bims-senagi 2021-06-27 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–06–27
25 papers selected by
Maria Grazia Vizioli, Mayo Clinic

HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence.
Extracellular vesicles from mesenchymal stromal cells: Therapeutic perspectives for senescence targeting in osteoarthritis.
Faces of Cellular Senescence in Skin Aging.
Senotherapeutics: Targeting senescent cells for the main age-related diseases.
The redox-senescence axis and its therapeutic targeting.
Aging and Mesenchymal Stem Cells: Therapeutic Opportunities and Challenges in the Older Group.
Baicalein Delays H2O2-Induced Astrocytic Senescence through Inhibition of Senescence-Associated Secretory Phenotype (SASP), Suppression of JAK2/STAT1/NF-κB Pathway, and Regulation of Leucine Metabolism.
Th17/IL-17 induces endothelial cell senescence via activation of NF-κB/p53/Rb signaling pathway.
Salamander Insights Into Ageing and Rejuvenation.
SARS-CoV-2 spike protein induces paracrine senescence and leukocyte adhesionin endothelial cells.
A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity.
Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice.
Sirtuin3 ameliorates lung senescence and improves type II alveolar epithelial cell function by enhancing the FoxO3a-dependent antioxidant defence mechanism.
CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice.
Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus.
miRNAs generated from Meg3-Mirg locus are downregulated during aging.
Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland.
A description of the relationship in healthy longevity and aging-related disease: from gene to protein.
Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging.
Age-related changes in metabolites in young donor livers and old recipient sera after liver transplantation from young to old rats.
SIGNS OF DIASTOLIC DYSFUNCTION ARE GRADED BY SERUM TESTOSTERONE LEVELS IN AGING C57BL/6 MALE MICE.
Caloric restriction disrupts the microbiota and colonization resistance.
Lipid droplets in the nervous system.
Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes.
Dissecting regulatory pathways for transcription recovery following DNA damage reveals a non-canonical function of the histone chaperone HIRA.

Mol Syst Biol. 2021 Jun;17(6): e9760

HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence.

Konstantinos Sofiadis, Natasa Josipovic, Milos Nikolic, Yulia Kargapolova, Nadine Übelmesser, Vassiliki Varamogianni-Mamatsi, Anne Zirkel, Ioanna Papadionysiou, Gary Loughran, James Keane, Audrey Michel, Eduardo G Gusmao, Christian Becker, Janine Altmüller, Theodore Georgomanolis, Athanasia Mizi, Argyris Papantonis.

  Spatial organization and gene expression of mammalian chromosomes are maintained and regulated in conjunction with cell cycle progression. This is perturbed once cells enter senescence and the highly abundant HMGB1 protein is depleted from nuclei to act as an extracellular proinflammatory stimulus. Despite its physiological importance, we know little about the positioning of HMGB1 on chromatin and its nuclear roles. To address this, we mapped HMGB1 binding genome-wide in two primary cell lines. We integrated ChIP-seq and Hi-C with graph theory to uncover clustering of HMGB1-marked topological domains that harbor genes involved in paracrine senescence. Using simplified Cross-Linking and Immuno-Precipitation and functional tests, we show that HMGB1 is also a bona fide RNA-binding protein (RBP) binding hundreds of mRNAs. It presents an interactome rich in RBPs implicated in senescence regulation. The mRNAs of many of these RBPs are directly bound by HMGB1 and regulate availability of SASP-relevant transcripts. Our findings reveal a broader than hitherto assumed role for HMGB1 in coordinating chromatin folding and RNA homeostasis as part of a regulatory loop controlling cell-autonomous and paracrine senescence.

Keywords:  3D chromatin folding; RNA splicing; loop; replicative senescence; senescence-associated secretory phenotype

DOI:  https://doi.org/10.15252/msb.20209760
Adv Drug Deliv Rev. 2021 Jun 21. pii: S0169-409X(21)00228-3. [Epub ahead of print] 113836

Extracellular vesicles from mesenchymal stromal cells: Therapeutic perspectives for senescence targeting in osteoarthritis.

Jérémy Boulestreau, Marie Maumus, Christian Jorgensen, Danièle Noel.

  Osteoarthritis (OA) is a common age-related disease that correlates with a high number of senescent cells in joint tissues. Senescence has been reported to be one of the main drivers of OA pathogenesis, in particular via the release of senescence-associated secretory phenotype (SASP) factors. SASP factors are secreted as single molecules and/or packaged within extracellular vesicles (EVs), thereby contributing to senescent phenotype dissemination. Targeting senescent cells using senolytics or senomorphics has therefore been tested and improvement of OA-associated features has been reported in murine models. Mesenchymal stromal cells (MSCs) and their derived EVs (MSC-EVs) are promising treatments for OA, exerting pleiotropic functions by producing a variety of factors. However, functions of MSCs and MSC-EVs are affected by aging. In this review, we discuss on the impact of the senescent environment on functions of aged MSC-EVs and on the anti-aging properties of MSC-EVs in the context of OA.

Keywords:  Aging; Extracellular vesicle; Mesenchymal stromal cell; Osteoarthritis; Regenerative medicine; Senescence

DOI:  https://doi.org/10.1016/j.addr.2021.113836
Mech Ageing Dev. 2021 Jun 21. pii: S0047-6374(21)00097-X. [Epub ahead of print] 111525

Faces of Cellular Senescence in Skin Aging.

Chin Yee Ho, Oliver Dreesen.

  The skin is comprised of different cell types with different proliferative capacities. Skin aging occurs with chronological age and upon exposure to extrinsic factors such as photodamage. During aging, senescent cells accumulate in different compartments of the human skin, leading to impaired skin physiology. Diverse skin cell types may respond differently to senescence-inducing stimuli and it is not clear how this results in aging-associated skin phenotypes and pathologies. This review aims to examine and provide an overview of current evidence of cellular senescence in the skin. We will focus on cellular characteristics and behaviour of different skin cell types undergoing senescence in the epidermis and dermis, with a particular focus on the complex interplay between mitochondrial dysfunction, autophagy and DNA damage pathways. We will also examine how the dermis and epidermis cope with the accumulation of DNA damage during aging.

Keywords:  DNA damage response; Skin aging; epidermal differentiation; senescence

DOI:  https://doi.org/10.1016/j.mad.2021.111525
Mech Ageing Dev. 2021 Jun 21. pii: S0047-6374(21)00098-1. [Epub ahead of print]197 111526

Senotherapeutics: Targeting senescent cells for the main age-related diseases.

Virginia Boccardi, Patrizia Mecocci.

  The review aims to summarize and discuss the current knowledge on targeting senescent cells to reduce the risk of age-related diseases in animal models and human studies. The role of cellular senescence in aging and the major age-related diseases -including Alzheimer's disease, atherosclerosis, and type 2 diabetes- as well as the use of senotherapeutic strategies in both experimental and preclinical studies, will be described. A large number of molecules, including synthetic agents and natural compounds, have been proposed for anti-senescence activities. Research on senotherapeutics, which includes senolytic and senomorphic, has a growing interest, and their safety and reliability as anti-aging drugs have been tested in clinical trials. Initial findings suggest that the senotherapeutic approach may be translatable to humans. Due to the lack of evidence, caution must be used against senolytic agents due to their potential side-effects. In this context, natural senolytic compounds should have the advantage of low toxicity and potentially more useful in humans, although the mechanisms of action need to be deﬁned.

Keywords:  Age-related diseases; Aging; Senescence; Senolytic; Senomorphic

DOI:  https://doi.org/10.1016/j.mad.2021.111526
Redox Biol. 2021 Jun 05. pii: S2213-2317(21)00190-7. [Epub ahead of print]45 102032

The redox-senescence axis and its therapeutic targeting.

Natalie Yl Ngoi, Angeline Qx Liew, Stephen J F Chong, Matthew S Davids, Marie-Veronique Clement, Shazib Pervaiz.

   SIGNIFICANCE: Cellular growth arrest, associated with 'senescence', helps to safeguard against the accumulation of DNA damage which is often recognized as the underlying mechanism of a wide variety of age-related pathologies including cancer. Cellular senescence has also been described as a 'double-edged sword'. In cancer, for example, the creation of an immune-suppressive milieu by senescent tumor cells through the senescence-associated secretory phenotype contributes toward carcinogenesis and cancer progression.
RECENT ADVANCES: The potential for cellular senescence to confer multi-faceted effects on tissue fate has led to a rejuvenated interest in its landscape and targeting. Interestingly, redox pathways have been described as both triggers and propagators of cellular senescence, leading to intricate cross-links between both pathways.
CRITICAL ISSUES: In this review, we describe the mechanisms driving cellular senescence, the interface with cellular redox metabolism as well as the role that chemotherapy-induced senescence plays in secondary carcinogenesis. Notably, the role that anti-apoptotic proteins of the Bcl-2 family play in inducing drug resistance via mechanisms that involve senescence induction.
FUTURE DIRECTIONS: Though the therapeutic targeting of senescent cells as cancer therapy remains in its infancy, we summarize the current development of senotherapeutics, including recognized senotherapies, as well as the repurposing of drugs as senomorphic/senolytic candidates.

Keywords:  Cancer therapy; ROS; SASP; Senescence; Senolytics

DOI:  https://doi.org/10.1016/j.redox.2021.102032
Gerontology. 2021 Jun 23. 1-14

Aging and Mesenchymal Stem Cells: Therapeutic Opportunities and Challenges in the Older Group.

Huan Chen, Ousheng Liu, Sijia Chen, Yueying Zhou.

  With aging, a portion of cells, including mesenchymal stem cells (MSCs), become senescent, and these senescent cells accumulate and promote various age-related diseases. Therefore, the older age group has become a major population for MSC therapy, which is aimed at improving tissue regeneration and function of the aged body. However, the application of MSC therapy is often unsatisfying in the aged group. One reasonable conjecture for this correlation is that aging microenvironment reduces the number and function of MSCs. Cellular senescence also plays an important role in MSC function impairment. Thus, it is necessary to explore the relationship between senescence and MSCs for improving the application of MSCs in the elderly. Here, we present the influence of aging on MSCs and the characteristics and functional changes of senescent MSCs. Furthermore, current therapeutic strategies for improving MSC therapy in the elderly group are also discussed.

Keywords:  Aged group; Antiaging; Cellular senescence; Mesenchymal stem cell therapy; Mesenchymal stem cells

DOI:  https://doi.org/10.1159/000516668
ACS Chem Neurosci. 2021 Jun 21.

Baicalein Delays H2O2-Induced Astrocytic Senescence through Inhibition of Senescence-Associated Secretory Phenotype (SASP), Suppression of JAK2/STAT1/NF-κB Pathway, and Regulation of Leucine Metabolism.

Li Gao, Wen-Ge Zheng, Xing-Kang Wu, Guan-Hua Du, Xue-Mei Qin.

  Baicalein is an active ingredient extracted from the dried roots of the Scutellaria baicalensis Georgi. It has been demonstrated to improve memory impairment in multiple animal models; however, the underlying mechanisms remain ambiguous. The accumulation of senescent astrocytes and senescence-associated secretory phenotype (SASP) secreted by senescent astrocytes has been deemed as potential contributors to neurodegenerative diseases. Therefore, this study explored the protective effects of baicalein against astrocyte senescence and investigated the molecular mechanisms and metabolic mechanisms of baicalein against astrocyte senescence. Our results demonstrated that treatment with baicalein protects T98G cells from H2O2-induced damage, delays cell senescence, inhibits the secretion of SASP (IL-6, IL-8, TNF-α, CXCL1, and MMP-1), and inhibits SASP-related pathways NF-κB and JAK2/STAT1. 1H NMR metabolomics analysis and correlation analysis revealed that leucine was significantly correlated with SASP factors. Further study demonstrated that supplement with leucine could restrain SASP secretion, and baicalein could significantly increase leucine level through down-regulation of BCAT1 and up-regulation of SLC7A5 expression. The above results revealed that baicalein exerted protective and antisenescence effects in H2O2-induced T98G cells possibly through inhibition of SASP, suppression of JAK2/STAT1/NF-κB pathway, and regulation of leucine metabolism. Consistent results were obtained in primary astrocytes of newborn SD rats, which suggests that baicalein significantly increases viabilities, delays senescence, inhibits IL-6 secretion, and increases leucine level in H2O2-induced primary astrocytes.

Keywords:  Baicalein; JAK2/STAT1; NF-κB; SASP; astrocytes senescence; leucine

DOI:  https://doi.org/10.1021/acschemneuro.1c00024
Lab Invest. 2021 Jun 25.

Th17/IL-17 induces endothelial cell senescence via activation of NF-κB/p53/Rb signaling pathway.

Liang Zhang, Manli Liu, Wenhua Liu, Chaojie Hu, Hongqi Li, Jie Deng, Qi Cao, Yiping Wang, Wei Hu, Qing Li.

Cellular senescence is a key mechanism of age-related vascular endothelial dysfunction. Interleukin-17A (IL-17A) is an inflammatory cytokine produced by Th17 cells (a subgroup of helper T cells), which is a key factor in the development of atherosclerosis. However, the effect of IL-17A on the senescence of vascular endothelial cells is still unclear. In this study, we aimed to explore the role of IL-17A on endothelial cell senescence and its signaling pathways associated with senescence. The proportion of Th17 cells in the spleen and the expression levels of IL-17A, IL-6, and vascular cell adhesion molecule-1 (VCAM-1) in mice of different ages were increased with aging. In vitro experiments showed that proliferation was inhibited, senescent β-galactosidase and senescence-associated proteins (p16, p19, p21, and p53) of mouse aortic endothelial cells (MAECs) were increased with IL-17A treatment. Blocking the NF-κB pathway with ammonium pyrrolidinedithiocarbamate (PDTC) successfully inhibited IL-17A-induced expression of senescence-associated proteins. In conclusion, our data reveal a previously unsuspected link between IL-17A and endothelial cell senescence, which was mediated by the NF-κB /p53/Rb pathway.

DOI: https://doi.org/10.1038/s41374-021-00629-y
Front Cell Dev Biol. 2021 ;9 689062

Salamander Insights Into Ageing and Rejuvenation.

Maximina H Yun.

  Exhibiting extreme regenerative abilities which extend to complex organs and entire limbs, salamanders have long served as research models for understanding the basis of vertebrate regeneration. Yet these organisms display additional noteworthy traits, namely extraordinary longevity, indefinite regenerative potential and apparent lack of traditional signs of age-related decay or "negligible senescence." Here, I examine existing studies addressing these features, highlight outstanding questions, and argue that salamanders constitute valuable models for addressing the nature of organismal senescence and the interplay between regeneration and ageing.

Keywords:  axolotl; cancer; cellular senescence; negligible senescence; newt; regeneration

DOI:  https://doi.org/10.3389/fcell.2021.689062
J Virol. 2021 Jun 23. JVI0079421

SARS-CoV-2 spike protein induces paracrine senescence and leukocyte adhesionin endothelial cells.

Keith Meyer, Tapas Patra, Vijayamahantesh, Ranjit Ray.

Increased mortality in COVID-19 often associates with microvascular complications. We have recently shown that SARS-CoV-2 spike protein promotes an inflammatory cytokine IL-6/IL-6R induced trans-signaling response and alarmin secretion. Virus infected or spike transfected human epithelial cells exhibited an increase in senescence state with the release of senescence associated secretory proteins (SASP) related inflammatory molecules. Introduction of BRD4 inhibitor AZD5153 to senescent epithelial cells reversed this effect and reduced SASP related inflammatory molecule release in TMNK-1 or EAhy926 as representative human endothelial cell line, when exposed to cell culture medium (CM) derived from A549 cells expressing SARS-CoV-2 spike protein, also exhibited a senescence phenotype with enhanced p16, p21, SA-β-galactosidase expression, and triggered SASP pathways. Inhibition of IL-6 trans-signaling by Tocilizumab and inhibition of inflammatory receptor signaling by the BTK inhibitor Zanubrutinib, prior to exposure of CM to endothelial cells, inhibited p21 and p16 induction. We also observed an increase in reactive oxygen species (ROS) in A549 spike transfected and endothelial cells exposed to spike transfected CM. ROS generation in endothelial cell lines was reduced after treatment with Tocilizumab and Zanubrutinib. Cellular senescence was associated with an increased level of the endothelial adhesion molecules, VCAM-1 and ICAM-1 with in vitro leukocyte attachment potential. Inhibition of senescence or SASP function prevented VCAM-1/ICAM-1 expression and leukocyte attachment. Taken together, we identified that the exposure of human endothelial cells to cell culture supernatant derived from SARS-CoV-2 spike protein expression displayed cellular senescence markers, leading to enhanced leukocyte adhesion. Importance: The present study was aimed at examining the underlying mechanism of extrapulmonary manifestations of SARS-CoV-2 spike protein associated pathogenesis, with the notion that infection of the pulmonary epithelium can lead to mediators that drive endothelial dysfunction. We utilized SARS-CoV-2 spike protein expression in cultured cells of human hepatocytes (Huh7.5) and pneumocytes (A549) to generate conditioned culture media (CM). Endothelial cell lines (TMNK-1 or EAhy926) treated with CM exhibited increase in cellular senescence markers by a paracrine mode, and lead to leukocyte adhesion. Overall, the link between these responses in endothelial cell senescence, and a potential contribution to microvascular complication in productively SARS-CoV-2 infected humans is implicated. Furthermore, the use of inhibitors (BTK, IL-6 and BRD4) showed reverse effect in the senescent cells. These results may support the selection of potential adjunct therapeutic modalities to impede SARS-CoV-2 associated pathogenesis.

DOI: https://doi.org/10.1128/JVI.00794-21
Front Genet. 2021 ;12 638558

A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity.

Saleh Almasabi, Afsar U Ahmed, Richard Boyd, Bryan R G Williams.

  Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. ILK functions as an adaptor and mediator protein linking the extracellular matrix with downstream signaling pathways. ILK is broadly expressed in many human tissues and cells. It is also overexpressed in many cancers, including colorectal cancer (CRC). Inflammation, as evidenced by inflammatory bowel disease (IBD), is one of the highest risk factors for initiating CRC. This has led to the hypothesis that targeting ILK therapeutically could have potential in CRC, as it regulates different cellular processes associated with CRC development and progression as well as inflammation in the colon. A number of studies have indicated an ILK function in senescence, a cellular process that arrests the cell cycle while maintaining active metabolism and transcription. Senescent cells produce different secretions collectively known as the senescence-associated secretory phenotype (SASP). The SASP secretions influence infiltration of different immune cells, either positively for clearing senescent cells or negatively for promoting tumor growth, reflecting the dual role of senescence in cancer. However, a role for ILK in senescence and immunity in CRC remains to be determined. In this review, we discuss the possible role for ILK in senescence and immunity, paying particular attention to the relevance of ILK in CRC. We also examine how activating Toll-like receptors (TLRs) and their agonists in CRC could trigger immune responses against cancer, as a combination therapy with ILK inhibition.

Keywords:  colorectal cancer; combination theraoy; immunity; integrin-linked kinase; senescence

DOI:  https://doi.org/10.3389/fgene.2021.638558
Elife. 2021 Jun 21. pii: e66522. [Epub ahead of print]10

Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice.

Seungjin Ryu, Irina Shchukina, Yun-Hee Youm, Hua Qing, Brandon Hilliard, Tamara Dlugos, Xinbo Zhang, Yuki Yasumoto, Carmen J Booth, Carlos Fernández-Hernando, Yajaira Suárez, Kamal Khanna, Tamas L Horvath, Marcelo O Dietrich, Maxim N Artyomov, Andrew Wang, Vishwa Deep Dixit.

  Increasing age is the strongest predictor of risk of COVID-19 severity and mortality. Immunometabolic switch from glycolysis to ketolysis protects against inflammatory damage and influenza infection in adults. To investigate how age compromises defense against coronavirus infection, and whether a pro-longevity ketogenic-diet (KD) impacts immune-surveillance, we developed an aging model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain-A59 (MHV-A59). When inoculated intranasally, mCoV is pneumotropic and recapitulates several clinical hallmarks of COVID-19 infection. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of γδ T cells in lungs. Activation of ketogenesis in aged mice expands tissue protective γδ T cells, deactivates the NLRP3 inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data establish harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against coronavirus infection in the aged.

Keywords:  immunology; inflammation; mouse

DOI:  https://doi.org/10.7554/eLife.66522
Stem Cells Dev. 2021 Jun 19.

Sirtuin3 ameliorates lung senescence and improves type II alveolar epithelial cell function by enhancing the FoxO3a-dependent antioxidant defence mechanism.

Jianxin Chen, Lei Yang, Lu Sun, Wei Chen, Jie Wu, Chunfeng Zhang, Kai-Yu Liu, Long Bai, Hongguang Lu, Tong Gao, Hai Tian, Shu-Lin Jiang.

Lung ageing alters the intrinsic structure of the lung and pulmonary surfactant system and increases the mortality and morbidity due to respiratory diseases in elderly individuals. We hypothesized that lung ageing results from an insufficiency of type II alveolar epithelial cells (AECIIs) in the lung tissue. Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that promote longevity in many organisms. Increased SIRT3 expression has been linked to an extended lifespan in humans. Hence, we speculated that the overexpression of SIRT3 may help to ameliorate lung senescence and improve AECII function. AECIIs were isolated from young and old patients with pneumothorax caused by pulmonary bullae. The expression of SIRT3, manganese superoxide dismutase and catalase, as well as cell function and senescence indicators of young and old AECIIs, were measured before and after SIRT3 overexpression. After SIRT3 overexpression, the aged state of old AECIIs improved, and anti-apoptotic activity, proliferation and secretion were dramatically enhanced. Surfactant protein C (SPC), which is secreted by AECIIs, reduces alveolar surface tension, repairs the alveolar structure and regulates inflammation. SPC deficiency in patients is associated with increased inflammation and delayed repair. SIRT3 deacetylated forkhead box O3a, thereby protecting mitochondria from oxidative stress and improving cell function and the senescent state of old AECIIs. These findings provide a possible direction for ageing-delaying therapies and interventions for diseases of the respiratory system.

DOI: https://doi.org/10.1089/scd.2021.0099
Signal Transduct Target Ther. 2021 Jun 11. 6(1): 223

CD38 deficiency alleviates Ang II-induced vascular remodeling by inhibiting small extracellular vesicle-mediated vascular smooth muscle cell senescence in mice.

Lu Gan, Demin Liu, Jing Liu, Erya Chen, Chan Chen, Lian Liu, Hang Hu, Xiaohui Guan, Wen Ma, Yanzi Zhang, Yarong He, Bofu Liu, Songling Tang, Wei Jiang, Jianxin Xue, Hongbo Xin.

CD38 is the main enzyme for nicotinamide adenine dinucleotide (NAD) degradation in mammalian cells. Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases. Our study showed that CD38 deficiency significantly alleviated angiotensin II (Ang II)-induced vascular remodeling in mice, as shown by decreased blood pressures; reduced vascular media thickness, media-to-lumen ratio, and collagen deposition; and restored elastin expression. However, our bone marrow transplantation assay showed that CD38 deficiency in lymphocytes led to lack of protection against Ang II-induced vascular remodeling, suggesting that the effects of CD38 on Ang II-induced vascular remodeling might rely primarily on vascular smooth muscle cells (VSMCs), not lymphocytes. In addition, we observed that CD38 deficiency or NAD supplementation remarkably mitigated Ang II-induced vascular senescence by suppressing the biogenesis, secretion, and internalization of senescence-associated small extracellular vesicles (SA-sEVs), which facilitated the senescence of neighboring non-damaged VSMCs. Furthermore, we found that the protective effects of CD38 deficiency on VSMC senescence were related to restoration of lysosome dysfunction, particularly with respect to the maintenance of sirtuin-mediated mitochondrial homeostasis and activation of the mitochondria-lysosomal axis in VSMCs. In conclusion, our findings demonstrated that CD38 and its associated intracellular NAD decline are critical for Ang II-induced VSMC senescence and vascular remodeling.

DOI: https://doi.org/10.1038/s41392-021-00625-0
Nat Commun. 2021 06 23. 12(1): 3892

Environmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus.

Sara Zocher, Rupert W Overall, Mathias Lesche, Andreas Dahl, Gerd Kempermann.

The decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Lifestyle interventions can improve brain function during aging, but their influence on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, we here show that experiencing a stimulus-rich environment counteracts age-related DNA methylation changes in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, which is critical to neuronal function. The genes at which environmental enrichment counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the human brain. Our results highlight the stimulating effects of environmental enrichment on hippocampal plasticity at the level of DNA methylation and give molecular insights into the specific aspects of brain aging that can be counteracted by lifestyle interventions.

DOI: https://doi.org/10.1038/s41467-021-23993-1
Aging (Albany NY). 2021 Jun 22. 13

miRNAs generated from Meg3-Mirg locus are downregulated during aging.

Ana-Mihaela Lupan, Evelyn-Gabriela Rusu, Mihai Bogdan Preda, Catalina Iolanda Marinescu, Cristina Ivan, Alexandrina Burlacu.

  Aging determines a multilevel functional decline and increases the risk for cardiovascular pathologies. MicroRNAs are recognized as fine tuners of all cellular functions, being involved in various cardiac diseases. The heart is one of the most affected organs in aged individuals, however little is known about the extent and robustness to which miRNA profiles are modulated in cardiac cells during aging. This paper provides a comprehensive characterization of the aging-associated miRNA profile in the murine cardiac fibroblasts, which are increasingly recognized for their active involvement in the cardiac physiology and pathology. Next-generation sequencing of cardiac fibroblasts isolated from young and old mice revealed that an important fraction of the miRNAs generated by the Meg3-Mirg locus was downregulated during aging. To address the specificity of this repression, four miRNAs selected as representative for this locus were further assessed in other cells and organs isolated from aged mice. The results suggested that the repression of miRNAs generated by the Meg3-Mirg locus was a general feature of aging in multiple organs. Bioinformatic analysis of the predicted target genes identified Integrin Beta-2 as an aged-upregulated gene, which was thereafter confirmed in multiple mouse organs. In conclusion, our study provides new data concerning the mechanisms of natural aging and highlights the robustness of the miRNA modulation during this process.

Keywords:  Meg3-Mirg locus; aging; cardiac fibroblasts; heart ventricles; miRNA

DOI:  https://doi.org/10.18632/aging.203208
Proc Natl Acad Sci U S A. 2021 Jun 22. pii: e2100052118. [Epub ahead of print]118(25):

Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland.

Annelies Vennekens, Emma Laporte, Florian Hermans, Benoit Cox, Elodie Modave, Adrian Janiszewski, Charlotte Nys, Hiroto Kobayashi, Bert Malengier-Devlies, Joel Chappell, Patrick Matthys, Marie-Isabelle Garcia, Vincent Pasque, Diether Lambrechts, Hugo Vankelecom.

  Stem cells in the adult pituitary are quiescent yet show acute activation upon tissue injury. The molecular mechanisms underlying this reaction are completely unknown. We applied single-cell transcriptomics to start unraveling the acute pituitary stem cell activation process as occurring upon targeted endocrine cell-ablation damage. This stem cell reaction was contrasted with the aging (middle-aged) pituitary, known to have lost damage-repair capacity. Stem cells in the aging pituitary show regressed proliferative activation upon injury and diminished in vitro organoid formation. Single-cell RNA sequencing uncovered interleukin-6 (IL-6) as being up-regulated upon damage, however only in young but not aging pituitary. Administering IL-6 to young mice promptly triggered pituitary stem cell proliferation, while blocking IL-6 or associated signaling pathways inhibited such reaction to damage. By contrast, IL-6 did not generate a pituitary stem cell activation response in aging mice, coinciding with elevated basal IL-6 levels and raised inflammatory state in the aging gland (inflammaging). Intriguingly, in vitro stem cell activation by IL-6 was discerned in organoid culture not only from young but also from aging pituitary, indicating that the aging gland's stem cells retain intrinsic activatability in vivo, likely impeded by the prevailing inflammatory tissue milieu. Importantly, IL-6 supplementation strongly enhanced the growth capability of pituitary stem cell organoids, thereby expanding their potential as an experimental model. Our study identifies IL-6 as a pituitary stem cell activator upon local damage, a competence quenched at aging, concomitant with raised IL-6/inflammatory levels in the older gland. These insights may open the way to interfering with pituitary aging.

Keywords:  aging; interleukin-6; organoids; pituitary; stem cells

DOI:  https://doi.org/10.1073/pnas.2100052118
Immun Ageing. 2021 Jun 25. 18(1): 30

A description of the relationship in healthy longevity and aging-related disease: from gene to protein.

Xiaolin Ni, Zhaoping Wang, Danni Gao, Huiping Yuan, Liang Sun, Xiaoquan Zhu, Qi Zhou, Ze Yang.

  Human longevity is a complex phenotype influenced by both genetic and environmental factors. It is also known to be associated with various types of age-related diseases, such as Alzheimer's disease (AD) and cardiovascular disease (CVD). The central dogma of molecular biology demonstrates the conversion of DNA to RNA to the encoded protein. These proteins interact to form complex cell signaling pathways, which perform various biological functions. With prolonged exposure to the environment, the in vivo homeostasis adapts to the changes, and finally, humans adopt the phenotype of longevity or aging-related diseases. In this review, we focus on two different states: longevity and aging-related diseases, including CVD and AD, to discuss the relationship between genetic characteristics, including gene variation, the level of gene expression, regulation of gene expression, the level of protein expression, both genetic and environmental influences and homeostasis based on these phenotypes shown in organisms.

Keywords:  Alzheimer’s disease; Cardiovascular disease; Genetic characteristics; Homeostasis; Longevity

DOI:  https://doi.org/10.1186/s12979-021-00241-0
Sci Adv. 2021 Jun;pii: eabg6082. [Epub ahead of print]7(26):

Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging.

Csaba Kerepesi, Bohan Zhang, Sang-Goo Lee, Alexandre Trapp, Vadim N Gladyshev.

The notion that the germ line does not age goes back to the 19th-century ideas of August Weismann. However, being metabolically active, the germ line accumulates damage and other changes over time, i.e., it ages. For new life to begin in the same young state, the germ line must be rejuvenated in the offspring. Here, we developed a multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e., rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal aging.

DOI: https://doi.org/10.1126/sciadv.abg6082
Aging Cell. 2021 Jun 22. e13425

Age-related changes in metabolites in young donor livers and old recipient sera after liver transplantation from young to old rats.

Qunhua Han, Hui Li, Mengyuan Jia, Lin Wang, Yulan Zhao, Mangli Zhang, Qin Zhang, Zhuoxian Meng, Jimin Shao, Yunmei Yang, Lijun Zhu.

  Liver ageing not only damages liver function but also harms systemic metabolism. To better understand the mechanisms underlying liver ageing, we transplanted the livers of young rats to young and old rats and performed untargeted metabolomics to detect changes in the metabolites in the liver tissues and sera. A total of 153 metabolites in the livers and 83 metabolites in the sera were different between the old and young rats that did not undergo liver transplantation; among these metabolites, 7 different metabolites were observed in both the livers and sera. Five weeks after liver transplantation, the levels of 25 metabolites in the young donor livers were similar to those in the old rats, and this result probably occurred due to the effect of the whole-body environment of the older recipients on the young livers. The 25 altered metabolites included organic acids and derivatives, lipids and lipid-like molecules, etc. In the sera, the differences in 78 metabolites, which were significant between the young and old rats, were insignificant in the old recipient rats and made the metabolic profile of the old recipients more similar to that of the young recipients. Finally, combining the above metabolomic data with the transcriptomic data from the GEO, we found that the altered metabolites and genes in the liver were enriched in 9 metabolic pathways, including glycerophospholipid, arachidonic acid, histidine and linoleate. Thus, this study revealed important age-related metabolites and potential pathways as well as the interaction between the liver and the whole-body environment.

Keywords:  liver ageing; metabolic pathways; orthotopic liver transplantation; transcriptomics; untargeted metabolomics

DOI:  https://doi.org/10.1111/acel.13425
Mech Ageing Dev. 2021 Jun 21. pii: S0047-6374(21)00095-6. [Epub ahead of print] 111523

SIGNS OF DIASTOLIC DYSFUNCTION ARE GRADED BY SERUM TESTOSTERONE LEVELS IN AGING C57BL/6 MALE MICE.

Shubham Banga, Stefan Heinze-Milne, Judith Godin, Susan E Howlett.

  We investigated whether maladaptive, age-associated changes in heart structure and function were linked to circulating testosterone levels. Male C57BL/6 mice had a gonadectomy (GDX) or sham surgery at 4 weeks and effects of GDX on the heart were examined with echocardiography. Serum testosterone was measured with ELISA. Left ventricular (LV) mass increased with age but was smaller in GDX mice than sham at 18 months (144.0 ± 8.7 vs 118.2 ± 11.9 mg; p = 0.009). The isovolumic relaxation time (IVRT) declined with age but was prolonged in GDX mice at 18 months (10.5 ± 0.8 vs 12.5 ± 0.5 msec, p = 0.008). Ejection fraction did not change with age or GDX, but E/A ratios were lower in GDX mice than controls at 18 months (1.6 ± 0.2 vs 1.3 ± 0.1, p = 0.021). When links between serum testosterone and cardiac parameters were examined longitudinally in 18-24-month-old mice, LV mass declined with decreasing testosterone (β = 37.70, p = 0.016), however IVRT increased as testosterone decreased (β=-2.69, p = 0.036). Since longer IVRT and lower E/A ratios are signs of diastolic dysfunction, low circulating testosterone may promote or exacerbate diastolic dysfunction in older males. These findings suggest that lower testosterone directly modifies heart structure and function to promote maladaptive remodeling and diastolic dysfunction in the aging heart.

Keywords:  aging; cardiac remodelling; diastolic dysfunction; testosterone

DOI:  https://doi.org/10.1016/j.mad.2021.111523
Nature. 2021 Jun 23.

Caloric restriction disrupts the microbiota and colonization resistance.

Reiner Jumpertz von Schwartzenberg, Jordan E Bisanz, Svetlana Lyalina, Peter Spanogiannopoulos, Qi Yan Ang, Jingwei Cai, Sophia Dickmann, Marie Friedrich, Su-Yang Liu, Stephanie L Collins, Danielle Ingebrigtsen, Steve Miller, Jessie A Turnbaugh, Andrew D Patterson, Katherine S Pollard, Knut Mai, Joachim Spranger, Peter J Turnbaugh.

Diet is a major factor that shapes the gut microbiome1, but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile, which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet-microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts.

DOI: https://doi.org/10.1038/s41586-021-03663-4
J Cell Biol. 2021 Jul 05. pii: e202102136. [Epub ahead of print]220(7):

Lipid droplets in the nervous system.

Isha Ralhan, Chi-Lun Chang, Jennifer Lippincott-Schwartz, Maria S Ioannou.

Lipid droplets are dynamic intracellular lipid storage organelles that respond to the physiological state of cells. In addition to controlling cell metabolism, they play a protective role for many cellular stressors, including oxidative stress. Despite prior descriptions of lipid droplets appearing in the brain as early as a century ago, only recently has the role of lipid droplets in cells found in the brain begun to be understood. Lipid droplet functions have now been described for cells of the nervous system in the context of development, aging, and an increasing number of neuropathologies. Here, we review the basic mechanisms of lipid droplet formation, turnover, and function and discuss how these mechanisms enable lipid droplets to function in different cell types of the nervous system under healthy and pathological conditions.

DOI: https://doi.org/10.1083/jcb.202102136
Theranostics. 2021 ;11(15): 7527-7545

Arginine starvation elicits chromatin leakage and cGAS-STING activation via epigenetic silencing of metabolic and DNA-repair genes.

Sheng-Chieh Hsu, Chia-Lin Chen, Mei-Ling Cheng, Cheng-Ying Chu, Chun A Changou, Yen-Ling Yu, Shauh-Der Yeh, Tse-Chun Kuo, Cheng-Chin Kuo, Chih-Pin Chuu, Chien-Feng Li, Lu-Hai Wang, Hong-Wu Chen, Yun Yen, David K Ann, Hung-Jung Wang, Hsing-Jien Kung.

  Rationale: One of the most common metabolic defects in cancers is the deficiency in arginine synthesis, which has been exploited therapeutically. Yet, challenges remain, and the mechanisms of arginine-starvation induced killing are largely unclear. Here, we sought to demonstrate the underlying mechanisms by which arginine starvation-induced cell death and to develop a dietary arginine-restriction xenograft model to study the in vivo effects. Methods: Multiple castration-resistant prostate cancer cell lines were treated with arginine starvation followed by comprehensive analysis of microarray, RNA-seq and ChIP-seq were to identify the molecular and epigenetic pathways affected by arginine starvation. Metabolomics and Seahorse Flux analyses were used to determine the metabolic profiles. A dietary arginine-restriction xenograft mouse model was developed to assess the effects of arginine starvation on tumor growth and inflammatory responses. Results: We showed that arginine starvation coordinately and epigenetically suppressed gene expressions, including those involved in oxidative phosphorylation and DNA repair, resulting in DNA damage, chromatin-leakage and cGAS-STING activation, accompanied by the upregulation of type I interferon response. We further demonstrated that arginine starvation-caused depletion of α-ketoglutarate and inactivation of histone demethylases are the underlying causes of epigenetic silencing. Significantly, our dietary arginine-restriction model showed that arginine starvation suppressed prostate cancer growth in vivo, with evidence of enhanced interferon responses and recruitment of immune cells. Conclusions: Arginine-starvation induces tumor cell killing by metabolite depletion and epigenetic silencing of metabolic genes, leading to DNA damage and chromatin leakage. The resulting cGAS-STING activation may further enhance these killing effects.

Keywords:  Arginine starvation; DNA leakage; Epigenetic gene silencing; cGAS-STING activation

DOI:  https://doi.org/10.7150/thno.54695
Nat Commun. 2021 06 22. 12(1): 3835

Dissecting regulatory pathways for transcription recovery following DNA damage reveals a non-canonical function of the histone chaperone HIRA.

Déborah Bouvier, Juliette Ferrand, Odile Chevallier, Michelle T Paulsen, Mats Ljungman, Sophie E Polo.

Transcription restart after a genotoxic challenge is a fundamental yet poorly understood process. Here, we dissect the interplay between transcription and chromatin restoration after DNA damage by focusing on the human histone chaperone complex HIRA, which is required for transcription recovery post UV. We demonstrate that HIRA is recruited to UV-damaged chromatin via the ubiquitin-dependent segregase VCP to deposit new H3.3 histones. However, this local activity of HIRA is dispensable for transcription recovery. Instead, we reveal a genome-wide function of HIRA in transcription restart that is independent of new H3.3 and not restricted to UV-damaged loci. HIRA coordinates with ASF1B to control transcription restart by two independent pathways: by stabilising the associated subunit UBN2 and by reducing the expression of the transcription repressor ATF3. Thus, HIRA primes UV-damaged chromatin for transcription restart at least in part by relieving transcription inhibition rather than by depositing new H3.3 as an activating bookmark.

DOI: https://doi.org/10.1038/s41467-021-24153-1