bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒02‒28
thirty papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Biofactors. 2021 Feb 23.
      Aging is a biological process caused by the accumulation of senescent cells with a permanent proliferative arrest. To the influence of aging on human life expectancy, there is essential for new biomarkers which possibly will assistance in recognizing age-associated pathologies. Exosomes, which are cell-secreted nanovesicles, make available a new biomarker detection and therapeutic approach for the transfer of different molecules with high capacity. Recently, non-coding RNAs (ncRNA) which are contained in exosomes have developed as important molecules regulating the complexity of aging and relevant human diseases. The discovery of ncRNA provided perceptions into an innovative regulatory platform that could interfere with cellular senescence. The non-coding transcriptome includes a different of RNA species, spanning from short ncRNAs (<200 nucleotides) to long ncRNAs, that are >200 bp long. Upgraded evidence displays that targeting ncRNAs possibly will influence senescence pathways. In this article, we will address ncRNAs that participated in age-related and cellular senescence diseases. Growing conception of ncRNAs in the aging process possibly will be responsible for new understandings into the improvement of age-related diseases and elongated life span.
    Keywords:  aging; circRNAs; exosome; lncRNAs; miRNAs; non-coding RNAs
  2. Front Med (Lausanne). 2021 ;8 600626
      Cellular senescence due to telomere dysfunction has been hypothesized to play a role in age-associated diseases including idiopathic pulmonary fibrosis (IPF). It has been postulated that paracrine mediators originating from senescent alveolar epithelia signal to surrounding mesenchymal cells and contribute to disease pathogenesis. However, murine models of telomere-induced alveolar epithelial senescence fail to display the canonical senescence-associated secretory phenotype (SASP) that is observed in senescent human cells. In an effort to understand human-specific responses to telomere dysfunction, we modeled telomere dysfunction-induced senescence in a human alveolar epithelial cell line. We hypothesized that this system would enable us to probe for differences in transcriptional and proteomic senescence pathways in vitro and to identify novel secreted protein (secretome) changes that potentially contribute to the pathogenesis of IPF. Following induction of telomere dysfunction, a robust senescence phenotype was observed. RNA-seq analysis of the senescent cells revealed the SASP and comparisons to previous murine data highlighted differences in response to telomere dysfunction. We conducted a proteomic analysis of the senescent cells using a novel biotin ligase capable of labeling secreted proteins. Candidate biomarkers selected from our transcriptional and secretome data were then evaluated in IPF and control patient plasma. Four novel proteins were found to be differentially expressed between the patient groups: stanniocalcin-1, contactin-1, tenascin C, and total inhibin. Our data show that human telomere-induced, alveolar epithelial senescence results in a transcriptional SASP that is distinct from that seen in analogous murine cells. Our findings suggest that studies in animal models should be carefully validated given the possibility of species-specific responses to telomere dysfunction. We also describe a pragmatic approach for the study of the consequences of telomere-induced alveolar epithelial cell senescence in humans.
    Keywords:  A549; IPF; SASP; aging; biomarker; mass spectrometry; secretome; telomerase
  3. Free Radic Biol Med. 2021 Feb 17. pii: S0891-5849(21)00093-9. [Epub ahead of print]
      AIMS: The senescence of alveolar epithelial type 2 (AT2) cells is implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Cigarette smoke (CS) is a strong risk factor for IPF and it is also a pro-senescent factor. Here we aimed to investigate whether and how CS induces AT2 cells senescence via a SIRT1/autophagy dependent pathway. Our results showed that CS extract (CSE) reduced autophagy and mitophagy and increased mitochondrial reactive oxygen species (mitoROS) in MLE-12 cells, an AT2 cell line. The autophagy inducer rapamycin (RAPA) and the mitochondria-targeted antioxidant mitoquinone (mitoQ) inhibited CSE-related senescence and decreased mitoROS. Next, we found that CSE promoted DNA damage, downregulated the nicotinamide adenine dinucleotide (NAD+)/nicotinamide adenine dinucleotide (NADH) ratio and suppressed SIRT1 activity. Activating SIRT1 with its activator SRT1720 attenuated senescence through an autophagy-dependent pathway. The NAD+ precursor nicotinamide mononucleotide and the poly ADP-ribose polymerase (PARP1) inhibitor olaparib also exerted anti-senescent effects by activating SIRT1. Moreover, the results showed that mitoQ and RAPA, in turn, elevated SIRT1 activity by inhibiting DNA damage. Consistent with these results, SRT1720 and mitoQ mitigated CS-induced AT2 cells senescence and lung fibrosis in vivo. Moreover, autophagy in AT2 cells was rescued by SRT1720. Taken together, our results suggested that CS-induced senescence of AT2 cells was due to decreased autophagy mediated by SIRT1 inactivation, which was attributed to competitive consumption of NAD+ caused by DNA damage-induced PARP1 activation. The reduction in autophagy, in turn, decreased SIRT1 activity by promoting mitochondrial oxidative stress-related DNA damage, thereby establishing a positive feedback loop between SIRT1 and autophagy in CS-induced AT2 cells senescence. Consequently, CS-inactivated SIRT1 promoted autophagy-dependent senescence of AT2 cells to induce pulmonary fibrosis.
    Keywords:  Pulmonary fibrosis; SIRT1; autophagy; cigarette smoke; senescence
  4. Cell Rep. 2021 Feb 23. pii: S2211-1247(21)00092-9. [Epub ahead of print]34(8): 108779
      In the tumor microenvironment, senescent non-malignant cells, including cancer-associated fibroblasts (CAFs), exhibit a secretory profile under stress conditions; this senescence-associated secretory phenotype (SASP) leads to cancer progression and chemoresistance. However, the role of senescent CAFs in metastatic lesions and the molecular mechanism of inflammation-related SASP induction are not well understood. We show that pro-inflammatory cytokine-driven EZH2 downregulation maintains the SASP by demethylating H3K27me3 marks in CAFs and enhances peritoneal tumor formation of gastric cancer (GC) through JAK/STAT3 signaling in a mouse model. A JAK/STAT3 inhibitor blocks the increase in GC cell viability induced by senescent CAFs and peritoneal tumor formation. Single-cell mass cytometry revealed that fibroblasts exist in the ascites of GC patients with peritoneal dissemination, and the fibroblast population shows p16 expression and SASP factors at high levels. These findings provide insights into the inflammation-related SASP maintenance by histone modification and the role of senescent CAFs in GC peritoneal dissemination.
    Keywords:  EZH2; H3K27me3 marks; JAK inhibitor; cancer-associated fibroblasts; gastric cancer; peritoneal dissemination; senescence-associated secretory phenotype
  5. Mol Metab. 2021 Feb 17. pii: S2212-8778(21)00035-1. [Epub ahead of print] 101195
      BACKGROUND: Nicotinamide adenine dinucleotide (NAD+), a critical coenzyme present in every living cell, is involved in a myriad of metabolic processes associated with cellular bioenergetics. For this reason, NAD+ is often studied in the context of aging, cancer, neurodegenerative and metabolic disorders.SCOPE OF REVIEW: Cellular NAD+ depletion is associated with compromised adaptive cellular stress responses, impaired neuronal plasticity, impaired DNA repair and cellular senescence. Growing evidence has shown the efficacy of boosting NAD+ levels by using NAD+ precursors in various diseases. This review aims to provide a comprehensive understanding into the role of NAD+ in aging and other pathologies and discusses potential therapeutic targets.
    MAJOR CONCLUSIONS: An alteration in the NAD+/NADH ratio or the NAD+ pool size can lead to derailment of the biological system and contribute to various neurodegenerative disorders, aging, and tumorigenesis. Due to the varied distribution of NAD+/NADH in different locations within the cell, the direct role of impaired NAD+-dependent processes in humans remains unestablished. In this regard, longitudinal studies are needed to quantify NAD+ and its related metabolites. Future research should focus on measuring the fluxes through pathways associated with NAD+ synthesis and degradation.
    Keywords:  Aging; Cancer; Metabolism; NAD(+); Neurodegeneration; Sirtuins
  6. Curr Opin Cell Biol. 2021 Feb 18. pii: S0955-0674(21)00004-1. [Epub ahead of print]70 91-99
      Micronuclei are small membrane-bounded compartments with a DNA content encapsulated by a nuclear envelope and spatially separated from the primary nucleus. Micronuclei have long been linked to chromosome instability, genome rearrangements, and mutagenesis. They are frequently found in cancers, during senescence, and after genotoxic stress. Compromised integrity of the micronuclear envelope delays or disrupts DNA replication, inhibits DNA repair, and exposes micronuclear DNA directly to cytoplasm. Micronuclei play a central role in tumorigenesis, with micronuclear DNA being a source of complex genome rearrangements (including chromothripsis) and promoting a cyclic GMP-AMP synthase (cGAS)-mediated cellular immune response that may contribute to cancer metastasis. Here, we discuss recent findings on how micronuclei are generated, what the consequences are, and what cellular mechanisms can be applied to protect against micronucleation.
  7. Cell Stem Cell. 2021 Feb 18. pii: S1934-5909(21)00015-1. [Epub ahead of print]
      Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. With advancing age, levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here, we show that the nuclear lamina protein lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs, whereas protein levels of SUN-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), increase. Balancing the levels of LB1 and SUN1 in aged NSCs restores the strength of the endoplasmic reticulum diffusion barrier that is associated with segregation of aging factors in proliferating NSCs. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a mechanism that mediates age-related decline of neurogenesis in the mammalian hippocampus.
    Keywords:  Lamin; aging; asymmetric segregation; diffusion barrier; hippocampus; neural stem cell; neurogenesis; nuclear lamina; proliferation
  8. Oncogene. 2021 Feb 24.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and devastating malignant tumors. Epigenetic modifications such as DNA methylation and histone modification regulate tumor initiation and progression. However, the contribution of histone variants in PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and that its overexpression correlates with poor prognosis. Moreover, all three H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1, and H2A.Z.2.2) are highly expressed in PDAC cell lines and PDAC patients. Knockdown of these H2A.Z isoforms in PDAC cell lines induces a senescent phenotype, cell cycle arrest in phase G2/M, increased expression of cyclin-dependent kinase inhibitor CDKN2A/p16, SA-β-galactosidase activity and interleukin 8 production. Transcriptome analysis of H2A.Z-depleted PDAC cells showed altered gene expression in fatty acid biosynthesis pathways and those that regulate cell cycle and DNA damage repair. Importantly, depletion of H2A.Z isoforms reduces the tumor size in a mouse xenograft model in vivo and sensitizes PDAC cells to gemcitabine. Overexpression of H2A.Z.1 and H2A.Z.2.1 more than H2A.Z.2.2 partially restores the oncogenic phenotype. Therefore, our data suggest that overexpression of H2A.Z isoforms enables cells to overcome the oncoprotective barrier associated with senescence, favoring PDAC tumor grow and chemoresistance. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC.
  9. Stem Cell Reports. 2021 Feb 16. pii: S2213-6711(21)00051-5. [Epub ahead of print]
      Human mesenchymal stem/stromal cell (hMSC)-based cell therapies are promising for treating a variety of diseases. The unique immunomodulatory properties of hMSCs have extended their therapeutic potential beyond tissue regeneration. However, extensive pre-clinical culture expansion inevitably drives cells toward replicative "aging" and a consequent decline in quality. These "in vitro-aged" hMSCs resemble biologically aged cells, which have been reported to show senescence signatures, diminished immunosuppressive capacity, and weakened regenerative potential as well as pro-inflammatory features. In this review, we have surveyed the literature to explore the intimate relationship between the inflammatory status of hMSCs and their in vitro aging process. We posit that a shift from an anti-inflammatory to a pro-inflammatory phenotype of culture-expanded hMSCs contributes to a deterioration in their therapeutic efficacy. Potential molecular and cellular mechanisms underpinning this phenomenon have been discussed. We have also highlighted studies that leverage these mechanisms to make culture-expanded hMSCs more amenable for clinical use.
    Keywords:  SASP; aging; allogeneic stem cell therapy; extracellular matrix; glycosaminoglycan; heparan sulfate; immunomodulation; inflammation; rejuvenating mesenchymal stem cells; secretome
  10. Ageing Res Rev. 2021 Feb 20. pii: S1568-1637(21)00055-6. [Epub ahead of print] 101308
      Corona virus disease 2019 (COVID-19) is a global emergency able to overwhelm the healthcare capacities worldwide and to affect the older generation especially. When addressing the pathophysiological mechanisms and clinical manifestations of COVID-19, it becomes evident that the disease targets pathways and domains affected by the main aging- and frailty-related pathophysiological changes. A closer analysis of the existing data supports a possible role of biological age rather than chronological age in the prognosis of COVID-19. There is a need for systematic, consequent action of identifying frail (not only older, not only multimorbid, not only symptomatic) persons at risk of poor outcomes in order to protect our oldest generation from COVID-19.
    Keywords:  Biological age; COVID-19; Corona virus disease 2019; Frailty; SARS-CoV-2; Severe acute respiratory syndrome-corona virus 2
  11. Aging (Albany NY). 2021 Feb 17. 13
      The interplay between microbiota and host metabolism plays an important role in health. Here, we examined the relationship between age, gut microbiome and host serum metabolites in male C57BL/6J mice. Fecal microbiome analysis of 3, 6, 18, and 28 months (M) old mice showed that the Firmicutes/Bacteroidetes ratio was highest in the 6M group; the decrease of Firmicutes in the older age groups suggests a reduced capacity of gut microflora to harvest energy from food. We found age-dependent increase in Proteobacteria, which may lead to altered mucus structure more susceptible to bacteria penetration and ultimately increased intestinal inflammation. Metabolomic profiling of polar serum metabolites at fed state in 3, 12, 18 and 28M mice revealed age-associated changes in metabolic cascades involved in tryptophan, purine, amino acids, and nicotinamide metabolism. Correlation analyses showed that nicotinamide decreased with age, while allantoin and guanosine, metabolites in purine metabolism, increased with age. Notably, tryptophan and its microbially derived compounds indole and indole-3-lactic acid significantly decreased with age, while kynurenine increased with age. Together, these results suggest a significant interplay between bacterial and host metabolism, and gut dysbiosis and altered microbial metabolism contribute to aging.
    Keywords:  aging; gut microbiome; metabolism; serum metabolome
  12. Aging Cell. 2021 Feb 24. e13321
      One of the hallmarks of aging is an accumulation of cells with defects in oxidative phosphorylation (OXPHOS) due to mutations of mitochondrial DNA (mtDNA). Rapidly dividing tissues maintained by stem cells, such as the colonic epithelium, are particularly susceptible to accumulation of OXPHOS defects over time; however, the effects on the stem cells are unknown. We have crossed a mouse model in which intestinal stem cells are labelled with EGFP (Lgr5-EGFP-IRES-creERT2) with a model of accelerated mtDNA mutagenesis (PolgAmut/mut ) to investigate the effect of OXPHOS dysfunction on colonic stem cell proliferation. We show that a reduction in complex I protein levels is associated with an increased rate of stem cell cycle re-entry. These changes in stem cell homeostasis could have significant implications for age-associated intestinal pathogenesis.
    Keywords:  aging; colon; complex I; mitochondria; stem cells
  13. Aging (Albany NY). 2021 Feb 25. 13
      Normal hair growth occurs in cycles, comprising growth (anagen), cessation (catagen) and rest (telogen). Upon aging, the initiation of anagen is significantly delayed, which results in impaired hair regeneration. Hair regeneration is driven by hair follicle stem cells (HFSCs). We show here that aged HFSCs present with a decrease in canonical Wnt signaling and a shift towards non-canonical Wnt5a driven signaling which antagonizes canonical Wnt signaling. Elevated expression of Wnt5a in HFSCs upon aging results in elevated activity of the small RhoGTPase Cdc42 as well as a change in the spatial distribution of Cdc42 within HFSCs. Treatment of aged HFSC with a specific pharmacological inhibitor of Cdc42 activity termed CASIN to suppress the aging-associated elevated activity of Cdc42 restored canonical Wnt signaling in aged HFSCs. Treatment of aged mice in vivo with CASIN induced anagen onset and increased the percentage of anagen skin areas. Aging-associated functional deficits of HFSCs are at least in part intrinsic to HFSCs and can be restored by rational pharmacological approaches.
    Keywords:  Cdc42; Wnt5a; anagen; hair follicle stem cells; polarity
  14. Ageing Res Rev. 2021 Feb 18. pii: S1568-1637(21)00053-2. [Epub ahead of print] 101306
      Extrachromosomal circular DNA (eccDNA) accumulates within the nucleus of eukaryotic cells during physiological aging and in age-related diseases (ARDs) and the accumulation could be caused by the declined exclusion of nuclear eccDNA in these states. This review focuses on the formation of eccDNA and the roles of some main factors, such as nuclear pore complexes (NPCs), nucleoplasmic reticulum (NR), and nuclear actin, in eccDNA exclusion. eccDNAs are mostly formed from non-coding DNA during DNA damage repair. They move to NPCs along nuclear actin and are excluded out of the nucleus through functional NPCs in young and healthy cells. However, it has been demonstrated that defective NPCs, abnormal NPC components and nuclear actin rods are increased in aged cells, various cancers and certain other ARDs such as cardiovascular diseases, premature aging, neurodegenerative diseases and myopathies. Therefore, mainly resulting from the increase of dysfunctional NPCs, the exclusion of nuclear eccDNAs may be reduced and eccDNAs thus accumulate within the nucleus in aging and the aforementioned ARDs. In addition, the protective function of non-coding DNA in tumorigenesis is further discussed.
    Keywords:  NPC; age-related diseases; aging; cancer; eccDNAs; non-coding DNA
  15. Geroscience. 2021 Feb 24.
      Frailty is a geriatric syndrome characterized by age-related declines in function and reserve resulting in increased vulnerability to stressors. The most consistent laboratory finding in frail subjects is elevation of serum IL-6, but it is unclear whether IL-6 is a causal driver of frailty. Here, we characterize a new mouse model of inducible IL-6 expression (IL-6TET-ON/+ mice) following administration of doxycycline (Dox) in food. In this model, IL-6 induction was Dox dose-dependent. The Dox dose that increased IL-6 levels to those observed in frail old mice directly led to an increase in frailty index, decrease in grip strength, and disrupted muscle mitochondrial homeostasis. Littermate mice lacking the knock-in construct failed to exhibit frailty after Dox feeding. Both naturally old mice and young Dox-induced IL-6TET-ON/+ mice exhibited increased IL-6 levels in sera and spleen homogenates but not in other tissues. Moreover, Dox-induced IL-6TET-ON/+ mice exhibited selective elevation in IL-6 but not in other cytokines. Finally, bone marrow chimera and splenectomy experiments demonstrated that non-hematopoietic cells are the key source of IL-6 in our model. We conclude that elevated IL-6 serum levels directly drive age-related frailty, possibly via mitochondrial mechanisms.
    Keywords:  Frailty; IL-6; Mouse; Transgenic models
  16. Blood. 2021 Feb 22. pii: blood.2020009779. [Epub ahead of print]
      Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vaso-occlusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vaso-occlusive events in SCD patients, however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia, but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance to investigate the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in SCD patients.
  17. Aging (Albany NY). 2021 Feb 17. 13
      BACKGROUND: Resveratrol improves cell apoptosis and tissue damage induced by high glucose, but the specific mechanism is unknown.METHODS: This is a basic research. We performed cell transfection, real-time fluorescence quantitative PCR (qPCR), flow cytometry, immunofluorescence, western blot, enzyme linked immunosorbent assay (ELISA) and cell viability assay to analyze cell viability, cell cycle, cellular oxidative stress, intracellular inflammatory factors and autophagy activities in vitro. Meanwhile, dual luciferase reporter assay was conducted to explore the influence of miR-142-3p and sprouty-related EVH1 domain 2 (SPRED 2) on human glycated low-density lipoprotein (Gly-LDL)-induced vascular endothelial cell apoptosis, inflammatory factor secretion and oxidative stress.
    RESULTS: Resveratrol inhibited the expression of miR-142-3p in human umbilical vein endothelial cells (HUVECs) induced by Gly-LDL in a dose-dependent manner, and the overexpression of miR-142-3p reverses the effect of resveratrol on the proliferation, apoptosis, secretion of inflammatory factors, oxidative stress, and autophagy. The dual-luciferase report analysis found a negative regulatory relationship between miR-142-3p and SPRED2. Inhibition of SPRED2 reversed the effects of resveratrol on Gly-LDL-induced HUVECs proliferation, apoptosis, inflammatory factor secretion and oxidative stress, and reversed the effects of resveratrol on Gly-LDL-induced HUVECs autophagy.
    CONCLUSION: miR-142-3p promotes the development of diabetes by inhibiting SPRED2-mediated autophagy, including inducing cell apoptosis, aggravating cellular oxidative stress and secretion of inflammatory factors, and resveratrol improves this effect.
    Keywords:  Gly-LDL; SPRED2; autophagy; miR-142-3p
  18. Stem Cell Res Ther. 2021 Feb 25. 12(1): 147
      BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy.METHODS: Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis.
    RESULTS: Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice.
    CONCLUSIONS: Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.
    Keywords:  Idiopathic pulmonary fibrosis; Mesenchymal stem cells; Rejuvenation; Senescence; miR-199a-5p
  19. Geroscience. 2021 Feb 26.
      The prevalence of rheumatic and musculoskeletal diseases (RMDs) including osteoarthritis (OA) and low back pain (LBP) in aging societies present significant cost burdens to health and social care systems. Intervertebral disc (IVD) degeneration, which is characterized by disc dehydration, anatomical alterations, and extensive changes in extracellular matrix (ECM) composition, is an important contributor to LBP. IVD cell homeostasis can be disrupted by mitochondrial dysfunction. Mitochondria are the main source of energy supply in IVD cells and a major contributor to the production of reactive oxygen species (ROS). Therefore, mitochondria represent a double-edged sword in IVD cells. Mitochondrial dysfunction results in oxidative stress, cell death, and premature cell senescence, which are all implicated in IVD degeneration. Considering the importance of optimal mitochondrial function for the preservation of IVD cell homeostasis, extensive studies have been done in recent years to evaluate the efficacy of small molecules targeting mitochondrial dysfunction. In this article, we review the pathogenesis of mitochondrial dysfunction, aiming to highlight the role of small molecules and a selected number of biological growth factors that regulate mitochondrial function and maintain IVD cell homeostasis. Furthermore, molecules that target mitochondria and their mechanisms of action and potential for IVD regeneration are identified. Finally, we discuss mitophagy as a key mediator of many cellular events and the small molecules regulating its function.
    Keywords:  Degeneration; Growth factor; Intervertebral disc (IVD); Mitochondrial dysfunction; Mitophagy; Small molecule; Therapeutic
  20. Clin Exp Pharmacol Physiol. 2021 Feb 25.
      Pulmonary senescence and fibrosis occur with deoxyribonucleic acid (DNA) damage response in the lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that pulmonary alveolar epithelial type 2 cells (AEC2) (alveolar stem cells) undergo not only replicative senescence, but also apoptosis and differentiation in association with increased innate immune natural killer (NK) cells in telomerase knockout (KO) mice. Telomerase ribonucleic acid (RNA) component (TERC) deficiency results in increased senescence-associated heterochromatin foci marker HP1γ, p21, p16 and apoptosis-associated cleaved caspase-3 in AEC2. However, p53 deficiency in the Trp53-/- allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated alveolar epithelial type 1 cells [AEC1]) in AEC2 of the late generation of TERC KO mice. Collectively, our findings suggest that pulmonary senescence takes place in deficiency of telomerase RNA component with the alveolar stem cells undergoing p53-dependent senescence and apoptosis as well as p53-independent differentiation.
    Keywords:  apoptosis; differentiation; lung alveolar type 2 cells; p53; senescence; telomerase RNA component; telomere shortening
  21. Aging Cell. 2021 Feb 20. e13324
      In aging Caenorhabditis elegans, as in higher organisms, there is more than one cause of death. C. elegans exhibit early death with a swollen, infected pharynx (P death), and later death with pharyngeal atrophy (p death). Interventions that alter lifespan can differentially affect frequency and timing of each type of death, generating complex survival curve shapes. Here, we use mortality deconvolution analysis to investigate how reduction of insulin/IGF-1 signaling (IIS), which increases lifespan (the Age phenotype), affects different forms of death. All daf-2 insulin/IGF-1 receptor mutants exhibit increased lifespan in the p subpopulation (p Age), while pleiotropic class 2 daf-2 mutants show an additional marked reduction in P death frequency. The latter is promoted by pharyngeal expression of the IIS-regulated DAF-16 FOXO transcription factor, and at higher temperature by reduced pharyngeal pumping rate. Pharyngeal DAF-16 also promotes p Age in class 2 daf-2 mutants, revealing a previously unknown role for the pharynx in the regulation of aging. Necropsy analysis of daf-2 interactions with the daf-12 steroid receptor implies that previously described opposing effects of daf-12 on daf-2 longevity are attributable to internal hatching of larvae, rather than complex interactions between insulin/IGF-1 and steroid signaling. These findings support the view that wild-type IIS acts through multiple distinct mechanisms which promote different life-limiting pathologies, each of which contribute to late-life mortality. This study further demonstrates the utility of mortality deconvolution analysis to better understand the genetics of lifespan.
    Keywords:  Caenorhabditis elegans; aging; genetics; insulin/IGF-1 signaling
  22. Biochem Pharmacol. 2021 Feb 22. pii: S0006-2952(21)00082-4. [Epub ahead of print] 114486
      Ferroptosis is a recently defined form of programmed cell death that is different from apoptosis. It is an iron-dependent programmed cell death and the accumulation of lipid hydroperoxides to lethal levels make ferroptosis distinct. Ferroptosis can be effectively regulated by a number of cellular variables including iron content, amino acid uptake, polyunsaturated fatty acid incorporation, glutathione biosynthesis, and NADPH levels. A number of severe and common degenerative diseases in humans such as Parkinson's disease and Huntington's disease, as well as several acute injury scenarios, such as stroke, intracerebral hemorrhage, traumatic brain injury, and ischemia-reperfusion injury are likely to be linked to ferroptosis. Ferroptosis may play a critical role in tumor-suppression and has been proposed as a potential target for cancer therapy. However, regulating ferroptosis in vivo remains difficult due to a lack of compounds that can effectively activate or repress ferroptosis. Here we review the cellular mechanisms underlying ferroptosis and the pathophysiological circumstances where its regulation could be beneficial.
  23. Drug Discov Today. 2021 Feb 19. pii: S1359-6446(21)00098-2. [Epub ahead of print]
      With a globally aging population, longevity is becoming the most promising market for the biotech industry. In animals, aging can be retarded and longevity extended, which, if translated to humans, would result in huge health benefits with remarkable commercial value. The potential to slow down human aging has led to a race to discover the most promising longevity drugs in animals and ultimately translate them to humans. Indeed, in recent years, there has been exponential growth in longevity drugs discovered in animal models. Investment in longevity biotech is also booming, and several clinical trials will soon shed light on which drugs extend healthy lives. Thus, the longevity pharmacology field promises to revolutionize the healthcare of a growing aging population.
  24. Oncotarget. 2021 Feb 02. 12(3): 131-144
      Although numerous drugs seemingly extend healthspan in mice, only a few extend lifespan in mice and only one does it consistently. Some of them, alone or in combination, can be used in humans, without further clinical trials.
    Keywords:  aging; longevity; mTOR; metformin; rapamycin
  25. Stem Cell Reports. 2021 Feb 11. pii: S2213-6711(21)00049-7. [Epub ahead of print]
      Cognitive deficits associated with Alzheimer's disease (AD) severely impact daily life for the millions of affected individuals. Progressive memory impairment in AD patients is associated with degeneration of the hippocampus. The dentate gyrus of the hippocampus, a region critical for learning and memory functions, is a site of adult neurogenesis in mammals. Recent evidence in humans indicates that hippocampal neurogenesis likely persists throughout life, but declines with age and is strikingly impaired in AD. Our understanding of how neurogenesis supports learning and memory in healthy adults is only beginning to emerge. The extent to which decreased neurogenesis contributes to cognitive decline in aging and AD remains poorly understood. However, studies in rodent models of AD and other neurodegenerative diseases raise the possibility that targeting neurogenesis may ameliorate cognitive dysfunction in AD. Here, we review recent progress in understanding how adult neurogenesis is impacted in the context of aging and AD.
    Keywords:  Alzheimer's disease; adult neurogenesis; aging; cognitive decline; neural stem cell
  26. Life Sci. 2021 Feb 19. pii: S0024-3205(21)00181-8. [Epub ahead of print] 119196
      Senescent cancer cells contribute to tumor refractoriness. The removal of senescent cells after chemotherapy prevents or delays cancer relapse. Our study showed that GL-V9 (5-hydroxy-8-methoxy-2-phenyl-7-(4-(pyrrolidin-1-yl) butoxy)-4-H-chromen-4-one), a potential anticancer drug, eliminated senescent MEFs (Mouse embryonic fibroblasts) and drug-induced senescent breast cancer cells. GL-V9 induced apoptosis in senescent MDA-MB-231 cells. Mechanistically, it alkalized lysosomes and increased the abundance of mitochondria as well as ROS (Reactive oxygen species). The senolytic effect of GL-V9 was also observed in epirubicin-treated mammary tumors in MMTV-PyMT mice. Our data thus indicated that GL-V9 is a promising senolytic drug which could be used to improve the outcome of cancer chemotherapy.
    Keywords:  Autophagy; Breast cancer; GL-V9; ROS; Senolytics
  27. Aging (Albany NY). 2021 Feb 24. 13
      The view of aging has evolved in parallel with the advances in biomedical sciences. Long considered as an irreversible process where interventions were only aimed at slowing down its progression, breakthrough discoveries like animal cloning and cell reprogramming have deeply changed our understanding of postnatal development, giving rise to the emerging view that the epigenome is the driver of aging. The idea was significantly strengthened by the converging discovery that DNA methylation (DNAm) at specific CpG sites could be used as a highly accurate biomarker of age defined by an algorithm known as the Horvath clock. It was at this point where epigenetic rejuvenation came into play as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards. Initial evidence suggests that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. In order to explain the results, a bimodular epigenome is proposed, where module A represents the DNAm clock component and module B the remainder of the epigenome. Epigenetic rejuvenation seems to hold the key to arresting or even reversing organismal aging.
    Keywords:  DNA methylation; aging; cell reprogramming; epigenetic clock; rejuvenation
  28. Nat Metab. 2021 Feb;3(2): 274-286
      The gut microbiome has important effects on human health, yet its importance in human ageing remains unclear. In the present study, we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique to individuals with age. We leverage three independent cohorts comprising over 9,000 individuals and find that compositional uniqueness is strongly associated with microbially produced amino acid derivatives circulating in the bloodstream. In older age (over ~80 years), healthy individuals show continued microbial drift towards a unique compositional state, whereas this drift is absent in less healthy individuals. The identified microbiome pattern of healthy ageing is characterized by a depletion of core genera found across most humans, primarily Bacteroides. Retaining a high Bacteroides dominance into older age, or having a low gut microbiome uniqueness measure, predicts decreased survival in a 4-year follow-up. Our analysis identifies increasing compositional uniqueness of the gut microbiome as a component of healthy ageing, which is characterized by distinct microbial metabolic outputs in the blood.
  29. Nature. 2021 Feb 24.
      Mitochondrial DNA double-strand breaks (mtDSBs) are toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function1. Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown2. Here, using mitochondrial-targeted transcription activator-like effector nucleases (TALENs)1,3,4, we show that mtDSBs activate a type-I interferon response that involves the phosphorylation of STAT1 and activation of interferon-stimulated genes. After the formation of breaks in the mtDNA, herniation5 mediated by BAX and BAK releases mitochondrial RNA into the cytoplasm and triggers a RIG-I-MAVS-dependent immune response. We further investigated the effect of mtDSBs on interferon signalling after treatment with ionizing radiation and found a reduction in the activation of interferon-stimulated genes when cells that lack mtDNA are exposed to gamma irradiation. We also show that mtDNA breaks synergize with nuclear DNA damage to mount a robust cellular immune response. Taken together, we conclude that cytoplasmic accumulation of mitochondrial RNA is an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including breaks produced by genotoxic agents.