bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒02‒07
33 papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Aging Cell. 2021 Feb 06. e13318
      Senescence, a state of stable growth arrest, plays an important role in ageing and age-related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up-regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down-regulates p16 levels and increases the pool of p16- p21- 'reversed' cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence.
    Keywords:  EGR2; Ink4a; cellular senescence; p16; replicative lifespan; senescence; transcription factor
  2. Nat Commun. 2021 02 01. 12(1): 720
      Cellular senescence is induced by stresses and results in a stable proliferation arrest accompanied by a pro-inflammatory secretome. Senescent cells accumulate during aging, promoting various age-related pathologies and limiting lifespan. The endoplasmic reticulum (ER) inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) calcium-release channel and calcium fluxes from the ER to the mitochondria are drivers of senescence in human cells. Here we show that Itpr2 knockout (KO) mice display improved aging such as increased lifespan, a better response to metabolic stress, less immunosenescence, as well as less liver steatosis and fibrosis. Cellular senescence, which is known to promote these alterations, is decreased in Itpr2 KO mice and Itpr2 KO embryo-derived cells. Interestingly, ablation of ITPR2 in vivo and in vitro decreases the number of contacts between the mitochondria and the ER and their forced contacts induce premature senescence. These findings shed light on the role of contacts and facilitated exchanges between the ER and the mitochondria through ITPR2 in regulating senescence and aging.
  3. Aging Cell. 2021 Feb 01. e13316
      The ageing of the global population brings about unprecedented challenges. Chronic age-related diseases in an increasing number of people represent an enormous burden for health and social care. The immune system deteriorates during ageing and contributes to many of these age-associated diseases due to its pivotal role in pathogen clearance, tissue homeostasis and maintenance. Moreover, in order to develop treatments for COVID-19, we urgently need to acquire more knowledge about the aged immune system, as older adults are disproportionally and more severely affected. Changes with age lead to impaired responses to infections, malignancies and vaccination, and are accompanied by chronic, low-degree inflammation, which together is termed immunosenescence. However, the molecular and cellular mechanisms that underlie immunosenescence, termed immune cell senescence, are mostly unknown. Cellular senescence, characterised by an irreversible cell cycle arrest, is thought to be the cause of tissue and organismal ageing. Thus, better understanding of cellular senescence in immune populations at single-cell level may provide us with insight into how immune cell senescence develops over the life time of an individual. In this review, we will briefly introduce the phenotypic characterisation of aged innate and adaptive immune cells, which also contributes to overall immunosenescence, including subsets and function. Next, we will focus on the different hallmarks of cellular senescence and cellular ageing, and the detection techniques most suitable for immune cells. Applying these techniques will deepen our understanding of immune cell senescence and to discover potential druggable pathways, which can be modulated to reverse immune ageing.
    Keywords:  ageing markers; immunosenescence; methods
  4. Aging Cell. 2021 Feb 04. e13315
      Chromatin organization and transcriptional profiles undergo tremendous reordering during senescence. However, uncovering the regulatory mechanisms between chromatin reconstruction and gene expression in senescence has been elusive. Here, we depicted the landscapes of both chromatin accessibility and gene expression to reveal gene regulatory networks in human umbilical vein endothelial cell (HUVEC) senescence and found that chromatin accessibilities are redistributed during senescence. Particularly, the intergenic chromatin was massively shifted with the increased accessibility regions (IARs) or decreased accessibility regions (DARs), which were mainly enhancer elements. We defined AP-1 transcription factor family as being responsible for driving chromatin accessibility reconstruction in IARs, where low DNA methylation improved binding affinity of AP-1 and further increased the chromatin accessibility. Among AP-1 transcription factors, we confirmed ATF3 was critical to reconstruct chromatin accessibility to promote cellular senescence. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program, we identified that AP-1 was capable of reorganizing the chromatin accessibility profile to regulate senescence.
    Keywords:  AP-1; ATF3; DARs; DNA methylation; IARs; chromatin accessibility; heterochromatin; senescence
  5. Biomaterials. 2021 Jan 16. pii: S0142-9612(21)00028-4. [Epub ahead of print]269 120677
      Senescent cells drive atherosclerosis at all stages and contribute to cardiovascular disease. However, the markers in these senescent aortic plaques have not been well studied, creating a huge obstacle in the exploration of a precise and efficient system for atherosclerosis treatment. Recently, CD9 has been found to induce cellular senescence and aggravated atherosclerotic plaque formation in apolipoprotein E knockout (ApoE-/-) mice. In the present study, this result has been leveraged to develop CD9 antibody-modified, hyaluronic acid-coated mesoporous silica nanoparticles with a hyaluronidase-responsive drug release profile. In invitro models of senescent foamy macrophages and senescent endothelial cells stimulated with oxidized high-density-lipoprotein, the CD9 antibody-modified mesoporous silica nanoparticles exhibit high cellular uptake; reduce the reactive oxygen species level, high-density lipoprotein oxidation, and production of TNF-α and IL-6; and attenuate the senescence process, contributing to improved cell viability. In vivo experiment demonstrated that these nanoparticles can successfully target the senescent lesion areas, deliver the anti-senescence drug rosuvastatin to the senescent atherosclerotic plaques (mainly endothelial cells and macrophages), and alleviate the progression of atherosclerosis in ApoE-/- mice. By providing deep insight regarding the markers in senescent atherosclerotic plaque and developing a nano-system targeting this lesion area, the study proposes a novel and an accurate therapeutic approach for mitigating atherosclerosis through senescent cell clearance.
    Keywords:  Atherosclerosis; CD9; Foamy macrophage; Mesoporous silica nanoparticles; Senescence
  6. Int J Mol Sci. 2021 Feb 03. pii: 1527. [Epub ahead of print]22(4):
      Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.
    Keywords:  Bcl-xL; aging; apoptosis; centenarians; immunosenescence; senescence; senolytics
  7. Biomed Pharmacother. 2021 Feb 02. pii: S0753-3322(21)00112-8. [Epub ahead of print]137 111327
      Increased life expectancies have significantly increased the number of individuals suffering from geriatric neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The financial cost for current and future patients with these diseases is overwhelming, resulting in substantial economic and societal costs. Unfortunately, most recent high-profile clinical trials for neurodegenerative diseases have failed to obtain efficacious results, indicating that novel approaches are desperately needed to treat these pathologies. Cell senescence, characterized by permanent cell cycle arrest, resistance to apoptosis, mitochondrial alterations, and secretion of senescence-associated secretory phenotype (SASP) components, has been extensively studied in mitotic cells such as fibroblasts, which is considered a hallmark of aging. Furthermore, multiple cell types in the senescent state in the brain, including neurons, microglia, astrocytes, and neural stem cells, have recently been observed in the context of neurodegenerative diseases, suggesting that these senescent cells may play an essential role in the pathological processes of neurodegenerative diseases. Therefore, this review begins by outlining key aspects of cell senescence constitution followed by examining the evidence implicating senescent cells in neurodegenerative diseases. In the final section, we review how cell senescence may be targeted as novel therapeutics to treat pathologies associated with neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Cell senescence; Multiple sclerosis; Neurodegenerative disease; Parkinson’s disease; Senolytics
  8. Ageing Res Rev. 2021 Feb 01. pii: S1568-1637(21)00011-8. [Epub ahead of print] 101264
      The metazoan nucleus is a highly structured organelle containing several well-defined sub-organelles. It is the largest organelle inside a cell taking up from one tenth to half of entire cell volume. This makes it one of the easiest organelles to identify and study under the microscope. Abnormalities in the nuclear morphology and architecture are commonly observed in an aged and senescent cell. For example, the nuclei enlarge, loose their shape, appear lobulated, harbour nuclear membrane invaginations, carry enlarged/fragmented nucleolus, loose heterochromatin, etc. In this review we discuss about the age-related changes in nuclear features and elaborate upon the molecular reasons driving the change. Many of these changes can be easily imaged under a microscope and analysed in silico. Thus, computational image analysis of nuclear features appears to be a promising tool to evaluate physiological age of a cell and offers to be a legitimate biomarker. It can be used to examine progression of age-related diseases and evaluate therapies.
    Keywords:  Biomarker; Nuclear architecture; Nuclear integrity; Nuclear morphology; Senescence
  9. Curr Protoc. 2021 Feb;1(2): e32
      Cellular senescence is a complex stress response that induces an essentially permanent cell cycle arrest and a complex secretory phenotype termed the senescence-associated secretory phenotype (SASP), which drives numerous aging pathologies. Characterization of the SASP can provide insights into aging and disease mechanisms, aging biomarker candidates, and targets for counteracting the deleterious effects of senescent cells. Here we describe a mass spectrometry (MS)-compatible protocol to (1) generate senescent cells using different stimuli, (2) collect conditioned medium containing proteins secreted by senescent cells (i.e., SASP), and (3) prepare the SASP for quantitative proteomic analysis using data-independent acquisition (DIA) MS. © 2021 The Authors. Basic Protocol 1: Generating ionizing radiation-induced senescent and control cells Alternate Protocol 1: Generating doxorubicin-induced senescent and control cells Alternate Protocol 2: Generating oncogenic RAS-induced senescent and control cells Alternate Protocol 3: Generating mitochondrial dysfunction-induced senescent and control cells Alternate Protocol 4: Generating atazanavir/ritonavir-induced senescent and control cells Support Protocol: A multiple-assay approach to confirm the phenotype of senescent cells Basic Protocol 2: Generating conditioned medium from senescent cells cultured in low serum and quiescent control cells Alternate Protocol 5: Generating conditioned medium from senescent cells cultured in complete medium and quiescent control cells Basic Protocol 3: Quantitative proteomic analysis of the SASP.
    Keywords:  aging; data-independent acquisition; mass spectrometry; quantitative proteomic analysis; secretome; senescence
  10. J Gerontol A Biol Sci Med Sci. 2021 Feb 02. pii: glab028. [Epub ahead of print]
      BACKGROUND: Cell senescence is implicated in numerous age-related conditions. Drugs and nutritional supplements developed for a variety of purposes kill senescent cells (senolytics) or suppress their secretions (senomorphics). There is interest in repurposing such drugs to treat or prevent age-related diseases. To date, only small-scale preliminary trials have been conducted.METHODS: At a workshop convened by the National Institute on Aging in August 2019, academic, industry and government scientists reviewed issues for Phase II trials of potentially repurposable drugs, or dietary supplements, to assess benefits and risks of their senolytic (killing senescent cells) or senomorphic (altering senescent cells' phenotypes) effects in treating or preventing age-related conditions.
    RESULTS: Participants reviewed mechanisms and effects of cellular senescence, senolytics and senomorphics of several classes and their potential role in treating or preventing disease, modulators of the senescence-associated secretory phenotype (SASP), needs for senescence markers, data and specimen resources, infrastructure for planning trials, and potential effects on outcomes in older patients with multimorbidity and polypharmacy.
    CONCLUSIONS: Participants noted the importance of considering potential effects of candidate drugs on multiple aging outcomes. It is important to assess drugs' specificity for killing senescent cells and the balance between senolytic and cytotoxic effects. Markers of specific senescent cell types are needed to assess intervention responses. There are potential interactions with coexisting diseases and their treatments in older persons. Standardized measures could enhance comparisons and pooling of data. Additional characterization of human cell senescent phenotypes is needed for developing better and more specific senolytics and senomorphics.
    Keywords:  cell senescence; clinical trials; geroscience
  11. Mech Ageing Dev. 2021 Jan 30. pii: S0047-6374(21)00015-4. [Epub ahead of print] 111443
      Caloric restriction (CR) can prolong aged skeletal muscle function, yet the molecular mechanisms are not completely understood. We performed phosphoproteomic analysis on muscle from young and old mice fed an ad libitum diet, and old mice fed a CR diet. CR promoted a youthful phosphoproteomic signature, suppressing several known "pro-aging" pathways including Protein kinase A (PKA). This study validates global signaling changes in skeletal muscle during CR.
    Keywords:  Aging; Caloric restriction; PKA; Phosphoproteome; mice
  12. Aging Cell. 2021 Feb 01. e13317
      Mesenchymal stem cells (MSCs) are promising source of cell-based regenerative therapy. In consideration of the risk of allosensitization, autologous MSC-based therapy is preferred over allogenic transplantation in patients with chronic kidney disease (CKD). However, it remains uncertain whether adequate cell functionality is maintained under uremic conditions. As chronic inflammation and oxidative stress in CKD may lead to the accumulation of senescent cells, we investigated cellular senescence of CKD MSCs and determined the effects of metformin on CKD-associated cellular senescence in bone marrow MSCs from sham-operated and subtotal nephrectomized mice and further explored in adipose tissue-derived MSCs from healthy kidney donors and patients with CKD. CKD MSCs showed reduced proliferation, accelerated senescence, and increased DNA damage as compared to control MSCs. These changes were significantly attenuated following metformin treatment. Lipopolysaccharide and transforming growth factor β1-treated HK2 cells showed lower tubular expression of proinflammatory and fibrogenesis markers upon co-culture with metformin-treated CKD MSCs than with untreated CKD MSCs, suggestive of enhanced paracrine action of CKD MSCs mediated by metformin. In unilateral ureteral obstruction kidneys, metformin-treated CKD MSCs more effectively attenuated inflammation and fibrosis as compared to untreated CKD MSCs. Thus, metformin preconditioning may exhibit a therapeutic benefit by targeting accelerated senescence of CKD MSCs.
    Keywords:  DNA damage; chronic kidney disease; mesenchymal stem cells; metformin; senescence
  13. Adv Exp Med Biol. 2021 ;1275 71-100
      Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the "Hayflick limit", and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double-stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length-associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell-cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.
    Keywords:  Ataxia- and Rad3-related (ATR); Ataxia-telangiectasia mutated (ATM); DNA damage response (DDR); DNA double-strand breaks (DSBs); Hayflick limit; Homologous recombination (HR); Homology directed repair (HDR); Human telomeric reverse transcriptase (hTERT); Nonhomologous end joining (NHEJ); Shelterin complex; T-loop; Telomerase; Telomere; telomeric repeat binding factor 2 (TRF2)
  14. Can J Physiol Pharmacol. 2021 Feb 02.
      AIM: Vascular endothelial cell senescence is a leading cause of age-associated diseases and cardiovascular diseases. Interventions and therapies targeting endothelial cell senescence and dysfunction would have important clinical implications. This study was aimed to evaluate the effect of 10 resveratrol analogues, including pterostilbene (Pts) and its derivatives, against endothelial senescence and dysfunction.METHODS AND RESULTS: All the tested compounds at the concentrations from 10-9 M to 10-6 M did not show cytotoxicity in endothelial cells. Among the 10 resveratrol analogues, Pts and Pts nicotinate attenuated the expression of senescence-associated β-galactosidase, downregulated p21 and p53, and increased the production of NO in both angiotensin II and H2O2-induced endothelial senescence models. In addition, Pts and Pts nicotinate elicited endothelium-dependent relaxations. Pts and Pts nicotinate did not alter Sirtuin 1 (SIRT1) expression but enhanced its activity. Both Pts and Pts nicotinate have high binding activities with SIRT1. Inhibition of SIRT1 by sirtinol reversed the anti-senescent effects of Pts and Pts nicotinate.
    CONCLUSIONS: This study suggests that the Pts and Pts nicotinate ameliorated vascular endothelial senescence and elicited endothelium-dependent relaxations via activation of SIRT1. These two compounds maybe potential drugs for the treatment of cardiovascular diseases related to endothelial senescence and dysfunction.
  15. Elife. 2021 Jan 28. pii: e65286. [Epub ahead of print]10
      eLife is publishing a special issue on aging, geroscience and longevity to mark the rapid progress made in this field over the past decade, both in terms of mechanistic understanding and translational approaches that are poised to have clinical impact on age-related diseases.
    Keywords:  aging; cell biology; geroscience; longevity; medicine
  16. J Cell Sci. 2021 Feb 01. pii: jcs.253203. [Epub ahead of print]
      Senescence is a tumor suppressor phenomenon. We have earlier shown that therapy induced senescence in residual disease glioblastoma (GBM) cells can reverse leading to relapse. Here we demonstrate that ciprofloxacin induced senescence in glioma-derived cell lines and primary cultures defined by β-gal positivity, SASP release, giant-cell formation, higher ROS, p-ATM, γ-H2AX, and senescence gene signature have three stages- initiation, pseudo-senescence and permanent-senescence. Drug withdrawal during initiation and pseudo-senescence reinitiated proliferation in vitro and tumor formation in vivo Importantly, prolonged ciprofloxacin treatment induced permanent-senescence that failed to reverse following drug withdrawal. RNA-Seq revealed downregulated p65 transcription network and incremental SMAD pathway genes expression from initiation to permanent-senescence. Drug withdrawal at initiation and pseudo-senescence but not permanent-senescence increased p65 nuclear localization, and escape from senescence. In contrast, permanent-senescent cells showed loss of nuclear p65 and increased apoptosis. Pharmacological or genetic p65 knockdown upholds senescence in vitro and inhibit tumor formation in vivo Together, this study demonstrates that levels of nuclear p65 defines the window of therapy induced senescence reversibility and coupling senotherapeutic drugs with p65 inhibitors induce permanent-senescence in GBM cells.
    Keywords:  Accelerated Senescence; Reactive oxygen species; SMADs; Therapy induced senescence/Reversible Senescence; p65
  17. Front Cell Dev Biol. 2020 ;8 620089
      Mammalian development involves an exquisite choreography of cell division, differentiation, locomotion, programmed cell death, and senescence that directs the transformation of a single cell zygote to a mature organism containing on the order of 40 trillion cells in humans. How a single totipotent zygote undergoes the rapid stages of embryonic development to form over 200 different cell types is complex in the extreme and remains the focus of active research. Processes such as programmed cell death or apoptosis has long been known to occur during development to help sculpt organs and tissue systems. Other processes such as cellular senescence, long thought to only occur in pathologic states such as aging and tumorigenesis have been recently reported to play a vital role in development. In this review, we focus on apoptosis and senescence; the former as an integral mechanism that plays a critical role not only in mature organisms, but that is also essential in shaping mammalian development. The latter as a well-defined feature of aging for which some reports indicate a function in development. We will dissect the dual roles of major gene families, pathways such as Hox, Rb, p53, and epigenetic regulators such as the ING proteins in both early and the late stages and how they play antagonistic roles by increasing fitness and decreasing mortality early in life but contribute to deleterious effects and pathologies later in life.
    Keywords:  Hox proteins; ING proteins; apoptosis; cancer; development; epigenetics; retinoblastoma; senescence
  18. Cell Prolif. 2021 Feb 01. e12991
      OBJECTIVE: Premature senescence is related to progerin and involves in endothelial dysfunction and liver diseases. Activating sirtuin 1 (SIRT1) ameliorates liver fibrosis. However, the mechanisms of premature senescence in defenestration of hepatic sinusoidal endothelial cells (HSECs) and how SIRT1 affects HSECs fenestrae remain elusive.METHODS: We employed the CCl4 -induced liver fibrogenesis rat models and cultured primary HSECs in vitro, administered with the SIRT1-adenovirus vector, the activator of SIRT1 and knockdown NOX2. We measured the activity of senescence-associated β-galactosidase (SA-β-gal) in HSECs. Meanwhile, the protein expression of SIRT1, NOX2, progerin, Lamin A/C, Ac p53 K381 and total p53 was detected by Western blot, co-immunoprecipitation and immunofluorescence.
    RESULTS: In vivo, premature senescence was triggered by oxidative stress during CCl4 -induced HSECs defenestration and liver fibrogenesis, whereas overexpressing SIRT1 with adenovirus vector lessened premature senescence to relieve CCl4 -induced HSECs defenestration and liver fibrosis. In vitro, HSECs fenestrae disappeared, with emerging progerin-associated premature senescence; these effects were aggravated by H2 O2 . Nevertheless, knockdown of NOX2, activation of SIRT1 with resveratrol and SIRT1-adenovirus vector inhibited progerin-associated premature senescence to maintain fenestrae through deacetylating p53. Furthermore, more Ac p53 K381 and progerin co-localized with the abnormal accumulation of actin filament (F-actin) in the nuclear envelope of H2 O2 -treated HSECs; in contrast, these effects were rescued by overexpressing SIRT1.
    CONCLUSION: SIRT1-mediated deacetylation maintains HSECs fenestrae and attenuates liver fibrogenesis through inhibiting oxidative stress-induced premature senescence.
    Keywords:  defenestration; hepatic sinusoidal endothelial cell; premature senescence; progerin; sirtuin 1
  19. J Invest Dermatol. 2021 Jan 28. pii: S0022-202X(20)32364-2. [Epub ahead of print]
      Aging can be defined as a state of progressive functional decline accompanied by an increase in mortality. Time-dependent accumulation of cellular damage, namely lesions and mutations in the DNA and misfolded proteins, impair organellar and cellular function. Ensuing cell fate alterations lead to the accumulation of dysfunctional cells and hamper homeostatic processes, thus limiting regenerative potential; trigger low-grade inflammation; and alter intercellular and intertissue communication. The accumulation of molecular damage together with modifications in the epigenetic landscape, dysregulation of gene expression, and altered endocrine communication, drive the aging process and establish age as the main risk factor for age-associated diseases and multimorbidity.
  20. Transl Res. 2021 Jan 27. pii: S1931-5244(21)00022-0. [Epub ahead of print]
      The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir and/or ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an antiapoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence.
  21. PLoS One. 2021 ;16(1): e0245235
      The use of agents that target both glia and neurons may represent a new strategy for the treatment of ageing disorders. Here, we confirmed the presence of the novel cyclic peptide Naturido that originates from a medicinal fungus (Isaria japonica) grown on domestic silkworm (Bombyx mori). We found that Naturido significantly enhanced astrocyte proliferation and activated the single copy gene encoding the neuropeptide VGF and the neuron-derived NGF gene. The addition of the peptide to the culture medium of primary hippocampal neurons increased dendrite length, dendrite number and axon length. Furthermore, the addition of the peptide to primary microglial cultures shifted CGA-activated microglia towards anti-inflammatory and neuroprotective phenotypes. These findings of in vitro glia-neuron interactions led us to evaluate the effects of oral administration of the peptide on brain function and hair ageing in senescence-accelerated mice (SAMP8). In vivo analyses revealed that spatial learning ability and hair quality were improved in Naturido-treated mice compared with untreated mice, to the same level observed in the normal ageing control (SAMR1). These data suggest that Naturido may be a promising glia-neuron modulator for the treatment of not only senescence, but also Alzheimer's disease and other neurodegenerative diseases.
  22. BMC Biol. 2021 Feb 01. 19(1): 19
      BACKGROUND: Hematopoietic stem cells (HSCs) are the guarantor of the proper functioning of hematopoiesis due to their incredible diversity of potential. During aging, heterogeneity of HSCs changes, contributing to the deterioration of the immune system. In this study, we revisited mouse HSC compartment and its transcriptional plasticity during aging at unicellular scale.RESULTS: Through the analysis of 15,000 young and aged transcriptomes, we identified 15 groups of HSCs revealing rare and new specific HSC abilities that change with age. The implantation of new trajectories complemented with the analysis of transcription factor activities pointed consecutive states of HSC differentiation that were delayed by aging and explained the bias in differentiation of older HSCs. Moreover, reassigning cell cycle phases for each HSC clearly highlighted an imbalance of the cell cycle regulators of very immature aged HSCs that may contribute to their accumulation in an undifferentiated state.
    CONCLUSIONS: Our results establish a new reference map of HSC differentiation in young and aged mice and reveal a potential mechanism that delays the differentiation of aged HSCs and could promote the emergence of age-related hematologic diseases.
    Keywords:  Aging; Cell cycle; Differentiation; Hematopoietic stem cell; Single-cell RNA-seq; Trajectories
  23. J Cell Sci. 2021 Feb 01. pii: jcs.252080. [Epub ahead of print]
      There is compelling evidence that senescent cells, through the senescence-associated secretory phenotype (SASP), can promote malignant transformation and invasion. IL-1 is a key mediator of this cytokine network, but the control of its activity in the senescence program has not been elucidated. IL-1 signalling is regulated by IL-1RA, which has four variants. Here, we show that expression of intracellular IL-1RA type 1 (icIL-1RA1), which competitively inhibits binding of IL-1 to its receptor, is progressively lost during oral carcinogenesis ex vivo and that the pattern of expression is associated with keratinocyte replicative fate in vitro We demonstrate icIL-1RA1 is an important regulator of the SASP in mortal cells, as CRISPR-CAS9 mediated icIL-1RA1 knockdown in normal and mortal dysplastic oral keratinocytes is followed by increased IL-6 and IL-8 secretion, and rapid senescence following release from ROCK inhibition. Thus, we suggest that downregulation of icIL-1RA1 in early stages of the carcinogenesis process can enable the development of a premature and de-regulated SASP, creating a pro-inflammatory state in which cancer is more likely to arise.
    Keywords:  Head and neck cancer; IL-1RA; Interleukin 1 receptor antagonist; SASP; Senescence
  24. Brief Bioinform. 2021 Feb 01. pii: bbaa439. [Epub ahead of print]
      Aging is the largest risk factor of major human diseases. Long noncoding RNAs (lncRNAs) as the key regulatory elements have shown a strong impact on multiple biological processes as well as human disease mechanisms. However, the roles of lncRNAs in aging/healthy aging processes remain largely unknown. Centenarians are good models for healthy aging studies due to avoiding major chronic diseases and disabilities. To illustrate their ubiquitous nature in the genome and the 'secrets' of healthy aging regulation from the perspective of lncRNAs, peripheral blood samples from two regions consisting 76 centenarians (CENs), 54 centenarian-children (F1) and 41 spouses of centenarian-children (F1SP) were collected for deep RNA-seq. We identified 11 CEN-specific lncRNAs that is particularly expressed in longevous individuals. By kmers clustering, hundreds of human lncRNAs show similarities with CEN-specific lncRNAs, especially with ENST00000521663 and ENST00000444998. Using F1SP as normal elder controls (age: 59.9 ± 6.6 years), eight lncRNAs that are differentially expressed in longevous elders (CEN group, age: 102.2 ± 2.4 years) were identified as candidate aging/health aging-related lncRNAs (car-lncs). We found that the expression of eight car-lncs in human diploid fibroblasts displayed dynamic changes during cell passage and/or H2O2/rapamycin treatment; of which, overexpression either of THBS1-IT1 and THBS1-AS1, two lncRNAs that highly expressed in CENs, can remarkably decrease p16, p21 and the activity of senescent related β-galactosidase, suggesting that THBS1-IT1 and THBS1-AS1 can inhibit cellular senescence. We provided the first comprehensive analysis of lncRNA expression in longevous populations, and our results hinted that dysregulated lncRNAs in CENs are potential protective factors in healthy aging process.
    Keywords:  aging; centenarians; healthy aging; long noncoding RNA; transcriptome
  25. J Int Med Res. 2021 Feb;49(2): 300060520986049
      OBJECTIVE: The primary aim of our study was to explore the mechanisms through which long non-coding RNA (lncRNA)-mediated sirtuin-1 (SIRT1) signaling regulates type II alveolar epithelial cell (AECII) senescence induced by a cigarette smoke-media suspension (CSM).METHODS: Pharmacological SIRT1 activation was induced using SRT2104 and senescence-associated lncRNA 1 (SAL-RNA1) was overexpressed. The expression of SIRT1, FOXO3a, p53, p21, MMP-9, and TIMP-1 in different groups was detected by qRT-PCR and Western blotting; the activity of SA-β gal was detected by staining; the binding of SIRT1 to FOXO3a and p53 gene transcription promoters was detected by Chip.
    RESULTS: We found that CSM increased AECII senescence, while SAL-RNA1 overexpression and SIRT1 activation significantly decreased levels of AECII senescence induced by CSM. Using chromatin immunoprecipitation, we found that SIRT1 bound differentially to transcriptional complexes on the FOXO3a and p53 promoters.
    CONCLUSION: Our results suggested that lncRNA-SAL1-mediated SIRT1 signaling reduces senescence of AECIIs induced by CSM. These findings suggest a new therapeutic target to limit the irreversible apoptosis of lung epithelial cells in COPD patients.
    Keywords:  Chronic obstructive pulmonary disease; alveolar epithelial cells; cellular senescence; cigarette smoke; long non-coding RNA; sirtuin-1
  26. Int J Mol Sci. 2021 Jan 28. pii: 1276. [Epub ahead of print]22(3):
      Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein that accelerates p16-dependent cellular senescence in vitro. We recently reported the ability of CREG1 to stimulate brown adipogenesis using adipocyte P2-CREG1-transgenic (Tg) mice; however, little is known about the effect of CREG1 on aging-associated phenotypes. In this study, we investigated the effects of CREG1 on age-related obesity and renal dysfunction in Tg mice. Increased brown fat formation was detected in aged Tg mice, in which age-associated metabolic phenotypes such as body weight gain and increases in blood glucose were improved compared with those in wild-type (WT) mice. Blood CREG1 levels increased significantly in WT mice with age, whereas the age-related increase was suppressed, and its levels were reduced, in the livers and kidneys of Tg mice relative to those in WT mice at 25 months. Intriguingly, the mRNA levels of Ink4a, Arf, and senescence-associated secretory phenotype (SASP)-related genes and p38MAPK activity were significantly lowered in the aged kidneys of Tg mice, in which the morphological abnormalities of glomeruli as well as filtering function seen in WT kidneys were alleviated. These results suggest the involvement of CREG1 in kidney aging and its potential as a target for improving age-related renal dysfunction.
    Keywords:  CREG1; age-related obesity; brown adipocyte; cellular senescence; renal dysfunction
  27. Aging Cell. 2021 Feb 01. e13310
      With age, the epidermis becomes hypoplastic and hypoproliferative. Hypoproliferation due to aging has been associated with decreased stem cell (SC) self-renewal in multiple murine tissues. The fate of SC self-renewal divisions can be asymmetric (one SC, one committed progenitor) or symmetric (two SCs). Increased asymmetric SC self-renewal has been observed in inflammatory-mediated hyperproliferation, while increased symmetric SC self-renewal has been observed in cancers. We analyzed SC self-renewal divisions in aging human epidermis to better understand the role of SCs in the hypoproliferation of aging. In human subjects, neonatal to 78 years, there was an age-dependent decrease in epidermal basal layer divisions. The balance of SC self-renewal shifted toward symmetric SC self-renewal, with a decline in asymmetric SC self-renewal. Asymmetric SC divisions maintain epidermal stratification, and this decrease may contribute to the hypoplasia of aging skin. P53 decreases in multiple tissues with age, and p53 has been shown to promote asymmetric SC self-renewal. Fewer aged than adult ALDH+CD44+ keratinocyte SCs exhibited p53 expression and activity and Nutlin-3 (a p53 activator) returned p53 activity as well as asymmetric SC self-renewal divisions to adult levels. Nutlin-3 increased Notch signaling (NICD, Hes1) and DAPT inhibition of Notch activation prevented Nutlin-3 (p53)-induced asymmetric SC self-renewal divisions in aged keratinocytes. These studies indicate a role for p53 in the decreased asymmetric SC divisions with age and suggest that in aged keratinocytes, Notch is required for p53-induced asymmetric SC divisions.
    Keywords:  asymmetric division; epidermis; keratinocyte; p53; self-renewal; stem cell
  28. Elife. 2021 Feb 02. pii: e63284. [Epub ahead of print]10
      A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of Zmpste24-deficient mice. However, we don't know whether Icmt inactivation improves phenotypes in an authentic HGPS mouse model. Moreover, it is unknown whether pharmacologic targeting of ICMT would be tolerated by cells and produce similar cellular effects as genetic inactivation. Here, we show that knockout of Icmt improves survival of HGPS mice and restores vascular smooth muscle cell numbers in the aorta. We also synthesized a potent ICMT inhibitor called C75 and found that it delays senescence and stimulates proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS.
    Keywords:  HGPS; ICMT; cell biology; inhibitor; methylation; mouse; progeria; senescence
  29. Sci Adv. 2021 Jan;pii: eabc7409. [Epub ahead of print]7(1):
      Inflammation is a hallmark of aging and is negatively affecting female fertility. In this study, we evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in WT mice during reproductive aging. High expression of NLRP3, caspase-1, and IL-1β was also observed in granulosa cells from patients with ovarian insufficiency. Ablation of NLRP3 improved the survival and pregnancy rates and increased anti-Müllerian hormone levels and autophagy rates in ovaries. Deficiency of NLRP3 also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3-/- mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.
  30. FEBS J. 2021 Feb 02.
      Regulatory T (Treg) cells are critical for the maintenance of immune homeostasis. Dysregulation of Treg cells has been implicated in the pathogenesis of autoimmunity and chronic inflammation, while aging is characterized by an accumulation of inflammatory markers in the peripheral blood, a phenomenon known as "inflammaging". The relationship between Treg cells and age-related diseases remains to be further studied. Increasing evidence revealed that Treg cells disfunction occurs in aged patients, suggesting that immune therapies targeting Treg cells may be a promising approach to treat diseases like cancers and autoimmune diseases. Furthermore, drugs targeting Treg cells show encouraging results and contribute to CD8+ T-cell-mediated cytotoxic killing of tumor and infected cells. In general, a better understanding of Treg cell function may help us to develop new immune therapies against ageing. In this review, we discuss potential therapeutic strategies to modify immune responses of relevance for aging to prevent and treat age-related diseases, as well as the challenges posed by the translation of novel immune therapies into clinical practice.
    Keywords:  Regulatory T cells; Treg-based immune therapy; age-related diseases
  31. Science. 2021 Feb 04. pii: eabc5386. [Epub ahead of print]
      The cyclic GMP-AMP synthase (cGAS) detects microbial and self-DNA in the cytosol to activate immune and inflammatory programs. cGAS also associates with chromatin especially after nuclear envelope breakdown when cells enter mitosis. How cGAS is regulated during cell cycle transition is not clear. Here we found direct biochemical evidence that cGAS activity was selectively suppressed during mitosis, and uncovered two parallel mechanisms underlying this suppression. First, cGAS was hyperphosphorylated at the N terminus by mitotic kinases, including Aurora kinase B. The N terminus of cGAS was critical for sensing nuclear chromatin, but not mitochondrial DNA. Chromatin sensing was blocked by hyperphosphorylation. Secondly, oligomerization of chromatin-bound cGAS, which is required for its activation,was prevented. Together, these mechanisms ensure that cGAS is inactive when associated with chromatin during mitosis, which may help to prevent autoimmune reaction.
  32. Int J Biochem Cell Biol. 2021 Jan 30. pii: S1357-2725(21)00016-9. [Epub ahead of print] 105932
      OBJECTIVE: Obesity is now a worldwide disease and is mainly attributable to increased body fat deposition. In a growing number of epidemiological studies, lutein has been revealed to have different degrees of anti-obesity properties, but the potential underlying mechanisms that have been reported are limited. Therefore, we aimed to clarify the protective effects of lutein against excessive lipid accumulation, and we explored the role of SIRT1 and SIRT1-mediated pathways both in abdominal adipose tissue and mature 3T3-L1 cells during lutein administration.METHODS: In our design, male Sprague-Dawley rats were fed either control or high-fat diets with or without 25 mg/kg·bw/day lutein for 5 weeks. Additionally, differentiated 3T3-L1 cells were incubated with 40 µM lutein or 10 µM Ex527 for 24 h.
    RESULTS: Lutein supplementation decreased the body weight, abdominal fat index ratio, frequency and mean area of larger adipocytes in HE staining induced by the high-fat diet and then activated the expression of SIRT1 and thus upregulated FoxO1, ATGL, and HSL expression and downregulated SREBP-1, FAS, and ACC expression both in abdominal adipose tissue and differentiated 3T3-L1 cells. However, coincubation with Ex527 and lutein suppressed the activation of SIRT1 and reversed the expression of FoxO1, ATGL, HSL, SREBP-1, FAS, and ACC in comparison to those in the Lut group.
    CONCLUSIONS: Overall, we suggest that the effects of lutein on attenuating excessive lipid accumulation are dependent on the SIRT1-mediated pathway in vivo and in vitro, which indicates that lutein administration may be a potential strategy for preventing excessive lipid accumulation and obesity.
    Keywords:  Abdominal adipose tissue; Differentiated 3T3-L1 cells; Lipid accumulation; Lutein; Sirtuin 1
  33. J Cell Biochem. 2021 Jan 31.
      Recent advances in the yeast Saccharomyces cerevisiae and higher eukaryotes have been increasingly connecting lipid droplet (LD) dynamics to the regulation of autophagy. In this review we will discuss implications that connect LD de novo synthesis and LD mobilization to autophagy and how autophagy is regulated by these mechanisms. Elucidating these connections might pose a chance to further understand autophagy induction and membrane biogenesis for the growing autophagosome under different conditions. Increasing our understanding of these mechanisms might provide a chance to understand several conditions that might be related to LD dysregulation and, possibly, as a consequence of this, dysregulation of autophagy.
    Keywords:  autophagy; lipid droplets; lipolysis; lipophagy; mammals; yeast