and that changes in gene regulation may be important to reach extreme old age. This centenarian study thus provides additional signatures that can be used to measure aging and provides specific circulating biomarkers of healthy aging and longevity, suggesting potential mechanisms that could help prolong health and support longevity.
    Keywords:  SomaLogic; aging; longevity; protein; senescence
    DOI:  https://doi.org/10.1111/acel.13290
  5. iScience. 2021 Jan 22. 24(1): 102016
    Hao X, Zhao B, Zhou W, Liu H, Fukumoto T, Gabrilovich D, Zhang R.
      Therapy-induced senescence-associated secretory phenotype (SASP) correlates with overcoming resistance to immune checkpoint blockade (ICB). Intrinsic resistance to ICB is a major clinical challenge. For example, ovarian cancer is largely resistant to ICB. Here we show that adoptive transfer of SASP-boosted ex vivo therapy-induced senescent cells sensitizes ovarian tumor to ICB. Topoisomerase 1 (TOP1) inhibitors such as irinotecan enhance cisplatin-induced SASP, which depends on the TOP1 cleavage complex-regulated cGAS pathway. Significantly, intraperitoneal transfer of cisplatin-induced, SASP-boosted senescent cells with irinotecan sensitizes ovarian tumor to anti-PD-1 antibody and improves the survival of tumor-bearing mice in an immunocompetent, syngeneic model. This correlates with the infiltration of transferred senescent cells in the established orthotopic tumors and an increase in the infiltration of activated CD8+ T cells and dendritic cells in the tumor bed. Our findings indicate that adoptive transfer of SASP-boosted therapy-induced senescent cells represents a potential therapeutic strategy to sensitize tumors to ICB.
    Keywords:  Cancer; Immunology; Molecular Biology
    DOI:  https://doi.org/10.1016/j.isci.2020.102016
  6. Elife. 2021 Jan 29. pii: e62852. [Epub ahead of print]10
    Yousefzadeh M, Henpita C, Vyas R, Soto-Palma C, Robbins P, Niedernhofer L.
      Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.
    Keywords:  Aging; DNA damage; DNA repair; genetics; genome instability; genomics; progeria
    DOI:  https://doi.org/10.7554/eLife.62852
  7. Int J Obes (Lond). 2021 Jan 28.
    Smith U, Li Q, Rydén M, Spalding KL.
      Cell senescence is defined as a state of irreversible cell cycle arrest combined with DNA damage and the induction of a senescence-associated secretory phenotype (SASP). This includes increased secretion of many inflammatory agents, proteases, miRNA's, and others. Cell senescence has been widely studied in oncogenesis and has generally been considered to be protective, due to cell cycle arrest and the inhibition of proliferation. Cell senescence is also associated with ageing and extensive experimental data support its role in generating the ageing-associated phenotype. Senescent cells can also influence proximal "healthy" cells through SASPs and, e.g., inhibit normal development of progenitor/stem cells, thereby preventing tissue replacement of dying cells and reducing organ functions. Recent evidence demonstrates that SASPs may also play important roles in several chronic diseases including diabetes and cardiovascular disease. White adipose tissue (WAT) cells are highly susceptible to becoming senescent both with ageing but also with obesity and type 2 diabetes, independently of chronological age. WAT senescence is associated with inappropriate expansion (hypertrophy) of adipocytes, insulin resistance, and dyslipidemia. Major efforts have been made to identify approaches to delete senescent cells including the use of "senolytic" compounds. The most established senolytic treatment to date is the combination of dasatinib, an antagonist of the SRC family of kinases, and the antioxidant quercetin. This combination reduces cell senescence and improves chronic disorders in experimental animal models. Although only small and short-term studies have been performed in man, no severe adverse effects have been reported. Hopefully, these or other senolytic agents may provide novel ways to prevent and treat different chronic diseases in man. Here we review the current knowledge on cellular senescence in both murine and human studies. We also discuss the pathophysiological role of this process and the potential therapeutic relevance of targeting senescence selectively in WAT.
    DOI:  https://doi.org/10.1038/s41366-021-00757-x
  8. Cells. 2021 Jan 21. pii: 208. [Epub ahead of print]10(2):
    Demirci D, Dayanc B, Mazi FA, Senturk S.
      Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of normal physiology with tumor suppressive functions. In the last few decades, novel cancer treatment strategies exploiting pro-senescence therapies have attracted considerable interest. Recent insight, however, suggests that therapy-induced senescence (TIS) elicits cell-autonomous and non-cell-autonomous implications that potentially entail detrimental consequences, reflecting the Jekyll and Hyde nature of cancer cell senescence. In essence, the undesirable manifestations that generally culminate in inflammation, cancer stemness, senescence reversal, therapy resistance, and disease recurrence are dictated by the persistent accumulation of senescent cells and the SASP. Thus, mitigating these pro-tumorigenic effects by eliminating these cells or inhibiting their SASP production holds great promise for developing innovative therapeutic strategies. In this review, we describe the fundamental aspects and dynamics of cancer cell senescence and summarize the comprehensive research on the adverse outcomes of TIS. Furthermore, we underline the rationale and motivation of emerging senotherapeutic modalities surrounding the removal of senescent cells and the SASP to help maximize the overall efficacy of cancer therapies.
    Keywords:  SASP; cancer; cellular senescence; senolytic; senostatic; therapy-induced senescence
    DOI:  https://doi.org/10.3390/cells10020208
  9. Anal Chem. 2021 Jan 27.
    Lozano-Torres B, Blandez JF, Galiana I, Lopez-Dominguez JA, Rovira M, Paez-Ribes M, González-Gualda E, Muñoz-Espín D, Serrano M, Sancenón F, Martínez-Máñez R.
      Cellular senescence is a state of stable cell cycle arrest that can negatively affect the regenerative capacities of tissues and can contribute to inflammation and the progression of various aging-related diseases. Advances in the in vivo detection of cellular senescence are still crucial to monitor the action of senolytic drugs and to assess the early onset or accumulation of senescent cells. Here, we describe a naphthalimide-styrene-based probe (HeckGal) for the detection of cellular senescence both in vitro and in vivo. HeckGal is hydrolyzed by the increased lysosomal β-galactosidase activity of senescent cells, resulting in fluorescence emission. The probe was validated in vitro using normal human fibroblasts and various cancer cell lines undergoing senescence induced by different stress stimuli. Remarkably, HeckGal was also validated in vivo in an orthotopic breast cancer mouse model treated with senescence-inducing chemotherapy and in a renal fibrosis mouse model. In all cases, HeckGal allowed the unambiguous detection of senescence in vitro as well as in tissues and tumors in vivo. This work is expected to provide a potential technology for senescence detection in aged or damaged tissues.
    DOI:  https://doi.org/10.1021/acs.analchem.0c05447
  10. Front Physiol. 2020 ;11 571416
    Bajaj V, Gadi N, Spihlman AP, Wu SC, Choi CH, Moulton VR.
      The novel coronavirus severe acute respiratory syndrome coronavirus 2 causing the Coronavirus disease (COVID-19) pandemic has ravaged the world with over 72 million total cases and over 1.6 million deaths worldwide as of early December 2020. An overwhelming preponderance of cases and deaths is observed within the elderly population, and especially in those with pre-existing conditions and comorbidities. Aging causes numerous biological changes in the immune system, which are linked to age-related illnesses and susceptibility to infectious diseases. Age-related changes influence the host immune response and therefore not only weaken the ability to fight respiratory infections but also to mount effective responses to vaccines. Immunosenescence and inflamm-aging are considered key features of the aging immune system wherein accumulation of senescent immune cells contribute to its decline and simultaneously increased inflammatory phenotypes cause immune dysfunction. Age-related quantitative and qualitative changes in the immune system affect cells and soluble mediators of both the innate and adaptive immune responses within lymphoid and non-lymphoid peripheral tissues. These changes determine not only the susceptibility to infections, but also disease progression and clinical outcomes thereafter. Furthermore, the response to therapeutics and the immune response to vaccines are influenced by age-related changes within the immune system. Therefore, better understanding of the pathophysiology of aging and the immune response will not only help understand age-related diseases but also guide targeted management strategies for deadly infectious diseases like COVID-19.
    Keywords:  COVID-19; SARS-CoV; aging; coronavirus; immune response; immunity; infection
    DOI:  https://doi.org/10.3389/fphys.2020.571416
  11. Mol Cancer Res. 2021 Jan 26. pii: molcanres.0879.2020. [Epub ahead of print]
    Garnett S, de Bruyns A, Provencher-Tom V, Dutchak K, Shu R, Dankort D.
      Cellular senescence is characterized by a prolonged and predominantly irreversible cell cycle arrest state that is linked to loss of tissue function and aging in mammals. Moreover, in response to aberrant oncogenic signals such as those from oncogenic RAS or BRAF, senescence functions as an intrinsic tumor suppressor mechanism restraining tumor progression. In addition to this durable proliferative block, senescent cells adopt altered morphologies, transcriptional profiles and metabolism, while often possessing unusual heterochromatin formation termed senescence associated heterochromatic foci (SAHF). To uncover genes that are required to permit proliferation in the face of sustained oncogene signaling, we conducted an shRNA-based genetic screen in primary cells expressing inducible BRAF. Here, we show that depletion of a known glycolysis regulator, IAPP (islet amylin polypeptide also known as amylin), prevents RAS and BRAF oncogene-induced senescence (OIS) in human cells. Importantly, depletion of IAPP, resulted in changes of the cells' metabolome and this metabolic reprogramming was associated with widespread alterations in chromatin modifications compared to senescent cells. Conversely exogenous treatment of IAPP depleted cells with amylin restored OIS. Together, our results demonstrate that the metabolic regulator IAPP is important regulator of oncogene induced senescence. Moreover, they suggest that IAPP analog treatment or activation of IAPP signaling in RAS/BRAF mutant tumors may have therapeutic potential through senescence induction. Implications: These findings demonstrate that IAPP is a novel metabolic regulator of oncogene induce senescence and use of IAPP analogs may be therapeutically effective to restore growth arrest to BRAF and/or RAS mutant cancers.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0879
  12. Eur J Clin Nutr. 2021 Jan 29.
    Shannon OM, Ashor AW, Scialo F, Saretzki G, Martin-Ruiz C, Lara J, Matu J, Griffiths A, Robinson N, Lillà L, Stevenson E, Stephan BCM, Minihane AM, Siervo M, Mathers JC.
      Ageing is a multifactorial process associated with reduced function and increased risk of morbidity and mortality. Recently, nine cellular and molecular hallmarks of ageing have been identified, which characterise the ageing process, and collectively, may be key determinants of the ageing trajectory. These include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication. Healthier dietary patterns reduce the risk of age-related diseases and increase longevity and may influence positively one or more of these hallmarks. The Mediterranean dietary pattern (MedDiet) is a plant-based eating pattern that was typical of countries such as Greece, Spain, and Italy pre-globalisation of the food system and which is associated with better health during ageing. Here we review the potential effects of a MedDiet on each of the nine hallmarks of ageing, and provide evidence that the MedDiet as a whole, or individual elements of this dietary pattern, may influence each hallmark positively-effects which may contribute to the beneficial effects of this dietary pattern on age-related disease risk and longevity. We also highlight potential avenues for future research.
    DOI:  https://doi.org/10.1038/s41430-020-00841-x
  13. Int J Mol Sci. 2021 Jan 22. pii: 1091. [Epub ahead of print]22(3):
    Brawek B, Skok M, Garaschuk O.
      Microglia, the innate immune cells of the brain, are commonly perceived as resident macrophages of the central nervous system (CNS). This definition, however, requires further specification, as under healthy homeostatic conditions, neither morphological nor functional properties of microglia mirror those of classical macrophages. Indeed, microglia adapt exceptionally well to their microenvironment, becoming a legitimate member of the cellular brain architecture. The ramified or surveillant microglia in the young adult brain are characterized by specific morphology (small cell body and long, thin motile processes) and physiology (a unique pattern of Ca2+ signaling, responsiveness to various neurotransmitters and hormones, in addition to classic "immune" stimuli). Their numerous physiological functions far exceed and complement their immune capabilities. As the brain ages, the respective changes in the microglial microenvironment impact the functional properties of microglia, triggering further rounds of adaptation. In this review, we discuss the recent data showing how functional properties of microglia adapt to age-related changes in brain parenchyma in a sex-specific manner, with a specific focus on early changes occurring at middle age as well as some strategies counteracting the aging of microglia.
    Keywords:  acetylcholine receptors of α7 subtype; brain aging; calcium signaling; caloric restriction; discoordination of microglial processes; in vivo calcium imaging; microglia; middle-age; senescence; sex-specific differences
    DOI:  https://doi.org/10.3390/ijms22031091
  14. Cell Death Dis. 2021 Jan 25. 12(1): 121
    Zhang HT, Gui T, Liu RX, Tong KL, Wu CJ, Li Z, Huang X, Xu QT, Yang J, Tang W, Sang Y, Liu W, Liu N, Ross RD, He QY, Zha ZG.
      Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-XL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.
    DOI:  https://doi.org/10.1038/s41419-021-03416-1
  15. Front Cell Dev Biol. 2020 ;8 619126
    Lee JW, Ong EBB.
      Aging is a complex biological process that occurs in all living organisms. Aging is initiated by the gradual accumulation of biomolecular damage in cells leading to the loss of cellular function and ultimately death. Cellular senescence is one such pathway that leads to aging. The accumulation of nucleic acid damage and genetic alterations that activate permanent cell-cycle arrest triggers the process of senescence. Cellular senescence can result from telomere erosion and ribosomal DNA instability. In this review, we summarize the molecular mechanisms of telomere length homeostasis and ribosomal DNA stability, and describe how these mechanisms are linked to cellular senescence and longevity through lessons learned from budding yeast.
    Keywords:  Saccharomyces cerevisiae; aging; longevity; rDNA stability; senescence; telomere length homeostasis
    DOI:  https://doi.org/10.3389/fcell.2020.619126
  16. Redox Biol. 2021 Jan 19. pii: S2213-2317(21)00011-2. [Epub ahead of print]40 101863
    Cheng X, Shihabudeen Haider Ali MS, Moran M, Viana MP, Schlichte SL, Zimmerman MC, Khalimonchuk O, Feinberg MW, Sun X.
      Obesity-induced insulin resistance is a risk factor for diabetes and cardiovascular disease. However, the mechanisms underlying endothelial senescence in obesity, and how it impacts obesity-induced insulin resistance remain incompletely understood. In this study, transcriptome analysis revealed that the long non-coding RNA (lncRNA) Maternally expressed gene 3 (Meg3) is one of the top differentially expressed lncRNAs in the vascular endothelium in diet-induced obese mice. Meg3 knockdown induces cellular senescence of endothelial cells characterized by increased senescence-associated β-galactosidase activity, increased levels of endogenous superoxide, impaired mitochondrial structure and function, and impaired autophagy. Moreover, Meg3 knockdown causes cellular senescence of hepatic endothelium in diet-induced obese mice. Furthermore, Meg3 expression is elevated in human nonalcoholic fatty livers and nonalcoholic steatohepatitis livers, which positively correlates with the expression of CDKN2A encoding p16, an important hallmark of cellular senescence. Meg3 knockdown potentiates obesity-induced insulin resistance and impairs glucose homeostasis. Insulin signaling is reduced by Meg3 knockdown in the liver and, to a lesser extent, in the skeletal muscle, but not in the visceral fat of obese mice. We found that the attenuation of cellular senescence of hepatic endothelium by ablating p53 expression in vascular endothelium can restore impaired glucose homeostasis and insulin signaling in obesity. In conclusion, our data demonstrate that cellular senescence of hepatic endothelium promotes obesity-induced insulin resistance, which is tightly regulated by the expression of Meg3. Our results suggest that manipulation of Meg3 expression may represent a novel approach to managing obesity-associated hepatic endothelial senescence and insulin resistance.
    Keywords:  Cellular senescence; Glucose homeostasis; Hepatic endothelium; Long noncoding RNAs; Obesity
    DOI:  https://doi.org/10.1016/j.redox.2021.101863
  17. Semin Cancer Biol. 2021 Jan 21. pii: S1044-579X(21)00010-9. [Epub ahead of print]
    Gal H, Majewska J, Krizhanovsky V.
      Cellular senescence, a stable form of cell cycle arrest, accompanied by pronounced secretory activity, has functional roles in both physiological and pathological conditions. Although senescence has been linked for a long time with cancer and ageing, recent studies have revealed a functional role of senescence in development, regeneration and reprogramming. Notably, the transient presence of senescent cells may be beneficial, in contrast to the potential deleterious effects of persistent senescence in aged or chronically damaged tissues. We will discuss how senescence contributes to embryonic development, cell plasticity and tissue regeneration, as a highly coordinated and programmed cellular state.
    Keywords:  Cellular senescence; Embryonic development; Placenta; Regeneration
    DOI:  https://doi.org/10.1016/j.semcancer.2021.01.004
  18. J Invest Dermatol. 2021 Jan 22. pii: S0022-202X(20)32192-8. [Epub ahead of print]
    Siametis A, Niotis G, Garinis GA.
      In mammals, genome instability and aging are intimately linked as illustrated by the growing list of patients with progeroid and animal models with inborn DNA repair defects. Until recently, DNA damage was thought to drive aging by compromising transcription or DNA replication, thereby leading to age-related cellular malfunction and somatic mutations triggering cancer. However, recent evidence suggests that DNA lesions also elicit widespread epigenetic alterations that threaten cell homeostasis as a function of age. In this review, we discuss the functional links of persistent DNA damage with the epigenome in the context of aging and age-related diseases.
    DOI:  https://doi.org/10.1016/j.jid.2020.10.006
  19. Front Physiol. 2020 ;11 601189
    Mijares A, Allen PD, Lopez JR.
      Aging causes skeletal muscles to become atrophied, weak, and easily fatigued. Here, we have tested the hypothesis that normal aging in skeletal muscle cells is associated with Ca2+ intracellular dyshomeostasis and oxidative stress. Intracellular Ca2+ concentration ([Ca2+]i), resting intracellular Na+ concentration ([Na+]i) and reactive oxygen species (ROS) production were measured in vivo (superficial gastrocnemius fibers) using double-barreled ion-selective microelectrodes, and in vitro [isolated single flexor digitorum brevis fibers] using fluorescent ROS sensor CM-H2DCFDA in young (3 months of age), middle-aged (12 months of age), and aged (24 months of age) mice. We found an age-related increase in [Ca2+]i from 121 ± 4 nM in young muscle cells which rose to 255 ± 36 nM in middle-aged and to 409 ± 25 nM in aged cells. [Na+]i also showed an age-dependent elevation, increasing from 8 ± 0.5 mM in young muscle fibers, to 12 ± 1 mM in middle-aged and to 17 ± 1 mM in old muscle fibers. Using the fluorescent ROS sensor CM-H2DCFDA we found that these increases in intracellular cation concentrations were associated with significantly increased basal ROS production as demonstrated by age related increases in the rate of dichlorodihydrofluorescein fluorescence. To determine is this could be modified by reducing ROS and/or blocking sarcolemmal Ca2+ influx we administered flufenamic acid (FFA), a non-steroidal anti-inflammatory drug which is also a non-selective blocker of the transient receptor potential canonical channels (TRPCs), for 4 weeks to determine if this would have a beneficial effect. FFA treatment reduced both basal ROS production and muscle [Ca2+]i and [Na+]i in middle-aged and aged muscle fibers compared to fibers and muscles of untreated 12 and 24-months old mice. [Ca2+]i was reduced to 134 ± 8 nM in middle-aged muscle and to 246 ± 40 nM in muscle from aged mice. Likewise [Na+]i was reduced to 9 ± 0.7 mM in middle-aged muscles and to 13 ± 1 mM in muscle from aged mice. FFA treatment also reduced age associated increases in plasma interleukin 6 and tumor necrosis factor-alpha (TNF-α) concentrations which were elevated in 12 and 24-months old mice compared to young mice and decreased age-related muscle damage as indicated by a reduction in serum creatine kinase (CK) activity. Our data provides a direct demonstration that normal aging is associated with a significant elevation [Ca2+]i, [Na+]i, and intracellular ROS production in skeletal muscle fibers. Furthermore, the fact that FFA reduced the intracellular [Ca2+], [Na+], and ROS production as well as the elevated IL6, TNF-α, and CK levels, led us to suggest that its pharmacological effect may be related to its action both as a TRPC channel blocker and as an anti-inflammatory.
    Keywords:  TRPC; aging; calcium; inflammation; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2020.601189
  20. Front Cell Dev Biol. 2020 ;8 599048
    Stagni V, Ferri A, Cirotti C, Barilà D.
      Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.
    Keywords:  ATM kinase; DDR; ataxia-telangiectasia; autophagy; senescence
    DOI:  https://doi.org/10.3389/fcell.2020.599048
  21. Nat Commun. 2021 01 28. 12(1): 640
    Hwang I, Uchida H, Dai Z, Li F, Sanchez T, Locasale JW, Cantley LC, Zheng H, Paik J.
      Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes like elevated oxidative stress. But how oxidative stress regulates NSPC and its neurogenic differentiation is less clear. Here we report that acutely elevated cellular oxidative stress in NSPCs modulates neurogenic differentiation through induction of Forkhead box protein O3 (FOXO3)-mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 and its transcriptional target glycine-N-methyltransferase (GNMT) whose upregulation triggers depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, we demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which induce cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING-IFN-I cascade to suppress neurogenic differentiation. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates long-term regenerative potential.
    DOI:  https://doi.org/10.1038/s41467-020-20839-0
  22. Cancers (Basel). 2021 Jan 27. pii: 484. [Epub ahead of print]13(3):
    Mongiardi MP, Pellegrini M, Pallini R, Levi A, Falchetti ML.
      Cellular senescence participates to fundamental processes like tissue remodeling in embryo development, wound healing and inhibition of preneoplastic cell growth. Most senescent cells display common hallmarks, among which the most characteristic is a permanent (or long lasting) arrest of cell division. However, upon senescence, different cell types acquire distinct phenotypes, which also depend on the specific inducing stimuli. Senescent cells are metabolically active and secrete a collection of growth factors, cytokines, proteases, and matrix-remodeling proteins collectively defined as senescence-associated secretory phenotype, SASP. Through SASP, senescent cells modify their microenvironment and engage in a dynamic dialog with neighbor cells. Senescence of neoplastic cells, at least temporarily, reduces tumor expansion, but SASP of senescent cancer cells as well as SASP of senescent stromal cells in the tumor microenvironment may promote the growth of more aggressive cancer subclones. Here, we will review recent data on the mechanisms and the consequences of cancer-therapy induced senescence, enlightening the potentiality and the risk of senescence inducing treatments.
    Keywords:  Senescence-Associated Secretory Phenotype (SASP); cancer cell; cancer therapy; senescence; tumor vasculature
    DOI:  https://doi.org/10.3390/cancers13030484
  23. Mol Cancer Res. 2021 Jan 25. pii: molcanres.0915.2020. [Epub ahead of print]
    Gadsden NJ, Fulcher CD, Li D, Shrivastava N, Thomas C, Segall JE, Prystowsky MB, Schlecht NF, Gavathiotis E, Ow TJ.
      We demonstrate that inhibition of cyclin dependent kinases 4/6 (CDK4/6) leads to senescence in human papillomavirus (HPV)-negative (-) head and neck squamous cell carcinoma (HNSCC), but not in HPV-positive (+) HNSCC. The BCL-2 family inhibitor, navitoclax, has been shown to eliminate senescent cells effectively. We evaluated the efficacy of combining palbociclib and navitoclax in HPV- HNSCC. Three HPV- HNSCC cell lines (CAL27, HN31, PCI15B) and three HPV+ HNSCC cell lines (UPCI-SCC-090, UPCI-SCC-154, UM-SCC-47) were treated with palbociclib. Treatment drove reduced expression of phosphorylated Rb (p-Rb) and phenotypic evidence of senescence in all HPV- cell lines, while HPV+ cell lines did not display a consistent response by Rb or p-Rb and did not exhibit morphologic changes of senescence in response to palbociclib. In addition, treatment of HPV- cells with palbociclib increased both β-galactosidase protein expression and BCL-xL protein expression compared to untreated controls in HPV- cells. Co-expression of β-galactosidase and BCL-xL occurred consistently indicating elevated BCL-xL expression in senescent cells. Combining palbociclib with navitoclax led to decreased HPV- HNSCC cell survival and led to increased apoptosis levels in HPV- cell lines compared to each agent given alone. Implications: This work exploits a key genomic hallmark of HPV- HNSCC (CDKN2A disruption) using palbociclib to induce BCL-xL dependent senescence, which subsequently causes the cancer cells to be vulnerable to the senolytic agent, navitoclax.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0915
  24. Aging (Albany NY). 2021 Jan 28. 13
    Liu J, Zhang J, Zhang G, Zhou T, Zou X, Guan H, Wang Y.
      Ultraviolet B (UVB) irradiation could trigger DNA double-strand breaks (DDSBs) and senescence in lens epithelial cells (LECs), thus inducing age-related cortical cataract (ARCC) formation. Cell-cycle irreversible arrest induced by DDSBs depended on excessive activation of ataxia-telangiectasia mutated kinase (ATM). We studied the up-regulated circular RNA circMRE11A_013 (circMRE11A) in LECs of ARCC and SRA01/04 cell lines under UVB exposure. In vitro, knockdown of circMRE11A in SRA01/04 cell lines enhanced cell viability and cell cycle, while over-expression of circMRE11A exhibited an opposite trend. Additionally, circMRE11A could bind to UBX domain-containing protein 1 (UBXN1), which might enhance excessive activation of ATM and initiate ATM/p53/p21 signaling pathway causing LECs cell-cycle arrest and senescence. In vivo, recombinant adeno-associated virus vectors (rAAV-2) virions of circMRE11A (circMRE11A-AAV2) was injected to Institute of Cancer Research mouse vitreous cavity. The circMRE11A-AAV2 could express in mouse lens at 4 weeks. The LECs aging and opacity lens were observed at 8 weeks after the injection. Together, our findings reveal a previously unidentified role of circMRE11A interacting with UBXN1 in enhancing ATM activity and inhibiting LECs cell-cycle in ARCC formation. The findings might give us a better understanding of ARC pathology and provide a novel and more effective therapeutic approaches for ARC treatment.
    Keywords:  ATM activation; UBXN1; age-related cataract; circular RNA; ultraviolet B
    DOI:  https://doi.org/10.18632/aging.202470
  25. Aging Cell. 2021 Jan 28. e13312
    Tobin SW, Alibhai FJ, Wlodarek L, Yeganeh A, Millar S, Wu J, Li SH, Weisel RD, Li RK.
      Recruited immune cells play a critical role in muscle repair, in part by interacting with local stem cell populations to regulate muscle regeneration. How aging affects their communication during myogenesis is unclear. Here, we investigate how aging impacts the cellular function of these two cell types after muscle injury during normal aging or after immune rejuvenation using a young to old (Y-O) or old to old (O-O) bone marrow (BM) transplant model. We found that skeletal muscle from old mice (20 months) exhibited elevated basal inflammation and possessed fewer satellite cells compared with young mice (3 months). After cardiotoxin muscle injury (CTX), old mice exhibited a blunted inflammatory response compared with young mice and enhanced M2 macrophage recruitment and IL-10 expression. Temporal immune and cytokine responses of old mice were partially restored to a young phenotype following reconstitution with young cells (Y-O chimeras). Improved immune responses in Y-O chimeras were associated with greater satellite cell proliferation compared with O-O chimeras. To identify how immune cell aging affects myoblast function, conditioned media (CM) from activated young or old macrophages was applied to cultured C2C12 myoblasts. CM from young macrophages inhibited myogenesis while CM from old macrophages reduced proliferation. These functional differences coincided with age-related differences in macrophage cytokine expression. Together, this study examines the infiltration and proliferation of immune cells and satellite cells after injury in the context of aging and, using BM chimeras, demonstrates that young immune cells retain cell autonomy in an old host to increase satellite cell proliferation.
    Keywords:  aging; bone marrow transplant; inflammation; myogenesis; satellite cells
    DOI:  https://doi.org/10.1111/acel.13312
  26. Eur Respir J. 2021 Jan 28. pii: 2000752. [Epub ahead of print]
    Beaulieu D, Attwe A, Breau M, Lipskaia L, Marcos E, Born E, Huang J, Abid S, Derumeaux G, Houssaini A, Maitre B, Lefevre M, Vienney N, Bertolino P, Jaber S, Noureddine H, Goehrig D, Vindrieux D, Bernard D, Adnot S.
      RATIONALE: Cell senescence is a key process in age-associated dysfunction and diseases, notably chronic obstructive pulmonary disease (COPD). We previously identified phospholipase A2-receptor 1 (PLA2R1) as a positive regulator of cell senescence acting via JAK/STAT signalling. Its role in pathology, however, remains unknown. Here, we assessed PLA2R1-induced senescence in COPD and lung emphysema pathogenesis.METHODS: Assessment of cell senescence in lungs and cultured lung cells from patients with COPD and controls subjected to PLA2R1 knock-down, PLA2R1 gene transduction and treatment with the JAK1/2 inhibitor ruxolitinib. To assess whether PLA2R1 upregulation caused lung lesions, we developed transgenic mice overexpressing PLA2R1 (PLA2R1-TG) and intratracheally injected wild-type mice with a lentiviral vector carrying the PLA2R1 gene (LV-PLA2R1 mice).
    MEASUREMENTS AND RESULTS: We found that PLA2R1 was overexpressed in various cell types exhibiting senescence characteristics in COPD lungs. PLA2R1 knockdown extended the population doubling capacity of these cells and inhibited their proinflammatory senescence-associated secretory phenotype (SASP). PLA2R1-mediated cell senescence in COPD was largely reversed by treatment with the potent JAK1/2 inhibitor ruxolitinib. 5 month-old PLA2R1-TG mice exhibited lung-cell senescence and developed lung emphysema and lung fibrosis together with pulmonary hypertension. Treatment with ruxolitinib induced reversal of lung emphysema and fibrosis. LV-PLA2R1-treated mice developed lung emphysema within 4 weeks, and this was markedly attenuated by concomitant ruxolitinib treatment.
    CONCLUSION: Our data support a major role for PLA2R1 activation in driving lung-cell senescence and lung alterations in COPD. Targeting JAK1/2 may represent a promising therapeutic approach for COPD.
    DOI:  https://doi.org/10.1183/13993003.00752-2020
  27. Front Aging Neurosci. 2020 ;12 614650
    Ganji R, Reddy PH.
      The coronavirus disease 2019 (COVID-19) has become a deadly pandemic with surging mortality rates and no cure. COVID-19 is caused by the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) with a range of clinical symptoms, including cough, fever, chills, headache, shortness of breath, difficulty breathing, muscle pain, and a loss of smell or taste. Aged individuals with compromised immunity are highly susceptible to COVID-19 and the likelihood of mortality increases with age and the presence of comorbidities such as hypertension, diabetes mellitus, cardiovascular disease, or chronic obstructive pulmonary disease. Emerging evidence suggests that COVID-19 highjacks mitochondria of immune cells, replicates within mitochondrial structures, and impairs mitochondrial dynamics leading to cell death. Mitochondria are the powerhouses of the cell and are largely involved in maintaining cell immunity, homeostasis, and cell survival/death. Increasing evidence suggests that mitochondria from COVID-19 infected cells are highly vulnerable, and vulnerability increases with age. The purpose of our article is to summarize the role of various age-related comorbidities such as diabetes, obesity, and neurological diseases in increasing mortality rates amongst the elderly with COVID-19. Our article also highlights the interaction between coronavirus and mitochondrial dynamics in immune cells. We also highlight the current treatments, lifestyles, and safety measures that can help protect against COVID-19. Further research is urgently needed to understand the molecular mechanisms between the mitochondrial virus and disease progression in COVID-19 patients.
    Keywords:  Alzheimer’s disease; COVID-19; SARS-CoV-2; diabetes; immune response; lifestyle; mitochondrial dynamics; obesity
    DOI:  https://doi.org/10.3389/fnagi.2020.614650
  28. Arch Toxicol. 2021 Jan 25.
    Rothmiller S, Jäger N, Meier N, Meyer T, Neu A, Steinritz D, Thiermann H, Scherer M, Rummel C, Mangerich A, Bürkle A, Schmidt A.
      Wound healing is a complex process, and disturbance of even a single mechanism can result in chronic ulcers developing after exposure to the alkylating agent sulfur mustard (SM). A possible contributor may be SM-induced chronic senescent mesenchymal stem cells (MSCs), unable to fulfil their regenerative role, by persisting over long time periods and creating a proinflammatory microenvironment. Here we show that senescence induction in human bone marrow derived MSCs was time- and concentration-dependent, and chronic senescence could be verified 3 weeks after exposure to between 10 and 40 µM SM. Morphological changes, reduced clonogenic and migration potential, longer scratch closure times, differences in senescence, motility and DNA damage response associated genes as well as increased levels of proinflammatory cytokines were revealed. Selective removal of these cells by senolytic drugs, in which ABT-263 showed initial potential in vitro, opens the possibility for an innovative treatment strategy for chronic wounds, but also tumors and age-related diseases.
    Keywords:  Chemical warfare agents; Mesenchymal stem cells; Senescence; Sulfur mustard; Wound healing disorder
    DOI:  https://doi.org/10.1007/s00204-020-02946-5
  29. J Invest Dermatol. 2021 Jan 25. pii: S0022-202X(20)32399-X. [Epub ahead of print]
    Stone RC, Aviv A, Paus R.
      In this review, we propose that telomere length dynamics play an important but underinvestigated role in the biology of the hair follicle (HF), a prototypic, cyclically remodeled miniorgan that shows an intriguing aging pattern in humans. Whereas the HF pigmentary unit ages quickly, its epithelial stem cell (ESC) component and regenerative capacity are surprisingly aging resistant. Telomerase-deficient mice with short telomeres display an aging phenotype of hair graying and hair loss that is attributed to impaired HF ESC mobilization. Yet, it remains unclear whether the function of telomerase and telomeres in murine HF biology translate to the human system. Therefore, we propose new directions for future telomere research of the human HF. Such research may guide the development of novel treatments for selected disorders of human hair growth or pigmentation (e.g., chemotherapy-induced alopecia, telogen effluvium, androgenetic alopecia, cicatricial alopecia, graying). It might also increase the understanding of the global role of telomeres in aging-related human disease.
    DOI:  https://doi.org/10.1016/j.jid.2020.12.006
  30. Semin Cell Dev Biol. 2021 Jan 25. pii: S1084-9521(21)00009-4. [Epub ahead of print]
    Higgins-Chen AT, Thrush KL, Levine ME.
      Quantifying biological aging is critical for understanding why aging is the primary driver of morbidity and mortality and for assessing novel therapies to counter pathological aging. In the past decade, many biomarkers relevant to brain aging have been developed using various data types and modeling techniques. Aging involves numerous interconnected processes, and thus many complementary biomarkers are needed, each capturing a different slice of aging biology. Here we present a hierarchical framework highlighting how these biomarkers are related to each other and the underlying biological processes. We review those measures most studied in the context of brain aging: epigenetic clocks, proteomic clocks, and neuroimaging age predictors. Many studies have linked these biomarkers to cognition, mental health, brain structure, and pathology during aging. We also delve into the challenges and complexities in interpreting these biomarkers and suggest areas for further innovation. Ultimately, a robust mechanistic understanding of these biomarkers will be needed to effectively intervene in the aging process to prevent and treat age-related disease.
    Keywords:  Aging; Biomarker; Epigenetic clock; Neurodegeneration; Neuroimaging; Proteomics
    DOI:  https://doi.org/10.1016/j.semcdb.2021.01.003
  31. Microbiome. 2021 Jan 28. 9(1): 31
    Arnold JW, Roach J, Fabela S, Moorfield E, Ding S, Blue E, Dagher S, Magness S, Tamayo R, Bruno-Barcena JM, Azcarate-Peril MA.
      BACKGROUND: Prebiotic galacto-oligosaccharides (GOS) have an extensively demonstrated beneficial impact on intestinal health. In this study, we determined the impact of GOS diets on hallmarks of gut aging: microbiome dysbiosis, inflammation, and intestinal barrier defects ("leaky gut"). We also evaluated if short-term GOS feeding influenced how the aging gut responded to antibiotic challenges in a mouse model of Clostridioides difficile infection. Finally, we assessed if colonic organoids could reproduce the GOS responder-non-responder phenotypes observed in vivo.RESULTS: Old animals had a distinct microbiome characterized by increased ratios of non-saccharolytic versus saccharolytic bacteria and, correspondingly, a lower abundance of β-galactosidases compared to young animals. GOS reduced the overall diversity, increased the abundance of specific saccharolytic bacteria (species of Bacteroides and Lactobacillus), increased the abundance of β-galactosidases in young and old animals, and increased the non-saccharolytic organisms; however, a robust, homogeneous bifidogenic effect was not observed. GOS reduced age-associated increased intestinal permeability and increased MUC2 expression and mucus thickness in old mice. Clyndamicin reduced the abundance Bifidobacterium while increasing Akkermansia, Clostridium, Coprococcus, Bacillus, Bacteroides, and Ruminococcus in old mice. The antibiotics were more impactful than GOS on modulating serum markers of inflammation. Higher serum levels of IL-17 and IL-6 were observed in control and GOS diets in the antibiotic groups, and within those groups, levels of IL-6 were higher in the GOS groups, regardless of age, and higher in the old compared to young animals in the control diet groups. RTqPCR revealed significantly increased gene expression of TNFα in distal colon tissue of old mice, which was decreased by the GOS diet. Colon transcriptomics analysis of mice fed GOS showed increased expression of genes involved in small-molecule metabolic processes and specifically the respirasome in old animals, which could indicate an increased oxidative metabolism and energetic efficiency. In young mice, GOS induced the expression of binding-related genes. The galectin gene Lgals1, a β-galactosyl-binding lectin that bridges molecules by their sugar moieties and is an important modulator of the immune response, and the PI3K-Akt and ECM-receptor interaction pathways were also induced in young mice. Stools from mice exhibiting variable bifidogenic response to GOS injected into colon organoids in the presence of prebiotics reproduced the response and non-response phenotypes observed in vivo suggesting that the composition and functionality of the microbiota are the main contributors to the phenotype.
    CONCLUSIONS: Dietary GOS modulated homeostasis of the aging gut by promoting changes in microbiome composition and host gene expression, which was translated into decreased intestinal permeability and increased mucus production. Age was a determining factor on how prebiotics impacted the microbiome and expression of intestinal epithelial cells, especially apparent from the induction of galectin-1 in young but not old mice. Video abstract.
    Keywords:  Antibiotics; Bifidobacterium; Diet; Gut microbiome; Host-microbiota interactions; Intestinal permeability; Metagenomics; Organoids; Prebiotics; Transcriptomics
    DOI:  https://doi.org/10.1186/s40168-020-00980-0
  32. Cells. 2021 Jan 20. pii: E198. [Epub ahead of print]10(2):
    Loving BA, Tang M, Neal MC, Gorkhali S, Murphy R, Eckel RH, Bruce KD.
      Microglia become increasingly dysfunctional with aging and contribute to the onset of neurodegenerative disease (NDs) through defective phagocytosis, attenuated cholesterol efflux, and excessive secretion of pro-inflammatory cytokines. Dysfunctional microglia also accumulate lipid droplets (LDs); however, the mechanism underlying increased LD load is unknown. We have previously shown that microglia lacking lipoprotein lipase (LPL KD) are polarized to a pro-inflammatory state and have impaired lipid uptake and reduced fatty acid oxidation (FAO). Here, we also show that LPL KD microglia show excessive accumulation of LD-like structures. Moreover, LPL KD microglia display a pro-inflammatory lipidomic profile, increased cholesterol ester (CE) content, and reduced cholesterol efflux at baseline. We also show reduced expression of genes within the canonical cholesterol efflux pathway. Importantly, PPAR agonists (rosiglitazone and bezafibrate) rescued the LD-associated phenotype in LPL KD microglia. These data suggest that microglial-LPL is associated with lipid uptake, which may drive PPAR signaling and cholesterol efflux to prevent inflammatory lipid distribution and LD accumulation. Moreover, PPAR agonists can reverse LD accumulation, and therefore may be beneficial in aging and in the treatment of NDs.
    Keywords:  PPAR agonists; lipid droplet; lipoprotein lipase; microglia; neurodegenerative disease
    DOI:  https://doi.org/10.3390/cells10020198
  33. Cancer Discov. 2021 Jan 26. pii: candisc.1375.2020. [Epub ahead of print]
    Duy C, Li M, Teater M, Meydan C, Garrett-Bakelman FE, Lee TC, Chin CR, Durmaz C, Kawabata KC, Dhimolea E, Mitsiades CS, Doehner H, D'Andrea RJ, Becker MW, Paietta EM, Mason CE, Carroll M, Melnick AM.
      Acute myeloid leukemia (AML) patients frequently relapse after chemotherapy, yet the mechanism by which AML reemerges is not fully understood. Herein, we show that primary AML cells enter a senescence-like phenotype following chemotherapy in vitro and in vivo. This is accompanied by induction of senescence/inflammatory and embryonic diapause transcriptional programs, with downregulation of MYC and leukemia stem cell genes. Single-cell RNA-seq suggested depletion of leukemia stem cells in vitro and in vivo, and enrichment for subpopulations with distinct senescence-like cells. This senescence effect was transient and conferred superior colony forming and engraftment potential. Entry into this senescence-like phenotype was dependent on ATR, and persistence of AML cells was severely impaired by ATR inhibitors. Altogether, we propose that AML relapse is facilitated by a senescence-like resilience phenotype that occurs regardless of their stem cell status. Upon recovery, these post-senescence AML cells give rise to relapsed AMLs with increased stem cell potential.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1375
  34. Mol Cell. 2021 Jan 15. pii: S1097-2765(20)30960-6. [Epub ahead of print]
    Vrtis KB, Dewar JM, Chistol G, Wu RA, Graham TGW, Walter JC.
      DNA damage impedes replication fork progression and threatens genome stability. Upon encounter with most DNA adducts, the replicative CMG helicase (CDC45-MCM2-7-GINS) stalls or uncouples from the point of synthesis, yet eventually resumes replication. However, little is known about the effect on replication of single-strand breaks or "nicks," which are abundant in mammalian cells. Using Xenopus egg extracts, we reveal that CMG collision with a nick in the leading strand template generates a blunt-ended double-strand break (DSB). Moreover, CMG, which encircles the leading strand template, "runs off" the end of the DSB. In contrast, CMG collision with a lagging strand nick generates a broken end with a single-stranded overhang. In this setting, CMG translocates along double-stranded DNA beyond the break and is then ubiquitylated and removed from chromatin by the same pathway used during replication termination. Our results show that nicks are uniquely dangerous DNA lesions that invariably cause replisome disassembly, and they suggest that CMG cannot be stored on dsDNA while cells resolve replication stress.
    Keywords:  CMG; DNA repair; DNA replication; double-strand break; fork collapse; homologous recombination; single molecule; single-strand break
    DOI:  https://doi.org/10.1016/j.molcel.2020.12.039
  35. Redox Biol. 2021 Jan 16. pii: S2213-2317(21)00013-6. [Epub ahead of print]40 101865
    Ma J, Qian C, Bao Y, Liu MY, Ma HM, Shen MQ, Li W, Wang JJ, Bao YX, Liu Y, Ke Y, Qian ZM.
      Association of both iron/hepcidin and apolipoprotein E (ApoE) with development of Alzheimer disease (AD) and atherosclerosis led us to hypothesize that ApoE might be required for body iron homeostasis. Here, we demonstrated that ApoE knock-out (KO) induced a progressive accumulation of iron with age in the liver and spleen of mice. Subsequent investigations showed that the increased iron in the liver and spleen was due to phosphorylated extracellular regulated protein kinases (pERK) mediated up-regulation of transferrin receptor 1 (TfR1), and nuclear factor erythroid 2-related factor-2 (Nrf2)-dependent down-regulation of ferroportin 1. Furthermore, replenishment of ApoE could partially reverse the iron-related phenotype in ApoE KO mice. The findings imply that ApoE may be essential for body iron homeostasis and also suggest that clinical late-onset diseases with unexplained iron abnormality may partly be related to deficiency or reduced expression of ApoE.
    Keywords:  Apolipoprotein E knock-out (ApoE(−/-)) mice; Extracellular regulated protein kinases (Erk); Ferroportin 1 (Fpn1); Hepcidin; Iron in liver and spleen; Nuclear factor erythroid 2-related factor-2 (Nrf2); Transferrin receptor 1 (TfR1)
    DOI:  https://doi.org/10.1016/j.redox.2021.101865
  36. Biomacromolecules. 2021 Jan 24.
    Xu L, Ma F, Huang J, Frankie Leung KL, Qin C, Lu WW, Guo XE, Tang B.
      Cartilage lesion is a common tissue defect and is challenging in clinical practice. Trauma-induced cellular senescence could decrease the chondrocyte capability of maintaining cartilage tissue regeneration. A previous investigation showed that, by controlling the cellular senescence, the cartilage regeneration can be significantly accelerated. Based on this finding, we design a novel hydrogel, Alg/MH-Sr, that combines metformin, an established drug for inhibiting senescence, and strontium, an effective anti-inflammatory material for cartilage tissue engineering. A RT-PCR test suggests the significant inhibitory effect of the hydrogel on senescent, apoptotic, oxidative, and inflammatory genes' expression. Histological examinations demonstrate that the Alg/MH-Sr hydrogel accelerated cartilage repairment, and chondrocyte senescence was significantly inhibited. Our study demonstrates that the Alg/MH-Sr hydrogel is effective for cartilage defect treatment and provides a new clue in accelerating tissue repairment by inhibiting the senescence of cells and tissues.
    DOI:  https://doi.org/10.1021/acs.biomac.0c01488
  37. Nat Commun. 2021 Jan 29. 12(1): 707
    Yin Z, Burger N, Kula-Alwar D, Aksentijević D, Bridges HR, Prag HA, Grba DN, Viscomi C, James AM, Mottahedin A, Krieg T, Murphy MP, Hirst J.
      Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia-reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the "deactive" state, usually formed only after prolonged inactivity. Despite its tendency to adopt the "deactive" state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.
    DOI:  https://doi.org/10.1038/s41467-021-20942-w
  38. Exp Gerontol. 2021 Jan 20. pii: S0531-5565(21)00022-X. [Epub ahead of print]146 111247
    Daussin FN, Boulanger E, Lancel S.
      Sarcopenia is characterized by a loss of muscle mass and function that reduces mobility, diminishes quality of life, and can lead to fall-related injuries. At the intracellular level, mitochondrial population alterations are considered as key contributors to the complex etiology of sarcopenia. Mitochondrial dysfunctions lead to reactive oxygen species production, altered cellular proteostasis, and promotes inflammation. Interestingly, the receptor for advanced glycation end-products (RAGE) is a pro-inflammatory receptor involved in inflammaging. In this review, after a brief description of sarcopenia, we will describe how mitochondria and the pathways controlling mitochondrial population quality could participate to age-induced muscle mass and force loss. Finally, we will discuss the RAGE-ligand axis during aging and its possible connection with mitochondria to control inflammaging and sarcopenia.
    Keywords:  Aging; Inflammaging; Inflammation; Mitochondria; RAGE; Sarcopenia
    DOI:  https://doi.org/10.1016/j.exger.2021.111247