bims-senagi 2021-02-14 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–02–14
38 papers selected by
Maria Grazia Vizioli, Mayo Clinic

Suppression of p16 alleviates the senescence-associated secretory phenotype.
Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition.
Senescent cells and the incidence of age-related diseases.
Cellular Senescence Triggers Altered Circadian Clocks With a Prolonged Period and Delayed Phases.
Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease.
Molecular Mechanisms of Senescence and Implications for the Treatment of Myeloid Malignancies.
Organotypic human skin culture models constructed with senescent fibroblasts show hallmarks of skin aging.
Hallmarks of aging and immunosenescence: Connecting the dots.
Overexpression of FOXA2 attenuates cigarette smoke-induced cellular senescence and lung inflammation through inhibition of the p38 and Erk1/2 MAPK pathways.
Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging.
IL-6 derived from therapy-induced senescence facilitates the glycolytic phenotype in glioblastoma cells.
Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice.
Targeting the Mitochondrial Permeability Transition Pore to Prevent Age-Associated Cell Damage and Neurodegeneration.
SIRT6 enhances telomerase activity to protect against DNA damage and senescence in hypertrophic ligamentum flavum cells from lumbar spinal stenosis patients.
Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/STAT3 pathway.
The senescence-associated secretory phenotype as a driver of tumor growth: does G3BP1 hold the key?
Senolytics for Cancer Therapy: Is All That Glitters Really Gold?
Taurine represses age-associated gut hyperplasia in Drosophila via counteracting endoplasmic reticulum stress.
Amphiregulin Regulates Melanocytic Senescence.
Programmed Cell Senescence in the Mouse Developing Spinal Cord and Notochord.
Metabolomic analysis to elucidate the change of the n-3 polyunsaturated fatty acids in senescent osteoblasts.
Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages.
The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer's disease pathology: from antioxidant to epigenetic therapy.
β-elemene promotes the senescence of glioma cells through regulating YAP-CDK6 signaling.
Connective Tissue and Fibroblast Senescence in Skin Aging.
To breathe or not to breathe: understanding how oxygen sensing contributes to age-related phenotypes.
Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress.
Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.
MicroRNA-7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF-κB signaling in pancreatic cancer cells.
Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.
Functional mechanisms and abnormalities of the nuclear lamina.
Tissue-Specific Landscape of Metabolic Dysregulation during Ageing.
Nicotinamide for the treatment of heart failure with preserved ejection fraction.
Regulation of the Wound Healing Response during Aging.
DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.
Imaging assay to probe the role of telomere length shortening on telomere-gene interactions in single cells.
Tomatidine ameliorates obesity-induced non-alcoholic fatty liver disease in mice: Tomatidine improves hepatic steatosis in mice.
"Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications.

Aging (Albany NY). 2021 Feb 06. 13

Suppression of p16 alleviates the senescence-associated secretory phenotype.

Raquel Buj, Kelly E Leon, Marlyn A Anguelov, Katherine M Aird.

  Oncogene-induced senescence (OIS) is characterized by increased expression of the cell cycle inhibitor p16, leading to a hallmark cell cycle arrest. Suppression of p16 in this context drives proliferation, senescence bypass, and contributes to tumorigenesis. OIS cells are also characterized by the expression and secretion of a widely variable group of factors collectively termed the senescence-associated secretory phenotype (SASP). The SASP can be both beneficial and detrimental and affects the microenvironment in a highly context-dependent manner. The relationship between p16 suppression and the SASP remains unclear. Here, we show that knockdown of p16 decreases expression of the SASP factors and pro-inflammatory cytokines IL6 and CXCL8 in multiple models, including OIS and DNA damage-induced senescence. Notably, this is uncoupled from the senescence-associated cell cycle arrest. Moreover, low p16 expression in both cancer cell lines and patient samples correspond to decreased SASP gene expression, suggesting this is a universal effect of loss of p16 expression. Together, our data suggest that p16 regulates SASP gene expression, which has implications for understanding how p16 modulates both the senescent and tumor microenvironment.

Keywords:  LMNB1; inflammation; interleukin-6; interleukin-8; melanoma

DOI:  https://doi.org/10.18632/aging.202640
Cell Metab. 2021 Feb 02. pii: S1550-4131(21)00011-5. [Epub ahead of print]

Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition.

Sergio Crespo-Garcia, Pamela R Tsuruda, Agnieszka Dejda, Rathi D Ryan, Frederik Fournier, Shawnta Y Chaney, Frederique Pilon, Taner Dogan, Gael Cagnone, Priyanka Patel, Manuel Buscarlet, Sonali Dasgupta, Gabrielle Girouard, Surabhi R Rao, Ariel M Wilson, Robert O'Brien, Rachel Juneau, Vera Guber, Alexandre Dubrac, Christian Beausejour, Scott Armstrong, Frederick A Mallette, Christopher B Yohn, Jean-Sebastien Joyal, Dan Marquess, Pedro J Beltran, Przemyslaw Sapieha.

  Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.

Keywords:  BCL-xL; UBX1967; aging; angiogenesis; cellular senescence; diabetes; p16(INK4A); retina; retinopathy; senolytic

DOI:  https://doi.org/10.1016/j.cmet.2021.01.011
Aging Cell. 2021 Feb 08. e13314

Senescent cells and the incidence of age-related diseases.

Itay Katzir, Miri Adler, Omer Karin, Netta Mendelsohn-Cohen, Avi Mayo, Uri Alon.

  Age-related diseases such as cancer, cardiovascular disease, kidney failure, and osteoarthritis have universal features: Their incidence rises exponentially with age with a slope of 6-8% per year and decreases at very old ages. There is no conceptual model which explains these features in so many diverse diseases in terms of a single shared biological factor. Here, we develop such a model, and test it using a nationwide medical record dataset on the incidence of nearly 1000 diseases over 50 million life-years, which we provide as a resource. The model explains incidence using the accumulation of senescent cells, damaged cells that cause inflammation and reduce regeneration, whose level rise stochastically with age. The exponential rise and late drop in incidence are captured by two parameters for each disease: the susceptible fraction of the population and the threshold concentration of senescent cells that causes disease onset. We propose a physiological mechanism for the threshold concentration for several disease classes, including an etiology for diseases of unknown origin such as idiopathic pulmonary fibrosis and osteoarthritis. The model can be used to design optimal treatments that remove senescent cells, suggeting that treatment starting at old age can sharply reduce the incidence of all age-related diseases, and thus increase the healthspan.

Keywords:  age-related disease; aging; cancer; cellular senescence; diabetes; electronic medical records; fibrosis; idiopathic pulmonary fibrosis; incidence rate; mathematical model; osteoarthritis

DOI:  https://doi.org/10.1111/acel.13314
Front Neurosci. 2021 ;15 638122

Cellular Senescence Triggers Altered Circadian Clocks With a Prolonged Period and Delayed Phases.

Rezwana Ahmed, Yasukazu Nakahata, Kazuyuki Shinohara, Yasumasa Bessho.

  Senescent cells, which show the permanent growth arrest in response to various forms of stress, accumulate in the body with the progression of age, and are associated with aging and age-associated diseases. Although the senescent cells are growth arrested, they still demonstrate high metabolic rate and altered gene expressions, indicating that senescent cells are still active. We recently showed that the circadian clock properties, namely phase and period of the cells, are altered with the establishment of replicative senescence. However, whether cellular senescence triggers the alteration of circadian clock properties in the cells is still unknown. In this study we show that the oxidative stress-induced premature senescence induces the alterations of the circadian clock, similar to the phenotypes of the replicative senescent cells. We found that the oxidative stress-induced premature senescent cells display the prolonged period and delayed phases. In addition, the magnitude of these changes intensified over time, indicating that cellular senescence changes the circadian clock properties. Our current results corroborate with our previous findings and further confirm that cellular senescence induces altered circadian clock properties, irrespective of the replicative senescence or the stress-induced premature senescence.

Keywords:  aging; circadian; clock; oxidative stress; senescence

DOI:  https://doi.org/10.3389/fnins.2021.638122
Cells. 2021 Feb 09. pii: 356. [Epub ahead of print]10(2):

Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease.

Alessia Lo Curto, Simona Taverna, Maria Assunta Costa, Rosa Passantino, Giuseppa Augello, Giorgia Adamo, Anna Aiello, Paolo Colomba, Carmela Zizzo, Marco Zora, Giulia Accardi, Giuseppina Candore, Daniele Francofonte, Tiziana Di Chiara, Riccardo Alessandro, Calogero Caruso, Giovanni Duro, Giuseppe Cammarata.

  Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population; therefore, the association with a premature aging process would be plausible. To assess this hypothesis, miR-126-3p, a senescence-associated microRNA (SA-miRNAs), was considered as an aging biomarker. The levels of miR-126-3p contained in small extracellular vesicles (sEVs), with about 130 nm of diameter, were measured in FD patients and healthy subjects divided into age classes, in vitro, in human umbilical vein endothelial cells (HUVECs) "young" and undergoing replicative senescence, through a quantitative polymerase chain reaction (qPCR) approach. We confirmed that, in vivo, circulating miR-126 levels physiologically increase with age. In vitro, miR-126 augments in HUVECs underwent replicative senescence. We observed that FD patients are characterized by higher miR-126-3p levels in sEVs, compared to age-matched healthy subjects. We also explored, in vitro, the effect on ECs of glycosphingolipids that are typically accumulated in FD patients. We observed that FD storage substances induced in HUVECs premature senescence and increased of miR-126-3p levels. This study reinforces the hypothesis that FD may aggravate the normal aging process.

Keywords:  Fabry disease; HUVEC; aging; endothelial cells; miR-126-3p; microRNA; senescence; small extracellular vesicles

DOI:  https://doi.org/10.3390/cells10020356
Cancers (Basel). 2021 Feb 04. pii: 612. [Epub ahead of print]13(4):

Molecular Mechanisms of Senescence and Implications for the Treatment of Myeloid Malignancies.

Philipp Ernst, Florian H Heidel.

  Senescence is a cellular state that is involved in aging-associated diseases but may also prohibit the development of pre-cancerous lesions and tumor growth. Senescent cells are actively secreting chemo- and cytokines, and this senescence-associated secretory phenotype (SASP) can contribute to both early anti-tumorigenic and long-term pro-tumorigenic effects. Recently, complex mechanisms of cellular senescence and their influence on cellular processes have been defined in more detail and, therefore, facilitate translational development of targeted therapies. In this review, we aim to discuss major molecular pathways involved in cellular senescence and potential therapeutic strategies, with a specific focus on myeloid malignancies.

Keywords:  SASP; leukemia; myelodysplastic syndrome; myeloproliferative neoplasms; senescence; senolytics

DOI:  https://doi.org/10.3390/cancers13040612
NPJ Aging Mech Dis. 2020 Mar 06. 6(1): 4

Organotypic human skin culture models constructed with senescent fibroblasts show hallmarks of skin aging.

Regina Weinmüllner, Barbara Zbiral, Adnan Becirovic, Elena Maria Stelzer, Fabian Nagelreiter, Markus Schosserer, Ingo Lämmermann, Lisa Liendl, Magdalena Lang, Lucia Terlecki-Zaniewicz, Orestis Andriotis, Michael Mildner, Bahar Golabi, Petra Waidhofer-Söllner, Karl Schedle, Gerhard Emsenhuber, Philipp J Thurner, Erwin Tschachler, Florian Gruber, Johannes Grillari.

Skin aging is driven by intrinsic and extrinsic factors impacting on skin functionality with progressive age. One factor of this multifaceted process is cellular senescence, as it has recently been identified to contribute to a declining tissue functionality in old age. In the skin, senescent cells have been found to markedly accumulate with age, and thus might impact directly on skin characteristics. Especially the switch from young, extracellular matrix-building fibroblasts to a senescence-associated secretory phenotype (SASP) could alter the microenvironment in the skin drastically and therefore promote skin aging. In order to study the influence of senescence in human skin, 3D organotypic cultures are a well-suited model system. However, only few "aged" skin- equivalent (SE) models are available, requiring complex and long-term experimental setups. Here, we adapted a previously published full-thickness SE model by seeding increasing ratios of stress-induced premature senescent versus normal fibroblasts into the collagen matrix, terming these SE "senoskin". Immunohistochemistry stainings revealed a shift in the balance between proliferation (Ki67) and differentiation (Keratin 10 and Filaggrin) of keratinocytes within our senoskin equivalents, as well as partial impairment of skin barrier function and changed surface properties. Monitoring of cytokine levels of known SASP factors confirmedly showed an upregulation in 2D cultures of senescent cells and at the time of seeding into the skin equivalent. Surprisingly, we find a blunted response of cytokines in the senoskin equivalent over time during 3D differentiation.

DOI: https://doi.org/10.1038/s41514-020-0042-x
Cytokine Growth Factor Rev. 2021 Jan 29. pii: S1359-6101(21)00006-X. [Epub ahead of print]

Hallmarks of aging and immunosenescence: Connecting the dots.

Leane Perim Rodrigues, Vitória Rodrigues Teixeira, Thuany Alencar-Silva, Bianca Simonassi-Paiva, Rinaldo Wellerson Pereira, Robert Pogue, Juliana Lott Carvalho.

  Aging is a natural physiological process that features various and variable challenges, associated with loss of homeostasis within the organism, often leading to negative consequences for health. Cellular senescence occurs when cells exhaust the capacity to renew themselves and their tissue environment as the cell cycle comes to a halt. This process is influenced by genetics, metabolism and extrinsic factors. Immunosenescence, the aging of the immune system, is a result of the aging process, but can also in turn act as a secondary inducer of senescence within other tissues. This review aims to summarize the current state of knowledge regarding hallmarks of aging in relation to immunosenescence, with a focus on aging-related imbalances in the medullary environment, as well as the components of the innate and adaptive immune responses. Aging within the immune system alters its functionality, and has consequences for the person's ability to fight infections, as well as for susceptibility to chronic diseases such as cancer and cardiovascular disease. The senescence-associated secretory phenotype is described, as well as the involvement of this phenomenon in the paracrine induction of senescence in otherwise healthy cells. Inflammaging is discussed in detail, along with the comorbidities associated with this process. A knowledge of these processes is required in order to consider possible targets for the application of senotherapeutic agents - interventions with the potential to modulate the senescence process, thus prolonging the healthy lifespan of the immune system and minimizing the secondary effects of immunosenescence.

Keywords:  Aging; Immune system; Immunosenescence; Inflammaging; Senescence; Senotherapeutics

DOI:  https://doi.org/10.1016/j.cytogfr.2021.01.006
Int Immunopharmacol. 2021 Feb 08. pii: S1567-5769(21)00063-1. [Epub ahead of print]94 107427

Overexpression of FOXA2 attenuates cigarette smoke-induced cellular senescence and lung inflammation through inhibition of the p38 and Erk1/2 MAPK pathways.

Yixiu Tao, Yingxin Sun, Bo Wu, Donghui Xu, Jun Yang, Liang Gu, Chunling Du.

  Chronic obstructive pulmonary disease (COPD) is characterized by irreversible and progressive airflow limitation and encompasses varying degrees of chronic obstructive bronchitis and emphysema. Our previous study showed that Forkhead box protein A2 (FOXA2) is involved in cigarette smoke (CS)-induced squamous metaplasia. However, the contribution of FOXA2 activity to CS-induced cellular senescence and lung inflammation remains largely unknown. Here, we report that FOXA2 was underexpressed in CS-exposed mouse lungs, and decreased expression of FOXA2 was related to cell senescence and inflammation. Subsequent investigation suggested that FOXA2 is an anti-senescence factor in lung that is involved in inflammatory responses. Furthermore, FOXA2 overexpression delayed CSE-induced senescence and inflammation, which correlated with regulation of the p38 and Erk1/2 MAPK signaling pathways by CSE-induced FOXA2 downregulation. Collectivelly, these findings reveal a protective role for FOXA2 as a regulator of cell senescence and inflammation during COPD.

Keywords:  COPD; FOXA2; Inflammation; MAPK; Senescence

DOI:  https://doi.org/10.1016/j.intimp.2021.107427
Cell Stem Cell. 2021 Feb 04. pii: S1934-5909(21)00010-2. [Epub ahead of print]

Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging.

Peng Deng, Quan Yuan, Yingduan Cheng, Jiong Li, Zhenqing Liu, Yan Liu, Ye Li, Trent Su, Jing Wang, Mari Ekimyan Salvo, Weiguang Wang, Guoping Fan, Karen Lyons, Bo Yu, Cun-Yu Wang.

  Skeletal aging is a complex process, characterized by a decrease in bone formation, an increase in marrow fat, and stem cell exhaustion. Loss of H3K9me3, a heterochromatin mark, has been proposed to be associated with aging. Here, we report that loss of KDM4B in mesenchymal stromal cells (MSCs) exacerbated skeletal aging and osteoporosis by reducing bone formation and increasing marrow adiposity via increasing H3K9me3. KDM4B epigenetically coordinated β-catenin/Smad1-mediated transcription by removing repressive H3K9me3. Importantly, KDM4B ablation impaired MSC self-renewal and promoted MSC exhaustion by inducing senescence-associated heterochromatin foci formation, providing a mechanistic explanation for stem cell exhaustion with aging. Moreover, while KDM4B was required for parathyroid hormone-mediated bone anabolism, KDM4B depletion accelerated bone loss and marrow adiposity induced by a high-fat diet. Our results suggest that the epigenetic rejuvenation and reversing bone-fat imbalance might be new strategies for preventing and treating skeletal aging and osteoporosis by activating KDM4B in MSCs.

Keywords:  bone marrow adiposity; bone metabolism; mesenchymal stem cells; mesenchymal stromal cells; osteoporosis; parathyroid hormone; senescence-associated heterochromatin foci; skeletal aging; stem cell self-renewal

DOI:  https://doi.org/10.1016/j.stem.2021.01.010
Am J Cancer Res. 2021 ;11(2): 458-478

IL-6 derived from therapy-induced senescence facilitates the glycolytic phenotype in glioblastoma cells.

Jiayu Gu, Jingyi Wang, Xincheng Liu, Ke Sai, Jialuo Mai, Fan Xing, Zhijie Chen, Xiaozhi Yang, Wanjun Lu, Cui Guo, Wenfeng Liu, Yang Xu, Shouxia Xie, Cheng Hu, Guangmei Yan, Wenbo Zhu.

Activation of the cyclic adenosine monophosphate (cAMP) pathway induces the glial differentiation of glioblastoma (GBM) cells, but the fate of differentiated cells remains poorly understood. Transcriptome analyses have revealed significant changes in the cell cycle- and senescence-related pathways in differentiated GBM cells induced by dibutyryl cAMP (dbcAMP). Further investigations showed that reactive oxygen species (ROS) derived from enhanced mitochondrial function are involved in senescence induction and proliferation inhibition. Moreover, we found that IL-6 from dbcAMP- or temozolomide (TMZ)-induced senescent cells facilitates the glycolytic phenotype of GBM cells and that inhibiting the IL-6-related pathway hinders the proglycolytic effect of either agent. In patient-derived GBM xenograft models, a specific antibody targeting the IL-6 receptor tocilizumab (TCZ) significantly prolongs the survival time of TMZ-treated mice. Taken together, these results suggest that both the differentiation-inducing agent dbcAMP and the chemotherapy drug TMZ are able to drive GBM cells to senescence, and the latter releases IL-6 to potentiate glycolysis, suggesting that IL-6 is a target for adjuvant chemotherapy in GBM treatment.

Keywords: Glioblastoma; IL-6; glycolysis; senescence
NPJ Aging Mech Dis. 2020 Aug 14. 6(1): 9

Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice.

Zhonghe Ke, Denis Firsanov, Brianna Spencer, Andrei Seluanov, Vera Gorbunova.

Calorie restriction (CR) improves health, reduces cancer incidence and extends lifespan in multiple organisms including mice. CR was shown to enhance base excision repair and nucleotide excision repair pathways of DNA repair, however, whether CR improves repair of DNA double-strand breaks has not been examined in in vivo system. Here we utilize non-homologous end joining (NHEJ) reporter mice to show that short-term CR strongly enhances DNA repair by NHEJ, which is associated with elevated levels of DNA-PK and SIRT6.

DOI: https://doi.org/10.1038/s41514-020-00047-2
Oxid Med Cell Longev. 2021 ;2021 6626484

Targeting the Mitochondrial Permeability Transition Pore to Prevent Age-Associated Cell Damage and Neurodegeneration.

Andrew C Kent, Khairat Bahgat Youssef El Baradie, Mark W Hamrick.

The aging process is associated with significant alterations in mitochondrial function. These changes in mitochondrial function are thought to involve increased production of reactive oxygen species (ROS), which over time contribute to cell death, senescence, tissue degeneration, and impaired tissue repair. The mitochondrial permeability transition pore (mPTP) is likely to play a critical role in these processes, as increased ROS activates mPTP opening, which further increases ROS production. Injury and inflammation are also thought to increase mPTP opening, and chronic, low-grade inflammation is a hallmark of aging. Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening; however, NAD+ levels are known to decline with age, further stimulating mPTP opening and increasing ROS release. Research on neurodegenerative diseases, particularly on Parkinson's disease (PD) and Alzheimer's disease (AD), has uncovered significant findings regarding mPTP openings and aging. Parkinson's disease is associated with a reduction in mitochondrial complex I activity and increased oxidative damage of DNA, both of which are linked to mPTP opening and subsequent ROS release. Similarly, AD is associated with increased mPTP openings, as evidenced by amyloid-beta (Aβ) interaction with the pore regulator cyclophilin D (CypD). Targeted therapies that can reduce the frequency and duration of mPTP opening may therefore have the potential to prevent age-related declines in cell and tissue function in various systems including the central nervous system.

DOI: https://doi.org/10.1155/2021/6626484
Aging (Albany NY). 2021 Feb 10. 13

SIRT6 enhances telomerase activity to protect against DNA damage and senescence in hypertrophic ligamentum flavum cells from lumbar spinal stenosis patients.

Jianwei Chen, Zude Liu, Hantao Wang, Lie Qian, Zhanchun Li, Qingxin Song, Guibin Zhong.

  Lumbar spinal stenosis (LSS) is a condition wherein patients exhibit age-related fibrosis, elastin-to-collagen ratio reductions, and ligamentum flavum hypertrophy. This study was designed to assess the relationship between SIRT6 and telomerase activity in hypertrophic ligamentum flavum (LFH) cells from LSS patients. We observed significant reductions in SIRT6, TPP1, and POT1 protein levels as well as increases in telomerase reverse transcriptase (TERT) levels and telomerase activity in LFH tissues relative to non- hypertrophic ligamentum flavum (LFN) tissues. When SIRT6 was overexpressed in these LFH cells, this was associated with significant increases in telomerase activity and a significant reduction in fibrosis-related protein expression. These effects were reversed, however, when telomerase activity was inactivated by hTERT knockdown in these same cells. SIRT6 overexpression was further found to reduce the frequency of senescence-associated β-galactosidase (SA-β-Gal)-positive LFH cells and to decrease p16, MMP3, and L1 mRNA levels and telomere dysfunction-induced foci (TIFs) in LFH cells. In contrast, hTERT knockdown-induced telomerase inactivation eliminated these SIRT6-dependent effects. Overall, our results indicate that SIRT6 functions as a key protective factor that prevents cellular senescence and telomere dysfunction in ligamentum flavum cells, with this effect being at least partially attributable to SIRT6-dependent telomerase activation.

Keywords:  DNA damage; SIRT6; senescence; telomerase activity; telomere dysfunction

DOI:  https://doi.org/10.18632/aging.202536
Cell Death Discov. 2020 Mar 30. 6(1): 17

Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/STAT3 pathway.

Sin-Ting Wang, Shi-Wei Huang, Kuang-Ting Liu, Teng-Yu Lee, Jeng-Jer Shieh, Chun-Ying Wu.

Hepatocellular carcinoma (HCC), a hepatic malignancy, has a poor prognosis and contributes to cancer-related death worldwide. Cellular senescence is an anticancer therapeutic strategy that causes irreversible cell cycle arrest and enables immune-mediated clearance of cancer cells. Atorvastatin, an HMG-CoA reductase inhibitor, has been shown to inhibit tumor growth and induce apoptosis or autophagy in malignant tumors. However, whether atorvastatin can induce HCC cell senescence and the mechanisms involved are poorly understood. The effects of atorvastatin-induced senescence were examined in both HCC cells and mouse xenograft models. The phenomenon and mechanism of senescence were examined by cell cycle analysis, senescence-associated β-galactosidase (SA-β-gal) staining and western blotting in HCC cells, and HCC tissues from mice were analyzed by immunohistochemical (IHC) staining. We demonstrated that atorvastatin induced cell growth inhibition and G0/G1 phase cell cycle arrest, leading to senescence in HCC cells. Atorvastatin-induced senescence was independent of p53, p14, and p16, and atorvastatin not only decreased the secretion of IL-6, a major senescence-associated secretory phenotype (SASP) factor, and the phosphorylation of STAT3 but also inhibited the expression of hTERT, a catalytic subunit of telomerase. Supplementation with exogenous IL-6 reversed both atorvastatin-induced suppression of STAT3 phosphorylation and hTERT expression and atorvastatin-induced senescence. Overexpression of constitutively activated STAT3 rescued HCC cells from atorvastatin-induced hTERT suppression and senescence. Moreover, atorvastatin decreased tumor growth in mouse xenograft models. Consistent with these results, atorvastatin decreased the IL-6, p-STAT3, and hTERT levels and increased β-gal expression in tumor sections. Taken together, these data indicate that atorvastatin can induce atypical cellular senescence in HCC cells to inhibit tumor growth, an effect mediated by downregulation of hTERT through suppression of the IL-6/STAT3 pathway.

DOI: https://doi.org/10.1038/s41420-020-0252-9
Mol Cell Oncol. 2021 Jan 11. 8(1): 1850161

The senescence-associated secretory phenotype as a driver of tumor growth: does G3BP1 hold the key?

Amr Omer, Sergio Di Marco, Imed-Eddine Gallouzi.

  Cellular senescence is a double-edged sword that, depending on the context, acts as either a potent tumor protective mechanism or an age-related driver of diseases such as cancer. Our recent findings show that the rasGAP SH3-binding protein 1 (G3BP1) activates the senescent-associated secretory phenotype (SASP) that, in turn, mediates cancer growth/progression.

Keywords:  G3BP1; SASPs; Senescence; cancer progression

DOI:  https://doi.org/10.1080/23723556.2020.1850161
Cancers (Basel). 2021 Feb 10. pii: 723. [Epub ahead of print]13(4):

Senolytics for Cancer Therapy: Is All That Glitters Really Gold?

Valerie J Carpenter, Tareq Saleh, David A Gewirtz.

  Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. Despite the unequivocal promise of senolytics, issues of universality, selectivity, resistance, and toxicity remain to be further clarified. In this review, we attempt to summarize and analyze the current preclinical literature involving the use of senolytics in senescent tumor cell models, and to propose tenable solutions and future directions to improve the understanding and use of this novel class of drugs.

Keywords:  ABT-263; adjuvant; cancer; chemotherapy; dormancy; navitoclax; recurrence; senescence; senolytic

DOI:  https://doi.org/10.3390/cancers13040723
Aging Cell. 2021 Feb 09. e13319

Taurine represses age-associated gut hyperplasia in Drosophila via counteracting endoplasmic reticulum stress.

Gang Du, Zhiming Liu, Zihua Yu, Zhangpeng Zhuo, Yuedan Zhu, Juanyu Zhou, Yang Li, Haiyang Chen.

  As they age, adult stem cells become more prone to functional decline, which is responsible for aging-associated tissue degeneration and diseases. One goal of aging research is to identify drugs that can repair age-associated tissue degeneration. Multiple organ development-related signaling pathways have recently been demonstrated to have functions in tissue homeostasis and aging process. Therefore, in this study, we tested several chemicals that are essential for organ development to assess their ability to delay intestinal stem cell (ISC) aging and promote gut function in adult Drosophila. We found that taurine, a free amino acid that supports neurological development and tissue metabolism in humans, represses ISC hyperproliferation and restrains the intestinal functional decline seen in aged animals. We found that taurine represses age-associated ISC hyperproliferation through a mechanism that eliminated endoplasmic reticulum (ER) stress by upregulation of the target genes of unfolded protein response in the ER (UPRER ) and inhibiting the c-Jun N-terminal kinase (JNK) signaling. Our findings show that taurine plays a critical role in delaying the aging process in stem cells and suggest that it may be used as a natural compound for the treatment of age-associated, or damage-induced intestinal dysfunction in humans.

Keywords:  ER stress; JNK signaling; aging; gut; intestinal stem cell; taurine; unfolded protein response

DOI:  https://doi.org/10.1111/acel.13319
Cells. 2021 Feb 05. pii: 326. [Epub ahead of print]10(2):

Amphiregulin Regulates Melanocytic Senescence.

Michaela Pommer, Silke Kuphal, Anja K Bosserhoff.

  Oncogene-induced senescence (OIS) is a decisive process to suppress tumor development, but the molecular details of OIS are still under investigation. Using an established OIS model of primary melanocytes transduced with BRAF V600E and compared to control cells, amphiregulin (AREG) was shown to be induced. In addition, AREG expression was observed in nevi, which by definition, are senescent cell clusters, compared to melanocytes. Interestingly, treatment of melanocytes with recombinant AREG did induce senescence. This led to the assumption that extracellular AREG has an important function in this process. Inhibition of the epidermal growth factor receptor (EGFR) using Gefitinib identified AREG as one of EGFR ligands responsible for senescence. Furthermore, depletion of AREG expression in senescent BRAF V600E melanocytes resulted in a significant reduction of senescent melanocytes. This study reveals AREG as an essential molecular component of signaling pathways leading to senescence in melanocytes.

Keywords:  AREG; OIS; amphiregulin; normal human primary melanocytes; oncogene induced senescence

DOI:  https://doi.org/10.3390/cells10020326
Front Cell Dev Biol. 2021 ;9 587096

Programmed Cell Senescence in the Mouse Developing Spinal Cord and Notochord.

Jorge Antolio Domínguez-Bautista, Pilar Sarah Acevo-Rodríguez, Susana Castro-Obregón.

  Programmed cell senescence is a cellular process that seems to contribute to embryo development, in addition to cell proliferation, migration, differentiation and programmed cell death, and has been observed in evolutionary distant organisms such as mammals, amphibians, birds and fish. Programmed cell senescence is a phenotype similar to stress-induced cellular senescence, characterized by the expression of the cell cycle inhibitors p21CIP1/WAF and p16INK4A, increased activity of a lysosomal enzyme with beta-galactosidase activity (coined senescence-associated beta-galactosidase) and secretion of growth factors, interleukins, chemokines, metalloproteases, etc., collectively known as a senescent-associated secretory phenotype that instructs surrounding tissue. How wide is the distribution of programmed cell senescence during mouse development and its specific mechanisms to shape the embryo are still poorly understood. Here, we investigated whether markers of programmed cell senescence are found in the developing mouse spinal cord and notochord. We found discrete areas and developmental windows with high senescence-associated beta galactosidase in both spinal cord and notochord, which was reduced in mice embryos developed ex-utero in the presence of the senolytic ABT-263. Expression of p21CIP1/WAF was documented in epithelial cells of the spinal cord and the notochord, while p16INK4A was observed in motoneurons. Treatment with the senolytic ABT-263 decreased the number of motoneurons, supporting their senescent phenotype. Our data suggest that a subpopulation of motoneurons in the developing spinal cord, as well as some notochord cells undergo programmed cell senescence.

Keywords:  Cdkn1a/p21CIP1/WAF; Cdkn2a/p16INK4A; endothelial cells; motoneurons; mouse development; notochord; spinal cord

DOI:  https://doi.org/10.3389/fcell.2021.587096
Biosci Biotechnol Biochem. 2021 Feb 13. pii: zbaa097. [Epub ahead of print]

Metabolomic analysis to elucidate the change of the n-3 polyunsaturated fatty acids in senescent osteoblasts.

Ying Wu, Mengjun Zhang, Xinwei Chen, Yu Zhou, Zhou Chen.

  Senile osteoporosis is a major public health concern, and yet, effective treatment methods do not exist. Herein, we used metabolomics to analyze the change of n-3 polyunsaturated fatty acids (PUFA) in senescent osteoblasts. We found that with an increase in the number of passages, the osteoblasts proliferative ability, alkaline phosphatase activity, and expression levels of bone metabolism genes decreased, the expression levels of aging-related genes increased, the damage caused by oxidative stress became more severe. Furthermore, levels of n-3 PUFA family members were downregulated in passage 10 than in passage 3 osteoblasts. These findings indicated that multiple passages led to more severe oxidative stress damage in senescent osteoblasts, which could be related to a decrease in n-3 PUFA levels. We believe that unsaturated fatty acid metabolism is a key factor involved in osteoblast senescence and that a proper dietary intake of n-3 PUFA may delay the occurrence senile osteoporosis.

Keywords:  n-3 polyunsaturated fatty acids; osteoblasts; oxidative stress; senile osteoporosis

DOI:  https://doi.org/10.1093/bbb/zbaa097
Cell Biochem Biophys. 2021 Feb 09.

Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages.

T Iwata, N Mizuno, S Ishida, M Kajiya, T Nagahara, E Kaneda-Ikeda, M Yoshioka, S Munenaga, K Ouhara, T Fujita, H Kawaguchi, H Kurihara.

  Mesenchymal stem cell (MSC) transplantation is an effective periodontal regenerative therapy. MSCs are multipotent, have self-renewal ability, and can differentiate into periodontal cells. However, senescence is inevitable for MSCs. In vitro, cell senescence can be induced by long-term culture with/without cell passage. However, the regulatory mechanism of MSC senescence remains unclear. Undifferentiated MSC-specific transcription factors can regulate MSC function. Herein, we identified the regulatory transcription factors involved in MSC senescence and elucidated their mechanisms of action. We cultured human MSCs (hMSCs) with repetitive cell passages to induce cell senescence and evaluated the mRNA and protein expression of cell senescence-related genes. Additionally, we silenced the cell senescence-induced transcription factors, GATA binding protein 6 (GATA6) and SRY-box 11 (SOX11), and investigated senescence-related signaling pathways. With repeated passages, the number of senescent cells increased, while the cell proliferation capacity decreased; GATA6 mRNA expression was upregulated and that of SOX11 was downregulated. Repetitive cell passages decreased Wnt and bone morphogenetic protein (BMP) signaling pathway-related gene expression. Silencing of GATA6 and SOX11 regulated Wnt and BMP signaling pathway-related genes and affected cell senescence-related genes; moreover, SOX11 silencing regulated GATA6 expression. Hence, we identified them as pair of regulatory transcription factors for cell senescence in hMSCs via the Wnt and BMP signaling pathways.

Keywords:  BMP; Cell senescence; GATA6; Mesenchymal stem cells; SOX11; Wnt

DOI:  https://doi.org/10.1007/s12013-021-00969-y
Ageing Res Rev. 2021 Feb 08. pii: S1568-1637(21)00018-0. [Epub ahead of print] 101271

The pleiotropic neuroprotective effects of resveratrol in cognitive decline and Alzheimer's disease pathology: from antioxidant to epigenetic therapy.

Christian Griñán-Ferré, Aina Bellver-Sanchis, Vanessa Izquierdo, Rubén Corpas, Joan Roig-Soriano, Miguel Chillón, Cristina Andres-Lacueva, Milán Somogyvári, Csaba Sőti, Coral Sanfeliu, Mercè Pallàs.

  While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer's disease and Parkinson's Disease. The dietary polyphenol Resveratrol (RV) possesses antioxidant and cytoprotective effects, producing neuroprotection in several organisms. The oxidative stress (OS) occurs because of Reactive oxygen species (ROS) accumulation that has been proposed to explain the cause of the ageing. One of the most harmful effects of ROS in the cell is DNA damage. Nevertheless, there is also evidence demonstrating that OS can produce other molecular changes such as mitochondrial dysfunction, inflammation, apoptosis, and epigenetic modifications, among others. Interestingly, the dietary polyphenol RV is a potent antioxidant and possesses pleiotropic actions, exerting its activity through various molecular pathways. In addition, recent evidence has shown that RV mediates epigenetic changes involved in ageing and the function of the CNS that persists across generations. Furthermore, it has been demonstrated that RV interacts with gut microbiota, showing modifications in bacterial composition associated with beneficial effects. In this review, we give a comprehensive overview of the main mechanisms of action of RV in different experimental models, including clinical trials and discuss how the interconnection of these molecular events could explain the neuroprotective effects induced by RV.

Keywords:  Antioxidants; epigenetic; gut microbiota; klotho; neurodegeneration; resveratrol; senescence

DOI:  https://doi.org/10.1016/j.arr.2021.101271
Am J Cancer Res. 2021 ;11(2): 370-388

β-elemene promotes the senescence of glioma cells through regulating YAP-CDK6 signaling.

Danlu Yang, Xingxing Xu, Xin Wang, Wenjin Feng, Xiya Shen, Jingjing Zhang, Huitao Liu, Changnan Xie, Qian Wu, Xuemeng Miao, Yifan Guo, Hao Cai, Lihao Wu, Shuxian Zhou, Xinfei Yao, Ying Wang, Tian Xie, Zhihui Huang.

Glioma is currently the most widespread and malignant primary intracranial tumor, which is characterized by high heterogeneity and high fatality rates. β-elemene, which is a bioactive compound extracted from a Chinese herb, Curcuma wenyujin, has been reported to reduce resistance of chemotherapeutic drugs and induce apoptosis in tumor cells. However, the role and mechanisms of β-elemene in glioma senescence remains unknown. In the present study, we found that a low concentration of β-elemene (10 μg/mL) induced senescence in glioma cells, including reduction of cell proliferation, hypertrophic morphology, increase of senescence-associated β-galactosidase (SA-β-Gal) activity, upregulation of several senescence-associated genes such as p16, p53 and NF-κB, and downregulation of Lamin B1. However, a high concentration of β-elemene induced apoptosis in glioma cells. Treatment with β-elemene caused a marked down-regulation of Yes-associated protein (YAP) expression in glioma cells, which is a key transcriptional co-activator in multiple cancers. Moreover, cyclin dependent kinase 6 (CDK6), which is a known downstream target of YAP, was decreased in glioma cells that treated with β-elemene. The overexpression of YAP and CDK6 significantly rescued β-elemene-induced senescence in glioma cells. Finally, β-elemene treatment also induced the senescence of glioma cells in glioma xenograft model through inactivation of YAP-CDK6 pathways, which might inhibit the glioma growth. Taken together, these results reveal a previously unknown role of β-elemene in glioma cell senescence in vitro and in vivo that is associated with YAP-CDK6 signaling pathway, which will enhance our understanding of glioma cell senescence, and provide novel strategies for the treatment of gliomas.

Keywords: YAP-CDK6 signaling; glioma; proliferation; senescence; β-elemene
J Invest Dermatol. 2021 Feb 06. pii: S0022-202X(20)32351-4. [Epub ahead of print]

Connective Tissue and Fibroblast Senescence in Skin Aging.

Meinhard Wlaschek, Pallab Maity, Evgenia Makrantonaki, Karin Scharffetter-Kochanek.

There is increasing evidence that skin aging is significantly enforced by the accumulation of senescent dermal fibroblasts. Various stressors damaging macromolecules inside and outside fibroblasts are responsible. In addition, NK cells fail to adequately remove senescent (SEN) fibroblasts from tissues. SEN fibroblasts by the release of the proinflammatory, tissue degrading senescent-associated secretory phenotype factors and vesicles with distinct cargo impact on their endogenous niche and spread senescence and skin aging. In this review, we will further discuss less noticed facets, including the plasticity of distinct dermal fibroblast phenotypes, the underestimated impact of the extracellular matrix itself, and the depletion of fibroblast subsets on skin homeostasis and aging.

DOI: https://doi.org/10.1016/j.jid.2020.11.010
Ageing Res Rev. 2021 Feb 05. pii: S1568-1637(21)00014-3. [Epub ahead of print] 101267

To breathe or not to breathe: understanding how oxygen sensing contributes to age-related phenotypes.

T van Vliet, F Casciaro, M Demaria.

  Aging is characterized by a progressive loss of tissue integrity and functionality due to disrupted homeostasis. Molecular oxygen is pivotal to maintain tissue functions, and aerobic species have evolved a sophisticated sensing system to ensure proper oxygen supply and demand. It is not surprising that aberrations in oxygen and oxygen-associated pathways subvert health and promote different aspects of aging. In this review, we discuss emerging findings on how oxygen-sensing mechanisms regulate different cellular and molecular processes during normal physiology, and how dysregulation of oxygen availability lead to disease and aging. We describe various clinical manifestations associated with deregulation of oxygen balance, and how oxygen-modulating therapies and natural oxygen oscillations influence longevity. We conclude by discussing how a better understanding of oxygen-related mechanisms that orchestrate aging processes may lead to the development of new therapeutic strategies to extend healthy aging.

Keywords:  Ageing; Aging; Hypoxia; Pathology; Senescence; oxygen

DOI:  https://doi.org/10.1016/j.arr.2021.101267
Biomedicines. 2021 Jan 29. pii: 130. [Epub ahead of print]9(2):

Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress.

Munehiro Kitada, Yoshio Ogura, Itaru Monno, Jing Xu, Daisuke Koya.

  Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect of MetR on lifespan extension and metabolic health is mediated partially through a reduction in oxidative stress. Methionine metabolism is involved in the supply of methyl donors such as S-adenosyl-methionine (SAM), glutathione synthesis and polyamine metabolism. SAM, a methionine metabolite, activates mechanistic target of rapamycin complex 1 and suppresses autophagy; therefore, MetR can induce autophagy. In the process of glutathione synthesis in methionine metabolism, hydrogen sulfide (H2S) is produced through cystathionine-β-synthase and cystathionine-γ-lyase; however, MetR can induce increased H2S production through this pathway. Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy. In addition, MetR decreases oxidative stress by inhibiting reactive oxygen species production in mitochondria. Thus, MetR can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health. In this review, we summarize the current understanding of the effects of MetR on lifespan extension and metabolic health, focusing on the reduction in oxidative stress.

Keywords:  autophagy; lifespan extension; metabolic health; methionine restriction; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines9020130
Nat Rev Mol Cell Biol. 2021 Feb 09.

Shaping human telomeres: from shelterin and CST complexes to telomeric chromatin organization.

Ci Ji Lim, Thomas R Cech.

The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires coordination between telomeric protein complexes and the ribonucleoprotein telomerase, which extends the telomeric DNA. Telomeric proteins modulate telomere architecture, recruit telomerase to accessible telomeres and orchestrate the conversion of the newly synthesized telomeric single-stranded DNA tail into double-stranded DNA. Dysfunctional telomere maintenance leads to telomere shortening, which causes human diseases including bone marrow failure, premature ageing and cancer. Recent studies provide new insights into telomerase-related interactions (the 'telomere replisome') and reveal new challenges for future telomere structural biology endeavours owing to the dynamic nature of telomere architecture and the great number of structures that telomeres form. In this Review, we discuss recently determined structures of the shelterin and CTC1-STN1-TEN1 (CST) complexes, how they may participate in the regulation of telomere replication and chromosome end-capping, and how disease-causing mutations in their encoding genes may affect specific functions. Major outstanding questions in the field include how all of the telomere components assemble relative to each other and how the switching between different telomere structures is achieved.

DOI: https://doi.org/10.1038/s41580-021-00328-y
Oncol Lett. 2021 Feb;21(2): 139

MicroRNA-7 modulates cellular senescence to relieve gemcitabine resistance by targeting PARP1/NF-κB signaling in pancreatic cancer cells.

Zhi-Qiang Ye, Han-Bin Chen, Tai-Yu Zhang, Zhi Chen, Ling Tian, Dian-Na Gu.

  Senescence is activated in response to gemcitabine to prevent the propagation of cancer cells. However, there is little evidence on whether senescence is involved in gemcitabine resistance in pancreatic cancer. Increasing evidence has demonstrated that microRNAs (miRs) are potential regulators of cellular senescence. The present study aimed to investigate whether aberrant miR-7 expression modulated senescence to influence pancreatic cancer resistance to chemotherapy. In the present study, cell senescence assay, ALDEFLUOR™ assay, luciferase reporter assay, flow cytometry, quantitative PCR, immunohistochemistry and western blot analysis were performed to explore the association between senescence and gemcitabine therapy response, and to clarify the underlying mechanisms. The present study revealed that gemcitabine-induced chronically existing senescent pancreatic cells possessed stemness markers. Therapy-induced senescence led to gemcitabine resistance. Additionally, it was found that miR-7 expression was decreased in gemcitabine-resistant pancreatic cancer cells, and that miR-7 acted as an important regulator of cellular senescence by targeting poly (ADP-ribose) polymerase 1 (PARP1)/NF-κB signaling. When miR-7 expression was restored, it was able to sensitize pancreatic cancer cells to gemcitabine. In conclusion, the present study demonstrated that miR-7 regulated cellular senescence and relieved gemcitabine resistance by targeting the PARP1/NF-κB axis in pancreatic cancer cells.

Keywords:  gemcitabine resistance; microRNA-7; pancreatic cancer; senescence

DOI:  https://doi.org/10.3892/ol.2020.12400
Front Genet. 2020 ;11 630186

Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.

Alexander Vaiserman, Dmytro Krasnienkov.

  Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.

Keywords:  age-related telomere shortening; aging-related disease; biomarker of biological age; leukocyte telomere length; mortality; telomerase

DOI:  https://doi.org/10.3389/fgene.2020.630186
Nat Cell Biol. 2021 Feb;23(2): 116-126

Functional mechanisms and abnormalities of the nuclear lamina.

Adam Karoutas, Asifa Akhtar.

Alterations in nuclear shape are present in human diseases and ageing. A compromised nuclear lamina is molecularly interlinked to altered chromatin functions and genomic instability. Whether these alterations are a cause or a consequence of the pathological state are important questions in biology. Here, we summarize the roles of nuclear envelope components in chromatin organization, phase separation and transcriptional and epigenetic regulation. Examining these functions in healthy backgrounds will guide us towards a better understanding of pathological alterations.

DOI: https://doi.org/10.1038/s41556-020-00630-5
Biomolecules. 2021 Feb 07. pii: 235. [Epub ahead of print]11(2):

Tissue-Specific Landscape of Metabolic Dysregulation during Ageing.

Fangrong Zhang, Jakob Kerbl-Knapp, Alena Akhmetshina, Melanie Korbelius, Katharina Barbara Kuentzel, Nemanja Vujić, Gerd Hörl, Margret Paar, Dagmar Kratky, Ernst Steyrer, Tobias Madl.

  The dysregulation of cellular metabolism is a hallmark of ageing. To understand the metabolic changes that occur as a consequence of the ageing process and to find biomarkers for age-related diseases, we conducted metabolomic analyses of the brain, heart, kidney, liver, lung and spleen in young (9-10 weeks) and old (96-104 weeks) wild-type mice [mixed genetic background of 129/J and C57BL/6] using NMR spectroscopy. We found differences in the metabolic fingerprints of all tissues and distinguished several metabolites to be altered in most tissues, suggesting that they may be universal biomarkers of ageing. In addition, we found distinct tissue-clustered sets of metabolites throughout the organism. The associated metabolic changes may reveal novel therapeutic targets for the treatment of ageing and age-related diseases. Moreover, the identified metabolite biomarkers could provide a sensitive molecular read-out to determine the age of biologic tissues and organs and to validate the effectiveness and potential off-target effects of senolytic drug candidates on both a systemic and tissue-specific level.

Keywords:  ageing; biomarker; metabolomics; tissue-specific

DOI:  https://doi.org/10.3390/biom11020235
Sci Transl Med. 2021 Feb 10. pii: eabd7064. [Epub ahead of print]13(580):

Nicotinamide for the treatment of heart failure with preserved ejection fraction.

Mahmoud Abdellatif, Viktoria Trummer-Herbst, Franziska Koser, Sylvère Durand, Rui Adão, Francisco Vasques-Nóvoa, Johanna K Freundt, Julia Voglhuber, Maria-Rosaria Pricolo, Michael Kasa, Clara Türk, Fanny Aprahamian, Elías Herrero-Galán, Sebastian J Hofer, Tobias Pendl, Lavinia Rech, Julia Kargl, Nathaly Anto-Michel, Senka Ljubojevic-Holzer, Julia Schipke, Christina Brandenberger, Martina Auer, Renate Schreiber, Chintan N Koyani, Akos Heinemann, Andreas Zirlik, Albrecht Schmidt, Dirk von Lewinski, Daniel Scherr, Peter P Rainer, Julia von Maltzahn, Christian Mühlfeld, Marcus Krüger, Saša Frank, Frank Madeo, Tobias Eisenberg, Andreas Prokesch, Adelino F Leite-Moreira, André P Lourenço, Jorge Alegre-Cebollada, Stefan Kiechl, Wolfgang A Linke, Guido Kroemer, Simon Sedej.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.

DOI: https://doi.org/10.1126/scitranslmed.abd7064
J Invest Dermatol. 2021 Feb 05. pii: S0022-202X(20)32360-5. [Epub ahead of print]

Regulation of the Wound Healing Response during Aging.

Xiaolei Ding, Parisa Kakanj, Maria Leptin, Sabine A Eming.

An effective healing response is critical to promote and ensure healthy aging. Major discoveries in both fields-repair and aging-have led to a better understanding of the mechanisms regulating the healing response and of the complexity of the aging process. It will now be important to translate and connect those findings to improve our insights into the decline of regeneration in the elderly. Furthermore, we need to understand how this process can be stalled to maintain and promote tissue resilience. Furthermore, it remains to be explored how the findings in model organisms are conserved in human wounds and how these findings might be translated into the clinic.

DOI: https://doi.org/10.1016/j.jid.2020.11.014
Aging (Albany NY). 2021 Feb 12. 13

DNA- and telomere-damage does not limit lifespan: evidence from rapamycin.

Mikhail V Blagosklonny.

  Failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor telomere shortening limits normal lifespan or causes normal aging.

Keywords:  antagonistic pleiotropy; hyperfunction theory; mTOR; natural selection; quasi-programmed aging

DOI:  https://doi.org/10.18632/aging.202674
Chromosoma. 2021 Feb 08.

Imaging assay to probe the role of telomere length shortening on telomere-gene interactions in single cells.

Ning Zhang, Yanhui Li, Tsung-Po Lai, Jerry W Shay, Gaudenz Danuser.

  Telomeres are repetitive non-coding nucleotide sequences (TTAGGGn) capping the ends of chromosomes. Progressive telomere shortening with increasing age has been associated with shifts in gene expression through models such as the telomere position effect (TPE), which suggests reduced interference of the telomere with transcriptional activity of increasingly more distant genes. A modification of the TPE model, referred to as Telomere Position Effects over Long Distance (TPE-OLD), explains why some genes 1-10 MB from a telomere are still affected by TPE, but genes closer to the telomere are not. Here, we describe an imaging approach to systematically examine the occurrence of TPE-OLD at the single cell level. Compared to existing methods, the pipeline allows rapid analysis of hundreds to thousands of cells, which is necessary to establish TPE-OLD as an acceptable mechanism of gene expression regulation. We examined two human genes, ISG15 and TERT, for which TPE-OLD has been described before. For both genes, we found less interaction with the telomere on the same chromosome in old cells compared to young cells; and experimentally elongated telomeres in old cells rescued the level of telomere interaction for both genes. However, the dependency of the interactions on the age progression from young to old cells varied. One model for the differences between ISG15 and TERT may relate to the markedly distinct interstitial telomeric sequence arrangement in the two genes. Overall, this provides a strong rationale for the role of telomere length shortening in the regulation of gene expression.

Keywords:  Fluorescense In Situ Hybridization; Image analysis; Telomere; Telomere position effect over long distance

DOI:  https://doi.org/10.1007/s00412-020-00747-4
J Nutr Biochem. 2021 Feb 03. pii: S0955-2863(21)00022-X. [Epub ahead of print] 108602

Tomatidine ameliorates obesity-induced non-alcoholic fatty liver disease in mice: Tomatidine improves hepatic steatosis in mice.

Shu-Ju Wu, Wen-Chung Huang, Ming-Chin Yu, Ya-Ling Chen, Szu-Chuan Shen, Kuo-Wei Yeh, Chian-Jiun Liou.

  Tomatidine is isolated from the leaves and green fruits of some plants in the Solanaceae family, and has been reported to have anti-inflammatory and anti-tumor effects. Previous studies have found that tomatidine decreases hepatic lipid accumulation via regulation of vitamin D receptor and activation of AMP-activated protein kinase (AMPK) phosphorylation. However, whether tomatidine reduces weight gain and improves non-alcoholic fatty liver disease (NAFLD) remains unclear. In this study, we investigated how tomatidine ameliorates NAFLD in obese mice and evaluated the regulatory mechanism of lipogenesis in hepatocytes. Male C57BL/6 mice were fed a high-fat diet (HFD) to induce obesity and NAFLD, and treated with tomatidine via intraperitoneal injection. In vitro, FL83B hepatocytes were incubated with oleic acid and treated with tomatidine to evaluate lipid metabolism. Our results demonstrate that tomatidine significantly decreases body weight and fat weight compared to HFD-fed mice. In addition, tomatidine decreased hepatic lipid accumulation and improved hepatocyte steatosis in HFD-induced obese mice. We also found that tomatidine significantly regulated serum total cholesterol, fasting blood glucose, low-density lipoprotein, and triglyceride levels, but the serum high-density lipoprotein and adiponectin concentrations were higher than in the HFD-fed obese mice. In vivo and in vitro, tomatidine significantly suppressed the expression of fatty acid synthase and transcription factors involved in lipogenesis, and increased the expression of adipose triglyceride lipase. Tomatidine promoted the sirtuin 1 (sirt1)/AMPK signaling pathway to increase lipolysis and β-oxidation in fatty liver cells. These findings suggest that tomatidine potentially ameliorates obesity and acts against hepatic steatosis by regulating lipogenesis and the sirt1/AMPK pathway.

Keywords:  FL83B; lipogenesis; lipolysis; non-alcoholic fatty liver disease; tomatidine

DOI:  https://doi.org/10.1016/j.jnutbio.2021.108602
Biomolecules. 2021 Feb 08. pii: 241. [Epub ahead of print]11(2):

"Cell Membrane Theory of Senescence" and the Role of Bioactive Lipids in Aging, and Aging Associated Diseases and Their Therapeutic Implications.

Undurti N Das.

  Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA and DHA and their metabolites. LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA and DHA noted in these conditions are due to the decreased activity of desaturases and elongases. PUFAs stimulate SIRT1 through protein kinase A-dependent activation of SIRT1-PGC1α complex and thus, increase rates of fatty acid oxidation and prevent lipid dysregulation associated with aging. SIRT1 activation prevents aging. Of all the SIRTs, SIRT6 is critical for intermediary metabolism and genomic stability. SIRT6-deficient mice show shortened lifespan, defects in DNA repair and have a high incidence of cancer due to oncogene activation. SIRT6 overexpression lowers LDL and triglyceride level, improves glucose tolerance, and increases lifespan of mice in addition to its anti-inflammatory effects at the transcriptional level. PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs (SIRt1 SIRT2, SIRT3, SIRT4, SIRT5, SIRT6), PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1-α). This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-, 12-, 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.

Keywords:  aging; bioactive lipids; cell membrane; inflammation; sirtuins; unsaturated fatty acids

DOI:  https://doi.org/10.3390/biom11020241