bims-senagi Biomed News
on Senescence and aging
Issue of 2021‒12‒05
nine papers selected by
Maria Grazia Vizioli
Mayo Clinic

  1. Sci Rep. 2021 Dec 01. 11(1): 23237
      The dysfunction of adipose tissue with aging and the accumulation of senescent cells has been implicated in the pathophysiology of chronic diseases. Recently interventions capable of reducing the burden of senescent cells and in particular the identification of a new class of drugs termed senolytics have been object of extensive investigation. We used an in vitro model of induced senescence by treating both pre-adipocytes as well as mature adipocytes with hydrogen peroxide (H2O2) at a sub-lethal concentration for 3 h for three consecutive days, and hereafter with 20 uM quercetin at a dose that in preliminary experiments resulted to be senolytic without cytotoxicity. H2O2 treated pre-adipocytes and adipocytes showed typical senescence-associated features including increased beta-galactosidase activity (SA-ß-gal) and p21, activation of ROS and increased expression of pro-inflammatory cytokines. The treatment with quercetin in senescent pre-adipocytes and adipocytes was associated to a significant decrease in the number of the SA-β-gal positive cells along with the suppression of ROS and of inflammatory cytokines. Besides, quercetin treatment decreased miR-155-5p expression in both models, with down-regulation of p65 and a trend toward an up-regulation of SIRT-1 in complete cell extracts. The senolytic compound quercetin could affect AT ageing by reducing senescence, induced in our in vitro model by oxidative stress. The downregulation of miRNA-155-5p, possibly through the modulation of NF-κB and SIRT-1, could have a key role in the effects of quercetin on both pre-adipocytes and adipocytes.
  2. Plast Reconstr Surg. 2021 Dec 01. 148(6S): 21S-26S
      SUMMARY: Skin aging is an outward manifestation of other cellular and molecular aging processes occurring elsewhere in the body. These processes are known collectively as the "hallmarks" of aging, which are a series of basic health maintenance mechanisms that fail over time. Cellular senescence is one of the most studied of the hallmarks of aging; senescent cells accumulate over time and are major drives of the aging process. Here, we discuss the impact of cellular senescence in the context of skin aging, and discuss the emerging landscape of interventions designed for their selective removal by targeted cell death (senolytics) or rejuvenation (senomorphics). We discuss the serotherapeutic strategies that are currently under investigation for systemic aging, which may bring eventual benefits for skin health. Next, we discuss a newly discovered hallmark of aging, dysregulated mRNA processing, which can be targeted for the senomorphic effect. Finally, we highlight a new modality for manipulation of disrupted mRNA processing, oligonucleotide therapeutics. The emerging field of senotherapeutics is set to revolutionize how we view and treat skin aging, and senotherapies are now poised to become a new class of skincare interventions.
  3. Rejuvenation Res. 2021 Nov 27.
      A major limitation in aging research is the lack of reliable biomarkers to assess phenotypic changes with age or monitor response to anti-aging interventions. The present study investigates the role of intracellular ferrous iron (Fe2+) as a potential biomarker of senescence. Iron is known to accumulate in various tissues with age and recent studies have demonstrated that its level increases dramatically in senescent cells. The techniques used are however cumbersome and only measure total iron. Also, it is still to be determined whether the damaging form of iron (Fe2+) is elevated in senescent cells. Here we assessed the potential use of a newly discovered Fe2+ reactive probe (SiRhoNox-1) for selective labeling of senescent cells in vitro. For this we have generated and characterized various senescent cell models and subjected them to SiRhoNox-1 labeling. Our results indicate that SiRhoNox-1 selectivity labels live senescent cells and was more specific and faster than current staining such as SA-βGal or a derived fluorescent probe C12FDG. By using SiRhoNox-1, we also showed that intracellular ferrous iron accumulation is secondary to senescence induction and it is not reversed by stress removal. Together these findings suggest that SiRhoNox-1 may serve as a convenient tool to detect senescent cells based on their ferrous iron level.
  4. Sci Rep. 2021 Dec 01. 11(1): 23250
      Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyper-inflammatory disorder. The mortality of HLH is higher in the elderly than in young adults. Senescence-accelerated mice (SAMP1/TA-1) exhibit characteristic accelerated aging after 30 weeks of age, and HLH-like features, including hematopoietic organ damage, are seen after lipopolysaccharide (LPS) treatment. Thus, SAMP1/TA-1 is a useful model of hematological pathophysiology in the elderly with HLH. In this study, dosing of SAMP1/TA-1 mice with LPS revealed that the suppression of myelopoiesis and B-lymphopoiesis was more severe in aged mice than in young mice. The bone marrow (BM) expression of genes encoding positive regulators of myelopoiesis (G-CSF, GM-CSF, and IL-6) and of those encoding negative regulators of B cell lymphopoiesis (TNF-α) increased in both groups, while the expression of genes encoding positive-regulators of B cell lymphopoiesis (IL-7, SDF-1, and SCF) decreased. The expression of the GM-CSF-encoding transcript was lower in aged mice than in young animals. The production of GM-CSF by cultured stromal cells after LPS treatment was also lower in aged mice than in young mice. The accumulation of the TNF-α-encoding transcript and the depletion of the IL-7-encoding transcript were prolonged in aged mice compared to young animals. LPS dosing led to a prolonged increase in the proportion of BM M1 macrophages in aged mice compared to young animals. The expression of the gene encoding p16INK4a and the proportion of β-galactosidase- and phosphorylated ribosomal protein S6-positive cells were increased in cultured stromal cells from aged mice compared to those from young animals, while the proportion of Ki67-positive cells was decreased in stromal cells from aged mice. Thus, age-related deterioration of stromal cells probably causes the suppression of hematopoiesis in aged mice. This age-related latent organ dysfunction may be exacerbated in elderly people with HLH, resulting in poor prognosis.
  5. Cell Death Dis. 2021 Nov 29. 12(12): 1115
      Age-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by D-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.
  6. Biochimie. 2021 Nov 24. pii: S0300-9084(21)00271-6. [Epub ahead of print]
      AMPK is an important kinase regulating energy homeostasis and also a key protein involved in a variety of signal transduction pathways. It plays a vitally regulatory role in cellular senescence. Activation of AMPK can delay or block the aging process, which is of great significance in the treatment of cardiovascular diseases and other aging related diseases, and provides a potential target for new indications such as Alzheimer's disease. Therefore, AMPK signaling pathway plays an important role in aging research. The in-depth study of AMPK activators will provide more new directions for the treatment of age-related maladies and the development of innovative drugs. Autophagy is a process that engulfs and degrades own cytoplasm or organelles. Thereby, meeting the metabolic demands and updating certain organelles of the cell has become a hotspot in the field of anti-aging in recent years. AMPK plays an important role between autophagy and senescence. In our review, the relationship among AMPK signaling, autophagy and aging will be clarified through the interaction between AMPK and mTOR, ULK1, FOXO, p53, SIRT1, and NF -κB.
    Keywords:  AMPK; Aging; Autophagy; Disease; Signaling pathways
  7. EMBO Rep. 2021 Dec 02. e53658
      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), known to be more common in the elderly, who also show more severe symptoms and are at higher risk of hospitalization and death. Here, we show that the expression of the angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 cell receptor, increases during aging in mouse and human lungs. ACE2 expression increases upon telomere shortening or dysfunction in both cultured mammalian cells and in vivo in mice. This increase is controlled at the transcriptional level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Both pharmacological global DDR inhibition of ATM kinase activity and selective telomeric DDR inhibition by the use of antisense oligonucleotides prevent Ace2 upregulation following telomere damage in cultured cells and in mice. We propose that during aging telomere dysfunction due to telomeric shortening or damage triggers DDR activation and this causes the upregulation of ACE2, the SARS-CoV-2 cell receptor, thus contributing to make the elderly more susceptible to the infection.
    Keywords:  Ace2; COVID-19; DNA damage response; aging; telomere
  8. FEBS J. 2021 Dec 01.
      Brother of Regulator of Imprinted Sites (BORIS) or CCCTC-Binding Factor Like (CTCFL) is a nucleotide-binding protein, aberrantly expressed in various malignancies. Expression of BORIS has been found to be associated with the expression of oncogenes which regulate the reactive oxygen species (ROS) biogenesis, DNA double-strand break repair, regulation of stemness, and induction of cellular senescence. In the present study, we have analyzed the effects of knockdown of BORIS, a potential oncogene, on the induction of senescence and tumor suppression. Loss of BORIS downregulated the expression of critical oncogenes such as BMI1, Akt, MYCN, and STAT3, whereas overexpression increased their respective expression levels in MYCN-amplified neuroblastoma cells. BORIS knockdown exhibited high levels of ROS biogenesis, indicating an upregulated mitochondrial superoxide production and thereby induction of senescence. Our study also showed that the loss of BORIS facilitated cellular senescence through the disruption of telomere integrity via altering the expression of various proteins required for telomere capping (POT1, TRF2, and TIN1). In addition to affecting ROS production and DNA damage, BORIS knockdown sensitized the cells towards chemotherapeutic drugs and induced apoptosis. Tumor induction studies on in-vivo xenograft mouse models showed that cells with loss of BORIS/CTCFL failed to induce tumors. From our study, we conclude that silencing BORIS/CTCFL influences tumor growth and proliferation by regulating key oncogenes. The results also indicated that the BORIS knockdown can cause cellular senescence and upon a combinatorial treatment with chemotherapeutic drugs can induce enhanced drug sensitivity in MYCN amplified neuroblastoma cells.
    Keywords:  BORIS/CTCFL; Cellular senescence; DNA damage; Drug-resistance; ROS
  9. Circulation. 2021 Nov 30. 144(22): 1795-1817
      Nicotinamide adenine dinucleotide (NAD+) is a central metabolite involved in energy and redox homeostasis as well as in DNA repair and protein deacetylation reactions. Pharmacological or genetic inhibition of NAD+-degrading enzymes, external supplementation of NAD+ precursors, and transgenic overexpression of NAD+-generating enzymes have wide positive effects on metabolic health and age-associated diseases. NAD+ pools tend to decline with normal aging, obesity, and hypertension, which are all major risk factors for cardiovascular disease, and NAD+ replenishment extends healthspan, avoids metabolic syndrome, and reduces blood pressure in preclinical models. In addition, experimental elevation of NAD+ improves atherosclerosis, ischemic, diabetic, arrhythmogenic, hypertrophic, or dilated cardiomyopathies, as well as different modalities of heart failure. Here, we critically discuss cardiomyocyte-specific circuitries of NAD+ metabolism, comparatively evaluate distinct NAD+ precursors for their preclinical efficacy, and raise outstanding questions on the optimal design of clinical trials in which NAD+ replenishment or supraphysiological NAD+ elevations are assessed for the prevention or treatment of major cardiac diseases. We surmise that patients with hitherto intractable cardiac diseases such as heart failure with preserved ejection fraction may profit from the administration of NAD+ precursors. The development of such NAD+-centered treatments will rely on technological and conceptual progress on the fine regulation of NAD+ metabolism.
    Keywords:  NAD; cardiomyopathy; heart failure; human; nicotinamide; nicotinamide mononucleotide; obesity