bims-senagi 2021-08-29 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–08–29
twenty-six papers selected by
Maria Grazia Vizioli, Mayo Clinic

Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer.
Targeting senescent cells for vascular aging and related diseases.
Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology.
Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain.
Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice.
p16INK4a Regulates Cellular Senescence in PD-1-Expressing Human T Cells.
Senescence in a cell culture model for burn wounds.
MicroRNA-29a Mitigates Osteoblast Senescence and Counteracts Bone Loss through Oxidation Resistance-1 Control of FoxO3 Methylation.
Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions.
Inflammation and Aging of Hematopoietic Stem Cells in Their Niche.
Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models.
Exosomes and Micro-RNAs in Aging Process.
Involvement of Extracellular vesicles in aging process and their beneficial effects in alleviating aging-associated symptoms.
Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime.
The role of transient receptor potential ankyrin 1 in age-related endothelial dysfunction.
Curcumin as Prospective Anti-Aging Natural Compound: Focus on Brain.
Age-related alteration in characteristics, function, and transcription features of ADSCs.
Altered sperm tsRNAs in aged male contribute to anxiety-like behavior in offspring.
Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome.
Crosstalk among DNA Damage, Mitochondrial Dysfunction, Impaired Mitophagy, Stem Cell Attrition, and Senescence in the Accelerated Ageing Disorder Werner Syndrome.
Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria.
The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage.
Age patterns of intra-pair DNA methylation discordance in twins: Sex difference in epigenomic instability and implication on survival.
NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging.
The Gut Microbiome, Metformin, and Aging.
PP-1β and PP-2Aα modulate cAMP response element-binding protein (CREB) functions in aging control and stress response through de-regulation of αB-crystallin gene and p300-p53 signaling axis.

Proc Natl Acad Sci U S A. 2021 Aug 31. pii: e2025647118. [Epub ahead of print]118(35):

Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer.

Kenichi Miyata, Yoshinori Imai, Satoshi Hori, Mika Nishio, Tze Mun Loo, Ryo Okada, Liying Yang, Tomoyoshi Nakadai, Reo Maruyama, Risa Fujii, Koji Ueda, Li Jiang, Hao Zheng, Shinya Toyokuni, Toyonori Sakata, Katsuhiko Shirahige, Ryosuke Kojima, Mizuho Nakayama, Masanobu Oshima, Satoshi Nagayama, Hiroyuki Seimiya, Toru Hirota, Hideyuki Saya, Eiji Hara, Akiko Takahashi.

  Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non-cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

Keywords:  CTCF; pericentromeric RNA; senescence; senescence-associated secretory phenotype; small extracellular vesicles

DOI:  https://doi.org/10.1073/pnas.2025647118
J Mol Cell Cardiol. 2021 Aug 23. pii: S0022-2828(21)00168-1. [Epub ahead of print]

Targeting senescent cells for vascular aging and related diseases.

Yang-Nan Ding, Hui-Yu Wang, Hou-Zao Chen, De-Pei Liu.

  Cardiovascular diseases are a serious threat to human health, especially in the elderly. Vascular aging makes people more susceptible to cardiovascular diseases due to significant dysfunction or senescence of vascular cells and maladaptation of vascular structure and function; moreover, vascular aging is currently viewed as a modifiable cardiovascular risk factor. To emphasize the relationship between senescent cells and vascular aging, we first summarize the roles of senescent vascular cells (endothelial cells, smooth muscle cells and immune cells) in the vascular aging process and inducers that contribute to cellular senescence. Then, we present potential strategies for directly targeting senescent cells (senotherapy) or preventively targeting senescence inducers (senoprevention) to delay vascular aging and the development of age-related vascular diseases. Finally, based on recent research, we note some important questions that still need to be addressed in the future.

Keywords:  Cell senescence; Senescence inducers; Senoprevention; Senotherapy; Vascular aging

DOI:  https://doi.org/10.1016/j.yjmcc.2021.08.009
Immunology. 2021 Aug 25.

Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology.

Carlos Henrique Fantecelle, Luciana Polaco Covre, Renan Garcia de Moura, Herbert Leonel de Matos Guedes, Camila Farias Amorim, Phillip Scott, David Mosser, Aloisio Falqueto, Arne N Akbar, Daniel Claudio Oliveira Gomes.

  The severity of lesions that develop in patients infected by Leishmania braziliensis is mainly associated with a highly cytotoxic and inflammatory cutaneous environment. Recently, we demonstrated that senescent T and NK cells play a role in the establishment and maintenance of this tissue inflammation. Here, we extended those findings using transcriptomic analyses that demonstrate a strong co-induction of senescence and pro-inflammatory gene signatures in cutaneous leishmaniasis (CL) lesions. The senescence-associated signature was characterized by marked expression of key genes such as ATM, Sestrin 2, p16, p21, p38. The cell type identification from deconvolution of bulk sequencing data showed that the senescence signature was linked with CD8+ effector memory and TEMRA subsets and also senescent NK cells. A key observation was that the senescence markers in the skin lesions are age-independent of patients and were correlated with lesion size. Moreover, a striking expression of the senescence-associated secretory phenotype (SASP), proinflammatory cytokine and chemokines genes were found within lesions that was most strongly associated with the senescent CD8 TEMRA subset. Collectively, our results confirm that there is a senescence transcriptomic signature in CL lesions and supports the hypothesis that lesional senescent cells have a major role in mediating immunopathology of the disease.

Keywords:   Leishmania braziliensis ; Cutaneous leishmaniasis; immunopathogenesis; immunosenescence; senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1111/imm.13410
Oxid Med Cell Longev. 2021 ;2021 6682336

Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain.

Elisa Gorostieta-Salas, Daniel Moreno-Blas, Cristian Gerónimo-Olvera, Bulmaro Cisneros, Felipe A Court, Susana Castro-Obregón.

Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson-Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-β-gal activity by restoring TFEB nuclear localization. Collectively, our data suggest that enhanced CRM1-mediated export of proteins during brain aging perturbs neuronal homeostasis, contributing to autophagy impairment, and neuronal senescence.

DOI: https://doi.org/10.1155/2021/6682336
Geroscience. 2021 Aug 24.

Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice.

Stefano Tarantini, Priya Balasubramanian, Jordan Delfavero, Tamas Csipo, Andriy Yabluchanskiy, Tamas Kiss, Ádám Nyúl-Tóth, Peter Mukli, Peter Toth, Chetan Ahire, Anna Ungvari, Zoltan Benyo, Anna Csiszar, Zoltan Ungvari.

  Moment-to-moment adjustment of regional cerebral blood flow to neuronal activity via neurovascular coupling (NVC or "functional hyperemia") has a critical role in maintenance of healthy cognitive function. Aging-induced impairment of NVC responses importantly contributes to age-related cognitive decline. Advanced aging is associated with increased prevalence of senescent cells in the cerebral microcirculation, but their role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that a validated senolytic treatment can improve NVC responses and cognitive performance in aged mice. To achieve this goal, aged (24-month-old) C57BL/6 mice were treated with ABT263/Navitoclax, a potent senolytic agent known to eliminate senescent cells in the aged mouse brain. Mice were behaviorally evaluated (radial arms water maze) and NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. ABT263/Navitoclax treatment improved NVC response, which was associated with significantly improved hippocampal-encoded functions of learning and memory. ABT263/Navitoclax treatment did not significantly affect endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, increased presence of senescent cells in the aged brain likely contributes to age-related neurovascular uncoupling, exacerbating cognitive decline. The neurovascular protective effects of ABT263/Navitoclax treatment highlight the preventive and therapeutic potential of senolytic treatments (as monotherapy or as part of combination treatment regimens) as effective interventions in patients at risk for vascular cognitive impairment (VCI).

Keywords:  Aging; Endothelial dysfunction; Functional hyperemia; Microcirculation; Senescence; Vascular cognitive impairment

DOI:  https://doi.org/10.1007/s11357-021-00440-z
Front Immunol. 2021 ;12 698565

p16INK4a Regulates Cellular Senescence in PD-1-Expressing Human T Cells.

Valérie Janelle, Mathieu Neault, Marie-Ève Lebel, Dave Maurice De Sousa, Salix Boulet, Ludovic Durrieu, Cédric Carli, Chloé Muzac, Sébastien Lemieux, Nathalie Labrecque, Heather J Melichar, Frédérick A Mallette, Jean-Sébastien Delisle.

  T-cell dysfunction arising upon repeated antigen exposure prevents effective immunity and immunotherapy. Using various clinically and physiologically relevant systems, we show that a prominent feature of PD-1-expressing exhausted T cells is the development of cellular senescence features both in vivo and ex vivo. This is associated with p16INK4a expression and an impaired cell cycle G1 to S-phase transition in repeatedly stimulated T cells. We show that these T cells accumulate DNA damage and activate the p38MAPK signaling pathway, which preferentially leads to p16INK4a upregulation. However, in highly dysfunctional T cells, p38MAPK inhibition does not restore functionality despite attenuating senescence features. In contrast, p16INK4a targeting can improve T-cell functionality in exhausted CAR T cells. Collectively, this work provides insights into the development of T-cell dysfunction and identifies T-cell senescence as a potential target in immunotherapy.

Keywords:  CAR T cells; T cells; adoptive immunotherapy; cellular senescence; exhaustion and activation markers; p16INK4a; p38MAPK

DOI:  https://doi.org/10.3389/fimmu.2021.698565
Exp Mol Pathol. 2021 Aug 23. pii: S0014-4800(21)00073-3. [Epub ahead of print] 104674

Senescence in a cell culture model for burn wounds.

Sarah Kerschbaum, Christina Wegrostek, Elisabeth Riegel, Thomas Czerny.

  Thermal injuries cause severe damage on the cellular and tissue level and are considered especially challenging in the clinical routine. Complex interactions of different cell types and pathways dictate the formation of burn wounds. Thus, complications like burn wound progression, where so far viable tissue becomes necrotic and the size and depth of the wound increases, are difficult to explain, mainly due to the lack of simple model systems. We tested the behavior of human fibroblasts after heat treatment. A prominent response of the cells is to activate the heat shock response (HSR), which is one of the primary emergency mechanisms of the cell to proteotoxic stress factors such as heat. However, after a powerful but not lethal heat shock we observed a delayed activation of the HSR. Extending this model system, we further investigated these static cells and observed the emergence of senescent cells. In particular, the cells became β-galactosidase positive, increased p16 levels and developed a senescence-associated secretory phenotype (SASP). The secretion of cytokines like IL-6 is reminiscent of burn wounds and generates a bystander effect in so far non-senescent cells. In agreement with burn wounds, a wave of cytokine secretion enhanced by invading immune cells could explain complications like burn wound progression. A simple cell culture model can thus be applied for the analysis of highly complex conditions in human tissues.

Keywords:  Burn wound progression; Burn wounds; Heat shock response; In vitro model; Senescence

DOI:  https://doi.org/10.1016/j.yexmp.2021.104674
Antioxidants (Basel). 2021 Aug 04. pii: 1248. [Epub ahead of print]10(8):

MicroRNA-29a Mitigates Osteoblast Senescence and Counteracts Bone Loss through Oxidation Resistance-1 Control of FoxO3 Methylation.

Wei-Shiung Lian, Re-Wen Wu, Yu-Shan Chen, Jih-Yang Ko, Shao-Yu Wang, Holger Jahr, Feng-Sheng Wang.

  Senescent osteoblast overburden accelerates bone mass loss. Little is understood about microRNA control of oxidative stress and osteoblast senescence in osteoporosis. We revealed an association between microRNA-29a (miR-29a) loss, oxidative stress marker 8-hydroxydeoxyguanosine (8-OHdG), DNA hypermethylation marker 5-methylcystosine (5mC), and osteoblast senescence in human osteoporosis. miR-29a knockout mice showed low bone mass, sparse trabecular microstructure, and osteoblast senescence. miR-29a deletion exacerbated bone loss in old mice. Old miR-29a transgenic mice showed fewer osteoporosis signs, less 5mC, and less 8-OHdG formation than age-matched wild-type mice. miR-29a overexpression reversed age-induced senescence and osteogenesis loss in bone-marrow stromal cells. miR-29a promoted transcriptomic landscapes of redox reaction and forkhead box O (FoxO) pathways, preserving oxidation resistance protein-1 (Oxr1) and FoxO3 in old mice. In vitro, miR-29a interrupted DNA methyltransferase 3b (Dnmt3b)-mediated FoxO3 promoter methylation and senescence-associated β-galactosidase activity in aged osteoblasts. Dnmt3b inhibitor 5'-azacytosine, antioxidant N-acetylcysteine, or Oxr1 recombinant protein attenuated loss in miR-29a and FoxO3 to mitigate oxidative stress, senescence, and mineralization matrix underproduction. Taken together, miR-29a promotes Oxr1, compromising oxidative stress and FoxO3 loss to delay osteoblast aging and bone loss. This study sheds light on a new antioxidation mechanism by which miR-29a protects against osteoblast aging and highlights the remedial effects of miR-29a on osteoporosis.

Keywords:  Dnmt3b; FoxO3; Oxr1; microRNA-29a; osteoporosis; senescence

DOI:  https://doi.org/10.3390/antiox10081248
J Mol Med (Berl). 2021 Aug 25.

Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions.

Antero Salminen.

  The functional competence of the immune system gradually declines with aging, a process called immunosenescence. The age-related remodelling of the immune system affects both adaptive and innate immunity. In particular, a chronic low-grade inflammation, termed inflammaging, is associated with the aging process. Immunosenescence not only is present in inflammaging state, but it also occurs in several pathological conditions in conjunction with chronic inflammation. It is known that persistent inflammation stimulates a counteracting compensatory immunosuppression intended to protect host tissues. Inflammatory mediators enhance myelopoiesis and induce the generation of immature myeloid-derived suppressor cells (MDSC) which in mutual cooperation stimulates the immunosuppressive network. Immunosuppressive cells, especially MDSCs, regulatory T cells (Treg), and M2 macrophages produce immunosuppressive factors, e.g., TGF-β, IL-10, ROS, arginase-1 (ARG1), and indoleamine 2,3-dioxygenase (IDO), which suppress the functions of CD4/CD8T and B cells as well as macrophages, natural killer (NK) cells, and dendritic cells. The immunosuppressive armament (i) inhibits the development and proliferation of immune cells, (ii) decreases the cytotoxic activity of CD8T and NK cells, (iii) prevents antigen presentation and antibody production, and (iv) suppresses responsiveness to inflammatory mediators. These phenotypes are the hallmarks of immunosenescence. Immunosuppressive factors are able to control the chromatin landscape, and thus, it seems that the immunosenescence state is epigenetically regulated.

Keywords:  Aging; Alzheimer’s; Cellular senescence; Immune tolerance; Immunosuppression; Kynurenine

DOI:  https://doi.org/10.1007/s00109-021-02123-w
Cells. 2021 Jul 21. pii: 1849. [Epub ahead of print]10(8):

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche.

Daozheng Yang, Gerald de Haan.

  Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging.

Keywords:  aging; hematopoietic stem cells; heterogeneity; inflammation; niche

DOI:  https://doi.org/10.3390/cells10081849
Cells. 2021 Jul 27. pii: 1906. [Epub ahead of print]10(8):

Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models.

Verónica A García-García, Josefa P Alameda, Angustias Page, María Llanos Casanova.

  Ageing is a complex process, induced by multifaceted interaction of genetic, epigenetic, and environmental factors. It is manifested by a decline in the physiological functions of organisms and associated to the development of age-related chronic diseases and cancer development. It is considered that ageing follows a strictly-regulated program, in which some signaling pathways critically contribute to the establishment and maintenance of the aged state. Chronic inflammation is a major mechanism that promotes the biological ageing process and comorbidity, with the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) as a crucial mediator of inflammatory responses. This, together with the finding that the activation or inhibition of NF-κB can induce or reverse respectively the main features of aged organisms, has brought it under consideration as a key transcription factor that acts as a driver of ageing. In this review, we focused on the data obtained entirely through the generation of knockout and transgenic mouse models of either protein involved in the NF-κB signaling pathway that have provided relevant information about the intricate processes or molecular mechanisms that control ageing. We have reviewed the relationship of NF-κB and premature ageing; the development of cancer associated with ageing and the implication of NF-κB activation in the development of age-related diseases, some of which greatly increase the risk of developing cancer.

Keywords:  NF-κB; age-related diseases; ageing; cancer; transgenic mouse models of NF-κB

DOI:  https://doi.org/10.3390/cells10081906
Biomedicines. 2021 Aug 06. pii: 968. [Epub ahead of print]9(8):

Exosomes and Micro-RNAs in Aging Process.

Yousra Hamdan, Loubna Mazini, Gabriel Malka.

  Exosomes are the main actors of intercellular communications and have gained great interest in the new cell-free regenerative medicine. These nanoparticles are secreted by almost all cell types and contain lipids, cytokines, growth factors, messenger RNA, and different non-coding RNA, especially micro-RNAs (mi-RNAs). Exosomes' cargo is released in the neighboring microenvironment but is also expected to act on distant tissues or organs. Different biological processes such as cell development, growth and repair, senescence, migration, immunomodulation, and aging, among others, are mediated by exosomes and principally exosome-derived mi-RNAs. Moreover, their therapeutic potential has been proved and reinforced by their use as biomarkers for disease diagnostics and progression. Evidence has increasingly shown that exosome-derived mi-RNAs are key regulators of age-related diseases, and their involvement in longevity is becoming a promising issue. For instance, mi-RNAs such as mi-RNA-21, mi-RNA-29, and mi-RNA-34 modulate tissue functionality and regeneration by targeting different tissues and involving different pathways but might also interfere with long life expectancy. Human mi-RNAs profiling is effectively related to the biological fluids that are reported differently between young and old individuals. However, their underlying mechanisms modulating cell senescence and aging are still not fully understood, and little was reported on the involvement of mi-RNAs in cell or tissue longevity. In this review, we summarize exosome biogenesis and mi-RNA synthesis and loading mechanism into exosomes' cargo. Additionally, we highlight the molecular mechanisms of exosomes and exosome-derived mi-RNA regulation in the different aging processes.

Keywords:  age-related disease; aging; exosomes; longevity; micro-RNA; molecular regulation; senescence

DOI:  https://doi.org/10.3390/biomedicines9080968
Cell Biol Int. 2021 Aug 24.

Involvement of Extracellular vesicles in aging process and their beneficial effects in alleviating aging-associated symptoms.

Madhurima Das, Vaijayanti Kale.

  Aging is a gradual and unavoidable physiological phenomenon that manifests in the natural maturation process and continues to progress from infanthood to adulthood. Many elderly people suffer from aging-associated hematological and non-hematological disorders. Recent advances in regenerative medicine have shown new revolutionary paths of treating such diseases using stem cells; however, aging also affects the quality and competence of stem and progenitor cells themselves and ultimately directs their death or apoptosis and senescence a decline in their regenerative potential. Recent research works show that extracellular vesicles (EVs) isolated from different types of stem cells may provide a safe treatment for aging-associated disorders. The cargo of EVs comprises packets of information in the form of various macromolecules that can modify the fate of the target cells. To harness the true potential of EVs in regenerative medicine, it is necessary to understand how this cargo contributes to the rejuvenation of aged stem and progenitor populations and to identify the aging-associated changes in the macromolecular profile of the EVs themselves. In this review, we endeavor to summarize the current knowledge on the involvement of EVs in the aging process and delineate the role of EVs in the reversal of aging-associated phenotypes. We have also analyzed the involvement of the molecular cargo of EVs in the generation of aging-associated disorders. This knowledge could not only help us in understanding the mechanism of the aging process. Still, it could also facilitate the development of new cell-free biologics to treat aging-related disorders in the future. This article is protected by copyright. All rights reserved.

Keywords:  Aging; Extracellular Vesicles (EVs); Mesenchymal Stem Cells (MSCs); Rejuvenation; Stem Cells

DOI:  https://doi.org/10.1002/cbin.11691
Front Genet. 2021 ;12 652497

Regular, Intense Exercise Training as a Healthy Aging Lifestyle Strategy: Preventing DNA Damage, Telomere Shortening and Adverse DNA Methylation Changes Over a Lifetime.

Maha Sellami, Nicola Bragazzi, Mohammad Shoaib Prince, Joshua Denham, Mohamed Elrayess.

  Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5'-TTAGGG n -3' tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.

Keywords:  epigenetic clock; epigenetics; gene; oxidative stress; physical activity; skeletal muscle; telomerase

DOI:  https://doi.org/10.3389/fgene.2021.652497
Exp Gerontol. 2021 Aug 19. pii: S0531-5565(21)00299-0. [Epub ahead of print] 111517

The role of transient receptor potential ankyrin 1 in age-related endothelial dysfunction.

Yi Yang, Dan Wang, Jindong Wan, Fei Ran, Lun Yang, Shizhao Chen, Fang Wang, Sen Liu, Xiaozhen Dai, Peng Zhou, Peijian Wang.

  Oxidative stress plays a key role in age-related vascular disease. The present study aimed to investigate the role of an antioxidant channel, transient receptor potential ankyrin 1 (TRPA1), in age-related endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) were grown to induce replicative senescence, and 6-month-old young, 12-month-old middle-aged, and 24-month-old aged mice were used. TRPA1 was downregulated in senescent HUVECs, so were endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2), and uncoupling protein 2 (UCP2). Activating TRPA1 with cinnamaldehyde prevented downregulation of eNOS, Nrf2, and UCP2, inhibited superoxide production and apoptosis, and preserved nitric oxide bioavailability in senescent HUVECs. TRPA1, phosphorylated eNOS, Nrf2 and UCP2 were significantly downregulated in aged aortas compared with young aortas after a compensatory upregulation in middle-aged aortas. Dietary administration of cinnamaldehyde for 12 months prevented mitochondrial dysfunction, improved endothelium-dependent relaxation, and increased expression of eNOS, Nrf2, and UCP2 in aged aortas. Importantly, the effects of cinnamaldehyde can be blocked by a TRPA1 antagonist HC-030031. These findings suggest that TRPA1 may play a critical role in age-related endothelial dysfunction and may become a therapeutic target for the treatment and prevention of age-related vascular disease.

Keywords:  Aging; Endothelial dysfunction; Nrf2; TRPA1; eNOS

DOI:  https://doi.org/10.1016/j.exger.2021.111517
Molecules. 2021 Aug 07. pii: 4794. [Epub ahead of print]26(16):

Curcumin as Prospective Anti-Aging Natural Compound: Focus on Brain.

Tarek Benameur, Raffaella Soleti, Maria Antonietta Panaro, Maria Ester La Torre, Vincenzo Monda, Giovanni Messina, Chiara Porro.

  The nutrients and their potential benefits are a new field of study in modern medicine for their positive impact on health. Curcumin, the yellow polyphenolic compound extracted from Curcuma longa species, is widely used in traditional Ayurvedic medicine to prevent and contrast many diseases, considering its antioxidant, immunomodulatory, anti-inflammatory, anti-microbial, cardio-protective, nephron-protective, hepato-protective, anti-neoplastic, and anti-rheumatic proprieties. In recent years, the investigations of curcumin have been focused on its application to aging and age-associated diseases. Aging is a physiological process in which there is a decreasing of cellular function due to internal or external stimuli. Oxidative stress is one of the most important causes of aging and age-related diseases. Moreover, many age-related disorders such as cancer, neuroinflammation, and infections are due to a low-grade chronic systemic inflammation. Curcumin acting on different proteins is able to contrast both oxidative stress than inflammation. In the brain, curcumin is able to modulate inflammation induced by microglia. Finally in brain tumors curcumin is able to reduce tumor growth by inhibition of telomerase activity. This review emphasizes the anti-aging role of curcumin focusing on its mechanism to counteract aging in the brain. Moreover, new formulations to increase the bioavailability of curcumin are discussed.

Keywords:  anti-aging; anti-inflammatory; antioxidant; curcumin; natural flavonoid; neuroinflammation; telomerases

DOI:  https://doi.org/10.3390/molecules26164794
Stem Cell Res Ther. 2021 Aug 23. 12(1): 473

Age-related alteration in characteristics, function, and transcription features of ADSCs.

Keya Li, Guiying Shi, Xuepei Lei, Yiying Huang, Xinyue Li, Lin Bai, Chuan Qin.

   BACKGROUND AND OBJECTIVES: Adipose tissue-derived stem cells (ADSCs) autologous transplantation has been a promising strategy for aging-related disorders. However, the relationship between ADSCs senescence and organismal aging has not been clearly established. Therefore, we aimed at evaluating senescence properties of ADSCs from different age donors and to verify the influence of organismal aging on the proliferation and function of ADSCs in vitro, providing the theoretical basis for the clinical application of autologous ADSCs transplantation.
METHODS AND RESULTS: The ADSCs were obtained from 1-month-old and 20-month-old mice. The cells characteristics, functions, gene expression levels, apoptosis proportion, cell cycle, SA-β-gal staining, and transcription features were evaluated. Compared to ADSCs from 1-month-old mice, ADSCs from 20-month-old mice exhibited some senescence-associated changes, including inhibited abilities to proliferate. Moreover, differentiation abilities, cell surface markers, and cytokines secreting differed between 1M and 20M ADSCs. SA-β-Gal staining did not reveal differences between the two donor groups, while cells exhibited more remarkable age-related changes through continuous passages. Based on transcriptome analysis and further detection, the CCL7-CCL2-CCR2 axis is the most probable mechanism for the differences.
CONCLUSIONS: ADSCs from old donors have some age-related alterations. The CCL7-CCL2-CCR2 axis is a potential target for gene therapy to reduce the harmful effects of ADSCs from old donors. To improve on autologous transplantation, we would recommend that ADSCs should be cryopreserved in youth with a minimum number of passages or block CCL7-CCL2-CCR2 to abolish the effects of age-related alterations in ADSCs through the Chemokine signaling pathway.

Keywords:  ADSCs; Aging; Autologous stem cell transplantation; Cell culture; Cell cycle; Chemokine

DOI:  https://doi.org/10.1186/s13287-021-02509-0
Aging Cell. 2021 Aug 27. e13466

Altered sperm tsRNAs in aged male contribute to anxiety-like behavior in offspring.

Yi Guo, Dandan Bai, Wenqiang Liu, Yingdong Liu, Yalin Zhang, Xiaochen Kou, Jiayu Chen, Hong Wang, Xiaoming Teng, Ji Zuo, Shaorong Gao.

  Parental age at first pregnancy is increasing worldwide. The offspring of aged father has been associated with higher risk of several neuropsychiatric disorders, such as schizophrenia and autism, but the underlying mechanism remains elusive. Here we report that advanced paternal age in mice alters the profile of transfer RNA-derived small RNAs (tsRNAs). Injection of sperm tsRNAs from aged male mice into zygotes induced anxiety-like behaviors in F1 males. RNA sequencing of the cerebral cortex and hippocampus of those F1 male mice altered the gene expression of dopaminergic synapse and neurotrophin. tsRNAs from aged male mice injection also altered the neuropsychiatry-related gene expression in two-cell and blastocyst stage embryos. More importantly, the sperm tsRNA profile changes significantly during aging in human. The up-regulated sperm tsRNA target genes were involved in neurogenesis and nervous system development. These results suggest that aging-related changes of sperm tsRNA may contribute to the intergenerational transmission of behavioral traits.

Keywords:  Advanced paternal age; anxiety; offspring; pre-implantation embryo; sperm; transfer RNA-derived small RNA

DOI:  https://doi.org/10.1111/acel.13466
Aging Cell. 2021 Aug 28. e13457

Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome.

Wayne A Cabral, Urraca L Tavarez, Indeevar Beeram, Diana Yeritsyan, Yoseph D Boku, Michael A Eckhaus, Ara Nazarian, Michael R Erdos, Francis S Collins.

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder most notably characterized by cardiovascular disease and premature death from myocardial infarction or stroke. The majority of cases are caused by a de novo single nucleotide mutation in the LMNA gene that activates a cryptic splice donor site, resulting in production of a toxic form of lamin A with a 50 amino acid internal deletion, termed progerin. We previously reported the generation of a transgenic murine model of progeria carrying a human BAC harboring the common mutation, G608G, which in the single-copy state develops features of HGPS that are limited to the vascular system. Here, we report the phenotype of mice bred to carry two copies of the BAC, which more completely recapitulate the phenotypic features of HGPS in skin, adipose, skeletal, and vascular tissues. We further show that genetic reduction of the mechanistic target of rapamycin (mTOR) significantly extends lifespan in these mice, providing a rationale for pharmacologic inhibition of the mTOR pathway in the treatment of HGPS.

Keywords:  S6 Kinase; lamin A/C; laminopathies; mTOR; progeria

DOI:  https://doi.org/10.1111/acel.13457
Cytogenet Genome Res. 2021 Aug 25. 1-8

Crosstalk among DNA Damage, Mitochondrial Dysfunction, Impaired Mitophagy, Stem Cell Attrition, and Senescence in the Accelerated Ageing Disorder Werner Syndrome.

Ruben Gudmundsrud, Tarjei H Skjånes, Brian C Gilmour, Domenica Caponio, Sofie Lautrup, Evandro F Fang.

  Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD+ depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD+ and mitophagy may shed light on potential therapeutic strategies for the WS patients.

Keywords:  Accelerated ageing; Ageing; DNA repair; Mitophagy; NAD+; Werner syndrome

DOI:  https://doi.org/10.1159/000516386
EMBO Mol Med. 2021 Aug 27. e14012

Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria.

Alvaro González-Dominguez, Raúl Montañez, Beatriz Castejón-Vega, Jéssica Nuñez-Vasco, Débora Lendines-Cordero, Chun Wang, Gabriel Mbalaviele, José M Navarro-Pando, Elísabet Alcocer-Gómez, Mario D Cordero.

  Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24-/- mice, which phenocopy the human disease. These data were further corroborated in LmnaG609G/G609G mice, another HGPS animal model. We also showed that pharmacological inhibition of the NLRP3 inflammasome by its selective inhibitor, MCC950, improved cellular phenotype, significantly extended the lifespan of progeroid animals, and reduced inflammasome-dependent inflammation. These findings suggest that inhibition of the NLRP3 inflammasome is a potential therapeutic approach for the treatment of HGPS.

Keywords:  NLRP3 inflammasome; aging; progeria

DOI:  https://doi.org/10.15252/emmm.202114012
Antioxidants (Basel). 2021 Aug 10. pii: 1269. [Epub ahead of print]10(8):

The Impact of Melatonin Supplementation and NLRP3 Inflammasome Deletion on Age-Accompanied Cardiac Damage.

Ramy K A Sayed, Marisol Fernández-Ortiz, Ibtissem Rahim, José Fernández-Martínez, Paula Aranda-Martínez, Iryna Rusanova, Laura Martínez-Ruiz, Reem M Alsaadawy, Germaine Escames, Darío Acuña-Castroviejo.

  To investigate the role of NLRP3 inflammasome in cardiac aging, we evaluate here morphological and ultrastructural age-related changes of cardiac muscles fibers in wild-type and NLRP3-knockout mice, as well as studying the beneficial effect of melatonin therapy. The results clarified the beginning of the cardiac sarcopenia at the age of 12 months, with hypertrophy of cardiac myocytes, increased expression of β-MHC, appearance of small necrotic fibers, decline of cadiomyocyte number, destruction of mitochondrial cristae, appearance of small-sized residual bodies, and increased apoptotic nuclei ratio. These changes were progressed in the cardiac myocytes of 24 old mice, accompanied by excessive collagen deposition, higher expressions of IL-1α, IL-6, and TNFα, complete mitochondrial vacuolation and damage, myofibrils disorganization, multivesicular bodies formation, and nuclear fragmentation. Interestingly, cardiac myocytes of NLRP3-/- mice showed less detectable age-related changes compared with WT mice. Oral melatonin therapy preserved the normal cardiomyocytes structure, restored cardiomyocytes number, and reduced β-MHC expression of cardiac hypertrophy. In addition, melatonin recovered mitochondrial architecture, reduced apoptosis and multivesicular bodies' formation, and decreased expressions of β-MHC, IL-1α, and IL-6. Fewer cardiac sarcopenic changes and highly remarkable protective effects of melatonin treatment detected in aged cardiomyocytes of NLRP3-/- mice compared with aged WT animals, confirming implication of the NLRP3 inflammasome in cardiac aging. Thus, NLRP3 suppression and melatonin therapy may be therapeutic approaches for age-related cardiac sarcopenia.

Keywords:  CSA; NLRP3 inflammasome; autophagosome; cardiomyocytes; melatonin; mitochondria; sarcopenia; ultrastructure; β-MHC

DOI:  https://doi.org/10.3390/antiox10081269
Aging Cell. 2021 Aug 24. e13460

Age patterns of intra-pair DNA methylation discordance in twins: Sex difference in epigenomic instability and implication on survival.

Qihua Tan, Shuxia Li, Mette Sørensen, Marianne Nygaard, Jonas Mengel-From, Kaare Christensen.

  Aging is a biological process linked to specific patterns and changes in the epigenome. We hypothesize that age-related variation in the DNA methylome could reflect cumulative environmental modulation to the epigenome which could impact epigenomic instability and survival differentially by sex. To test the hypothesis, we performed sex-stratified epigenome-wide association studies on age-related intra-pair DNA methylation discordance in 492 twins aged 56-80 years. We identified 3084 CpGs showing increased methylation variability with age (FDR < 0.05, 7 CpGs with p < 1e-07) in male twins but no significant site found in female twins. The results were replicated in an independent cohort of 292 twins aged 30-74 years with 37% of the discovery CpGs successfully replicated in male twins. Functional annotation showed that genes linked to the identified CpGs were significantly enriched in signaling pathways, neurological functions, extracellular matrix assembly, and cancer. We further explored the implication of discovery CpGs on individual survival in an old cohort of 224 twins (220 deceased). In total, 264 CpGs displayed significant association with risk of death in male twins. In female twins, 175 of the male discovery CpGs also showed non-random correlation with mortality. Intra-pair comparison showed that majority of the discovery CpGs have higher methylation in the longer-lived twins suggesting that lose of DNA methylation during aging contributes to increased risk of death which is more pronounced in male twins. In conclusion, age-related epigenomic instability in the DNA methylome is more evident in males than in females and could impact individual survival and contribute to sex difference in human lifespan.

Keywords:  DNA methylation; aging; epigenomic instability; mortality; twins

DOI:  https://doi.org/10.1111/acel.13460
Aging (Albany NY). 2021 Aug 25. 13(undefined):

NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging.

Li-Zhen Liao, Zhi-Chong Chen, Sui-Sui Wang, Wen-Bin Liu, Chang-Lin Zhao, Xiao-Dong Zhuang.

   OBJECTIVE: The NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) inflammasome is associated with many physiological processes related to aging. We investigated whether NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging dissected the underlying mechanism.
METHODS: H9c2 cells were treated with different concentrations of D-galactose (D-gal, 0, 2, 10 and 50 g/L) for 24 hours. The cytochemical staining, flow cytometry and fluorescence microscope analysis were employed to detect the β-galactosidase (β-gal) activity. Western blot analysis was used to detect the age-associated proteins (P53, P21) and NLRP3 inflammasome proteins [NLRP3, apoptosis-associated speck-like protein (ASC)]. Confocal fluorescent images were applied to capture the colocalization of NLRP3 and caspase-1. Intracellular reactive oxygen species (ROS) was measured using 2'7'-dichlorodihydrofluorescein diacetate (DCFH-DA) by flow cytometry and visualized using a fluorescence microscope. The IL-1β, IL-18 and lactate dehydrogenase (LDH) release were also detected.
RESULTS: D-gal induced-H9c2 cells caused cardiocytes' aging changes (β-gal staining, CellEvent™ Senescence Green staining, P53, P21) in a concentration-dependent manner. NLRP3 inflammasomes were activated, IL-1β, IL-18 and LDH release and ROS generation were increased in the cardiocytes aging progress. When MCC950 inhibited NLRP3 inflammasomes, it attenuated the cardiocytes aging, yet the ROS generation was similar. Inhibition of ROS by NAC attenuated cardiocytes aging and inhibited the NLRP3 inflammasome activation at the same time. NLRP3 inflammasome activation by nigericin-induced cardiocytes cells aging progress.
CONCLUSIONS: NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging, and ROS generation may serve as a potential mechanism by which NLRP3 inflammasome is activated.

Keywords:  NLRP3 inflammasome activation; ROS; cardiocytes aging

DOI:  https://doi.org/10.18632/aging.203435
Annu Rev Pharmacol Toxicol. 2021 Aug 24.

The Gut Microbiome, Metformin, and Aging.

Sri Nitya Reddy Induri, Payalben Kansara, Scott C Thomas, Fangxi Xu, Deepak Saxena, Xin Li.

Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pharmtox-051920-093829
Aging Cell. 2021 Aug 23. e13458

PP-1β and PP-2Aα modulate cAMP response element-binding protein (CREB) functions in aging control and stress response through de-regulation of αB-crystallin gene and p300-p53 signaling axis.

Ling Wang, Lan Zhang, Xiao-Dong Gong, Jia-Ling Fu, Yu-Wen Gan, Min Hou, Qian Nie, Jia-Wen Xiang, Yuan Xiao, Yan Wang, Shu-Yu Zheng, Lan Yang, Huimin Chen, Meng-Qing Xiang, Yizhi Liu, David Wan-Cheng Li.

  The function of the transcription factor, cAMP response element-binding protein (CREB), is activated through S133 phosphorylation by PKA and others. Regarding its inactivation, it is not well defined. cAMP response element-binding protein plays an essential role in promoting cell proliferation, neuronal survival and the synaptic plasticity associated with long-term memory. Our recent studies have shown that CREB is an important player in mediating stress response. Here, we have demonstrated that CREB regulates aging process through suppression of αB-crystallin and activation of the p300-p53-Bak/Bax signaling axis. First, we determined that two specific protein phosphatases, PP-1β and PP-2Aα, can inactivate CREB through S133 dephosphorylation. Subsequently, we demonstrated that cells expressing the S133A-CREB, a mutant mimicking constant dephosphorylation at S133, suppress CREB functions in aging control and stress response. Mechanistically, S133A-CREB not only significantly suppresses CREB control of αB-crystallin gene, but also represses CREB-mediated activation of p53 acetylation and downstream Bak/Bax genes. cAMP response element-binding protein suppression of αB-crystallin and its activation of p53 acetylation are major molecular events observed in human cataractous lenses of different age groups. Together, our results demonstrate that PP-1β and PP-2Aα modulate CREB functions in aging control and stress response through de-regulation of αB-crystallin gene and p300-p53-Bax/Bak signaling axis, which regulates human cataractogenesis in the aging lens.

Keywords:  Bak; Bax; P300; PP-1β; PP-2Aα; CREB; Pcaf; aging; apoptosis; cataract; oxidative stress; p53

DOI:  https://doi.org/10.1111/acel.13458