bims-senagi 2021-03-14 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021‒03‒14
twenty-six papers selected by
Maria Grazia Vizioli
Mayo Clinic

Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo.
SIRT3 consolidates heterochromatin and counteracts senescence.
Senolytics: Potential for Alleviating Diabetes and Its Complications.
Intersection of immunometabolism and immunosenescence during aging.
Sirtuins and the prevention of immunosenescence.
Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes.
CTCF Mediates Replicative Senescence Through POLD1.
Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss.
β cell aging and age-related diabetes.
Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence.
Functional genomics of inflamm-aging and immunosenescence.
Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.
Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and β-caryophyllene association on human endothelial and monocytic cells.
Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging.
Radiation induces primary osteocyte senescence phenotype and affects osteoclastogenesis in vitro.
DNA methylation-based age clocks: from age prediction to age reversion.
The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps.
Activation of CREB-mediated autophagy by thioperamide ameliorates β-amyloid pathology and cognition in Alzheimer's disease.
Intermittent fasting: from calories to time restriction.
Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney.
MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence.
FGFR/RACK1 interacts with MDM2, promotes P53 degradation, and inhibits cell senescence in lung squamous cell carcinoma.
DNA methylation predicts age and provides insight into exceptional longevity of bats.
From DNA damage to mutations: all roads lead to aging.
B-cell capacity for differentiation changes with age.
Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.

Aging Cell. 2021 Mar 12. e13338

Cellular aging beyond cellular senescence: Markers of senescence prior to cell cycle arrest in vitro and in vivo.

Mikolaj Ogrodnik.

  The field of research on cellular senescence experienced a rapid expansion from being primarily focused on in vitro aspects of aging to the vast territories of animal and clinical research. Cellular senescence is defined by a set of markers, many of which are present and accumulate in a gradual manner prior to senescence induction or are found outside of the context of cellular senescence. These markers are now used to measure the impact of cellular senescence on aging and disease as well as outcomes of anti-senescence interventions, many of which are at the stage of clinical trials. It is thus of primary importance to discuss their specificity as well as their role in the establishment of senescence. Here, the presence and role of senescence markers are described in cells prior to cell cycle arrest, especially in the context of replicative aging and in vivo conditions. Specifically, this review article seeks to describe the process of "cellular aging": the progression of internal changes occurring in primary cells leading to the induction of cellular senescence and culminating in cell death. Phenotypic changes associated with aging prior to senescence induction will be characterized, as well as their effect on the induction of cell senescence and the final fate of cells reviewed. Using published datasets on assessments of senescence markers in vivo, it will be described how disparities between quantifications can be explained by the concept of cellular aging. Finally, throughout the article the applicational value of broadening cellular senescence paradigm will be discussed.

Keywords:  aging; cellular senescence; evolutionary biology; molecular biology of aging; molecular damage; theories of aging; wound healing

DOI:  https://doi.org/10.1111/acel.13338
Nucleic Acids Res. 2021 Mar 12. pii: gkab161. [Epub ahead of print]

SIRT3 consolidates heterochromatin and counteracts senescence.

Zhiqing Diao, Qianzhao Ji, Zeming Wu, Weiqi Zhang, Yusheng Cai, Zehua Wang, Jianli Hu, Zunpeng Liu, Qiaoran Wang, Shijia Bi, Daoyuan Huang, Zhejun Ji, Guang-Hui Liu, Si Wang, Moshi Song, Jing Qu.

Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

DOI: https://doi.org/10.1093/nar/gkab161
Endocrinology. 2021 Mar 11. pii: bqab058. [Epub ahead of print]

Senolytics: Potential for Alleviating Diabetes and Its Complications.

Allyson K Palmer, Tamar Tchkonia, James L Kirkland.

  Therapeutics that target cellular senescence, including novel "senolytic" compounds, hold significant promise for treating or preventing obesity-induced metabolic dysfunction, type 2 diabetes, and the multiple complications of diabetes and obesity. Senolytics selectively clear senescent cells, which accumulate with aging and obesity and represent a fundamental mechanism of aging that contributes to metabolic dysfunction and diabetes pathogenesis. In addition to improving metabolic function, targeting senescent cells holds promise as a preventative strategy to reduce incidence and severity of diabetes complications. The intermittent administration schedule utilized for senolytic therapy may confer benefits in terms of improving adherence and limiting adverse effects. It is necessary to design effective clinical trials that will safely translate discoveries from preclinical models into human studies that may pave the way for a novel therapeutic class for treating obesity, diabetes, and their complications. In this review, we outline what is known regarding the role of cellular senescence in the pathogenesis of type 2 diabetes and its complications, present evidence from preclinical models that targeting cellular senescence is beneficial, review senolytic drugs, and outline the features of clinical trials investigating the role of targeting senescent cells for diabetes.

Keywords:  aging; cellular senescence; diabetes complications; diabetes mellitus

DOI:  https://doi.org/10.1210/endocr/bqab058
Curr Opin Pharmacol. 2021 Mar 05. pii: S1471-4892(21)00004-7. [Epub ahead of print]57 107-116

Intersection of immunometabolism and immunosenescence during aging.

Kyoo-A Lee, Paul D Robbins, Christina D Camell.

  Aging is associated with the highest risk for morbidity and mortality to chronic or metabolic diseases, which are present in 50% of the elderly. Improving metabolic and immune function of the elderly would improve quality of life and reduce the risk for all other diseases. Tissue-resident macrophages and the NLRP3 inflammasome are established drivers of inflammaging and metabolic dysfunction. Energy-sensing signaling pathways connect sterile and metabolic inflammation with cellular senescence and tissue dysfunction. We discuss recent advances in the immunometabolism field. Common themes revealed by recent publications include the alterations in metabolic signaling (SIRTUIN, AMPK, or mTOR pathways) in aged immune cells, the impact of senescence on inflammaging and tissue dysfunction, and the age-related changes in metabolic tissues, especially adipose tissue, as an immunological organ. Promising gerotherapeutics are candidates to broadly target nutrient and energy sensing, inflammatory and senescence pathways, and have potential to improve healthspan and treat age-related diseases.

Keywords:  AMPK-mTOR pathway; Adipose tissue; Aging; Immunometabolism; Inflammaging; Macrophage; NAD metabolism; NLRP3 inflammasome; SIRTUIN pathway

DOI:  https://doi.org/10.1016/j.coph.2021.01.003
Vitam Horm. 2021 ;pii: S0083-6729(20)30059-5. [Epub ahead of print]115 221-264

Sirtuins and the prevention of immunosenescence.

Denise Lasigliè.

  Aging of hematopoietic stem cells (HSCs) has been largely described as one underlying cause of senescence of the immune-hematopoietic system (immunosenescence). A set of well-defined hallmarks characterizes aged HSCs contributing to unbalanced hematopoiesis and aging-associated functional alterations of both branches of the immune system. In this chapter, the contribution of sirtuins, a family of conserved NAD+ dependent deacetylases with key roles in metabolism, genome integrity, aging and lifespan, to immunosenescence, will be addressed. In particular, the role of SIRT6 will be deeply analyzed highlighting a multifaceted part of this deacetylase in HSCs aging as well as in the immunosenescence of dendritic cells (DCs). These and other emerging data are currently paving the way for future design and development of rejuvenation means aiming at rescuing age-related changes in immune function in the elderly and combating age-associated hematopoietic diseases.

Keywords:  Dendritic cells (DCs); Epigenetics; Hematopoiesis; Hematopoietic stem cells (HSCs); IGF-1; Immunosenescence; NAD(+) dependent deacetylases; Niche; Rejuvenation; SIRT6

DOI:  https://doi.org/10.1016/bs.vh.2020.12.011
Front Oncol. 2020 ;10 584683

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes.

Heather Fairfield, Samantha Costa, Carolyne Falank, Mariah Farrell, Connor S Murphy, Anastasia D'Amico, Heather Driscoll, Michaela R Reagan.

  Within the bone marrow microenvironment, mesenchymal stromal cells (MSCs) are an essential precursor to bone marrow adipocytes and osteoblasts. The balance between this progenitor pool and mature cells (adipocytes and osteoblasts) is often skewed by disease and aging. In multiple myeloma (MM), a cancer of the plasma cell that predominantly grows within the bone marrow, as well as other cancers, MSCs, preadipocytes, and adipocytes have been shown to directly support tumor cell survival and proliferation. Increasing evidence supports the idea that MM-associated MSCs are distinct from healthy MSCs, and their gene expression profiles may be predictive of myeloma patient outcomes. Here we directly investigate how MM cells affect the differentiation capacity and gene expression profiles of preadipocytes and bone marrow MSCs. Our studies reveal that MM.1S cells cause a marked decrease in lipid accumulation in differentiating 3T3-L1 cells. Also, MM.1S cells or MM.1S-conditioned media altered gene expression profiles of both 3T3-L1 and mouse bone marrow MSCs. 3T3-L1 cells exposed to MM.1S cells before adipogenic differentiation displayed gene expression changes leading to significantly altered pathways involved in steroid biosynthesis, the cell cycle, and metabolism (oxidative phosphorylation and glycolysis) after adipogenesis. MM.1S cells induced a marked increase in 3T3-L1 expression of MM-supportive genes including Il-6 and Cxcl12 (SDF1), which was confirmed in mouse MSCs by qRT-PCR, suggesting a forward-feedback mechanism. In vitro experiments revealed that indirect MM exposure prior to differentiation drives a senescent-like phenotype in differentiating MSCs, and this trend was confirmed in MM-associated MSCs compared to MSCs from normal donors. In direct co-culture, human mesenchymal stem cells (hMSCs) exposed to MM.1S, RPMI-8226, and OPM-2 prior to and during differentiation, exhibited different levels of lipid accumulation as well as secreted cytokines. Combined, our results suggest that MM cells can inhibit adipogenic differentiation while stimulating expression of the senescence associated secretory phenotype (SASP) and other pro-myeloma molecules. This study provides insight into a novel way in which MM cells manipulate their microenvironment by altering the expression of supportive cytokines and skewing the cellular diversity of the marrow.

Keywords:  adipocytes; bone marrow; mesenchymal stromal cells (MSCs); microarray; myeloma; preadipocytes ; senescence

DOI:  https://doi.org/10.3389/fonc.2020.584683
Front Cell Dev Biol. 2021 ;9 618586

CTCF Mediates Replicative Senescence Through POLD1.

Yuli Hou, Qiao Song, Shichao Gao, Xiaomin Zhang, Yaqi Wang, Jing Liu, Jingxuan Fu, Min Cao, Peichang Wang.

  POLD1, the catalytic subunit of DNA polymerase δ, plays a critical role in DNA synthesis and DNA repair processes. Moreover, POLD1 is downregulated in replicative senescence to mediate aging. In any case, the components of age-related downregulation of POLD1 expression have not been fully explained. In this article, we elucidate the mechanism of the regulation of POLD1 at the transcription level and found that the transcription factor CCCTC-binding factor (CTCF) was bound to the POLD1 promoter area in two sites. The binding level of CTCF for the POLD1 promoter appeared to be related to aging and was confirmed to be positively controlled by the CTCF level. Additionally, cell senescence characteristics were detected within the cells transfected with short hairpin RNA (shRNA)-CTCF, pLenti-CMV-CTCF, shRNA-POLD1, and pLenti-CMV-POLD1, and the results showed that the CTCF may contribute to the altered expression of POLD1 in aging. In conclusion, the binding level of CTCF for the POLD1 promoter intervened by an age-related decrease in CTCF and downregulated the POLD1 expression in aging. Moreover, the decrease in CTCF-mediated POLD1 transcription accelerates the progression of cell aging.

Keywords:  CTCF; POLD1; aging; transcription factor; transcriptional regulation

DOI:  https://doi.org/10.3389/fcell.2021.618586
Front Endocrinol (Lausanne). 2020 ;11 622950

Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss.

Yujue Li, Lingyun Lu, Ying Xie, Xiang Chen, Li Tian, Yan Liang, Huifang Li, Jie Zhang, Yi Liu, Xijie Yu.

  Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice in vitro, while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.

Keywords:  IL-6; bone mesenchymal stem cells; obesity; osteoporosis; senecence

DOI:  https://doi.org/10.3389/fendo.2020.622950
Aging (Albany NY). 2021 Mar 03. 13

β cell aging and age-related diabetes.

Min Zhu, Xiaohong Liu, Wen Liu, Yanrong Lu, Jingqiu Cheng, Younan Chen.

  Type 2 diabetes is characterized by insulin resistance and loss of β cell mass and function. Aging is considered as a major risk factor for development of type 2 diabetes. However, the roles of pancreatic β cell senescence and systemic aging in the pathogenesis of type 2 diabetes in elderly people remain poorly understood. In this review, we aimed to discuss the current findings and viewpoints focusing on β cell aging and the development of type 2 diabetes.

Keywords:  age-related diabetes; aging; type 2 diabetes (T2D); β cell function; β cell senescence

DOI:  https://doi.org/10.18632/aging.202593
Geroscience. 2021 Mar 11.

Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence.

Yu Hu, Yun Zhu, Skyler D Gerber, Jared M Osland, Min Chen, Krishna A Rao, Heng Gu, Rong Yuan.

  Our previous studies found that deletion of nuclear receptor interacting protein 1 (Nrip1) extended longevity in female mice and delayed cell senescence. The current study investigates the role of NRIP1 in regulating functions of adipose-derived mesenchymal stem cells (ADMSCs) and explores the mechanisms of NRIP1 in skin aging. We first verified the skin aging phenotypes in young (6 months) and old (20 months) C57BL/6J (B6) mice and found deletion of Nrip1 can delay skin aging phenotypes, including reduced thickness of dermis and subcutaneous white adipose tissue (sWAT), as well as the accumulation of senescent cells in sWAT. In ADMSCs isolated from sWAT, we found that deletion of Nrip1 could decrease cell proliferation, prevent cell apoptosis, and suppress adipogenesis. Interestingly, deletion of Nrip1 also reduced cell senescence and maintain cell quiescence of ADMSCs. Moreover, the expressions of genes associated with senescence (p21, and p53), inflammation (p65, IL6, and IL1a), and growth factor (mTOR, Igf1) were reduced in Nrip1 knockout ADMSCs, as well as in siNrip1-treated ADMSCs. Suppression of Nrip1 by siNrip1 also decreased the expressions of mTOR, p-mTOR, p65, and p-p65 in ADMSCs. Reduced expressions of p65 and p-p65 were also confirmed in the skin of Nrip1 knockout mice. These findings suggest that NRIP1 plays an important role in delaying skin aging by reducing ADMSCs senescence and maintaining ADMSCs quiescence.

Keywords:  ADMSC; NRIP1; Quiescence; Senescence; Skin aging

DOI:  https://doi.org/10.1007/s11357-021-00344-y
Brief Funct Genomics. 2021 Mar 05. pii: elab009. [Epub ahead of print]

Functional genomics of inflamm-aging and immunosenescence.

Ryan J Lu, Emily K Wang, Bérénice A Benayoun.

  The aging population is at a higher risk for age-related diseases and infections. This observation could be due to immunosenescence: the decline in immune efficacy of both the innate and the adaptive immune systems. Age-related immune decline also links to the concept of 'inflamm-aging,' whereby aging is accompanied by sterile chronic inflammation. Along with a decline in immune function, aging is accompanied by a widespread of 'omics' remodeling. Transcriptional landscape changes linked to key pathways of immune function have been identified across studies, such as macrophages having decreased expression of genes associated to phagocytosis, a major function of macrophages. Therefore, a key mechanism underlying innate immune cell dysfunction during aging may stem from dysregulation of youthful genomic networks. In this review, we discuss both molecular and cellular phenotypes of innate immune cells that contribute to age-related inflammation.

Keywords:  immunosenescence; inflammaging; inflammation; macrophages; neutrophil

DOI:  https://doi.org/10.1093/bfgp/elab009
Aging (Albany NY). 2021 Mar 09. 13

Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.

Daniel Stein, Amir Mizrahi, Anastasia Golova, Adam Saretzky, Alfredo Garcia Venzor, Zeev Slobodnik, Shai Kaluski, Monica Einav, Ekaterina Khrameeva, Debra Toiber.

  Brain-specific SIRT6-KO mice present increased DNA damage, learning impairments, and neurodegenerative phenotypes, placing SIRT6 as a key protein in preventing neurodegeneration. In the aging brain, SIRT6 levels/activity decline, which is accentuated in Alzheimer's patients. To understand SIRT6 roles in transcript pattern changes, we analyzed transcriptomes of young WT, old WT and young SIRT6-KO mice brains, and found changes in gene expression related to healthy and pathological aging. In addition, we traced these differences in human and mouse samples of Alzheimer's and Parkinson's diseases, healthy aging and calorie restriction (CR). Our results define four gene expression categories that change with age in a pathological or non-pathological manner, which are either reversed or not by CR. We found that each of these gene expression categories is associated with specific transcription factors, thus serving as potential candidates for their category-specific regulation. One of these candidates is YY1, which we found to act together with SIRT6 regulating specific processes. We thus argue that SIRT6 has a pivotal role in preventing age-related transcriptional changes in brains. Therefore, reduced SIRT6 activity may drive pathological age-related gene expression signatures in the brain.

Keywords:  SIRT6; YY1; aging; neurodegeneration; transcription regulation

DOI:  https://doi.org/10.18632/aging.202755
Biogerontology. 2021 Mar 11.

Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and β-caryophyllene association on human endothelial and monocytic cells.

Giulia Matacchione, Felicia Gurău, Andrea Silvestrini, Mattia Tiboni, Luca Mancini, Debora Valli, Maria Rita Rippo, Rina Recchioni, Fiorella Marcheselli, Oliana Carnevali, Antonio Domenico Procopio, Luca Casettari, Fabiola Olivieri.

  A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and can contribute to fuel the inflammaging. We investigated both the anti-SASP and anti-inflammatory activities of a nutritional supplement, namely Fenoxidol™, composed of turmeric extract bioCurcumin (bCUR), Polydatin (the natural glycosylated precursor of Resveratrol-RSV), and liposomal β-caryophyllene (BCP), in two human cellular models, such as the primary endothelial cell line, HUVECs and the monocytic cell line, THP-1. Replicative and Doxorubicin-induced senescent HUVECs, both chosen as cellular models of SASP, and lipopolysaccharides (LPS)-stimulated THP-1, selected as a model of the inflammatory response, were treated with the three single natural compounds or with a combination of them (MIX). In both senescent HUVEC models, MIX treatment significantly reduced IL-1β and IL-6 expression levels and p16ink4a protein, and also increased SIRT1 protein level, as well as downregulated miR-146a and miR-21 expression, two of the so-called inflamma-miRNAs, more effectively than the single compounds. In THP-1 cells stimulated with LPS, the MIX showed a significant effect in decreasing IL-1β, IL-6, TNF-α, and miR-146a expression levels and Caspase-1 activation, in association with an up-regulation of SIRT1 protein, compared to the single compounds. Overall, our results suggest that the three analysed compounds can have a combined effect in restraining SASP in senescent HUVECs as well as the inflammatory response in LPS-stimulated THP-1 cells.

Keywords:  Inflammaging; Nutraceuticals; Polyphenols; SASP; Senescence

DOI:  https://doi.org/10.1007/s10522-021-09915-0
Front Immunol. 2021 ;12 584538

Terminally Differentiated CD4+ T Cells Promote Myocardial Inflammaging.

Murilo Delgobo, Margarete Heinrichs, Nils Hapke, DiyaaElDin Ashour, Marc Appel, Mugdha Srivastava, Tobias Heckel, Ioakim Spyridopoulos, Ulrich Hofmann, Stefan Frantz, Gustavo Campos Ramos.

  The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

Keywords:  CD4+ T-cells; NSG animals; immunosenescence; inflammaging; lymphocytes; myocardial aging

DOI:  https://doi.org/10.3389/fimmu.2021.584538
Int J Mol Med. 2021 May;pii: 76. [Epub ahead of print]47(5):

Radiation induces primary osteocyte senescence phenotype and affects osteoclastogenesis in vitro.

Yuyang Wang, Linshan Xu, Jianping Wang, Jiangtao Bai, Jianglong Zhai, Guoying Zhu.

Irradiation‑induced bone remodeling imbalances arise as a consequence of the dysregulation of bone formation and resorption. Due to the abundance of osteocytes, their long life and their dual‑regulatory effects on both osteoblast and osteoclast function, they serve as critical coordinators of bone remolding. In the present study, femur and tibia‑derived primary osteocytes were cultured and irradiated to observe the functional changes and the cellular senescence phenotype in vitro. Irradiation directly reduced cell viability, affected the crucial dendritic morphology and altered the expression of functional proteins, including upregulation of receptor activator of nuclear factor‑κB ligand and sclerostin, and downregulation of osteoprotegerin. Irradiated osteocytes were shown to exhibit notable DNA damage, which resulted in the initiation of a typical cellular senescence phenotype. Furthermore, it was found that irradiation‑induced prematurely senescent osteocytes stimulate molecular secretion, referred to as senescence‑associated secretory phenotype (SASP), which may be involved in modulation of the bone microenvironment, including the promotion of osteoclastogenesis. Taken together, the results showed that irradiation triggered osteocyte senescence and the acquisition of an associated secretory phenotype. This further resulted in an imbalance of bone remodeling through senescent influence on proliferation, morphology and marker protein production, but also indirectly via a paracrine pathway through SASP secretion. The results of the present study may highlight the potential of SASP‑targeted interventions for the management of radiation‑induced bone loss.

DOI: https://doi.org/10.3892/ijmm.2021.4909
Ageing Res Rev. 2021 Mar 05. pii: S1568-1637(21)00061-1. [Epub ahead of print] 101314

DNA methylation-based age clocks: from age prediction to age reversion.

Rezvan Noroozi, Soudeh Ghafouri-Fard, Aleksandra Pisarek, Joanna Rudnicka, Magdalena Spólnicka, Wojciech Branicki, Mohammad Taheri, Ewelina Pośpiech.

  Aging as an irretrievable occurrence throughout the entire life is characterized by a progressive decline in physiological functionality and enhanced disease vulnerability. Numerous studies have demonstrated that epigenetic modifications, particularly DNA methylation (DNAm), correlate with aging and age-related diseases. Several investigations have attempted to predict chronological age using the age-related alterations in the DNAm of certain CpG sites. Here we categorize different studies that tracked the aging process in the DNAm landscape to show how epigenetic age clocks evolved from a chronological age estimator to an indicator of lifespan and healthspan. We also describe the health and disease predictive potential of estimated epigenetic age acceleration regarding different clinical conditions and lifestyle factors. Considering the revealed age-related epigenetic changes, the recent age-reprogramming strategies are discussed which are promising methods for resetting the aging clocks.

Keywords:  DNA methylation; biological age; epigenetic age; epigenetic age acceleration; epigenetic clocks; epigenetic reprogramming; phenotypic age

DOI:  https://doi.org/10.1016/j.arr.2021.101314
Sci Signal. 2021 Mar 09. pii: eaax7942. [Epub ahead of print]14(673):

The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps.

Falko Apel, Liudmila Andreeva, Lorenz Sebastian Knackstedt, Robert Streeck, Christian Karl Frese, Christian Goosmann, Karl-Peter Hopfner, Arturo Zychlinsky.

Neutrophil extracellular traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation, and activate myeloid cells to produce type I interferons (IFNs), proinflammatory cytokines that regulate the immune system. Here, we showed that macrophages and other myeloid cells phagocytosed NETs. Once in phagosomes, NETs translocated to the cytosol, where the DNA backbones of these structures activated the innate immune sensor cyclic GMP-AMP synthase (cGAS) and induced type I IFN production. The NET-associated serine protease neutrophil elastase (NE) mediated the activation of this pathway. We showed that NET induction in mice treated with the lectin concanavalin A, a model of autoimmune hepatitis, resulted in cGAS-dependent stimulation of an IFN response, suggesting that NETs activated cGAS in vivo. Thus, our findings suggest that cGAS is a sensor of NETs, mediating immune cell activation during infection.

DOI: https://doi.org/10.1126/scisignal.aax7942
Aging Cell. 2021 Mar 08. e13333

Activation of CREB-mediated autophagy by thioperamide ameliorates β-amyloid pathology and cognition in Alzheimer's disease.

Jiangong Wang, Bin Liu, Yong Xu, Meizi Yang, Chaoyun Wang, Mengmeng Song, Jing Liu, Wentao Wang, Jingjing You, Fengjiao Sun, Dan Wang, Dunjiang Liu, Haijing Yan.

  Alzheimer's disease (AD) is an age-related neurodegenerative disease, and the imbalance between production and clearance of β-amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up-regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up-regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ-induced injury. The neuroprotection by thioperamide against AD was reversed by 3-MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic-related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic-lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB-dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD.

Keywords:  Alzheimer’s disease; autophagy; cognitive dysfunction; cyclic AMP response element-binding protein; histamine; histamine H3 receptor; lysosome; neuronal loss; β-amyloid; β-secretase 1

DOI:  https://doi.org/10.1111/acel.13333
Geroscience. 2021 Mar 09.

Intermittent fasting: from calories to time restriction.

Eleonora Duregon, Laura C D D Pomatto-Watson, Michel Bernier, Nathan L Price, Rafael de Cabo.

  The global human population has recently experienced an increase in life expectancy with a mounting concern about the steady rise in the incidence of age-associated chronic diseases and socio-economic burden. Calorie restriction (CR), the reduction of energy intake without malnutrition, is a dietary manipulation that can increase health and longevity in most model organisms. However, the practice of CR in day-to-day life is a challenging long-term goal for human intervention. Recently, daily fasting length and periodicity have emerged as potential drivers behind CR's beneficial health effects. Numerous strategies and eating patterns have been successfully developed to recapitulate many of CR's benefits without its austerity. These novel feeding protocols range from shortened meal timing designed to interact with our circadian system (e.g., daily time-restricted feeding) to more extended fasting regimens known as intermittent fasting. Here, we provide a glimpse of the current status of knowledge on different strategies to reap the benefits of CR on metabolic health in murine models and in humans, without the rigor of continuous reduction in caloric intake as presented at the USU State of the Science Symposium.

Keywords:  Calorie restriction; Calories; Fasting; Intermittent Fasting; Time Restricted Feeding

DOI:  https://doi.org/10.1007/s11357-021-00335-z
Elife. 2021 Mar 09. pii: e62585. [Epub ahead of print]10

Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney.

Yuka Takemon, Joel M Chick, Isabela Gerdes Gyuricza, Daniel A Skelly, Olivier Devuyst, Steven P Gygi, Gary A Churchill, Ron Korstanje.

  Little is known about the molecular changes that take place in the kidney during the aging process. In order to better understand these changes, we measured mRNA and protein levels in genetically diverse mice at different ages. We observed distinctive change in mRNA and protein levels as a function of age. Changes in both mRNA and protein are associated with increased immune infiltration and decreases in mitochondrial function. Proteins show a greater extent of change and reveal changes in a wide array of biological processes including unique, organ-specific features of aging in kidney. Most importantly, we observed functionally important age-related changes in protein that occur in the absence of corresponding changes in mRNA. Our findings suggest that mRNA profiling alone provides an incomplete picture of molecular aging in the kidney and that examination of changes in proteins is essential to understand aging processes that are not transcriptionally regulated.

Keywords:  computational biology; mouse; systems biology

DOI:  https://doi.org/10.7554/eLife.62585
Cancer Lett. 2021 Mar 05. pii: S0304-3835(21)00052-5. [Epub ahead of print]

MMP1 drives tumor progression in large cell carcinoma of the lung through fibroblast senescence.

Marta Gabasa, Evette S Radisky, Rafael Ikemori, Giulia Bertolini, Marselina Arshakyan, Alexandra Hockla, Paula Duch, Ornella Rondinone, Alejandro Llorente, Maria Maqueda, Albert Davalos, Elena Gavilán, Alexandre Perera, Josep Ramírez, Pere Gascón, Noemí Reguart, Luca Roz, Derek C Radisky, Jordi Alcaraz.

  Large cell carcinoma (LCC) is a rare and aggressive lung cancer subtype with poor prognosis and no targeted therapies. Tumor-associated fibroblasts (TAFs) derived from LCC tumors exhibit premature senescence, and coculture of pulmonary fibroblasts with LCC cell lines selectively induces fibroblast senescence, which in turn drives LCC cell growth and invasion. Here we identify MMP1 as overexpressed specifically in LCC cell lines, and we show that expression of MMP1 by LCC cells is necessary for induction of fibroblast senescence and consequent tumor promotion in both cell culture and mouse models. We also show that MMP1, in combination with TGF-β1, is sufficient to induce fibroblast senescence and consequent LCC promotion. Furthermore, we implicate PAR-1 and oxidative stress in MMP1/TGF-β1-induced TAF senescence. Our results establish an entirely new role for MMP1 in cancer, and support a novel therapeutic strategy in LCC based on targeting senescent TAFs.

Keywords:  Cancer-associated fibroblasts; MMP1; TGF-β; lung cancer; senescence

DOI:  https://doi.org/10.1016/j.canlet.2021.01.028
Cancer Biol Med. 2021 Mar 12. pii: j.issn.2095-3941.2020.0389. [Epub ahead of print]

FGFR/RACK1 interacts with MDM2, promotes P53 degradation, and inhibits cell senescence in lung squamous cell carcinoma.

Tao Chen, Fei Wang, Shupei Wei, Yingjie Nie, Xiaotao Zheng, Yu Deng, Xubin Zhu, Yuezhen Deng, Nanshan Zhong, Chengzhi Zhou.

  OBJECTIVE: FGFR is considered an important driver gene of lung squamous cell carcinoma (LSCC). Thus, identification of the biological events downstream of FGFR is important for the treatment of this malignancy. Our previous study has shown that the FGFR/RACK1 complex interacts with PKM2 and consequently promotes glycolysis in LSCC cells. However, the biological functions of the FGFR/RACK1 complex remain poorly understood.METHODS: Anchorage-independent assays and in vivo tumorigenesis assays were performed to evaluate cancer cell malignancy. Distant seeding assays were performed to evaluate cancer cell metastasis. β-gal staining was used to examine cell senescence, and immunoprecipitation assays were performed to examine the interactions among FGFR, RACK1, and MDM2.
RESULTS: FGFR/RACK1 was found to regulate the senescence of LSCC cells. Treatment with PD166866, an inhibitor of FGFR, or knockdown of RACK1 induced senescence in LSCC cells (P < 0.01). A molecular mechanistic study showed that FGFR/RACK1/MDM2 form a complex that promotes the degradation of p53 and thus inhibits cell senescence. PD166866 and RG7112, an MDM2/p53 inhibitor, cooperatively inhibited the colony formation and distal seeding of LSCC cells (P < 0.01), and upregulated the expression of p53 and p21.
CONCLUSIONS: Together, our findings revealed the regulatory roles and mechanisms of FGFR/RACK1 in cell senescence. This understanding should be important in the treatment of LSCC.

Keywords:  FGFR; MDM2; P53; RACK1; senescence

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2020.0389
Nat Commun. 2021 Mar 12. 12(1): 1615

DNA methylation predicts age and provides insight into exceptional longevity of bats.

Gerald S Wilkinson, Danielle M Adams, Amin Haghani, Ake T Lu, Joseph Zoller, Charles E Breeze, Bryan D Arnold, Hope C Ball, Gerald G Carter, Lisa Noelle Cooper, Dina K N Dechmann, Paolo Devanna, Nicolas J Fasel, Alexander V Galazyuk, Linus Günther, Edward Hurme, Gareth Jones, Mirjam Knörnschild, Ella Z Lattenkamp, Caesar Z Li, Frieder Mayer, Josephine A Reinhardt, Rodrigo A Medellin, Martina Nagy, Brian Pope, Megan L Power, Roger D Ransome, Emma C Teeling, Sonja C Vernes, Daniel Zamora-Mejías, Joshua Zhang, Paul A Faure, Lucas J Greville, Steve Horvath.

Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.

DOI: https://doi.org/10.1038/s41467-021-21900-2
Ageing Res Rev. 2021 Mar 09. pii: S1568-1637(21)00063-5. [Epub ahead of print] 101316

From DNA damage to mutations: all roads lead to aging.

Jan Vijg.

  Damage to the repository of genetic information in cells has plagued life since its very beginning 3-4 billion years ago. Initially, in the absence of an ozone layer, especially damage from solar UV radiation must have been frequent, with other sources, most notably endogenous sources related to cell metabolism, gaining in importance over time. To cope with this high frequency of damage to the increasingly long DNA molecules that came to encode the growing complexity of cellular functions in cells, DNA repair evolved as one of the earliest genetic traits. Then as now, errors during the repair of DNA damage generated mutations, which provide the substrate for evolution by natural selection. With the emergence of multicellular organisms also the soma became a target of DNA damage and mutations. In somatic cells selection against the adverse effects of DNA damage is greatly diminished, especially in postmitotic cells after the age of first reproduction. Based on an abundance of evidence, DNA damage is now considered as the single most important driver of the degenerative processes that collectively cause aging. Here I will first briefly review the evidence for DNA damage as a cause of aging since the beginning of life. Then, after discussing the possible direct adverse effects of DNA damage and its cellular responses, I will provide an overview of the considerable progress that has recently been made in analyzing a major consequence of DNA damage in humans and other complex organisms: somatic mutations and the resulting genome mosaicism. Recent advances in studying somatic mutagenesis and genome mosaicism in different human and animal tissues will be discussed with a focus on the possible mechanisms through which loss of DNA sequence integrity could cause age-related functional decline and disease.

Keywords:  DNA damage; Somatic mutation; ageing; pathogenic consequences; transcriptional noise

DOI:  https://doi.org/10.1016/j.arr.2021.101316
Aging Cell. 2021 Mar 12. e13341

B-cell capacity for differentiation changes with age.

Xuanxiao Xie, Jennifer Shrimpton, Gina M Doody, Philip G Conaghan, Frederique Ponchel.

  BACKGROUND: Age-related immune deficiencies are thought to be responsible for increased susceptibility to infection in older adults, with alterations in lymphocyte populations becoming more prevalent over time. The loss of humoral immunity in ageing was attributed to the diminished numbers of B cells and the reduced ability to generate immunoglobulin.AIMS: To compare the intrinsic B-cell capacity for differentiation into mature plasma cells (PCs), between young and old donors, using in vitro assays, providing either effective T-cell help or activation via TLR engagement.
METHODS: B cells were isolated from healthy individuals, in younger (30-38 years) and older (60-64 years) donors. An in vitro model system of B-cell differentiation was used, analysing 5 differentiation markers by flow cytometry, under T-dependent (TD: CD40/BCR stimulation) or T-independent (TI: TLR7/BCR activation) conditions. Antibody secretion was measured by ELISA and gene expression using qPCR.
RESULTS: TI and TD differentiation resulted in effective proliferation of B cells followed by their differentiation into PC. B-cell-executed TI differentiation was faster, all differentiation marker and genes being expressed earlier than under TD differentiation (day 6), although generating less viable cells and lower antibody levels (day 13). Age-related differences in B-cell capacity for differentiation were minimal in TD differentiation. In contrast, in TI differentiation age significantly affected proliferation, viability, differentiation, antibody secretion and gene expression, older donors being more efficient.
CONCLUSION: Altogether, B-cell differentiation into PC appeared similar between age groups when provided with T-cell help, in contrast to TI differentiation, where multiple age-related changes suggest better capacities in older donors. These new findings may help explain the emergence of autoantibodies in ageing.

Keywords:  B-cell differentiation; T-cell dependent; T-cell independent; ageing

DOI:  https://doi.org/10.1111/acel.13341
Nat Commun. 2021 Mar 12. 12(1): 1626

Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.

Ryan M Baxley, Wendy Leung, Megan M Schmit, Jacob Peter Matson, Lulu Yin, Marissa K Oram, Liangjun Wang, John Taylor, Jack Hedberg, Colette B Rogers, Adam J Harvey, Debashree Basu, Jenny C Taylor, Alistair T Pagnamenta, Helene Dreau, Jude Craft, Elizabeth Ormondroyd, Hugh Watkins, Eric A Hendrickson, Emily M Mace, Jordan S Orange, Hideki Aihara, Grant S Stewart, Edward Blair, Jeanette Gowen Cook, Anja-Katrin Bielinsky.

Minichromosome maintenance protein 10 (MCM10) is essential for eukaryotic DNA replication. Here, we describe compound heterozygous MCM10 variants in patients with distinctive, but overlapping, clinical phenotypes: natural killer (NK) cell deficiency (NKD) and restrictive cardiomyopathy (RCM) with hypoplasia of the spleen and thymus. To understand the mechanism of MCM10-associated disease, we modeled these variants in human cell lines. MCM10 deficiency causes chronic replication stress that reduces cell viability due to increased genomic instability and telomere erosion. Our data suggest that loss of MCM10 function constrains telomerase activity by accumulating abnormal replication fork structures enriched with single-stranded DNA. Terminally-arrested replication forks in MCM10-deficient cells require endonucleolytic processing by MUS81, as MCM10:MUS81 double mutants display decreased viability and accelerated telomere shortening. We propose that these bi-allelic variants in MCM10 predispose specific cardiac and immune cell lineages to prematurely arrest during differentiation, causing the clinical phenotypes observed in both NKD and RCM patients.

DOI: https://doi.org/10.1038/s41467-021-21878-x