bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒02‒27
fifty-one papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Cells. 2022 Feb 15. pii: 672. [Epub ahead of print]11(4):
      Senescence is a complex cellular stress response that abolishes proliferative capacity and generates a unique secretory pattern that is implicated in organismal aging and age-related disease. How a cell transitions to a senescent state is multifactorial and often requires transcriptional regulation of multiple genes. Epigenetic alterations to DNA and chromatin are powerful regulators of genome architecture and gene expression, and they play a crucial role in mediating the induction and maintenance of senescence. This review will highlight the changes in chromatin, DNA methylation, and histone alterations that establish and maintain cellular senescence, alongside the specific epigenetic regulation of the senescence-associated secretory phenotype (SASP).
    Keywords:  DNA methylation; SASP; aging; epigenetics; histone modification; senescence
  2. Int J Mol Sci. 2022 Feb 11. pii: 1989. [Epub ahead of print]23(4):
      Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases. The mechanism underlying the aging-related susceptibility to LOAD is unknown. Cellular senescence, a state of permanent cell growth arrest, is believed to contribute importantly to aging and aging-related diseases, including AD. Senescent astrocytes, microglia, endothelial cells, and neurons have been detected in the brain of AD patients and AD animal models. Removing senescent cells genetically or pharmacologically ameliorates β-amyloid (Aβ) peptide and tau-protein-induced neuropathologies, and improves memory in AD model mice, suggesting a pivotal role of cellular senescence in AD pathophysiology. Nonetheless, although accumulated evidence supports the role of cellular senescence in aging and AD, the mechanisms that promote cell senescence and how senescent cells contribute to AD neuropathophysiology remain largely unknown. This review summarizes recent advances in this field. We believe that the removal of senescent cells represents a promising approach toward the effective treatment of aging-related diseases, such as AD.
    Keywords:  Alzheimer’s disease; aging; cellular senescence; late-onset Alzheimer’s disease (LOAD); neurodegeneration; oxidative stress; plasminogen activator inhibitor 1 (PAI-1); tauopathy; telomere shortening; β-amyloid peptides (Aβ)
  3. Cell Mol Life Sci. 2022 Feb 26. 79(3): 155
      Cellular senescence is closely related to tissue aging including bone. Bone homeostasis is maintained by the tight balance between bone-forming osteoblasts and bone-resorbing osteoclasts, but it undergoes deregulation with age, causing age-associated osteoporosis, a main cause of which is osteoblast dysfunction. Oxidative stress caused by the accumulation of reactive oxygen species (ROS) in bone tissues with aging can accelerate osteoblast senescence and dysfunction. However, the regulatory mechanism that controls the ROS-induced senescence of osteoblasts is poorly understood. Here, we identified Peptidyl arginine deiminase 2 (PADI2), a post-translational modifying enzyme, as a regulator of ROS-accelerated senescence of osteoblasts via RNA-sequencing and further functional validations. PADI2 downregulation by treatment with H2O2 or its siRNA promoted cellular senescence and suppressed osteoblast differentiation. CCL2, 5, and 7 known as the elements of the senescence-associated secretory phenotype (SASP) which is a secretome including proinflammatory cytokines and chemokines emitted by senescent cells and a representative feature of senescence, were upregulated by H2O2 treatment or Padi2 knockdown. Furthermore, blocking these SASP factors with neutralizing antibodies or siRNAs alleviated the senescence and dysfunction of osteoblasts induced by H2O2 treatment or Padi2 knockdown. The elevated production of these SASP factors was mediated by the activation of NFκB signaling pathway. The inhibition of NFκB using the pharmacological inhibitor or siRNA effectively relieved H2O2 treatment- or Padi2 knockdown-induced senescence and osteoblast dysfunction. Together, our study for the first time uncover the role of PADI2 in ROS-accelerated cellular senescence of osteoblasts and provide new mechanistic and therapeutic insights into excessive ROS-promoted cellular senescence and aging-related bone diseases.
    Keywords:  NFκB; Osteoblast; Peptidyl arginine deiminase 2; Reactive oxygen species; Senescence; Senescence-associated secretory phenotype
  4. iScience. 2022 Feb 18. 25(2): 103848
      Cellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.
    Keywords:  Biological sciences; Cell biology; Molecular biology; Transcriptomics
  5. J Pers Med. 2022 Feb 04. pii: 215. [Epub ahead of print]12(2):
      Atherosclerosis is probably one of the paradigms of disease linked to aging. Underlying the physiopathology of atherosclerosis are cellular senescence, oxidative stress, and inflammation. These factors are increased in the elderly and from chronic disease patients. Elevated levels of oxidative stress affect cellular function and metabolism, inducing senescence. This senescence modifies the cell phenotype into a senescent secretory phenotype. This phenotype activates immune cells, leading to chronic systemic inflammation. Moreover, due to their secretory phenotype, senescence cells present an increased release of highlighted extracellular vesicles that will change nearby/neighborhood cells and paracrine signaling. For this reason, searching for specific senescent cell biomarkers and therapies against the development/killing of senescent cells has become relevant. Recently, senomorphic and senolityc drugs have become relevant in slowing down or eliminating senescence cells. However, even though they have shown promising results in experimental studies, their clinical use is still yet to be determined.
    Keywords:  atherosclerosis; cellular senescence; endothelial senescence; extracellular vesicles; inflammation; senolityc
  6. Endocr Rev. 2022 Feb 19. pii: bnac008. [Epub ahead of print]
      Over 2.1 million age-related fractures occur in the United States annually, resulting in an immense socioeconomic burden. Importantly, the age-related deterioration of bone structure is associated with impaired bone healing. Fracture healing is a dynamic process which can be divided into four stages. While the initial hematoma generates an inflammatory environment in which mesenchymal stem cells and macrophages orchestrate the framework for repair, angiogenesis and cartilage formation mark the second healing period. In the central region, endochondral ossification favors soft callus development while next to the fractured bony ends, intramembranous ossification directly forms woven bone. The third stage is characterized by removal and calcification of the endochondral cartilage. Finally, the chronic remodeling phase concludes the healing process. Impaired fracture healing due to aging is related to detrimental changes at the cellular level. Macrophages, osteocytes and chondrocytes express markers of senescence, leading to reduced self-renewal and proliferative capacity. A prolonged phase of "inflammaging" results in an extended remodeling phase, characterized by a senescent microenvironment and deteriorating healing capacity. Although there is evidence that in the setting of injury, at least in some tissues, senescent cells may play a beneficial role in facilitating tissue repair, recent data demonstrate that clearing senescent cells enhances fracture repair. In this review, we summarize the physiological as well as pathological processes during fracture healing in endocrine disease and aging in order to establish a broad understanding of the biomechanical as well as molecular mechanisms involved in bone repair.
    Keywords:  Aging; Bone; Bone healing; Fracture; Fracture healing; Osteoporosis; Senescence
  7. Acta Histochem. 2022 Feb 19. pii: S0065-1281(22)00026-5. [Epub ahead of print]124(3): 151867
      OBJECTIVES: Despite the presence of chondrogenic progenitor cells (CPCs) in knee osteoarthritis patients they are unable to repair the damaged cartilage. This study aimed to evaluate the oxidative stress, cellular senescence, and senescence-associated secretory phenotype (SASP) in the CPCs derived from osteoarthritic cartilage and compare with the CPCs of healthy articular cartilage.METHODS: Isolated CPCs were characterized based on phenotypic expression of stem cell markers, clonogenicity, and tri-lineage differentiation assay. Production of ROS was measured using DCFDA assay. Cellular senescence in CPCs was assessed by senescence-associated beta-galactosidase assay and expression of senescence markers at the gene level using real-time PCR. Morphological features associated with senescent OA-CPCs were studied using scanning electron microscopy. To study SASP, the production of inflammatory cytokines was assessed in the culture supernatant using a flow-cytometer based cytometric bead array.
    RESULTS: OA-CPCs exhibited elevated ROS levels along with a relatively high percentage of senescent cells compared to non-OA CPCs, and a positive correlation exists between ROS production and senescence. The morphological assessment of senescent CPCs revealed increased cell size and multiple nuclei in senescent OA-CPCs. These results were further validated by elevated expression of senescence genes p16, p21, and p53. Additionally, culture supernatant of senescent OA-CPCs expressed IL-6 and IL-8 cytokines indicative of SASP.
    CONCLUSIONS: Despite exhibiting similar expression of stem cell markers and clonogenicity, CPCs undergo oxidative stress in diseased knee joint leading to increased production of intracellular ROS in chondrogenic progenitor cells that support cellular senescence. Further, senescence in OA-CPCs is mediated via the release of pro-inflammatory cytokines, IL-6 and IL-8.
    Keywords:  Articular cartilage; Cellular senescence; Chondrogenic progenitor cells; Knee osteoarthritis; Senescence-associated secretory phenotype
  8. J Agric Food Chem. 2022 Feb 22.
      The induction of cellular senescence is considered as a potent strategy to suppress cancer progression. Cucurbitacin E (CE) belongs to the triterpenoids and has received substantial attention for its antineoplastic property. However, the function of CE on cellular senescence remained elusive. Herein, we revealed that CE significantly induced cellular senescence in colorectal cancer (CRC) cells. The CE effects on the cellular senescence in CRC cells were confirmed by observing the common features of the senescence, such as the enhanced activity of senescence-associated β-galactosidase, γ-H2AX positive staining, and upregulation of senescence-associated proteins including p53, p27, and p21. Moreover, CE exerted pro-senescent effects in CRC cells via attenuating the transcription factor activating enhancer-binding protein 4 (TFAP4) expression, and the ectopic expression of TFAP4 blocked the CE-induced senescence. Mechanistically, CE treatment caused a robust increase in miR-371b-5p, which markedly repressed TFAP4. In contrast, silencing of miR-371b-5p counteracted the percentages of CE-induced senescent cells from 37.49 ± 2.61 to 7.06 ± 0.91% in HCT-116 cells via derepressing TFAP4 to attenuate the expression of p53, p21, and p16. Altogether, these results demonstrated that dietary CE induces CRC cellular senescence via modulating the miR-371b-5p/TFAP4 axis and presents opportunities for potential therapeutic strategies against CRC.
    Keywords:  cellular senescence; colorectal cancer; cucurbitacin E; miR-371b-5p
  9. Front Cardiovasc Med. 2021 ;8 795747
      The aging of endothelial cells plays a critical role in the development of age-related vascular disease. We established a model of endothelial premature senescence by application of Advanced oxidation protein products (AOPPs) modified bovine serum albumin (AOPP-BSA) in human umbilical vein endothelial cells (HUVECs). This cellular senescence was accompanied with endothelial barrier dysfunction and angiogenesis impairment. It was further revealed that these senescent HUVECs underwent apoptosis evasion and the receptor for advanced glycation endproducts (RAGE) played a role in these processes. The AOPP-induced senescence was regulated by the state of autophagy in HUVECs. We further proved that AOPP-BSA attenuated the autophagy of HUVECs, led to p53 SUMOylation at K386, resulting in endothelial senescence. We also established the animal model of vascular senescence by using ApoE-/- mice fed with high-fat diet plus daily injection of AOPP-BSA to verify the role of p53 SUMOylation in vascular senescence. Combined with intraperitoneal injection of rapamycin, the effect of autophagy on AOPP-induced p53 SUMOylation was also confirmed in vivo. Our data indicates that p53 SUMOylation at K386 plays an important role in AOPP-induced endothelial senescence and apoptosis evasion, suggesting that p53 K386 SUMOylation may serve as a potential therapeutic target in protecting against vascular senescence.
    Keywords:  autophagy; endothelial senescence; evasion of apoptosis; p53 SUMOylation; vascular disease
  10. Neuroscience. 2022 Feb 22. pii: S0306-4522(22)00079-3. [Epub ahead of print]
      Chronic macrophage activation was implicated as one of the main culprits for chronical, low-grade inflammation which significantly contributes to development of age-related diseases. Microglia as the brain macrophages have been recently implicated as key players in neuroinflammation and neurodegeneration in the aged brain. Microglial cell functions are indispensable in early development, however, activation or senescence of microglia in aging cells may be detrimental. Depletion of microglia using genetical or pharmacological approaches leads to opposite results regarding effects on brain cognition. In this study we pharmacologically depleted microglia using orally delivered low and high doses of the CSF1R inhibitor PLX5622 and assessed the expression levels of known inflammation markers (TNF-α, IL1-β, IL-6, IL-10), glia markers (Iba-1 and Gfap) and specific senescence marker p16Ink4a in the aged murine brain. Our results indicate that treatment with low and high doses of PLX5622 leads to a dose-dependent depletion of microglial cells with similar levels in young and aged mice. We also show that treatment with low and high PLX5622 differentially affected cytokine levels in young and old brains. By using low doses we could achieve reduction in inflammation circumventing the astrocyte activation. Removal of microglia cells led to decreased expression of the senescence marker p16Ink4a in the aged brain, indicating a relevant contribution of these cells to the expression of this marker and their senescent status in the healthy aging brain. Our results indicate that increased and detrimental brain inflammation in aged murine brain can be impaired by selectively reducing the microglial cell population.
    Keywords:  Aging; Depletion; Inflammaging; Microglia; PLX5622; Senescence
  11. Mol Biol Cell. 2022 Feb 23. mbcE20080523
      Cellular senescence is a terminal cell fate characterized by growth arrest, and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction and rapamycin. This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence, but continued to divide at a slow rate even at high passage, in contrast to either rapamycin treatment or methionine restriction, both of which extended lifespan but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism, including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence.
  12. Aging Cell. 2022 Feb 23. e13574
      Aging is an independent risk factor for acute kidney injury and subsequent chronic kidney diseases, while the underlying mechanism is still elusive. Here, we found that renal tubules highly express a conserved lysosomal endopeptidase, legumain, which is significantly downregulated with the growing of age. Tubule-specific legumain-knockout mice exhibit spontaneous renal interstitial fibrosis from the 3rd month. In the tubule-specific legumain-knockout mice and the cultured legumain-knockdown HK-2 cells, legumain deficiency induces the activation of tubular senescence and thus increases the secretion of profibrotic senescence-associated cytokines, which in turn accelerates the activation of fibroblasts. Blockage of senescence mitigates the fibrotic lesion caused by legumain deficiency. Mechanistically, we found that silencing down of legumain leads to the elevated lysosome pH value, enlargement of lysosome size, and increase of lysosomal voltage dependent membrane channel proteins. Either legumain downregulation or aging alone induces the activation of nuclear transcription factors EB (TFEB) while it fails to further upregulate in the elderly legumain-knockdown tubules, accompanied with impaired mitophagy and increased mitochondrial ROS (mtROS) accumulation. Therapeutically, supplementation of exosomal legumain ameliorated fibronectin and collagen I production in an in vitro coculture system of tubular cells and fibroblasts. Altogether, our data demonstrate that loss of legumain in combined with aging dysregulates lysosomal homeostasis, although either aging or legumain deficiency alone induces lysosome adaptation via stimulating lysosomal biogenesis. Consequently, impaired mitophagy leads to mtROS accumulation and therefore activates tubular senescence and boosts the interstitial fibrosis.
    Keywords:  aging-related renal fibrosis; autophagy; legumain (asparagine endopetidase); premature senescence
  13. Burns Trauma. 2022 ;10 tkab045
      Chronic wounds (e.g. diabetic wounds, pressure wounds, vascular ulcers, etc.) do not usually heal in a timely and orderly manner but rather last for years and may lead to irreversible adverse events, resulting in a substantial financial burden for patients and society. Recently, a large amount of evidence has proven that cellular senescence has a crucial influence on chronic nonhealing wounds. As a defensive mechanism, cell senescence is a manner of cell-cycle arrest with increased secretory phenotype to resist death, preventing cells from stress-induced damage in cancer and noncancer diseases. A growing amount of research has advanced the perception of cell senescence in various chronic wounds and focuses on pathological and physiological processes and therapies targeting senescent cells. However, previous reviews have failed to sum up novel understandings of senescence in chronic wounds and emerging strategies targeting senescence. Herein, we discuss the characteristics and mechanisms of cellular senescence and the link between senescence and chronic wounds as well as some novel antisenescence strategies targeting other diseases that may be applied for chronic wounds.
    Keywords:  Chronic wounds; Diabetic wound; Pressure wound; Senescence; Senolytics; Targeted therapies; Vascular ulcer
  14. Genes (Basel). 2022 Jan 24. pii: 208. [Epub ahead of print]13(2):
      Cellular senescence is a state of permanent growth arrest that arises once cells reach the limit of their proliferative capacity. It creates an inflammatory microenvironment favouring the initiation and progression of various age-related diseases, including prostate cancer. Non-coding RNAs (ncRNAs) have emerged as important regulators of cellular gene expression. Nonetheless, very little is known about the interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and how deregulation of ncRNA networks promotes cellular senescence. To investigate this, human prostate epithelial cells were cultured through different passages until senescent, and their RNA was extracted and sequenced using RNA sequencing (RNAseq) and microRNA sequencing (miRNA-seq) miRNAseq. Differential expression (DE) gene analysis was performed to compare senescent and proliferating cells with Limma, miRNA-target interactions with multiMiR, lncRNA-target interactions using TCGA data and network evaluation with miRmapper. We found that miR-335-3p, miR-543 and the lncRNAs H19 and SMIM10L2A all play central roles in the regulation of cell cycle and DNA repair processes. Expression of most genes belonging to these pathways were down-regulated by senescence. Using the concept of network centrality, we determined the top 10 miRNAs and lncRNAs, with miR-335-3p and H19 identified as the biggest hubs for miRNAs and lncRNA respectively. These ncRNAs regulate key genes belonging to pathways involved in cell senescence and prostate cancer demonstrating their central role in these processes and opening the possibility for their use as biomarkers or therapeutic targets to mitigate against prostate ageing and carcinogenesis.
    Keywords:  DNA repair; cell cycle; cell senescence; lncRNA; miRNA; ncRNA; network biology; prostate cell; transcriptomics
  15. Int J Mol Sci. 2022 Feb 20. pii: 2339. [Epub ahead of print]23(4):
      Myotonic dystrophy (DM) is a dominantly inherited multisystemic disorder affecting various organs, such as skeletal muscle, heart, the nervous system, and the eye. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by expanded CTG and CCTG repeats, respectively. In both forms, the mutant transcripts containing expanded repeats aggregate as nuclear foci and sequester several RNA-binding proteins, resulting in alternative splicing dysregulation. Although certain alternative splicing events are linked to the clinical DM phenotypes, the molecular mechanisms underlying multiple DM symptoms remain unclear. Interestingly, multi-systemic DM manifestations, including muscle weakness, cognitive impairment, cataract, and frontal baldness, resemble premature aging. Furthermore, cellular senescence, a critical contributor to aging, is suggested to play a key role in DM cellular pathophysiology. In particular, several senescence inducers including telomere shortening, mitochondrial dysfunction, and oxidative stress and senescence biomarkers such as cell cycle inhibitors, senescence-associated secretory phenotype, chromatin reorganization, and microRNA have been implicated in DM pathogenesis. In this review, we focus on the clinical similarities between DM and aging, and summarize the involvement of cellular senescence in DM and the potential application of anti-aging DM therapies.
    Keywords:  accelerated aging; alternative splicing; repeat expansion
  16. Antioxidants (Basel). 2022 Jan 31. pii: 301. [Epub ahead of print]11(2):
      Chronic kidney disease (CKD) can be considered as a clinical model for premature aging. However, non-invasive biomarkers to detect early kidney damage and the onset of a senescent phenotype are lacking. Most of the preclinical senescence studies in aging have been done in very old mice. Furthermore, the precise characterization and over-time development of age-related senescence in the kidney remain unclear. To address these limitations, the age-related activation of cellular senescence-associated mechanisms and their correlation with early structural changes in the kidney were investigated in 3- to 18-month-old C57BL6 mice. Inflammatory cell infiltration was observed by 12 months, whereas tubular damage and collagen accumulation occurred later. Early activation of cellular-senescence-associated mechanisms was found in 12-month-old mice, characterized by activation of the DNA-damage-response (DDR), mainly in tubular cells; activation of the antioxidant NRF2 pathway; and klotho downregulation. However, induction of tubular-cell-cycle-arrest (CCA) and overexpression of renal senescent-associated secretory phenotype (SASP) components was only found in 18-month-old mice. In aging mice, both inflammation and oxidative stress (marked by elevated lipid peroxidation and NRF2 inactivation) remained increased. These findings support the hypothesis that prolonged DDR and CCA, loss of nephroprotective factors (klotho), and dysfunctional redox regulatory mechanisms (NRF2/antioxidant defense) can be early drivers of age-related kidney-damage progression.
    Keywords:  NRF2; aging kidney; cellular senescence; fibrosis; inflammaging; oxidation
  17. Br J Cancer. 2022 Feb 23.
      Neuroblastoma is a tumour that arises from the sympathoadrenal lineage occurring predominantly in children younger than five years. About half of the patients are diagnosed with high-risk tumours and undergo intensive multi-modal therapy. The success rate of current treatments for high-risk neuroblastoma is disappointingly low and survivors suffer from multiple therapy-related long-term side effects. Most chemotherapeutics drive cancer cells towards cell death or senescence. Senescence has long been considered to represent a terminal non-proliferative state and therefore an effective barrier against tumorigenesis. This dogma, however, has been challenged by recent observations that infer a much more dynamic and reversible nature for this process, which may have implications for the efficacy of therapy-induced senescence-oriented treatment strategies. Neuroblastoma cells in a dormant, senescent-like state may escape therapy, whilst their senescence-associated secretome may promote inflammation and invasiveness, potentially fostering relapse. Conversely, due to its distinct molecular identity, senescence may also represent an opportunity for the development of novel (combination) therapies. However, the limited knowledge on the molecular dynamics and diversity of senescence signatures demands appropriate models to study this process in detail. This review summarises the molecular knowledge about cellular senescence in neuroblastoma and investigates current and future options towards therapeutic exploration.
  18. Phytomedicine. 2022 Feb 12. pii: S0944-7113(22)00068-X. [Epub ahead of print]99 153990
      BACKGROUND: Astrocytes senescence has been demonstrated in the aging brain and Alzheimer's disease (AD). Moreover, lower glucose metabolism has been confirmed in the early stage of AD. However, whether low glucose could induce astrocytes senescence remain ambiguous. Studies have shown that the ethanol extracts of Scutellaria baicalensis Georgi (SGE) exert neuroprotective and anti-aging effects, while whether SGE could delay astrocytes senescence was unclear.PURPOSE: This study investigated the anti-senescence effect of SGE in low glucose-induced T98G cells and primary astrocytes, and explored the possible mechanisms based on boolean network.
    METHODS: The neuroprotective effects of SGE in low glucose-induced T98G cells were evaluated by measurement of cell viability, LDH, ROS and ATP. The anti-senescence effects of SGE were investigated by detection of senescence-associated β-galactosidase (SA-β-Gal), senescence-associated secretory phenotype (SASP), cell cycle and senescence-related markers. The possible mechanisms of SGE in delaying astrocytes senescence were discovered through integrating transcriptomics with boolean network, and validation experiments were further performed.
    RESULTS: Our results revealed that low glucose could induce astrocytes senescence, and SGE could delay astrocytes senescence by decreasing the staining rate of SA-β-gal, reducing secretions of SASP factors (IL-6, CXCL1, MMP-1), alleviating cell cycle arrest in G0/G1 phase, decreasing the formation of punctate DNA foci and down-regulating the expression of p16INK4A, p21 and γH2A.X. Transcriptomics and further verification results showed that SGE could markedly inhibit the mRNA expression levels of SASP factors (CXCL10, CXCL2, CCL2, IL-6, CXCR4, CCR7). Moreover, C-X-C motif chemokine 10 (CXCL10) was predicted to be the key SASP factor affecting the network stability by using boolean network. Further experiments validated that SGE could markedly reduce CXCL10 level, decrease the secretion of IL-6 and inhibit cell migration in CXCL10 induced primary astrocytes.
    CONCLUSION: In summary, our research unmasks that the anti-senescence effects of SGE were highly correlated with the suppression of SASP secretions, and CXCL10 mediated the SASP inhibition effect of SGE in low glucose-induced astrocytes. Our study highlights that the delay of astrocytes senescence and the inhibition of SASP might be a new mechanism of SGE for alleviating neurodegenerative diseases such as AD.
    Keywords:  Astrocytes senescence; Boolean network; CXCL10; SASP; SGE
  19. Cells. 2022 Feb 15. pii: 675. [Epub ahead of print]11(4):
      Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components-in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions.
    Keywords:  exosomes; extracellular vesicles; inflamm-aging; mitochondrial damage; mitochondrial dynamics; mitochondrial-derived vesicles; mitochondrial-lysosomal axis; mitophagy; oxidative stress; senescence
  20. Gene. 2022 Feb 17. pii: S0378-1119(22)00167-6. [Epub ahead of print] 146348
      Aging is referred to progressive dysfunction of body organs, including the brain. This study aims to explore the anti-aging effect of combing nicotinamide mononucleotide (NMN) and lycopene (Lyco) (NMN+Lyco) on aging rats and senescent PC12 cells. Both in vivo and in vitro aging models were established using D-galactose (D-gal). The combination showed a trend to superiority over monotherapy in preventing aging in vivo and in vitro. Morris water maze test showed that NMN+Lyco effectively improved the ability of spatial location learning and memory of aging model rats. NMN+Lyco mitigated the oxidative stress of rat brains, livers, and PC12 cells by elevating the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), GSH, as well as total antioxidant capacity (T-AOC), and reducing malondialdehyde (MDA) content. CCK-8 assay, senescence-associated β-galactosidase staining, and flow cytometer confirmed the cellular senescence of PC12 cells after exposing D-gal, and indicated the anti-senescence effect of NMN+Lyco in vitro. Moreover, NMN+Lyco effectively down-regulated the expressions of p53, p21, and p16 (senescence-related genes), and activated Keap1-Nrf2 signaling in both in vivo and in vitro aging models. In total, NMN+Lyco protected rats and PC12 cells from cognitive impairment and cellular senescence induced by D-gal, of which effects might be linked to the reduction of oxidative stress and the activation of Keap1-Nrf2 signaling.
    Keywords:  Keap1-Nrf2 signaling; aging; lycopene; nicotinamide mononucleotide; oxidative stress
  21. Antioxidants (Basel). 2022 Feb 09. pii: 336. [Epub ahead of print]11(2):
      Medical advances and the availability of diagnostic tools have considerably increased life expectancy and, consequently, the elderly segment of the world population. As age is a major risk factor in cardiovascular disease (CVD), it is critical to understand the changes in cardiac structure and function during the aging process. The phenotypes and molecular mechanisms of cardiac aging include several factors. An increase in oxidative stress is a major player in cardiac aging. Reactive oxygen species (ROS) production is an important mechanism for maintaining physiological processes; its generation is regulated by a system of antioxidant enzymes. Oxidative stress occurs from an imbalance between ROS production and antioxidant defenses resulting in the accumulation of free radicals. In the heart, ROS activate signaling pathways involved in myocyte hypertrophy, interstitial fibrosis, contractile dysfunction, and inflammation thereby affecting cell structure and function, and contributing to cardiac damage and remodeling. In this manuscript, we review recent published research on cardiac aging. We summarize the aging heart biology, highlighting key molecular pathways and cellular processes that underlie the redox signaling changes during aging. Main ROS sources, antioxidant defenses, and the role of dysfunctional mitochondria in the aging heart are addressed. As metabolism changes contribute to cardiac aging, we also comment on the most prevalent metabolic alterations. This review will help us to understand the mechanisms involved in the heart aging process and will provide a background for attractive molecular targets to prevent age-driven pathology of the heart. A greater understanding of the processes involved in cardiac aging may facilitate our ability to mitigate the escalating burden of CVD in older individuals and promote healthy cardiac aging.
    Keywords:  aged heart; cardiac metabolism; cardiac remodeling; reactive oxygen species; senescence
  22. Cell Death Dis. 2022 Feb 19. 13(2): 163
      During this last decade, the development of prosenescence therapies has become an attractive strategy as cellular senescence acts as a barrier against tumour progression. In this context, CDK4/6 inhibitors induce senescence and reduce tumour growth in breast cancer patients. However, even though cancer cells are arrested after CDK4/6 inhibitor treatment, genes regulating senescence in this context are still unknown limiting their antitumour activity. Here, using a functional genome-wide CRISPR/Cas9 genetic screen we found several genes that participate in the proliferation arrest induced by CDK4/6 inhibitors. We find that downregulation of the coagulation factor IX (F9) using sgRNA and shRNA prevents the cell cycle arrest and senescent-like phenotype induced in MCF7 breast tumour cells upon Palbociclib treatment. These results were confirmed using another breast cancer cell line, T47D, and with an alternative CDK4/6 inhibitor, Abemaciclib, and further tested in a panel of 22 cancer cells. While F9 knockout prevents the induction of senescence, treatment with a recombinant F9 protein was sufficient to induce a cell cycle arrest and senescence-like state in MCF7 tumour cells. Besides, endogenous F9 is upregulated in different human primary cells cultures undergoing senescence. Importantly, bioinformatics analysis of cancer datasets suggest a role for F9 in human tumours. Altogether, these data collectively propose key genes involved in CDK4/6 inhibitor response that will be useful to design new therapeutic strategies in personalised medicine in order to increase their efficiency, stratify patients and avoid drug resistance.
  23. Int J Mol Sci. 2022 Feb 16. pii: 2176. [Epub ahead of print]23(4):
      The aging of mammals is accompanied by the progressive atrophy of tissues and organs and the accumulation of random damage to macromolecular DNA, protein, and lipids. Flavonoids have excellent antioxidant, anti-inflammatory, and neuroprotective effects. Recent studies have shown that flavonoids can delay aging and prolong a healthy lifespan by eliminating senescent cells, inhibiting senescence-related secretion phenotypes (SASPs), and maintaining metabolic homeostasis. However, only a few systematic studies have described flavonoids in clinical treatment for anti-aging, which needs to be explored further. This review first highlights the association between aging and macromolecular damage. Then, we discuss advances in the role of flavonoid molecules in prolonging the health span and lifespan of organisms. This study may provide crucial information for drug design and developmental and clinical applications based on flavonoids.
    Keywords:  aging; flavonoids; health span; macromolecular damage
  24. Mol Cancer Res. 2022 Feb 21. pii: molcanres.MCR-21-0029-A.2021. [Epub ahead of print]
      Glioblastoma is a rapidly fatal malignancy typically treated with radiation and Temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable, and may be driven by surviving tumor cells eventually escaping senescence. A growing number of socalled "senolytic" drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs are under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for glioblastoma. We evaluated a panel of 10 previously described senolytic drugs to determine if any could exhibit selective activity against human glioblastoma persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZtreated glioma. This senolytic activity was observed in 12/12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect. Implications: These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced Bcl-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.
  25. Front Immunol. 2022 ;13 826880
      Cyclic GMP-AMP synthase (cGAS) recognizes double-stranded DNA (dsDNA) derived from invading pathogens and induces an interferon response via activation of the key downstream adaptor protein stimulator of interferon genes (STING). This is the most classic biological function of the cGAS-STING signaling pathway and is critical for preventing pathogenic microorganism invasion. In addition, cGAS can interact with various types of nucleic acids, including cDNA, DNA : RNA hybrids, and circular RNA, to contribute to a diverse set of biological functions. An increasing number of studies have revealed an important relationship between the cGAS-STING signaling pathway and autophagy, cellular senescence, antitumor immunity, inflammation, and autoimmune diseases. This review details the mechanism of action of cGAS as it interacts with different types of nucleic acids, its rich biological functions, and the potential for targeting this pathway to treat various diseases.
    Keywords:  Disease treatment strategy; Interferon; Nucleic acid recognition; STING; cGAS
  26. Aging Cell. 2022 Feb 24. e13569
      Age-related muscle atrophy and weakness, or sarcopenia, are significant contributors to compromised health and quality of life in the elderly. While the mechanisms driving this pathology are not fully defined, reactive oxygen species, neuromuscular junction (NMJ) disruption, and loss of innervation are important risk factors. The goal of this study is to determine the impact of mitochondrial hydrogen peroxide on neurogenic atrophy and contractile dysfunction. Mice with muscle-specific overexpression of the mitochondrial H2 O2  scavenger peroxiredoxin3 (mPRDX3) were crossed to Sod1KO mice, an established mouse model of sarcopenia, to determine whether reduced mitochondrial H2 O2 can prevent or delay the redox-dependent sarcopenia. Basal rates of H2 O2  generation were elevated in isolated muscle mitochondria from Sod1KO, but normalized by mPRDX3 overexpression. The mPRDX3 overexpression prevented the declines in maximum mitochondrial oxygen consumption rate and calcium retention capacity in Sod1KO. Muscle atrophy in Sod1KO was mitigated by ~20% by mPRDX3 overexpression, which was associated with an increase in myofiber cross-sectional area. With direct muscle stimulation, maximum isometric specific force was reduced by ~20% in Sod1KO mice, and mPRDX3 overexpression preserved specific force at wild-type levels. The force deficit with nerve stimulation was exacerbated in Sod1KO compared to direct muscle stimulation, suggesting NMJ disruption in Sod1KO. Notably, this defect was not resolved by overexpression of mPRDX3. Our findings demonstrate that muscle-specific PRDX3 overexpression reduces mitochondrial H2 O2  generation, improves mitochondrial function, and mitigates loss of muscle quantity and quality, despite persisting NMJ impairment in a murine model of redox-dependent sarcopenia.
    Keywords:  aging; hydrogen peroxide; mitochondria; peroxiredoxin3; sarcopenia
  27. Bioengineered. 2022 Mar;13(3): 5434-5442
      Aging is an important risk factor for osteoarthritis (OA). Butorphanol is a preoperative sedative and analgesic that possesses anti-inflammatory activity. However, the effect of butorphanol on OA has not been reported. Here we aimed to explore the effect of butorphanol tartrate on the cellular senescence of human chondrocyte-articular (HC-A) cells in response to tumor necrosis factor-α (TNF-α) stimulation. Butorphanol tartrate attenuated the TNF-α-caused cellular senescence of HC-A cells, with decreased positive senescence-associated-β-galactosidase (SA-β-gal) staining and elevated telomerase activity. Butorphanol tartrate prevented TNF-α-caused cell cycle arrest in the G0/G1 phase in HC-A cells and decreased p21 expression. The TNF-α-induced production of interleukin (IL)-6 and IL-8 in HC-A cells were mitigated by butorphanol tartrate. In addition, butorphanol tartrate reduced p-NF-κB p65/total p65 and p-STAT3/STAT3 ratios in HC-A cells cultured with TNF-α. Taken together, butorphanol tartrate protected HC-A cells from TNF-α-caused cellular senescence through inactivation of NF-κB and STAT3. These results imply that butorphanol tartrate might be used as a potential agent for the treatment of aging-related OA.
    Keywords:  Butorphanol tartrate; NF-κB; STAT3; human chondrocyte-articular (HC-A) cells; inflammation; osteoarthritis (OA); senescence
  28. Elife. 2022 02 25. pii: e77180. [Epub ahead of print]11
      Associations between plasma protein levels and DNA methylation patterns can be used to predict the onset of age-related chronic disease.
    Keywords:  aging; biomarker; epidemiology; epigenetic; genetics; genomics; global health; human; morbidity; prediction; proteomics
  29. Pharmacol Res. 2022 Feb 21. pii: S1043-6618(22)00086-X. [Epub ahead of print] 106141
      BACKGROUND: Aging plays a critical role in the genesis of atrial fibrillation (AF) and also changes the gut microbes. Whether the aging-associated gut dysbiosis contributes to the development of aging-related AF and whether the gut microbes can be a target to prevent aging-related AF remains unknown.METHODS AND RESULTS: 16S rRNA gene sequencing was performed to reveal the changes of gut microbes in elderly patients with AF, and the result showed that the intestinal abundance of B.fragilis was significantly decreased in elderly patients with AF. Subsequently, we examined the impact of B.fragilis supplementation on AF promotion, atrial structural remodeling and inflammation response in D-galactose induced aging rats. We found that oral administration of B. fragilis prevented AF inducibility and duration, which was associated with attenuation of atrial senescence, apoptosis and fibrosis. Furthermore, B.fragilis significantly diminished the systemic and atrial inflammation, which is accompanied by an increase in the number of Treg cells in the spleen and blood. More importantly, we found that the circulation level of polysaccharide A (PSA), the metabolite synthesized by B.fragilis, was reduced in elderly patients with AF and could predict the occurrence of AF, and B.fragilis increased the circulation concentration of PSA in D-galactose induced aging rats.
    CONCLUSIONS: The abundance of B.fragilis was lower in elderly patients with AF. Oral administration of B.fragilis significantly attenuated inflammatory response by increasing Treg cells, thereby preventing atrial structural remodeling and inhibiting AF promotion in D-galactose induced aging rats. This study provides experimental evidence for the effectiveness of targeting gut microbes in the prevention of aging-related AF.
    Keywords:  Aging; atrial fibrillation; atrial remodeling; gut microbes; inflammation
  30. Front Neurol. 2022 ;13 790884
      Antigen-induced T-cell exhaustion and T-cell senescence are peripheral regulatory mechanisms that control effector T-cell responses. Markers of exhaustion and senescence on T Cells indicate the previous activation by repetitive stimulation with specific antigens. Malignant tumors are accompanied by enhanced T-cell exhaustion and T-cell senescence resulting in immune evasion, while these control mechanisms might be diminished in autoimmune diseases including multiple sclerosis (MS). To better understand the involvement of antigen-induced T-cell senescence in controlling CD4+ T-cell-mediated autoimmune responses in MS, we have analyzed the re-expression of CD45RA and the downregulation of CD28 and CD27 molecules as markers of antigen-induced T-cell senescence in fresh cerebrospinal fluid (CSF)-infiltrating and paired circulating T cells from patients with MS. Patients with different levels of CD4+ T-cell senescence were identified and characterized regarding demographical and clinical features as well as intrathecal markers of neurodegeneration. CD4+ T-cell senescence was also analyzed in control patients to explore a putative deficit of this regulatory mechanism in MS. This study shows heterogeneity of markers of CD4+ T-cell senescence in patients with MS. Patients with high levels of CD4+ T-cell senescence in peripheral blood showed increased frequencies of CSF-infiltrating CD28+ CD27-EM CD4+ T cells with a proinflammatory Th1 functional phenotype. The correlation of these cells with the intrathecal levels of neurofilament light chain, a marker of neurodegeneration, suggests their relevance in disease pathogenesis and the involvement of T-cell senescence in their regulation. Markers of antigen-induced T-senescence, therefore, show promise as a tool to identify pathogenic CD4+ T cells in patients with MS.
    Keywords:  CD4; T-cell; T-cell senescence; multiple sclerosis (MS); regulation
  31. Curr Opin Pharmacol. 2022 Feb 18. pii: S1471-4892(22)00003-0. [Epub ahead of print]63 102184
      Recent studies have implicated cellular senescence as a disease-related process linked to progressive forms of multiple sclerosis (MS). Herein, we present an overview of the current pharmacopeia of cellular senescence affecting compounds and evidence for their effects, if known, in murine and cellular models of MS. Consideration is also given to the utility of these compounds for the treatment of progressive MS, with an examination of past and current clinical trials that have tested these agents, often for other purposes, in the MS patient population. Lastly, we discuss the implications and potential utility for targeting cellular senescence as a strategy to fulfil the unmet need of treatment options for the progressive MS population.
  32. Science. 2022 Feb 25. 375(6583): eabh3021
      Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness. Aged Hcrt neurons showed hyperexcitability with lower KCNQ2 expression and impaired M-current, mediated by KCNQ2/3 channels. Single-nucleus RNA-sequencing revealed adaptive changes to Hcrt neuron loss in the aging brain. Disruption of Kcnq2/3 genes in Hcrt neurons of young mice destabilized sleep, mimicking aging-associated sleep fragmentation, whereas the KCNQ-selective activator flupirtine hyperpolarized Hcrt neurons and rejuvenated sleep architecture in aged mice. Our findings demonstrate a mechanism underlying sleep instability during aging and a strategy to improve sleep continuity.
  33. Cell Death Dis. 2022 Feb 21. 13(2): 166
      The complex interaction between cancer cells and the immune microenvironment is a central regulator of tumor growth and the treatment response. Chemotherapy-induced senescence is accompanied by the senescence-associated secretion phenotype (SASP). However, the mechanisms underlying the regulation of the SASP remain the most poorly understood element of senescence. Here, we show that nuclear erythroid factor 2-like factor 2 (Nrf2), a master antioxidative transcription factor, accumulates upon doxorubicin-induced senescence. This is due to the increased cytoplasmic Inhibitor of Apoptosis Stimulating Protein of P53, iASPP, which binds with Keap1, interrupting Keap1/Nrf2 interaction and promoting Nrf2 stabilization and activation. Activated Nrf2 transactivates a novel target gene of SASP factor, macrophage colony-stimulating factor (M-CSF), which subsequently acts on macrophages and induces polarization from M1 to M2 via a paracrine mechanism. Genetic inhibition of iASPP-Nrf2 suppresses the growth of apoptosis-resistant xenografts, with further analysis revealing that M-CSF/M-CSFR-regulated macrophage polarization is critical for the functional outcomes delineated above. Overall, our data uncover a novel function of iASPP-Nrf2 in skewing the immune microenvironment under treatment-induced senescence. Targeting the iASPP-Nrf2 axis could be a powerful strategy for the implementation of new chemotherapy-based therapeutic opportunities.
  34. Commun Biol. 2022 Feb 25. 5(1): 173
      Malfunction of autophagy contributes to the progression of many chronic age-associated diseases. As such, improving normal proteostatic mechanisms is an active target for biomedical research and a key focal area for aging research. Endoplasmic reticulum (ER)-based acetylation has emerged as a mechanism that ensures proteostasis within the ER by regulating the induction of ER specific autophagy. ER acetylation is ensured by two ER-membrane bound acetyltransferases, ATase1 and ATase2. Here, we show that ATase inhibitors can rescue ongoing disease manifestations associated with the segmental progeria-like phenotype of AT-1 sTg mice. We also describe a pipeline to reliably identify ATase inhibitors with promising druggability properties. Finally, we show that successful ATase inhibitors can rescue the proteopathy of a mouse model of Alzheimer's disease. In conclusion, our study proposes that ATase-targeting approaches might offer a translational pathway for many age-associated proteopathies affecting the ER/secretory pathway.
  35. Int J Mol Sci. 2022 Feb 17. pii: 2219. [Epub ahead of print]23(4):
      Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout (KO) mice. While young GHS-R KO mice showed marginal changes in Bacteroidetes and Firmicutes, aged GHS-R KO mice exhibited reduced Bacteroidetes and increased Firmicutes, featuring a disease-susceptible microbiome profile. To further study the role of GHS-R in intestinal inflammation in aging, we induced acute colitis in young and aged GHS-R KO mice using dextran sulfate sodium (DSS). The GHS-R KO mice showed more severe disease activity scores, higher proinflammatory cytokine expression, and decreased expression of tight junction markers. These results suggest that GHS-R plays an important role in microbiome homeostasis and gut inflammation during aging; GHS-R suppression exacerbates intestinal inflammation in aging and increases vulnerability to colitis. Collectively, our finding reveals for the first time that GHS-R is an important regulator of intestinal health in aging; targeting GHS-R may present a novel therapeutic strategy for prevention/treatment of aging leaky gut and inflammatory bowel disease.
    Keywords:  aging; ghrelin; growth hormone secretagogue receptor (GHS-R); gut permeability; inflammatory bowel disease (IBD); microbiome; ulcerative colitis
  36. Int J Mol Sci. 2022 Feb 09. pii: 1948. [Epub ahead of print]23(4):
      Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism's life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence suggests that HSCs alter their function and become less active during organismal aging, leading ultimately to the disruption of hematopoietic homeostasis, such as anemia, perturbed immunity and increased propensity to hematological malignancies. Thus, understanding how HSCs alter their function during aging is a matter of critical importance to prevent or overcome these age-related changes in the blood system. Recent advances in clonal analysis have revealed the functional heterogeneity of murine HSC pools that is established upon development and skewed toward the clonal expansion of functionally poised HSCs during aging. In humans, next-generation sequencing has revealed age-related clonal hematopoiesis that originates from HSC subsets with acquired somatic mutations, and has highlighted it as a significant risk factor for hematological malignancies and cardiovascular diseases. In this review, we summarize the current fate-mapping strategies that are used to track and visualize HSC clonal behavior during development or after stress. We then review the age-related changes in HSCs that can be inherited by daughter cells and act as a cellular memory to form functionally distinct clones. Altogether, we link aging of the hematopoietic system to HSC clonal evolution and discuss how HSC clones with myeloid skewing and low regenerative potential can be expanded during aging.
    Keywords:  aging; clonal hematopoiesis; fate mapping; hematopoietic stem cells
  37. Nutrients. 2022 Feb 20. pii: 889. [Epub ahead of print]14(4):
      A number of factors contribute to the complex process of aging, which finally define whether someone will or not develop age-associated chronic diseases in late life. These determinants comprise genetic susceptibility as well as various behavioral, environmental, and dietary factors, all of which have been shown to influence specific pathways regulating the aging process and the extension of life, which makes longevity a multidimensional phenomenon. Although a "miraculous elixir" or a "nutrition pill" are not plausible, researchers agree on the notion that nutritional factors have major impact on the risk of age-associated chronic non-communicable diseases and mortality. In recent years nutrition research in relation to health outcomes has considerably changed from focusing exclusively on single nutrients to considering combinations of foods rather than nutrients in isolation. Although research on specific nutrients is scientifically valid providing crucial evidence on the mechanisms by which nutrition impacts health, the recent switch targeting the multifaceted synergistic interplay among nutrients, other dietary constituents, and whole foods, has promoted emerging interest on the actions of total dietary patterns. This narrative review aims to describe some specific dietary patterns with evidence of associations with reduction in the incidence of chronic diseases allowing older adults to live a long-lasting and healthier life, and confirming the powerful impact nutrition can exert on healthy aging.
    Keywords:  aging; cardiovascular; chronic; diet; dietary pattern; healthy aging; lifestyle; longevity; morbidity; mortality
  38. Nucleic Acids Res. 2022 Feb 22. pii: gkac079. [Epub ahead of print]
      Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is activated in cells with defective DNA damage repair and signaling (DDR) factors, but a direct role for DDR factors in regulating cGAS activation in response to micronuclear DNA is still poorly understood. Here, we provide novel evidence that Nijmegen breakage syndrome 1 (NBS1) protein, a well-studied DNA double-strand break (DSB) sensor-in coordination with Ataxia Telangiectasia Mutated (ATM), a protein kinase, and Carboxy-terminal binding protein 1 interacting protein (CtIP), a DNA end resection factor-functions as an upstream regulator that prevents cGAS from binding micronuclear DNA. When NBS1 binds to micronuclear DNA via its fork-head-associated domain, it recruits CtIP and ATM via its N- and C-terminal domains, respectively. Subsequently, ATM stabilizes NBS1's interaction with micronuclear DNA, and CtIP converts DSB ends into single-strand DNA ends; these two key events prevent cGAS from binding micronuclear DNA. Additionally, by using a cGAS tripartite system, we show that cells lacking NBS1 not only recruit cGAS to a major fraction of micronuclear DNA but also activate cGAS in response to these micronuclear DNA. Collectively, our results underscore how NBS1 and its binding partners prevent cGAS from binding micronuclear DNA, in addition to their classical functions in DDR signaling.
  39. Aging (Albany NY). 2022 Feb 23. 14(undefined):
      Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy is a rare, genetic, premature aging disease named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. In previous in vitro studies, we have already described several hallmarks of aging, including genetic damage, telomere shortening, cell senescence and proliferation defects. Since a clear connection has been reported between telomere shortening and mitochondria malfunction to initiate the aging process, we explored the role that mitochondrial metabolism and activity play in pathogenesis of MDPL Syndrome, an aspect that has not been addressed yet. We thus evaluated mtDNA copy number, assessing a significant decrease in mutated cells. The expression level of genes related to mitochondrial biogenesis and activity also revealed a significant reduction, highlighting a mitochondrial dysfunction in MDPL cells. Even the expression levels of mitochondrial marker SOD2, as assessed by immunofluorescence, were reduced. The decrease in this antioxidant enzyme correlated with increased production of mitochondrial ROS in MDPL cells, compared to WT. Consistent with these data, Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) analysis revealed in MDPL cells fewer mitochondria, which also displayed morphological abnormalities. Accordingly, we detected autophagic vacuoles containing partially digested mitochondria. Overall, our results demonstrate a dramatic impairment of mitochondrial biogenesis and activity in MDPL Syndrome. Administration of Metformin, though unable to restore mitochondrial impairment, proved efficient in rescuing nuclear abnormalities, suggesting its use to specifically ameliorate the premature aging phenotype.
    Keywords:  FIB/SEM; MDPL syndrome; ROS production; SOD2; autophagy; metformin; mitochondria; premature aging syndrome
  40. Trends Endocrinol Metab. 2022 Feb 17. pii: S1043-2760(22)00017-0. [Epub ahead of print]
      Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model organisms, clinical studies on potential geroprotectors are exceedingly rare, especially in healthy elders. This review aims to classify potential geroprotectors based on the mechanisms by which they influence aging. These pharmacological interventions can be classified into the following groups: those that prevent oxidation; proteostasis regulators; suppressors of genomic instability; epigenetic drugs; those that preserve mitochondrial function; inhibitors of aging-associated signaling pathways; hormetins; senolytics/senostatics; anti-inflammatory drugs; antifibrotic agents; neurotrophic factors; factors preventing the impairment of barrier function; immunomodulators; and prebiotics, metabiotics, and enterosorbents.
    Keywords:  anti-aging; antioxidant; geroprotector; hormetin; senolytic; senostatic
  41. Dose Response. 2022 Jan-Mar;20(1):20(1): 15593258221075321
      Objective: To explore the effect and mechanism of ultraviolet B (UVB) on melanin synthesis and premature senescence in human immortalized keratinocytes (HaCaT) cells.Methods: HaCaT cells were irradiated with 0, 20, 50, 80, 100, 150, and 200 mJ/cm2 of UVB. NaOH method was used for melanin content assay, cellular tyrosinase (TYR) activity was determined by 3,4-Dihydroxy-L-phenylalanine (L-DOPA) oxidation to dopachrome, premature senescence was analyzed by senescence-associated beta-galactosidase (SA-β-gal) staining kit, and the levels of p21, p16, p62, and GATA4 proteins were detected by Western blotting. Premature senescence was inhibited by the inhibitors of ataxia telangiectasia mutated (ATM) or ataxia telangiectasia and Rad3-related (ATR), and the p53 signaling pathway was activated by Nutlin-3. The mRNA levels of senescence-associated secretory phenotype (SASP) factors including tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor A (VEGF-A), and interleukin-8 (IL-8) were measured by real-time quantitative polymerase chain reaction in HaCaT cells after 80 mJ/cm2 of UVB irradiation.
    Results: The melanin level increased significantly with the elevation of irradiation dose (F = 28.19, 43.82, 143.60, P < .05), reaching the peak at the dose of 80 mJ/cm2. The tyrosinase activity increased significantly (F = 84.50, P < .05), the percentage of premature senescence increased (F = 16.31, P < .05), the levels of p62 decreased, and the level of GATA4 increased obviously with the increase of UVB dose after irradiation. The UVB-induced promotion of GATA4 level was significantly inhibited by being treated with ATM or ATR inhibitor. However, this did not occur in the Nutlin-3-treated group. The mRNA and protein expression of TNF-α increased significantly at 72 h at 80 mJ/cm2 of UVB irradiation.
    Conclusions: Melanin contents increased first and decreased afterward with the increasing of UVB irradiation. The decrease of p62-mediated selective autophagy was accompanied by the accumulation of GATA4 after different doses of UVB irradiation. Activation of this p62/GATA4 pathway depends on the ATM and ATR but is independent of p53, and the SASP factor was activated in HaCaT cells at 80 mJ/cm2 of UVB irradiation.
    Keywords:  GATA4; UVB; melanin content; p62; premature senescence; tyrosinase (TYR)
  42. J Am Coll Cardiol. 2022 Mar 01. pii: S0735-1097(21)08447-3. [Epub ahead of print]79(8): 837-847
      Aging and inflammation both contribute pivotally to cardiovascular (CV) and cerebrovascular disease, the leading causes of death and disability worldwide. The concept of inflamm-aging recognizes that low-grade inflammatory pathways observed in the elderly contribute to CV risk. Understanding the mechanisms that link inflammation and aging could reveal new therapeutic targets and offer options to cope with the growing aging population worldwide. This review reports recent scientific advances in the pathways through which inflamm-aging mediates age-dependent decline in CV function and disease onset and considers critically the translational potential of such concepts into everyday clinical practice.
    Keywords:  cardiovascular disease; inflamm-aging; inflammation; vascular aging
  43. J Mol Histol. 2022 Feb 25.
      Ovarian functions decrease with perimenopause. The ovary has extrinsic innervation, but the neural influence on ovarian functions and dysfunction is not well-studied. The present study aimed to biochemically and morphometrically characterize the intrinsic neurons in ovaries from young adult, middle-aged, and senescent Long Evans CII-ZV rats (3, 12, and 15 months old, respectively). Ovaries were extracted from four rats of each age group (n = 12 total), cryopreserved, and processed for immunofluorescence studies with the primary NeuN/β-tubulin and NeuN/tyrosine hydroxylase (TH) antibodies. The soma area and number of intrinsic neurons in the ovarian stroma, surrounding follicles, corpus luteum, or cyst were evaluated. The intrinsic neurons were grouped in cluster-like shapes in ovarian structures. In senescent rats, the intrinsic neurons were mainly localized in the ovarian stroma and around the cysts. The number of neurons was lower in senescent rats than in young adult rats (p < 0.05), but the soma size was larger than in young adult rats. Immunoreactivity to TH indicated the presence of noradrenergic neurons in the ovary with the same characteristics as NeuN/β-tubulin, which indicates that they are part of the same neuronal group. Taken together, the findings indicate that the intrinsic neurons may be related to the loss of ovarian functions associated with aging.
    Keywords:  Intrinsic neurons; Ovarian function; Ovarian innervation; Senescent rat
  44. Nucleic Acids Res. 2022 Feb 25. pii: gkac104. [Epub ahead of print]
      The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterized by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-κB transcriptional pathway and leads to excessive phagocytic clearance of neuronal material. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. Activation of non-canonical NF-κB signalling is also observed in cerebellar microglia of individuals with Ataxia-telangiectasia. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in ATM deficiency, potentially contributing to neurodegeneration in Ataxia-telangiectasia.
  45. Adv Drug Deliv Rev. 2022 Feb 21. pii: S0169-409X(22)00065-5. [Epub ahead of print] 114175
      Vaccination is the most effective measure to protect against infections. However, with increasing age, there is a progressive decline in the ability of the immune system to both protect against infection and develop protective immunity from vaccination. This age-related decline of the immune system is due to age-related changes in both the innate and adaptive immune systems. With an aging world population and increased risk of pandemics, there is a need to continue to develop strategies to increase vaccine responses in the elderly. Here, the major age-related changes that occur in both the innate and adaptive immune responses that impair the response to vaccination in the elderly will be highlighted. Existing and future strategies to improve vaccine efficacy in the elderly will then be discussed, including adjuvants, delivery methods, and formulation. These strategies provide mechanisms to improve the efficacy of existing vaccines and develop novel vaccines for the elderly.
    Keywords:  Adaptive immunity; Adjuvant; Age; Clostridioides difficile; Elderly; Inflammaging; Influenza; Innate immunity; SARS-CoV-2; Vaccination; Varicella Zoster; mRNA vaccine
  46. Hum Immunol. 2022 Feb 18. pii: S0198-8859(22)00032-5. [Epub ahead of print]
      Older kidney transplant recipients demonstrate increased rates of infection, and lower rates of rejection, compared with younger kidney transplant recipients. However, the mechanism behind this observation remains unknown. To develop a multifaceted view of age-associated immune dysfunction, we determined the function and phenotype of T cells predisposing to vulnerability to infection on a molecular level. Overlapping peptide pools representing the dominant CMV antigens were used to stimulate PBMC collected from 51 kidney transplant recipients, using cytokine secretion to determine specificity and intensity of response. Staphylococcal endotoxin B (SEB) was analyzed in parallel. To define immune cell subsets, we used single cell RNA sequencing (scRNAseq) to evaluate cellular surface markers and gene expression. We found increased frequency of SEB- and CMV-specific T cells was associated with freedom from infection, especially in older patients. Spatialized t-SNE analysis revealed decreased frequency of naïve T cells, increased frequency of TEMRA cells, and decreased frequency of IFNγ secreting T cells in patients with infection. Application of scRNAseq analysis revealed increased frequency of terminally differentiated T cells expressing NK-associated receptors and inhibitory markers. These findings offer unique insight into the mechanism behind vulnerability to infection in the kidney transplant recipient, revealing a specific T cell subtype of impaired antigen response and terminal effector phenotype as markers of T cell senescence.
    Keywords:  Aging; Exhaustion; IFNγ; Inflammation; Senescence; T cell; Transplantation
  47. Cells. 2022 Feb 11. pii: 625. [Epub ahead of print]11(4):
      Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-β, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation.
    Keywords:  blood-brain barrier; exosomes; extracellular vesicles; glia; neuroinflammation; sEV
  48. Nat Med. 2022 Feb 21.
      Hematopoietic stem cell transplantation (HSCT) is a therapy used for multiple malignant and nonmalignant diseases, with chemotherapy used for pretransplantation myeloablation. The post-HSCT brain contains peripheral engrafted parenchymal macrophages, despite their absence in the normal brain, with the engraftment mechanism still undefined. Here we show that HSCT chemotherapy broadly disrupts mouse brain regenerative populations, including a permanent loss of adult neurogenesis. Microglial density was halved, causing microglial process expansion, coinciding with indicators of broad senescence. Although microglia expressed cell proliferation markers, they underwent cell cycle arrest in S phase with a majority expressing the senescence and antiapoptotic marker p21. In vivo single-cell tracking of microglia after recovery from chemical depletion showed loss of their regenerative capacity, subsequently replaced with donor macrophages. We propose that HSCT chemotherapy causes microglial senescence with a gradual decrease to a critical microglial density, providing a permissive niche for peripheral macrophage engraftment of the brain.
  49. Aging Cell. 2022 Feb 23. e13571
      We present a novel platform for testing the effects of interventions on the life- and healthspan of a short-lived freshwater organism with complex behavior and physiology-the planktonic crustacean Daphnia magna. Within this platform, dozens of complex behavioral features of both routine motion and response to stimuli are continuously quantified over large synchronized cohorts via an automated phenotyping pipeline. We build predictive machine-learning models calibrated using chronological age and extrapolate onto phenotypic age. We further apply the model to estimate the phenotypic age under pharmacological perturbation. Our platform provides a scalable framework for drug screening and characterization in both life-long and instant assays as illustrated using a long-term dose-response profile of metformin and a short-term assay of well-studied substances such as caffeine and alcohol.
    Keywords:   Daphnia magna ; intervention testing platform; long-term culture; machine learning; phenotypic age; phenotyping
  50. Biochem Biophys Res Commun. 2022 Feb 11. pii: S0006-291X(22)00231-5. [Epub ahead of print]599 134-141
      Metabolic abnormalities are tightly connected to the perturbation of normal brain functions, thereby causing multiple neurodegenerative diseases. The hypothalamus is the master unit that controls the whole-body energy homeostasis. Thus, altered metabolic activity in the hypothalamus could be a crucial clue to better understand the development of metabolic disorders during aging. The current study aimed to investigate the changes in hypothalamic metabolites according to the aging process using gas chromatography-mass spectrometry. We identified that multiple metabolites and neurotransmitters were effectively reduced in the hypothalamus of aged mice. In addition, we observed increased levels of genes linked to the production and utilization of monocarboxylates in the aged hypothalamus, indicating the initiation of metabolic activity to produce alternative nutrient sources. Lastly, we found a reduced number of astrocytes in the hypothalamus of aged mice, suggesting that reduced nutrient availability in the hypothalamus might be associated with the decreased activity of astrocytes during aging. Collectively, the present study suggests that the deterioration of metabolic activities in the hypothalamus might be a primary cause and/or outcome of metabolic diseases associated with the aging process.
    Keywords:  Aging; Astrocytes; Degeneration; Hypothalamus; Metabolites
  51. Clin Epigenetics. 2022 Feb 24. 14(1): 30
      PURPOSE: Age is one of the strongest risk factors for the development of breast cancer, however, the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression.METHODS: Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls).
    RESULTS: The Levine (p = 0.0037) and Yang clocks (p = 0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb-related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb-related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p = 0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration.
    CONCLUSIONS: Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb-related genes can be used to assess the risk of developing breast cancer among unaffected individuals.
    Keywords:  Breast cancer; Epigenetic clocks; Methylation changes; Polycomb-related genes