bims-senagi Biomed News
on Senescence and aging
Issue of 2022‒02‒13
twenty-six papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Science. 2022 Feb 11. 375(6581): 671-677
      The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.
  2. Curr Opin Nephrol Hypertens. 2022 Feb 09.
      PURPOSE OF REVIEW: Chronic kidney disease (CKD) is often viewed as an accelerated and premature ageing of the kidney, as they share common pathological features characterized by cellular senescence. In this review, we summarize the experimental evidence linking cellular senescence to the pathobiology of kidney ageing and CKD, and discuss the strategies for targeting senescent cells in developing therapeutics for ageing-related kidney disorders.RECENT FINDINGS: Kidney ageing and CKD are featured with increased cellular senescence, an irreversible state of cell cycle arrest and the cessation of cell division. Senescent cells secrete a diverse array of proinflammatory and profibrotic factors known as senescence-associated secretory phenotype (SASP). Secondary senescence can be induced by primary senescent cells via a mechanism involving direct contact or the SASP. Various senolytic therapies aiming to selectively remove senescent cells in vivo have been developed. Senostatic approaches to suppress senescence or inhibit SASP, as well as nutrient signalling regulators are also validated in animal models of ageing.
    SUMMARY: These recent studies provide experimental evidence supporting the notion that accumulation of senescent cells and their associated SASP is a main driver leading to structural and functional organ degeneration in CKD and other ageing-related disorder.
  3. Aging Cell. 2022 Feb 11. e13557
      Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age-related subcutaneous adipose tissue (SAT) dysfunction, and increases risk of type 2 diabetes (T2D). First-degree relatives of T2D individuals (FDR) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDR more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APC from FDR and individuals with no diabetes familiarity (CTRL), ZMAT3 emerged as one of the top-ranked senescence-related genes featuring hypomethylation in FDR and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APC from FDR individuals revealed increases in multiple senescence markers compared to CTRL. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APC led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APC determined senescence and activation of the p53/p21 pathway, as observed in FDR APC. Adipogenesis was also inhibited in ZMAT3-overexpressing APC. In FDR APC, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, aging and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APC accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDR predisposition for T2D.
    Keywords:   ZMAT3 ; DNA methylation; adipose precursor cells; aging; cellular senescence; first-degree relatives of type 2 diabetics; senolytics; type 2 diabetes
  4. Semin Cancer Biol. 2022 Feb 07. pii: S1044-579X(22)00026-8. [Epub ahead of print]
      Cancer therapies, including conventional chemotherapy, radiation, and molecularly targeted agents, can lead to tumor eradication through a variety of mechanisms. In addition to their effects on tumor cell growth and survival, these regimens can also influence the surrounding tumor-immune microenvironment in ways that ultimately impact therapy responses. A unique biological outcome of cancer therapy is induction of cellular senescence. Senescence is a damage-induced stress program that leads to both the durable arrest of tumor cells and remodeling the tumor-immune microenvironment through activation of a collection pleiotropic cytokines, chemokines, growth factors, and proteinases known as the senescence-associated secretory phenotype (SASP). Depending on the cancer context and the mechanism of action of the therapy, the SASP produced following therapy-induced senescence (TIS) can promote anti-tumor immunity that enhances therapeutic efficacy, or alternatively chronic inflammation that leads to therapy failure and tumor relapse. Thus, a deeper understanding of the mechanisms regulating the SASP and components necessary for robust anti-immune surveillance in different cancer and therapy contexts are key to harnessing senescence for tumor control. Here we draw a roadmap to modulate TIS and its immune-stimulating features for cancer immunotherapy.
    Keywords:  Cellular senescence; Immunotherapy; Senescence-associated secretory phenotype; Senotherapeutics; Tumor microenvironment
  5. Aging Cell. 2022 Feb 11. e13566
      The molecular mechanisms underlying functional decline during normal brain aging are poorly understood. Here, we identified the actin-associated protein tropomyosin 1 (TPM1) as a new systemic pro-aging factor associated with function deficits in normal aging retinas. Heterochronic parabiosis and blood plasma treatment confirmed that systemic factors regulated age-related inflammatory responses and the ectopic dendritic sprouting of rod bipolar (RBC) and horizontal (HC) cells in the aging retina. Proteomic analysis revealed that TPM1 was a potential systemic molecule underlying structural and functional deficits in the aging retina. Recombinant TPM1 protein administration accelerated the activation of glial cells, the dendritic sprouting of RBCs and HCs and functional decline in the retina of young mice, whereas anti-TPM1 neutralizing antibody treatment ameliorated age-related structural and function changes in the retina of aged mice. Old mouse plasma (OMP) induced glial cell activation and the dendritic outgrowth of RBCs and HCs in young mice, and yet TMP1-depleted OMP failed to reproduce the similar effect in young mice. These results confirmed that TPM1 was a systemic pro-aging factor. Moreover, we demonstrated that systematic TPM1 was an immune-related molecule, which elicited endogenous TPM1 expression and inflammation by phosphorylating PKA and regulating FABP5/NF-κB signaling pathway in normal aging retinas. Interestingly, we observed TPM1 upregulation and the ectopic dendritic sprouting of RBCs and HCs in young mouse models of Alzheimer's disease, indicating a potential role of TPM1 in age-related neurodegenerative diseases. Our data indicate that TPM1 could be targeted for combating the aging process.
    Keywords:  aging; dendritic sprouting; inflammation; parabiosis; retina; tropomyosin 1
  6. Front Immunol. 2021 ;12 823935
      Objective: Continuous overactivation of the renal sympathetic nerve is considered to be an important cause of renal fibrosis. Accumulated senescent cells in the damaged kidney have metabolic activities and secrete amounts of proinflammatory factors as part of the SASP (the senescence-associated secretory phenotype), which induce chronic inflammation and fibrosis. It is still unclear whether renal sympathetic nerves affect renal inflammation and fibrosis by regulating cellular senescence. Therefore, we hypothesize that sympathetic activation in the injured kidney induces cellular senescence, which contributes to progressive renal inflammation and fibrosis.Methods: Renal denervation was performed 2 days before the UUO (unilateral ureteral obstruction) and UIRI (unilateral ischemia-reperfusion injury) models. The effects of renal denervation on renal fibrosis and cellular senescence were observed. In vitro, cellular senescence was induced in renal proximal tubular epithelial cell lines (TKPTS cells) by treatment with norepinephrine (NE). The selective α2A-adrenergic receptor (α2A-AR) antagonists BRL44408 and β-arrestin2 siRNA, were administered to inhibit NE-induced cellular senescence. A significantly altered pathway was identified through immunoblotting, immunofluorescence, immunocytochemistry, and functional assays involved in mitochondrial function.
    Results: Renal fibrosis and cellular senescence were significantly increased in UUO and UIRI models, which were partially reversed by renal denervation. In vitro, NE induced epithelial cells secreting proinflammatory cytokines and promoted cell senescence by activating α2A-AR. Importantly, the effects of NE during cellular senescence were blocked by α2A-AR selective antagonist and β-arrestin2 (downstream of α2A-AR) siRNA.
    Conclusion: Renal sympathetic activation and cellular senescence are important neurometabolic and neuroimmune mechanisms in the development of renal fibrosis. Renal sympathetic neurotransmitter NE acting on the α2A-AR of epithelial cells promotes cellular senescence through the downstream β-arrestin2 signaling, which is a potential preventive target for renal fibrosis.
    Keywords:  cellular senescence; neuroimmune; neurometabolic; renal fibrosis.; sympathetic denervation
  7. Saudi Pharm J. 2022 Jan;30(1): 91-101
      Emerging evidence has shown that the therapy-induced senescent growth arrest in cancer cells is of durable nature whereby a subset of cells can reinstate proliferative capacity. Promising new drugs named senolytics selectively target senescent cells and commit them into apoptosis. Accordingly, senolytics have been proposed as adjuvant cancer treatment to cull senescent tumor cells, and thus, screening for agents that exhibit senolytic properties is highly warranted. Our study aimed to investigate three agents, sorafenib, rapamycin, and venetoclax for their senolytic potential in doxorubicin-induced senescence in HCT116 cells. HCT116 cells were treated with one of the three agents, sorafenib (5 µM), rapamycin (100 nM), or venetoclax (10 µM), in the absence or presence of doxorubicin (1 µM). Senescence was evaluated using microscopy-based and flow cytometry-based Senescence-associated-β-galactosidase staining (SA-β-gal), while apoptosis was assessed using annexin V-FITC/PI, and Muse caspase-3/-7 activity assays. We screened for potential genes through which the three drugs exerted senolytic-like action using the Human Cancer Pathway Finder PCR array. The three agents reduced doxorubicin-induced senescent cell subpopulations and significantly enhanced the apoptotic effect of doxorubicin compared with those treated only with doxorubicin. The senescence genes IGFBP5 and BMI1 and the apoptosis genes CASP7 and CASP9 emerged as candidate genes through which the three drugs exhibited senolytic-like properties. These results suggest that the attenuation of doxorubicin-induced senescence might have shifted HCT116 cells to apoptosis by exposure to the tested pharmacological agents. Our work argues for the use of senolytics to reduce senescence-mediated resistance in tumor cells and to enhance chemotherapy efficacy.
    Keywords:  Apoptosis; Doxorubicin; Rapamycin; Senescence; Senolytic; Sorafenib; Venetoclax
  8. Exp Mol Med. 2022 Feb 08.
      α-Synuclein is a crucial element in the pathogenesis of Parkinson's disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence. Transcriptome analysis showed that α-synuclein overexpression led to cellular senescence with activation of the p53 pathway and DNA damage responses (DDRs). Chromatin immunoprecipitation analyses using p53 and γH2AX, chromosomal markers of DNA damage, revealed that these proteins bind to promoters and regulate the expression of DDR and cellular senescence genes. Cellular marker analyses confirmed cellular senescence and the accumulation of DNA double-strand breaks. The non-homologous end joining (NHEJ) DNA repair pathway was activated in α-synuclein-overexpressing cells. However, the expression of MRE11, a key component of the DSB repair system, was reduced, suggesting that the repair pathway induction was incomplete. Neuropathological examination of α-synuclein transgenic mice showed increased levels of phospho-α-synuclein and DNA double-strand breaks, as well as markers of cellular senescence, at an early, presymptomatic stage. These results suggest that the accumulation of DNA double-strand breaks (DSBs) and cellular senescence are intermediaries of α-synuclein-induced pathogenesis in PD.
  9. J Transl Int Med. 2021 Dec 01. 9(4): 239-248
      Vascular senescence plays a vital role in cardiovascular diseases and it is closely related to cellular senescence. At the molecular level, aging begins with a single cell, and it is characterized by telomere shortening, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, and so on. Epigenetics is an independent discipline that modifies DNA activity without altering the DNA sequence. The application of epigenetics helps to alleviate the occurrence of human diseases, inhibit senescence, and even inhibit tumor occurrence. Epigenetics mainly includes the modification of DNA, histone, and noncoding RNA. Herein, the application of epigenetics in vascular senescence and aging has been reviewed to provide the prospects and innovative inspirations for future research.
    Keywords:  aging; epigenetic; vascular senescence
  10. Nat Rev Endocrinol. 2022 Feb 10.
      Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches.
  11. Aging (Albany NY). 2022 Jan 30. 14(2): 1014-1032
      The functions of stem cells decline progressively with aging, and some metabolic changes occur during the process. However, the molecular mechanisms of stem cell aging remain unclear. In this study, the combined application of metabolomics and transcriptomics technologies can effectively describe the possible molecular mechanisms of rat bone marrow mesenchymal stem cell (BMSC) senescence. Metabolomic profiles revealed 23 differential metabolites which were abundant in "glycerophospholipid metabolism", "linoleic acid metabolism" and "biosynthesis of unsaturated fatty acids". In addition, transcriptomics analysis identified 590 genes with enormously differential expressions in young and old BMSCs. KEGG enrichment analyses showed that metabolism-related pathways in BMSC senescence had stronger responses. Furthermore, the integrated analysis of the interactions between the differentially expressed genes (DEGs) and metabolites indicated the differential genes related to lipid metabolism of Scd, Scd2, Dgat2, Fads2, Lpin1, Gpat3, Acaa2, Lpcat3, Pcyt2 and Pla2g4a may be closely associated with the aging of BMSCs. Finally, Scd2 was identified as the most significant DEG, and Scd2 over-expression could alleviate cellular senescence in aged BMSCs. In conclusion, this work provides a validated understanding that the DEGs and metabolites related to lipid metabolism present more apparent changes in the senescence of rat BMSCs.
    Keywords:  BMSCs; aging; lipid metabolism; metabolomics; transcriptomics
  12. Aging Cell. 2022 Feb 11. e13567
      Metformin, a widely prescribed first-line drug for the treatment of type II diabetes mellitus, has been shown to extend lifespan and delay the onset of age-related diseases. The precisely mechanisms by which these effects are realized remain elusive. We find that metformin exposure is restricted to adults, which is sufficient to extend lifespan. However, limiting metformin exposure to the larvae has no significant effect on Caenorhabditis elegans longevity. Here, we show that after metformin treatment, the level of S-adenosylmethionine (SAM) is reduced in adults but not in the larvae. Potential mechanisms by which reduced SAM might increase lifespan include altering the histone methylation. However, the molecular connections between metformin, SAM limitation, methyltransferases, and healthspan-associated phenotypes are unclear. Through genetic screening of C. elegans, we find that metformin promotes the healthspan through an H3K4 methyltransferase/demethylase complex to downregulate the targets, including mTOR and S6 kinase. Thus, our studies provide molecular links between meformin, SAM limitation, histone methylation, and healthspan and elucidate the mode action of metformin-regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.
    Keywords:   Caenorhabditis elegans ; Metformin; histone methylation; lifespan; mTOR signaling
  13. J Gerontol A Biol Sci Med Sci. 2022 Feb 09. pii: glac034. [Epub ahead of print]
      Frailty is an age-related syndrome that exposes individuals to increased vulnerability. Although it is potentially reversible, in most cases it leads to negative outcomes, including mortality. The different methods proposed identify frailty after the onset of clinical manifestations. An early diagnosis might make it possible to manage the frailty progression better. The frailty pathophysiology is still unclear although mechanisms, in particular those linked to inflammation and immunosenescence, have been investigated. A common feature of several clinical aspects involved in senescent organisms is the increase of oxidative stress, described as one of the major causes of DNA damage accumulation in aged cells including the adult stem cell compartment. Likely, this accumulation is implicated in frailty status. The oxidative status of our frail, pre-frail and non-frail population was characterized. In addition, the DNA damage in hematopoietic cells was evidenced by analyzing the peripheral blood mononuclear cells (PBMC) and their T lymphocyte, monocyte, circulating hematopoietic progenitor stem cell (cHPSC) subpopulations. The phosphorylation of C-terminal of histone H2AX at amino acid Ser 139 (γ-H2AX), which occurs at the DNA double strand break focus, was evaluated. In our frail population an increased oxidative stress and a high level of DNA damage in cHPSC was found. This study may have potential implications because the increment of DNA damage in cHPSC could be suggestive of an organism impairment preceding the evident frailty. In addition, it may open the possibility for attenuation of frailty progression throughout specific drugs acting on preventing DNA damage or removing damaged cells.
    Keywords:  Biology of aging; Cellular senescence; Oxidative stress; γ-H2AX
  14. Semin Immunopathol. 2022 Feb 09.
      Two vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are recognized as autoimmune and autoinflammatory diseases that manifest exclusively within the aorta and its large branches. In both entities, the age of the affected host is a critical risk factor. TAK manifests during the 2nd-4th decade of life, occurring while the immune system is at its height of performance. GCA is a disease of older individuals, with infrequent cases during the 6th decade and peak incidence during the 8th decade of life. In both vasculitides, macrophages and T cells infiltrate into the adventitia and media of affected vessels, induce granulomatous inflammation, cause vessel wall destruction, and reprogram vascular cells to drive adventitial and neointimal expansion. In GCA, abnormal immunity originates in an aged immune system and evolves within the aged vascular microenvironment. One hallmark of the aging immune system is the preferential loss of CD8+ T cell function. Accordingly, in GCA but not in TAK, CD8+ effector T cells play a negligible role and anti-inflammatory CD8+ T regulatory cells are selectively impaired. Here, we review current evidence of how the process of immunosenescence impacts the risk for GCA and how fundamental differences in the age of the immune system translate into differences in the granulomatous immunopathology of TAK versus GCA.
    Keywords:  CD8+ Treg cells; Giant cell arteritis; Immunosenescence; Inflammaging; NOTCH; Takayasu arteritis; mTOR
  15. Mol Cell Biochem. 2022 Feb 11.
      Cystathionine gamma-lyase (CSE)-derived hydrogen sulfide (H2S) plays an essential role in preserving cardiac functions. Angiotensin-converting enzyme 2 (ACE2) acts as the negative regulator of the renin-angiotensin system, exerting anti-oxidative stress and anti-inflammatory properties within the body. The interplays of CSE/H2S signaling and ACE2 in cardiac aging are unclear. In this study, the regulatory roles of H2S on ACE2 expression in mouse heart tissue and rat cardiomyocytes under different stress conditions were investigated. It was found that ACE2 protein level was lower in heart tissues from old mice (56-week-old) than young mice (8-week-old), and the knockout of CSE (CSE KO) induced moderate oxidative stress and further inhibited ACE2 protein level in mouse hearts at both young and old age. Incubation of rat cardiac cells (H9C2) with a low dose of H2O2 (50 µM) suppressed ACE2 protein level and induced cellular senescence, which was completely reversed by co-incubation with 30 µM NaHS (a H2S donor). Prolonged nutrient excess is an increased risk of heart disorders by causing metabolic dysfunction and cardiac remodeling. We further found high-fat diet feeding stimulated ACE2 expression and induced severe oxidative stress in CSE KO heart in comparison with wild-type heart. Lipid overload in H9C2 cells to mimic a status of nutrient excess also enhanced the expression of ACE2 protein and induced severe oxidative stress and cell senescence, which were significantly attenuated by the supplementation of exogenous H2S. Furthermore, the manipulation of ACE2 expression partially abolished the protective role of H2S against cellular senescence. These results demonstrate the dynamic roles of H2S in the maintenance of ACE2 levels under different levels of oxidative stress, pointing to the potential implications in targeting the CSE/H2S system for the interruption of aging and diabetes-related heart disorders.
    Keywords:  ACE2; Aging; Diabetes; H2S; Heart
  16. Acta Pharm Sin B. 2022 Jan;12(1): 50-75
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling exert essential regulatory function in microbial-and onco-immunology through the induction of cytokines, primarily type I interferons. Recently, the aberrant and deranged signaling of the cGAS-STING axis is closely implicated in multiple sterile inflammatory diseases, including heart failure, myocardial infarction, cardiac hypertrophy, nonalcoholic fatty liver diseases, aortic aneurysm and dissection, obesity, etc. This is because of the massive loads of damage-associated molecular patterns (mitochondrial DNA, DNA in extracellular vesicles) liberated from recurrent injury to metabolic cellular organelles and tissues, which are sensed by the pathway. Also, the cGAS-STING pathway crosstalk with essential intracellular homeostasis processes like apoptosis, autophagy, and regulate cellular metabolism. Targeting derailed STING signaling has become necessary for chronic inflammatory diseases. Meanwhile, excessive type I interferons signaling impact on cardiovascular and metabolic health remain entirely elusive. In this review, we summarize the intimate connection between the cGAS-STING pathway and cardiovascular and metabolic disorders. We also discuss some potential small molecule inhibitors for the pathway. This review provides insight to stimulate interest in and support future research into understanding this signaling axis in cardiovascular and metabolic tissues and diseases.
    Keywords:  AA, amino acids; AAD, aortic aneurysm and dissection; AKT, protein kinase B; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; Ang II, angiotensin II; CBD, C-binding domain; CDG, c-di-GMP; CDNs, cyclic dinucleotides; CTD, C-terminal domain; CTT, C-terminal tail; CVDs, cardiovascular diseases; Cardiovascular diseases; Cys, cysteine; DAMPs, danger-associated molecular patterns; Damage-associated molecular patterns; DsbA-L, disulfide-bond A oxidoreductase-like protein; ER stress; ER, endoplasmic reticulum; GTP, guanosine triphosphate; HAQ, R71H-G230A-R293Q; HFD, high-fat diet; ICAM-1, intracellular adhesion molecule 1; IFN, interferon; IFN-I, type 1 interferon; IFNAR, interferon receptors; IFNIC, interferon-inducible cells; IKK, IκB kinase; IL, interleukin; IRF3, interferon regulatory factor 3; ISGs, IRF-3-dependent interferon-stimulated genes; Inflammation; LBD, ligand-binding pocket; LPS, lipopolysaccharides; MI, myocardial infarction; MLKL, mixed lineage kinase domain-like protein; MST1, mammalian Ste20-like kinases 1; Metabolic diseases; Mitochondria; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor-kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; NO2-FA, nitro-fatty acids; NTase, nucleotidyltransferase; PDE3B/4, phosphodiesterase-3B/4; PKA, protein kinase A; PPI, protein–protein interface; Poly: I.C, polyinosinic-polycytidylic acid; ROS, reactive oxygen species; SAVI, STING-associated vasculopathy with onset in infancy; SNPs, single nucleotide polymorphisms; STIM1, stromal interaction molecule 1; STING; STING, stimulator of interferon genes; Ser, serine; TAK1, transforming growth factor β-activated kinase 1; TBK1, TANK-binding kinase 1; TFAM, mitochondrial transcription factor A; TLR, Toll-like receptors; TM, transmembrane; TNFα, tumor necrosis factor-alpha; TRAF6, tumor necrosis factor receptor-associated factor 6; TREX1, three prime repair exonuclease 1; YAP1, Yes-associated protein 1; cGAMP, 2′,3′-cyclic GMP–AMP; cGAS; cGAS, cyclic GMP–AMP synthase; dsDNA, double-stranded DNA; hSTING, human stimulator of interferon genes; mTOR, mammalian target of rapamycin; mtDNA, mitochondrial DNA
  17. Curr Opin Immunol. 2022 Feb 03. pii: S0952-7915(22)00004-8. [Epub ahead of print]74 164-171
      The recognition of DNA through the cGAS-STING pathway plays a critical role in antiviral immunity, but can also drive maladaptive immune responses underlying several pathological conditions. Despite its importance, understanding the organization of cGAS-STING signaling axis in the 3D space of a cell is relatively limited. In this review, we discuss recent progress in understanding the spatial coordination of DNA-induced cGAS-STING activity and its relevance in balancing innate immune responses toward (self-) DNA. We also consider the importance of context-specific co-factors and end by suggesting interesting areas for further research into spatial aspects of DNA-induced innate immunity.
  18. Front Physiol. 2021 ;12 742004
      Long non-coding RNAs (lncRNAs) are thought to function as "sponges" for microRNAs, but a role for such competing endogenous RNAs (ceRNAs) in muscle aging is not well understood. We therefore examined in skeletal muscles of young (4-6 months) and aged (22-24) male and female mice the expression of lncRNA MALAT1, which is predicted in silico to bind the senescence-associated microRNA miR-34a-5p. Results indicate a significant decrease in lncRNA MALAT1 expression in mouse skeletal muscle with age that coincides with an age-related increase in miR-34a-5p expression. In vitro studies using mouse C2C12 myoblasts demonstrate that MALAT1 silencing using siRNA increases miR-34a expression, consistent with a role for MALAT1 as an inhibitor of miR-34a-5p activity. Levels of reactive oxygen species (ROS) are known to increase in muscle with age, and so we treated C2C12 cells with hydrogen peroxide (10 and 100 μM) to examine changes in MALAT1 expression. MALAT1 expression decreased significantly with H2O2 treatment, but this effect was attenuated with p53 siRNA. Finally, miR-34a-5p is implicated in tissue fibrosis, and so we assessed the expression of TGF-β1 after MALAT1 silencing. MALAT1 siRNA significantly increased the expression of TGF-β1 in C2C12 cells. These findings suggest that age-related fibrosis and muscle atrophy mediated by ROS may result at least in part from an increase in miR-34a bioavailability resulting from a decline in miR-34a "sponging" due to ceRNA MALAT1 depletion. Crosstalk between MALAT1 and miR-34a may therefore represent a therapeutic target for improving muscle function with aging.
    Keywords:  fibrosis; oxidative stress; sarcopenia; senescence; siRNA
  19. Exp Mol Med. 2022 Feb 10.
      Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with a high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death and the development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as a damage-associated molecular pattern (DAMP) that is monitored by the cGAS-STING axis to trigger the immune response in many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis is a type of inflammatory programmed death that promotes a chronic inflammatory response and tissue degeneration. However, the relationship between the cGAS-STING axis and NLRP3 inflammasome-induced pyroptosis in the pathogenesis of IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) and histopathology to demonstrate that cGAS, STING, and NLRP3 are associated with the degree of IVD degeneration. Oxidative stress induced cGAS-STING axis activation and NLRP3 inflammasome-mediated pyroptosis in a STING-dependent manner in human NP cells. Interestingly, the canonical morphological and functional characteristics of mitochondrial permeability transition pore (mPTP) opening with the cytosolic escape of mitochondrial DNA (mtDNA) were observed in human NP cells under oxidative stress. Furthermore, the administration of a specific pharmacological inhibitor of mPTP and self-mtDNA cytosolic leakage effectively reduced NLRP3 inflammasome-mediated pyroptotic NP cell death and microenvironmental inflammation in vitro and degenerative progression in a rat disc needle puncture model. Collectively, these data highlight the critical roles of the cGAS-STING-NLRP3 axis and pyroptosis in the progression of IVD degeneration and provide promising therapeutic approaches for discogenic LBP.
  20. Trends Cell Biol. 2022 Feb 07. pii: S0962-8924(22)00005-8. [Epub ahead of print]
      Aging is a universal biological process that increases the risk of multiple diseases including cancer. Growing evidence shows that alterations in the genome and epigenome, driven by similar mechanisms, are found in both aged cells and cancer cells. In this review, we detail the genetic and epigenetic changes associated with normal aging and the mechanisms responsible for these changes. By highlighting genetic and epigenetic alterations in the context of tumorigenesis, cancer progression, and the aging tumor microenvironment, we examine the possible impacts of the normal aging process on malignant transformation. Finally, we examine the implications of age-related genetic and epigenetic alterations in both tumors and patients for the treatment of cancer.
    Keywords:  aging; cancer; epigenetics; genetics; tumor microenvironment
  21. Geroscience. 2022 Feb 05.
       Vascular aging has a central role in the pathogenesis of cardiovascular diseases contributing to increased mortality of older adults. There is increasing evidence that, in addition to the documented role of cell-autonomous mechanisms of aging, cell-nonautonomous mechanisms also play a critical role in the regulation of vascular aging processes. Our recent transcriptomic studies (Kiss T. et al. Geroscience. 2020;42(2):727-748) demonstrated that circulating anti-geronic factors from young blood promote vascular rejuvenation in aged mice. The present study was designed to expand upon the results of this study by testing the hypothesis that circulating pro-geronic factors also contribute to the genesis of vascular aging phenotypes. To test this hypothesis, through heterochronic parabiosis, we determined the extent to which shifts in the vascular transcriptome (RNA-seq) are modulated by the old systemic environment. We reanalyzed existing RNA-seq data, comparing the transcriptome in the aorta arch samples isolated from isochronic parabiont aged (20-month-old) C57BL/6 mice [A-(A); parabiosis for 8 weeks] and young isochronic parabiont (6-month-old) mice [Y-(Y)] and also assessing transcriptomic changes in the aortic arch in young (6-month-old) parabiont mice [Y-(A); heterochronic parabiosis for 8 weeks] induced by the presence of old blood derived from aged (20-month-old) parabionts. We identified 528 concordant genes whose expression levels differed in the aged phenotype and were shifted towards the aged phenotype by the presence of old blood in young Y-(A) animals. Among them, the expression of 221 concordant genes was unaffected by the presence of young blood in A-(Y) mice. GO enrichment analysis suggests that old blood-regulated genes may contribute to pathologic vascular remodeling. IPA Upstream Regulator analysis (performed to identify upstream transcriptional regulators that may contribute to the observed transcriptomic changes) suggests that the mechanism of action of pro-geronic factors present in old blood may include inhibition of pathways mediated by SRF (serum response factor), insulin-like growth factor-1 (IGF-1) and VEGF-A. In conclusion, relatively short-term exposure to old blood can accelerate vascular aging processes. Our findings provide additional evidence supporting the significant plasticity of vascular aging and the existence of circulating pro-geronic factors mediating pathological remodeling of the vascular smooth muscle cells and the extracellular matrix.
    Keywords:  Aging; Aneurysm; Aorta; Atherosclerosis; Heterochronic parabiosis; Transcriptome; Vascular aging
  22. Nat Commun. 2022 Feb 09. 13(1): 779
      Aging and mechanical overload are prominent risk factors for osteoarthritis (OA), which lead to an imbalance in redox homeostasis. The resulting state of oxidative stress drives the pathological transition of chondrocytes during OA development. However, the specific molecular pathways involved in disrupting chondrocyte redox homeostasis remain unclear. Here, we show that selenophosphate synthetase 1 (SEPHS1) expression is downregulated in human and mouse OA cartilage. SEPHS1 downregulation impairs the cellular capacity to synthesize a class of selenoproteins with oxidoreductase functions in chondrocytes, thereby elevating the level of reactive oxygen species (ROS) and facilitating chondrocyte senescence. Cartilage-specific Sephs1 knockout in adult mice causes aging-associated OA, and augments post-traumatic OA, which is rescued by supplementation of N-acetylcysteine (NAC). Selenium-deficient feeding and Sephs1 knockout have synergistic effects in exacerbating OA pathogenesis in mice. Therefore, we propose that SEPHS1 is an essential regulator of selenium metabolism and redox homeostasis, and its dysregulation governs the progression of OA.
  23. Front Neurosci. 2021 ;15 806260
      The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options.
    Keywords:  Alzheimer’s disease; T cells; adaptive immune system; antigen presentation; epitope mapping; neurodegeneration; neuroimmunology
  24. Blood. 2022 Feb 10. 139(6): 813-821
      The role of telomeres in human health and disease is yet to be fully understood. The limitations of mouse models for the study of human telomere biology and difficulties in accurately measuring the length of telomere repeats in chromosomes and cells have diverted attention from many important and relevant observations. The goal of this perspective is to summarize some of these observations and to discuss the antagonistic role of telomere loss in aging and cancer in the context of developmental biology, cell turnover, and evolution. It is proposed that both damage to DNA and replicative loss of telomeric DNA contribute to aging in humans, with the differences in leukocyte telomere length between humans being linked to the risk of developing specific diseases. These ideas are captured in the Telomere Erosion in Disposable Soma theory of aging proposed herein.
  25. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Feb 04. pii: S1388-1981(22)00008-7. [Epub ahead of print] 159118
      Adipose tissue is a critical organ for nutrient sensing, energy storage and maintaining metabolic health. The failure of adipose tissue homeostasis leads to metabolic disease that is seen during obesity or aging. Local metabolic processes are coordinated by interacting microenvironments that make up the complexity and heterogeneity of the adipose tissue. Catecholamine-induced lipolysis, a critical pathway in adipocytes that drives the release of stored triglyceride as free fatty acid after stimulation, is impaired during aging. The impairment of this pathway is associated with a failure to maintain a healthy body weight, body-temperature or mount an immune response. Along with impairments in aged adipocytes, aging is associated with an accumulation of inflammation, immune cell activation, and increased dysfunction in the nervous and lymphatic systems within the adipose tissue. Together these microenvironments support the initiation of stimulated lipolysis and the transport of free fatty acid under conditions of metabolic homeostasis. However, during aging, the defects in these cellular systems result in a reduction in ability to stimulate lipolysis. This review will focus on how the immune, nervous and lymphatic systems interact during tissue homeostasis, review areas that are impaired with aging and discuss areas of research that are currently unclear.
    Keywords:  Adipose tissue lipolysis; Aging; Immune cells; Inflammation; Lymphatic vessels; Sympathetic nervous system