bims-senagi Biomed News
on Senescence and aging
Issue of 2020‒12‒27
eighteen papers selected by
Maria Grazia Vizioli
Mayo Clinic


  1. Blood Adv. 2020 Dec 22. 4(24): 6175-6188
    Tanabe Y, Kawamoto S, Takaku T, Morishita S, Hirao A, Komatsu N, Hara E, Mukaida N, Baba T.
      BCR-ABL, an oncogenic fusion gene, plays a central role in the pathogenesis of chronic myeloid leukemia (CML). Oncogenic signaling induces oncogene-induced senescence and senescence-associated secretory phenotype (SASP), which is characterized by enhanced production of various cytokines. BCR-ABL gene transduction confers senescent phenotype in vitro; however, the in vivo relevance of senescence has not been explored in this context. Transplantation of BCR-ABL-expressing hematopoietic stem/progenitor cells caused CML in mice with an increase in bone marrow BCR-ABL+CD41+CD150+ leukemic megakaryocyte-lineage (MgkL) cells, which exhibited enhanced senescence-associated β-galactosidase staining and increased expression of p16 and p21, key molecules that are crucially involved in senescence. Moreover, knockout of p16 and p21 genes reduced both BCR-ABL-induced abnormal megakaryopoiesis and the maintenance of CML cell leukemogenic capacity, as evidenced by attenuated leukemogenic capacity at secondary transplantation. The expression of transforming growth factor-β1 (TGF-β1), a representative SASP molecule, was enhanced in the leukemic MgkL cells, and TGF-β1 inhibition attenuated CML cell leukemogenic capacity both in vitro and in vivo. Furthermore, BCR-ABL-expressing MgkL cells displayed enhanced autophagic activity, and autophagy inhibition reduced bone marrow MgkL cell number and prolonged the survival of CML mice, which had transiently received the tyrosine kinase inhibitor, imatinib, earlier. Thus, BCR-ABL induced the expansion of senescent leukemic MgkL cells, which supported CML leukemogenesis by providing TGF-β1.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003117
  2. Cell Death Dis. 2020 Dec 15. 11(12): 1075
    Zhang Y, Guo L, Han S, Chen L, Li C, Zhang Z, Hong Y, Zhang X, Zhou X, Jiang D, Liang X, Qiu J, Zhang J, Li X, Zhong S, Liao C, Yan B, Tse HF, Lian Q.
      Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6-/-) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6-/--BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6-/--BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6-/--BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.
    DOI:  https://doi.org/10.1038/s41419-020-03289-w
  3. J Invest Dermatol. 2020 Dec 18. pii: S0022-202X(20)32284-3. [Epub ahead of print]
    Fitsiou E, Pulido T, Campisi J, Alimirah F, Demaria M.
      Chronic exposure to UVR is known to disrupt tissue homeostasis, accelerate the onset of age-related phenotypes, and increase the risk for skin cancer-a phenomenon defined as photoaging. In this paper, we review the current knowledge on how UV exposure causes cells to prematurely enter cellular senescence. We describe the mechanisms contributing to the accumulation of senescent cells in the skin and how the persistence of cellular senescence can promote impaired regenerative capacity, chronic inflammation, and tumorigenesis associated with photoaging. We conclude by highlighting the potential of senolytic drugs in delaying the onset and progression of age-associated phenotypes in the skin.
    DOI:  https://doi.org/10.1016/j.jid.2020.09.031
  4. Neuroscience. 2020 Dec 17. pii: S0306-4522(20)30773-9. [Epub ahead of print]
    Kim YJ, Choo OS, Lee JS, Jang JH, Woo HG, Choung YH.
      Clearance of dysfunctional mitochondria via mitophagy is essential for cell survival and cochlear functions. However, it is not clear which genes are significantly involved in this process. Here, we investigated the changes in mitophagy and mitophagy-associated genes in auditory cells to determine a possible correlation between mitophagy and age-related hearing loss (ARHL). Here, we show that most transcripts associated with mitophagy were downregulated in an age-dependent manner. We identified one significant differentially expressed gene associated with mitophagy, BNIP3L/NIX. Mitophagy-inhibited cells with BNIP3L/NIX knockdown showed hyperresponsiveness to oxidative stress resulting in cell senescence with increased levels of TOMM20 and LC3B. Overexpression of BNIP3L/NIX promotes the degradation of TOMM20 and LC3B during premature cell senescence. In conclusion, BNIP3L/NIX may play an important role in mitochondria degradation maintaining cochlear cell homeostasis during the aging process of hearing.
    Keywords:  BNIP3L/NIX; age-related hearing loss; hair cell; mitophagy; spiral ganglion cell
    DOI:  https://doi.org/10.1016/j.neuroscience.2020.12.005
  5. FEBS Open Bio. 2020 Dec 19.
    Deng X, Liang X, Yang H, Huang Z, Huang X, Liang C, Kuang Y, Qin Y, Lin F, Luo Z.
      An increasing number of studies have shown that nicotinamide mononucleotide (NMN) can inhibit not only ageing but also oxidative stress and inflammatory reactions by improving energy metabolism. However, the role of NMN in regulating the anti-apoptotic, antioxidative stress and inflammatory responses of brain microvascular endothelial cells is still unknown. Therefore, here we studied the effects of NMN on H2 O2 -induced oxidative damage of bEnd.3 cells. In this study, we found that NMN could inhibit the NF-κBp65 inflammatory signalling pathway and increase the expression of the enzymes NAMPT, VEGF and eNOS, alleviating H2 O2 -induced apoptosis in bEnd.3 cells. Taken together, these results suggest that NMN reduces H2 O2 -induced oxidative stress, apoptosis and improves cell functions by inhibiting the NF-κBp65 inflammatory pathway and increasing NAMPT expression.
    Keywords:  Brain microvascular endothelial cells; Inflammatory pathway; Nicotinamide mononucleotide; Nicotinamide phosphoribosyltransferase; Oxidative stress
    DOI:  https://doi.org/10.1002/2211-5463.13067
  6. J Periodontol. 2020 Dec 20.
    Aquino-Martinez R, Eckhardt BA, Rowsey JL, Fraser DG, Khosla S, Farr JN, Monroe DG.
      BACKGROUND: Coinciding with other chronic co-morbidities, the prevalence of periodontal disease increases with aging. Mounting evidence has established that senescent cells accumulate at sites of age-related pathologies, where they promote "non-microbial" inflammation. We hypothesized that alveolar bone osteocytes develop senescence characteristics in old age.METHODS: Alveolar bone samples were obtained from young (6 months) and old (20-22 months) mice to evaluate the expression of senescence biomarkers by immunofluorescent staining. Osteocyte-enriched fractions were used to characterize the age-related senescence-associated secretory phenotype (SASP) gene expression profile. Primary alveolar bone cells were exposed to the SASP via in vitro senescent conditioned media (SCM) administration. A multiplex assay confirmed protein levels of specific cytokines. Interactions with bacterial components were evaluated by stimulating cells with lipopolysaccharide (LPS).
    RESULTS: Increased senescence-associated distension of satellites (SADS) and p16Ink4a mRNA expression were identified in alveolar bone osteocytes with aging. These findings were associated with increased levels of DNA damage, and activated p38 MAPK, both inducers of senescence. Furthermore, interleukin-6 (Il6), Il17, Igfbp4 and Mmp13 were significantly upregulated with aging in osteocyte-enriched samples. Interestingly, SCM potentiated the LPS-induced expression of Il1α, Il1β, and Il6. Cell migration and differentiation were also impeded by SCM. These in vitro effects were ameliorated by the p38 MAPK inhibitor SB202190.
    CONCLUSIONS: Accumulation of senescent osteocytes contributes to deterioration of the periodontal environment by exacerbating chronic inflammation and reducing regeneration in old age. Cellular senescence is a cell-intrinsic response to DNA damage, and a host-related mechanism associated with aging that could potentiate inflammation induced by bacterial components. This article is protected by copyright. All rights reserved.
    Keywords:  Aging; Alveolar Bone Loss; Cellular Senescence; DNA damage; Inflammation; Periodontal Diseases
    DOI:  https://doi.org/10.1002/JPER.20-0529
  7. Plast Reconstr Surg. 2021 Jan 01. 147(1S-2): 25S-32S
    Bramwell LR, Harries LW.
      SUMMARY: Cellular senescence is a state of stable cell cycle arrest that has increasingly been linked with cellular, tissue, and organismal aging; targeted removal of senescent cells brings healthspan and lifespan benefits in animal models. Newly emerging approaches to specifically ablate or rejuvenate senescent cells are now the subject of intense study to explore their utility to provide novel treatments for the aesthetic signs and diseases of aging in humans. Here, we discuss different strategies that are being trialed in vitro, and more recently in vivo, for the targeted removal or reversal of senescent cells. Finally, we describe the evidence for a newly emerging molecular mechanism that may underpin senescence; dysregulation of alternative splicing. We will explore the potential of restoring splicing regulation as a novel "senotherapeutic" approach and discuss strategies by which this could be integrated into the established portfolio of skin aging therapeutics.
    DOI:  https://doi.org/10.1097/PRS.0000000000007618
  8. Ageing Res Rev. 2020 Dec 16. pii: S1568-1637(20)30372-X. [Epub ahead of print] 101237
    Bayliak MM, Lushchak VI.
      An intermediate of tricarboxylic acid cycle alpha-ketoglutarate (AKG) is involved in pleiotropic metabolic and regulatory pathways in the cell, including energy production, biosynthesis of certain amino acids, collagen biosynthesis, epigenetic regulation of gene expression, regulation of redox homeostasis, and detoxification of hazardous substances. Recently, AKG supplement was found to extend lifespan and delay the onset of age-associated decline in experimental models such as nematodes, fruit flies, yeasts, and mice. This review summarizes current knowledge on metabolic and regulatory functions of AKG and its potential anti-ageing effects. Impact on epigenetic regulation of ageing via being an obligate substrate of DNA and histone demethylases, direct antioxidant properties, and function as mimetic of caloric restriction and hormesis-induced agent are among proposed mechanisms of AKG geroprotective action. Due to influence on mitochondrial respiration, AKG can stimulate production of reactive oxygen species (ROS) by mitochondria. According to hormesis hypothesis, moderate stimulation of ROS production could have rather beneficial biological effects, than detrimental ones, because of the induction of defensive mechanisms that improve resistance to stressors and age-related diseases and slow down functional senescence. Discrepancies found in different models and limitations of AKG as a geroprotective drug are discussed.
    Keywords:  TCA cycle; antioxidant; collagen; epigenetics; hormesis; stress resistance
    DOI:  https://doi.org/10.1016/j.arr.2020.101237
  9. Biochem Biophys Res Commun. 2020 Dec 16. pii: S0006-291X(20)32033-7. [Epub ahead of print]535 39-46
    Yu X, Luo Y, Chen G, Liu H, Tian N, Zen X, Huang Y.
      BACKGROUND: Age-related macular degeneration (AMD) may lead to irreversibly vision loss among aging populations. In this work, in an in vitro AMD cell model, we examined the expression and function of long non-coding RNA, Prader-Willi Region Non-Protein Coding RNA 2 (PWRN2) in injured human retinal pigment epithelial cells.METHOD: ARPE-19 cell line was maintained in vitro and treated with multi-module stressful conditions, including hydrogen peroxide (H2O2) tert-butylhydroperoxide (t-BuOOH) and ultraviolet B (UVB). Multi-module-stressor-induced cell death was monitored by a viability assay, and PWRN2 expression by qRT-PCR. PWRN2 was either downregulated or upregulated in ARPE-19 cells. The effects of PWRN2 downregulation or upregulation on t-BuOOH-induced cell death, cellular apoptosis and mitochondrial injuries were then quantitatively evaluated.
    RESULTS: Multi-module stressful conditions induced cell death and PWRN2 upregulation in ARPE-19 cells in vitro. We created ARPE-19 subpopulations with either downregulated or upregulated PWRN2 expressions. Quantitative assays demonstrated that, PWRN2 downregulation effectively alleviated t-BuOOH-induced cell death, apoptosis and various-type of mitochondrial injuries. On the other hand, PWRN2 upregulation worsened t-BuOOH-induced cellular damages in ARPE-19 cells.
    CONCLUSION: We demonstrated that downregulating PWRN2 protected multi-module-stressor-induced cell death, apoptosis and mitochondrial injuries in human retinal pigment epithelial cells, suggesting PWRN2 may be an active factor in human AMD.
    Keywords:  AMD; Apoptosis; Cell death; PWRN2; Retina; lncRNA
    DOI:  https://doi.org/10.1016/j.bbrc.2020.10.104
  10. Front Sports Act Living. 2019 ;1 50
    Uchida M, Horii N, Hasegawa N, Fujie S, Oyanagi E, Yano H, Iemitsu M.
      Age-induced chronic inflammation is prevented by aerobic and resistance exercise training. However, the effects of the mechanism of exercise on chronic inflammation in each tissue remains unclear. The aim of this study was to investigate the effects of resistance and aerobic training on gene expression profiles for macrophage infiltration and polarization (M1/M2 ratio) with chronic inflammation in various tissues of aged model mice. Male 38-week-old SAMP1 (senescence-accelerated prone mouse 1) mice were randomly divided into three groups-sedentary (Aged-Sed-SAMP1), aerobic training (Aged-AT-SAMP1; voluntary running), and resistance training-for 12 weeks (Aged-RT-SAMP1; climbing ladder). Resistance and aerobic exercise training prevented an increase in circulating TNF-α levels (a marker of systemic inflammation) in aged SAMP1 mice, along with decreases in tissue inflammatory cytokine (TNF-α and IL-1β) mRNA expression in the heart, liver, small intestine, brain, aorta, adipose, and skeletal muscle, but it did not change the levels in the lung, spleen, and large intestine. Moreover, resistance and aerobic exercise training attenuated increases in F4/80 mRNA expression (macrophage infiltration), the ratio of CD11c/CD163 mRNA expression (M1/M2 macrophage polarization), and MCP-1 mRNA expression (chemokine: a regulator of chronic inflammation) in the chronic inflamed tissues of aged SAMP1 mice. These results suggested that resistance and aerobic exercise training-induced changes in gene expression for macrophage infiltration and polarization in various tissues might be involved in the prevention of age-related tissue chronic inflammation, and lead to a reduction of the increase in circulating TNF-α levels, as a marker of systemic inflammation, in aged SAMP1 mice.
    Keywords:  aging; chemokine; chronic inflammation; exercise training; macrophage polarization
    DOI:  https://doi.org/10.3389/fspor.2019.00050
  11. Mech Ageing Dev. 2020 Dec 16. pii: S0047-6374(20)30214-1. [Epub ahead of print] 111418
    Ukraintseva S, Arbeev K, Duan M, Akushevich I, Kulminski A, Stallard E, Yashin A.
      Decline in biological resilience (ability to recover) is a key manifestation of aging that contributes to increase in vulnerability to death with age eventually limiting longevity even in people without major chronic diseases. Understanding the mechanisms of this decline is essential for developing efficient anti-aging and pro-longevity interventions. In this paper we discuss: a) mechanisms of the decline in resilience with age, and aging components that contribute to this decline, including depletion of body reserves, imperfect repair mechanisms, and slowdown of physiological processes and responses with age; b) anti-aging interventions that may improve resilience or attenuate its decline; c) biomarkers of resilience available in human and experimental studies; and d) genetic factors that could influence resilience. There are open questions about optimal anti-aging interventions that would oppose the decline in resilience along with extending longevity limits. However, the area develops quickly, and prospects are exciting.
    Keywords:  aging; anti-aging interventions; biomarkers; cell repair; debris accumulation; genetics of resilience; longevity; reserve depletion; resilience; robustness; slowdown
    DOI:  https://doi.org/10.1016/j.mad.2020.111418
  12. Blood Adv. 2020 Dec 22. 4(24): 6218-6229
    Klei TRL, Dalimot JJ, Beuger BM, Veldthuis M, Ichou FA, Verkuijlen PJJH, Seignette IM, Ligthart PC, Kuijpers TW, van Zwieten R, van Bruggen R.
      Senescence of erythrocytes is characterized by a series of changes that precede their removal from the circulation, including loss of red cell hydration, membrane shedding, loss of deformability, phosphatidyl serine exposure, reduced membrane sialic acid content, and adhesion molecule activation. Little is known about the mechanisms that initiate these changes nor is it known whether they are interrelated. In this study, we show that Ca2+-dependent K+ efflux (the Gardos effect) drives erythrocyte senescence. We found that increased intracellular Ca2+ activates the Gardos channel, leading to shedding of glycophorin-C (GPC)-containing vesicles. This results in a loss of erythrocyte deformability but also in a marked loss of membrane sialic acid content. We found that GPC-derived sialic acid residues suppress activity of both Lutheran/basal cell adhesion molecule (Lu/BCAM) and CD44 by the formation of a complex on the erythrocyte membrane, and Gardos channel-mediated shedding of GPC results in Lu/BCAM and CD44 activation. This phenomenon was observed as erythrocytes aged and on erythrocytes that were otherwise prone to clearance from the circulation, such as sickle erythrocytes, erythrocytes stored for transfusion, or artificially dehydrated erythrocytes. These novel findings provide a unifying concept on erythrocyte senescence in health and disease through initiation of the Gardos effect.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003077
  13. Front Mol Biosci. 2020 ;7 618088
    Song Y, Hu G, Jia J, Yao M, Wang X, Lu W, Hutchins AP, Chen J, Ozato K, Yao H.
      The bromodomain-containing protein BRD4 has been thought to transmit epigenetic information across cell divisions by binding to both mitotic chromosomes and interphase chromatin. UV-released BRD4 mediates the recruitment of active P-TEFb to the promoter, which enhances transcriptional elongation. However, the dynamic associations between BRD4 and P-TEFb and BRD4-mediated gene regulation after UV stress are largely unknown. In this study, we found that BRD4 dissociates from chromatin within 30 min after UV treatment and thereafter recruits chromatin. However, P-TEFb binds tightly to chromatin right after UV treatment, suggesting that no interactions occur between BRD4 and P-TEFb within 30 min after UV stress. BRD4 knockdown changes the distribution of P-TEFb among nuclear soluble and chromatin and downregulates the elongation activity of RNA polymerase II. Inhibition of JNK kinase but not other MAP kinases impedes the interactions between BRD4 and P-TEFb. RNA-seq and ChIP assays indicate that BRD4 both positively and negatively regulates gene transcription in cells treated with UV stress. These results reveal previously unrecognized dynamics of BRD4 and P-TEFb after UV stress and regulation of gene transcription by BRD4 acting as either activator or repressor in a context-dependent manner.
    Keywords:  BRD4; JNK pathway; P-TEFb; UV stress; gene transcription
    DOI:  https://doi.org/10.3389/fmolb.2020.618088
  14. Biochem J. 2020 Dec 21. pii: BCJ20200705. [Epub ahead of print]
    Mundhara N, Majumder A, Panda D.
      Human body temperature limits below 40 °C during heat stroke or fever. The implications of prolonged exposure to the physiologically relevant temperature (40 °C) on cellular mechanobiology is poorly understood. Here, we have examined the effects of heat stress (40 °C for 72 h incubation) in human lung adenocarcinoma (A549), mouse melanoma (B16F10), and non-cancerous mouse origin adipose tissue cells (L929). Hyperthermia increased the level of ROS, γ-H2AX, and HSP70 and decreased mitochondrial membrane potential in the cells. Heat stress impaired cell division, caused G1 arrest, induced cellular senescence, and apoptosis in all the tested cell lines. The cells incubated at 40 °C for 72 h displayed a significant decrease in the f-actin level and cellular traction as compared to cells incubated at 37 °C. Also, the cells showed a larger focal adhesion area and stronger adhesion at 40 °C than at 37 °C. The mitotic cells at 40 °C were unable to round up properly and displayed retracting actin stress fibers. Hyperthermia downregulated HDAC6, increased the acetylation level of microtubules, and perturbed the chromosome alignment in the mitotic cells at 40 °C. Overexpression of HDAC6 rescued the cells from the G1 arrest and reduced the delay in cell rounding at 40 °C suggesting a crucial role of HDAC6 in hyperthermia mediated responses. This study elucidates the significant role of cellular traction, focal adhesions, and cytoskeletal networks in mitotic cell rounding and chromosomal misalignment. It also highlights the significance of HDAC6 in heat-evoked senile cellular responses.
    Keywords:  Chromosomal misalignment; HDAC6; Mitotic cell rounding; Prolonged hyperthermia; Traction force; Trypsin deadhesion assay
    DOI:  https://doi.org/10.1042/BCJ20200705
  15. Cell Cycle. 2020 Dec 22. 1-12
    Chen G, Zhou X, Li H, Xu Z.
      It has been unraveled that microRNAs (miRNAs) played crucial roles in processes of human diseases, while the role of miR-494-5p in intervertebral disc degeneration (IDD) remains scarcely studied. We aimed to investigate the mechanisms of miR-494-5p in IDD with the involvement of tissue inhibitor of metalloproteinase 3 (TIMP3). Expression of miR-494-5p and TIMP3 in IDD clinical specimens was assessed. The IDD models were established by needle punching, which were then injected with low expression of miR-494-5p or TIMP3 overexpression lentivirus to observe their effects on pathology and apoptosis in IDD mice. The nucleus pulposus cells were isolated and, respectively, treated with miR-494-5p inhibitor or TIMP3 overexpression plasmid to determine the viability, apoptosis, and senescence in vitro. Furthermore, the expression of Aggrecan, Col-2, Caveolin-1, and SA-β-gal in nucleus pulposus cells in vitro were measured. The target relation between miR-494-5p and TIMP3 was determined. An increased expression of miR-494-5p and a decreased expression of TIMP3 were found in IDD. Downregulation of miR-494-5p or overexpression of TIMP3 could relieve pathology and suppress nucleus pulposus cell apoptosis in IDD mice, as well as promote the viability and attenuate the apoptosis and senescence of nucleus pulposus cells from IDD mice. Moreover, inhibition of miR-494-5p or overexpression of TIMP3 upregulated Aggrecan and Col-2 expression while downregulated Caveolin-1 and SA-β-gal expression, and TIMP3 was the target gene of miR-494-5p. Results of this study indicated that the degradation of miR-494-5p ameliorates the development of IDD by elevating TIPM3, which may provide new targets for IDD treatment.
    Keywords:  Intervertebral disc degeneration; MicroRNA-494-5p; cellular senescence; differentiation; nucleus pulposus cells; proliferation; tissue inhibitor of metalloproteinase 3
    DOI:  https://doi.org/10.1080/15384101.2020.1843812
  16. Ageing Res Rev. 2020 Dec 18. pii: S1568-1637(20)30375-5. [Epub ahead of print] 101240
    Martel J, Chang SH, Wu CY, Peng HH, Hwang TL, Ko YF, Young JD, Ojcius DM.
      Caloric restriction (CR) mimetics are molecules that produce beneficial effects on health and longevity in model organisms and humans, without the challenges of maintaining a CR diet. Conventional CR mimetics such as metformin, rapamycin and spermidine activate autophagy, leading to recycling of cellular components and improvement of physiological function. We review here novel CR mimetics and anti-aging compounds, such as alpha-ketoglutarate, 4,4'-dimethoxychalcone, fungal polysaccharides, inorganic nitrate, and trientine, highlighting their possible molecular targets and mechanisms of action. The activity of these compounds can be understood within the context of hormesis, a biphasic dose response that involves beneficial effects at low or moderate doses and toxic effects at high doses. The concept of hormesis has widespread implications for the identification of CR mimetics in experimental assays, testing in clinical trials, and use in healthy humans. We also discuss the promises and limitations of CR mimetics and anti-aging molecules for delaying aging and treating chronic diseases.
    Keywords:  Aging; Autophagy; Hormesis; Phytochemicals; Polysaccharides
    DOI:  https://doi.org/10.1016/j.arr.2020.101240
  17. Am J Hypertens. 2020 Dec 22. pii: hpaa218. [Epub ahead of print]
    Bai HY, Min LJ, Shan BS, Iwanami J, Kan-No H, Kanagawa M, Mogi M, Horiuchi M.
      BACKGROUND: Amyloid-β (Aβ) induces cerebrovascular damage and is reported to stimulate endothelial cell senescence. We previously demonstrated that angiotensin II (Ang II) promoted vascular senescence. We examined the possible cross-talk between Ang II and Aβ in regulating brain vascular smooth muscle cell (BVSMC) senescence.METHODS: BVSMC were prepared from adult male mice and stimulated with Ang II (0, 0.1, 1, 10, 100 nmol/L) and/or Aβ 1-40 (0, 0.1, 0.3, 0.5, 1, 3, 5 µmol/L) for the indicated times. Cellular senescence was evaluated by senescence-associated β-galactosidase staining.
    RESULTS: Treatment with Ang II (100 nmol/L) or Aβ (1 µmol/L) at a higher dose increased senescent cells compared with control at 6 days. Treatment with Ang II (10 nmol/L) or Aβ (0.5 µmol/L) at a lower dose had no effect on senescence whereas a combined treatment with lower doses of Ang II and Aβ significantly enhanced senescent cells. This senescence enhanced by lower dose combination was markedly blocked by valsartan (Ang II type 1 receptor inhibitor) or TAK-242 (Aβ receptor TLR4 inhibitor) treatment. Moreover, lower dose combination caused increases in superoxide anion levels and p-ERK expression for 2 days, NF-κB activity, p-IκB, p-IKKα/β, p16 and p53 expression for 4 days, and an obvious decrease in pRb expression. These changes by lower dose combination, except in p-IκB expression and NF-κB activity, were significantly inhibited by pretreatment with U0126 (ERK inhibitor).
    CONCLUSIONS: Ang II and Aβ synergistically promoted BVSMC senescence at least due to enhancement of the p-ERK-p16-pRb signaling pathway, oxidative stress and NF-κB/IκB activity.
    Keywords:  BVSMC senescence; amyloid-β; angiotensin II; cerebrovascular disorders; signal transduction
    DOI:  https://doi.org/10.1093/ajh/hpaa218
  18. Free Radic Biol Med. 2020 Dec 18. pii: S0891-5849(20)31676-2. [Epub ahead of print]
    Zhu L, Zhou Q, He L, Chen L.
      Mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which the transcriptional activation programs of mitochondrial chaperone proteins and proteases are initiated to maintain proteostasis in mitochondria. Additionally, the activation of UPRmt delays aging and extends lifespan by maintaining mitochondrial proteostasis. Growing evidences suggests that UPRmt plays an important role in diverse human diseases, especially ageing-related diseases. Therefore, this review focuses on the role of UPRmt in ageing and ageing-related neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The activation of UPRmt and the high expression of UPRmt components contribute to longevity extension. The activation of UPRmt may ameliorate Alzheimer's disease, Parkinson's disease and Huntington's disease. Besides, UPRmt is also involved in the occurrence and development of cancers and heart diseases. UPRmt contributes to the growth, invasive and metastasis of cancers. UPRmt has paradoxical roles in heart diseases. UPRmt not only protects against heart damage, but may sometimes aggravates the development of heart diseases. Considering the pleiotropic actions of UPRmt system, targeting UPRmt pathway may be a potent therapeutic avenue for neurodegenerative diseases, cancers and heart diseases.
    Keywords:  UPR(mt); ageing; cancers; diseases; heart; neurodegenerative
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.12.013