bims-senagi 2021-07-18 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–07–18
forty-one papers selected by
Maria Grazia Vizioli, Mayo Clinic

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.
The mechanisms of vascular aging.
Putting the DOT on IL1A.
HDAC2 and 7 down-regulation induces senescence in dermal fibroblasts.
Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies.
The protein inputs of an ultra-predictive aging clock represent viable anti-aging drug targets.
Age-related alterations and senescence of mesenchymal stromal cells: Implications for regenerative treatments of bones and joints.
Roles and Mechanisms of DNA Methylation in Vascular Aging and Related Diseases.
Analysis of Age-Related Circular RNA Expression Profiles in Mesenchymal Stem Cells of Rat Bone Marrow.
Cerebroprotein hydrolysate-I protects senescence-induced by D-galactose in PC12 cells and mice.
Molecular pathology of rare progeroid diseases.
The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm.
FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology.
Long-term intake of Lactobacillus paracasei KW3110 prevents age-related circadian Locomotor activity and changes in gut metabolism in physiologically aged mice.
The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults.
Rejuvenation of Senescent Bone Marrow Mesenchymal Stromal Cells by Pulsed Triboelectric Stimulation.
Nuclear cGAS: guard or prisoner?
Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis.
The dual distinct role of telomerase in repression of senescence and myofibroblast differentiation.
Telomeres: New players in immune-mediated inflammatory diseases?
Involvement of miR-199a-3p/DDR1 in vascular endothelial cell senescence in diabetes.
Single-oocyte transcriptome analysis reveals aging-associated effects influenced by life stage and calorie restriction.
Senescence in neurons: an open issue.
Implication of integrin α2β1 in senescence of SK-Mel-147 human melanoma cells.
Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.
Telomere dysfunction instigates inflammation in inflammatory bowel disease.
MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells.
'Inflammation clock' can reveal body's biological age.
Aged vasculature drives neutrophils mad.
Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing.
Dietary thiols accelerate aging of C. elegans.
High Fat Diet-Induced CD8+ T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation.
Daily briefing: 'Inflammation clock' shows your immune system's age.
A high-fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the AppNL-F/NL-F knock-in mouse model.
Gonadotropin-releasing hormone receptor pathway affects the function of human EBV-transformed B lymphocytes in an age-independent way.
The regulation of healthspan and lifespan by dietary amino acids.
Determination of Biological Age: Geriatric Assessment vs Biological Biomarkers.
Dietary supplementation with sulforaphane ameliorates skin aging through activation of the Keap1-Nrf2 pathway.
Gut Microbiota: Critical Controller and Intervention Target in Brain Aging and Cognitive Impairment.
cGAS senses translation stress.
Telomere Length, SIRT1, and Insulin in Male Master Athletes: The Path to Healthy Longevity?

Nat Aging. 2021 May;1(5): 454-472

KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype.

Boyi Zhang, Qilai Long, Shanshan Wu, Qixia Xu, Shuling Song, Liu Han, Min Qian, Xiaohui Ren, Hanxin Liu, Jing Jiang, Jianming Guo, Xiaoling Zhang, Xing Chang, Qiang Fu, Eric W-F Lam, Judith Campisi, James L Kirkland, Yu Sun.

Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of prostate cancer patients post-chemotherapy. Global chromatin accessibility mapping via ATAC-seq, and expression profiling through RNA-seq, reveal global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment (TME), and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a novel therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies including cancer.

DOI: https://doi.org/10.1038/s43587-021-00063-1
Aging Med (Milton). 2021 Jun;4(2): 153-158

The mechanisms of vascular aging.

Shan Wang, Song Hu, Yongjun Mao.

  Vascular senescence is one of the hotspots in current research. With global average life expectancy increasing, delaying or reducing aging and age-related diseases has become a pressing issue for improving quality of life. Vascular senescence is an independent risk factor for age-related cardiovascular diseases (CVD) and results in the deterioration of CVD. Nevertheless, the underlying mechanisms of the vascular senescence have not been expressly illustrated. In this review, we attempt to summarize the recent literature in the field and discuss the major mechanisms involved in vascular senescence. We also underline key molecular aspects of aging-associated vascular dysfunction in the attempt to highlight potential innovative therapeutic targets to delay the onset of age-related diseases.

Keywords:  mechanisms; senescence; vascular aging

DOI:  https://doi.org/10.1002/agm2.12151
J Cell Biol. 2021 Aug 02. pii: e202106164. [Epub ahead of print]220(8):

Putting the DOT on IL1A.

Ioana Olan, Masashi Narita.

IL-1α is an upstream component of the senescence-associated secretory phenotype. In this issue, Leon et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202008101) show that DOT1L-mediated H3K79 methylation at the IL1A gene plays a key role in its induction during oncogene-induced senescence.

DOI: https://doi.org/10.1083/jcb.202106164
Aging (Albany NY). 2021 Jul 12. 13

HDAC2 and 7 down-regulation induces senescence in dermal fibroblasts.

Céline Warnon, Karim Bouhjar, Noëlle Ninane, Mathilde Verhoyen, Antoine Fattaccioli, Maude Fransolet, Catherine Lambert de Rouvroit, Yves Poumay, Géraldine Piel, Denis Mottet, Florence Debacq-Chainiaux.

  Originally simply reported to be in a stable and irreversible growth arrest in vitro, senescent cells are now clearly associated with normal and pathological ageing in vivo. They are characterized by several biomarkers and changes in gene expression that may depend on epigenetic factors, such as histone acetylation, involving a balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we investigate the expression and the role of HDACs on the senescent phenotype of dermal fibroblasts. We report that during replicative senescence, most canonical HDACs are less expressed. Moreover, treatment with SAHA, a histone deacetylase inhibitor (HDACi) also known as Vorinostat, or the specific downregulation of HDAC2 or HDAC7 by siRNA, induces the appearance of senescence biomarkers of dermal fibroblasts. Conversely, the ectopic re-expression of HDAC7 by lentiviral transduction in pre-senescent dermal fibroblasts extends their proliferative lifespan. These results demonstrate that HDACs expression can modulate the senescent phenotype, highlighting their pharmaceutical interest in the context of healthy ageing.

Keywords:  SAHA; SASP; fibroblasts; histone deacetylases; senescence

DOI:  https://doi.org/10.18632/aging.203304
Front Oncol. 2021 ;11 674354

Senescence-Induced Chemoresistance in Triple Negative Breast Cancer and Evolution-Based Treatment Strategies.

Anindita Chakrabarty, Shayantani Chakraborty, Ranjini Bhattacharya, Goutam Chowdhury.

  Triple negative breast cancer (TNBC) is classically treated with combination chemotherapies. Although, initially responsive to chemotherapies, TNBC patients frequently develop drug-resistant, metastatic disease. Chemotherapy resistance can develop through many mechanisms, including induction of a transient growth-arrested state, known as the therapy-induced senescence (TIS). In this paper, we will focus on chemoresistance in TNBC due to TIS. One of the key characteristics of senescent cells is a complex secretory phenotype, known as the senescence-associated secretory proteome (SASP), which by prompting immune-mediated clearance of senescent cells maintains tissue homeostasis and suppresses tumorigenesis. However, in cancer, particularly with TIS, senescent cells themselves as well as SASP promote cellular reprograming into a stem-like state responsible for the emergence of drug-resistant, aggressive clones. In addition to chemotherapies, outcomes of recently approved immune and DNA damage-response (DDR)-directed therapies are also affected by TIS, implying that this a common strategy used by cancer cells for evading treatment. Although there has been an explosion of scientific research for manipulating TIS for prevention of drug resistance, much of it is still at the pre-clinical stage. From an evolutionary perspective, cancer is driven by natural selection, wherein the fittest tumor cells survive and proliferate while the tumor microenvironment influences tumor cell fitness. As TIS seems to be preferred for increasing the fitness of drug-challenged cancer cells, we will propose a few tactics to control it by using the principles of evolutionary biology. We hope that with appropriate therapeutic intervention, this detrimental cellular fate could be diverted in favor of TNBC patients.

Keywords:  adaptive therapy; chemotherapy; evolution; senescence; senescence-associated stemness; therapy-induced senescence; triple negative breast cancer

DOI:  https://doi.org/10.3389/fonc.2021.674354
Ageing Res Rev. 2021 Jul 06. pii: S1568-1637(21)00151-3. [Epub ahead of print]70 101404

The protein inputs of an ultra-predictive aging clock represent viable anti-aging drug targets.

Adiv A Johnson, Maxim N Shokhirev, Benoit Lehallier.

  Machine learning models capable of predicting age given a set of inputs are referred to as aging clocks. We recently developed an aging clock that utilizes 491 plasma protein inputs, has an exceptional accuracy, and is capable of measuring biological age. Here, we demonstrate that this clock is extremely predictive (r = 0.95) when used to measure age in a novel plasma proteomic dataset derived from 370 human subjects aged 18-69 years. Over-representation analyses of the proteins that make up this clock in the Gene Ontology and Reactome databases predominantly implicated innate and adaptive immune system processes. Immunological drugs and various age-related diseases were enriched in the DrugBank and GLAD4U databases. By performing an extensive literature review, we find that at least 269 (54.8 %) of these inputs regulate lifespan and/or induce changes relevant to age-related disease when manipulated in an animal model. We also show that, in a large plasma proteomic dataset, the majority (57.2 %) of measurable clock proteins significantly change their expression level with human age. Different subsets of proteins were overlapped with distinct epigenetic, transcriptomic, and proteomic aging clocks. These findings indicate that the inputs of this age predictor likely represent a rich source of anti-aging drug targets.

Keywords:  Age prediction; Aging clock; Bioinformatics; Biomarker; Healthspan; Machine learning

DOI:  https://doi.org/10.1016/j.arr.2021.101404
Mech Ageing Dev. 2021 Jul 06. pii: S0047-6374(21)00111-1. [Epub ahead of print] 111539

Age-related alterations and senescence of mesenchymal stromal cells: Implications for regenerative treatments of bones and joints.

Janja Zupan, Klemen Strazar, Roland Kocijan, Thomas Nau, Johannes Grillari, Darja Marolt Presen.

  The most common clinical manifestations of age-related musculoskeletal degeneration are osteoarthritis and osteoporosis, and these represent an enormous burden on modern society. Mesenchymal stromal cells (MSCs) have pivotal roles in musculoskeletal tissue development. In adult organisms, MSCs retain their ability to regenerate tissues following bone fractures, articular cartilage injuries, and other traumatic injuries of connective tissue. However, their remarkable regenerative ability appears to be impaired through aging, and in particular in age-related diseases of bones and joints. Here, we review age-related alterations of MSCs in musculoskeletal tissues, and address the underlying mechanisms of aging and senescence of MSCs. Furthermore, we focus on the properties of MSCs in osteoarthritis and osteoporosis, and how their changes contribute to onset and progression of these disorders. Finally, we consider current treatments that exploit the enormous potential of MSCs for tissue regeneration, as well as for innovative cell-free extracellular-vesicle-based and anti-aging treatment approaches.

Keywords:  Aging; Mesenchymal stromal cells; Osteoarthritis; Osteoporosis; Senescence

DOI:  https://doi.org/10.1016/j.mad.2021.111539
Front Cell Dev Biol. 2021 ;9 699374

Roles and Mechanisms of DNA Methylation in Vascular Aging and Related Diseases.

Hui Xu, Shuang Li, You-Shuo Liu.

  Vascular aging is a pivotal risk factor promoting vascular dysfunction, the development and progression of vascular aging-related diseases. The structure and function of endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and macrophages are disrupted during the aging process, causing vascular cell senescence as well as vascular dysfunction. DNA methylation, an epigenetic mechanism, involves the alteration of gene transcription without changing the DNA sequence. It is a dynamically reversible process modulated by methyltransferases and demethyltransferases. Emerging evidence reveals that DNA methylation is implicated in the vascular aging process and plays a central role in regulating vascular aging-related diseases. In this review, we seek to clarify the mechanisms of DNA methylation in modulating ECs, VSMCs, fibroblasts, and macrophages functions and primarily focus on the connection between DNA methylation and vascular aging-related diseases. Therefore, we represent many vascular aging-related genes which are modulated by DNA methylation. Besides, we concentrate on the potential clinical application of DNA methylation to serve as a reliable diagnostic tool and DNA methylation-based therapeutic drugs for vascular aging-related diseases.

Keywords:  DNA methylation; aging; endothelial cells; vascular diseases; vascular smooth muscle cells

DOI:  https://doi.org/10.3389/fcell.2021.699374
Front Genet. 2021 ;12 600632

Analysis of Age-Related Circular RNA Expression Profiles in Mesenchymal Stem Cells of Rat Bone Marrow.

Hui Sun, Yanan Sun, Xiao Yu, Xingyu Gao, Huan Wang, Lin Zhang, Yingai Shi, Xu He.

  As multicellular organisms age, they undergo a reduction in tissue and organ function. Researchers have put forward a theory that stem cell aging is the main factor responsible for decreased tissue and organ function. The adult stem cells guarantee the maintenance and repair of adult tissues and organs. Among adult stem cells, mesenchymal stem cells (MSCs) are emerging as hopeful candidates for cell-based therapy of numerous diseases. In recent years, high-throughput sequencing technologies have evolved to identify circular RNAs (circRNAs) associated with an increasing number of diseases, such as cancer and age-related diseases. It has been reported that circRNAs can compete with microRNAs (miRNAs) to affect the stability or translation of target RNAs and further regulate gene expression at the transcriptional level. However, the role of circRNAs expressed in MSCs in aging mechanisms has not yet been deciphered. The aim of this study was to explore and analyze the expression profiles of age-related circRNAs in MSCs. In this study, bone marrow MSCs were extracted from aged and young rats and analyzed using high-throughput sequencing and bioinformatics. The reliability of high-throughput RNA sequencing was verified by quantitative real-time polymerase chain reaction. The most important circRNA functions and pathways were further selected by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) analysis. Age-related circRNAs were found in the circrNA-miRNA-mRNA interaction network. The results of high-throughput sequencing showed that 4,229 circRNAs were involved in age-related senescence of MSCs. Compared with the young group, there were 29 differentially expressed circRNAs in the aged group, of which four were upregulated and 25 were downregulated. GO analysis covered three domains: biological process (BP), cellular component (CC), and molecular function (MF). The terms assigned to the BP domain were cellular metabolic processes and cellular macromolecule metabolic processes. The identified CC terms were intracellular and intracellular part, and the identified MF terms were binding and protein binding. The top five KEGG pathways were mitophagy-animal-Rattus norvegicus, prostate cancer-Rattus norvegicus, pathways in cancer-Rattus norvegicus, lysosome-Rattus norvegicus, and autophagy-animal-Rattus norvegicus. Altogether, circRNAs may play a major role in age-related MSC senescence. This study provides new mechanistic insights into MSC senescence, possibly leading to novel therapeutic strategies for age-related diseases.

Keywords:  MSCs; bioinformatics; circular RNA; high-throughput sequencing; senescence

DOI:  https://doi.org/10.3389/fgene.2021.600632
Food Sci Nutr. 2021 Jul;9(7): 3722-3731

Cerebroprotein hydrolysate-I protects senescence-induced by D-galactose in PC12 cells and mice.

Lin Zhu, Yingjuan Liu, Xiaolin Wu, Yuqian Ren, Qinghua Zhang, Leiming Ren, Yunliang Guo.

  Cerebroprotein hydrolysate-I (CH-I)，a mixture of peptides extracted from porcine brain tissue，has shown a neuroprotective effect, but its role in brain senescence is unclear. In the present study, we established a senescence model of PC12 cells and mice to investigate the effect of CH-I on brain senescence via JAK2/STAT3 pathway. The results showed that CH-I could improve cell viability, inhibit the apoptosis of cells, and reduce the senescence-positive cells induced by D-galactose. In vivo, CH-I improved the learning ability and memory of aging mice, reduced neuronal damage in mice hippocampus. Mechanism studies showed that CH-I could adjust BDNF protein expressions, activate JAK2/STAT3 pathway, and finally enhance telomerase activity. All these findings indicated that CH-I showed a neuroprotective effect against brain senescence. These results might provide further reference and support for the application of CH-I in delaying aging.

Keywords:  D‐galactose; PC12 cells; cerebroprotein hydrolysate‐I; mice; senescence; telomerase

DOI:  https://doi.org/10.1002/fsn3.2333
Trends Mol Med. 2021 Jul 13. pii: S1471-4914(21)00178-7. [Epub ahead of print]

Molecular pathology of rare progeroid diseases.

Matthias Rieckher, George A Garinis, Björn Schumacher.

  Progeroid syndromes (PSs) are characterized by the premature onset of age-related pathologies. The genetic mutations underlying PSs are functionally linked to genome maintenance and repair, supporting the causative role of DNA damage accumulation in aging. Recent advances from studies in animal models of PSs have provided new insight into the role of DNA repair mechanisms in human disease and the physiological adaptations to accumulating DNA damage during aging. The molecular pathology of PSs is reminiscent of the natural aging process, highlighting the relevance for a wide range of age-related diseases. Recent progress has led to the development of novel therapeutic strategies against age-related diseases that are relevant to rare diseases as well as the general aging population.

Keywords:  DNA damage response; DNA repair; age-related diseases; aging; progeroid syndromes

DOI:  https://doi.org/10.1016/j.molmed.2021.06.011
Ageing Res Rev. 2021 Jul 13. pii: S1568-1637(21)00154-9. [Epub ahead of print] 101407

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm.

David Gems, João Pedro de Magalhães.

  With the goal of representing common denominators of aging in different organisms López-Otín et al. in 2013 described nine hallmarks of aging. Since then, this representation has become a major reference point for the biogerontology field. The template for the hallmarks of aging account originated from landmark papers by Hanahan and Weinberg (2000, 2011) defining first six and later ten hallmarks of cancer. Here we assess the strengths and weaknesses of the hallmarks of aging account. As a checklist of diverse major foci of current aging research, it has provided a useful shared overview for biogerontology during a time of transition in the field. It also seems useful in applied biogerontology, to identify interventions (e.g. drugs) that impact multiple symptomatic features of aging. However, while the hallmarks of cancer provide a paradigmatic account of the causes of cancer with profound explanatory power, the hallmarks of aging do not. A worry is that as a non-paradigm the hallmarks of aging have obscured the urgent need to define a genuine paradigm, one that can provide a useful basis for understanding the mechanistic causes of the diverse aging pathologies. We argue that biogerontology must look and move beyond the hallmarks to understand the process of aging.

Keywords:  aging; geroscience; hallmarks; paradigm; senescence; theory

DOI:  https://doi.org/10.1016/j.arr.2021.101407
Aging Cell. 2021 Jul 11. e13432

FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology.

Shuqi Du, Feng Jin, Laure Maneix, Manasee Gedam, Yin Xu, Andre Catic, Meng C Wang, Hui Zheng.

  The rise of life expectancy of the human population is accompanied by the drastic increases of age-associated diseases, in particular Alzheimer's disease (AD), and underscores the need to understand how aging influences AD development. The Forkhead box O transcription factor 3 (FoxO3) is known to mediate aging and longevity downstream of insulin/insulin-like growth factor signaling across species. However, its function in the adult brain under physiological and pathological conditions is less understood. Here, we report a region and cell-type-specific regulation of FoxO3 in the central nervous system (CNS). We found that FoxO3 protein levels were reduced in the cortex, but not hippocampus, of aged mice. FoxO3 was responsive to insulin/AKT signaling in astrocytes, but not neurons. Using CNS Foxo3-deficient mice, we reveal that loss of FoxO3 led to cortical astrogliosis and altered lipid metabolism. This is associated with impaired metabolic homoeostasis and β-amyloid (Aβ) uptake in primary astrocyte cultures. These phenotypes can be reversed by expressing a constitutively active FOXO3 but not a FOXO3 mutant lacking the transactivation domain. Loss of FoxO3 in 5xFAD mice led to exacerbated Aβ pathology and synapse loss and altered local response of astrocytes and microglia in the vicinity of Aβ plaques. Astrocyte-specific overexpression of FOXO3 displayed opposite effects, suggesting that FoxO3 functions cell autonomously to mediate astrocyte activity and also interacts with microglia to address Aβ pathology. Our studies support a protective role of astroglial FoxO3 against brain aging and AD.

Keywords:  Alzheimer's disease; FoxO3; aging; astrocytes; mice; β-amyloid

DOI:  https://doi.org/10.1111/acel.13432
Exp Gerontol. 2021 Jul 13. pii: S0531-5565(21)00259-X. [Epub ahead of print] 111477

Long-term intake of Lactobacillus paracasei KW3110 prevents age-related circadian Locomotor activity and changes in gut metabolism in physiologically aged mice.

Yuji Morita, Kenta Jounai, Yasuyuki Tomita, Mitsuo Maruyama.

  Aging involves age-progressive loss of physiological functions in organs and tissues. We previously showed that Lactobacillus paracasei KW3110 suppressed age-related inflammation and prevented age-related retinal ganglion cell (RGC) loss. As RGCs mediate biological behaviors associated with responses to ambient light, we assessed whether L. paracasei KW3110 affects circadian locomotor activities in physiologically aged mice. The ratio of locomotor activity during the nighttime (active phase) to daytime (inactive phase) significantly decreased in physiologically aged mice compared with young mice: intake of L. paracasei KW3110 prevented this decrease. We also performed metabolomics analysis of cecal contents using both capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry to better understand the benefical effects for aging of L. paracasei KW3110 through a gut retina axis, since our previous study showed that L. paracasei KW3110 mitigated not only age-related expansions of intestinal inflammatory immune cells but age-related alternation of gut microbiome composition. Principal component analysis showed clear changes in metabolites between physiologically aged mice fed a diet containing L. paracasei KW3110 and age-matched control mice. Furthermore, we found that intake of L. paracasei KW3110 mitigated age-related changes in some fatty acids compared with age-matched control mice. Taken together, L. paracasei KW3110 might regulate age-related alternation of metabolites in cecal contents, potentially leading to suppression of age-related decline in physiological functions, including impairment of circadian locomotor activities.

Keywords:  Aging; Circadian; KW3110; Lactic acid bacteria; Locomotor activity; Senescence

DOI:  https://doi.org/10.1016/j.exger.2021.111477
Kidney Int. 2021 Jul 08. pii: S0085-2538(21)00665-7. [Epub ahead of print]

The ketone body β-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults.

Yudong Fang, Bohan Chen, Athena Y Gong, Deepak Malhotra, Rajesh Gupta, Lance D Dworkin, Rujun Gong.

  Diabetic kidney disease (DKD) is one of the most common complications of diabetes and clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte senescence. Burgeoning evidence suggests that ketosis, in particular β-hydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, β-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of γH2AX foci, reduced staining for senescence-associated-β-galactosidase activity, diminished expression of key mediators of senescence signaling like p16INK4A and p21, and preserved expression of synaptopodin. This beneficial action of β-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, β-hydroxybutyrate inhibition of glycogen synthase kinase 3β (GSK3β), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3β abolished, whereas selective activation of Nrf2 was sufficient for the anti-senescent and podocyte protective effects of β-hydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that β-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3β and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, β-hydroxybutyrate therapy inhibited GSK3β and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a β-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.

Keywords:  GSKβ; Nrf2 antioxidant response; aging; diabetic nephropathy; intermittent fasting; ketosis; time-restricted feeding

DOI:  https://doi.org/10.1016/j.kint.2021.06.031
Adv Sci (Weinh). 2021 Jul 14. e2100964

Rejuvenation of Senescent Bone Marrow Mesenchymal Stromal Cells by Pulsed Triboelectric Stimulation.

Gaocai Li, Qianqian Zhu, Bingjin Wang, Rongjin Luo, Xiaohui Xiao, Yi Zhang, Liang Ma, Xiaobo Feng, Jingang Huang, Xuhui Sun, Zhen Wen, Yue Pan, Cao Yang.

  Stem cell senescence contributes to stem cell exhaustion and drives various aging-associated disorders. However, strategies to rejuvenate senescent stem cells are limited. The present study proposes an approach based on triboelectric stimulation to rejuvenate senescent bone marrow mesenchymal stromal cells (BMSCs) by fabricating a pulsed triboelectric nanogenerator (P-TENG) that can produce stable pulsed current output unaffected by the triggered frequency. The senescence phenotypes of aged BMSCs are reversed by triboelectric stimulation at 30 µA at 1.5 Hz. Triboelectric stimulation enhances the proliferation of aged BMSCs and increases their pluripotency and differentiation capacity. Additionally, mechanistic investigations reveal that pulsed triboelectric stimulation by P-TENG rejuvenates senescent BMSCs by enhancing MDM2-dependent p53 degradation, which is demonstrated by loss-of-function studies of MDM2 and p53. Overall, this study identifies a new approach for the rejuvenation of senescent BMSCs and describes a promising therapeutic intervention for many diseases associated with aged BMSCs.

Keywords:  electrical stimulation; mesenchymal stromal cells; osteogenesis; pulsed current; rejuvenation; triboelectric nanogenerator

DOI:  https://doi.org/10.1002/advs.202100964
EMBO J. 2021 Jul 12. e108293

Nuclear cGAS: guard or prisoner?

Carina C de Oliveira Mann, Karl-Peter Hopfner.

  cGAS, an innate immune sensor of cellular stress, recognizes double-stranded DNA mislocalized in the cytosol upon infection, mitochondrial stress, DNA damage, or malignancy. Early models suggested that cytosolic localization of cGAS prevents autoreactivity to nuclear and mitochondrial self-DNA, but this paradigm has shifted in light of recent findings of cGAS as a predominantly nuclear protein tightly bound to chromatin. This has raised the question how nuclear cGAS is kept inactive while being surrounded by chromatin, and what function nuclear localization of cGAS may serve in the first place? Cryo-EM structures have revealed that cGAS interacts with nucleosomes, the minimal units of chromatin, mainly via histones H2A/H2B, and that these protein-protein interactions block cGAS from DNA binding and thus prevent autoreactivity. Here, we discuss the biological implications of nuclear cGAS and its interaction with chromatin, including various mechanisms for nuclear cGAS inhibition, release of chromatin-bound cGAS, regulation of different cGAS pools in the cell, and chromatin structure/chromatin protein effects on cGAS activation leading to cGAS-induced autoimmunity.

Keywords:  DNA sensing; chromatin; cyclic GMP-AMP synthase; innate immunity; nucleosome

DOI:  https://doi.org/10.15252/embj.2021108293
Sci Rep. 2021 Jul 16. 11(1): 14608

Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis.

Sakiko Honda, Koji Ikeda, Ryota Urata, Ekura Yamazaki, Noriaki Emoto, Satoaki Matoba.

Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; however, whether and the mechanism by which endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear. We here investigate a role of EC senescence in atherosclerosis by utilizing EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 or vascular endothelial cadherin promoter. EC-specific progeria accelerated atherosclerosis in mice with target deletion of ApoE. Mechanistically, senescent ECs were markedly sensitive for inflammation-mediated VCAM-1 induction, leading to enhanced monocyte adhesion. Inhibition of NF-κB signaling abolished the enhanced inflammatory responses in senescent ECs, while NF-κB nuclear translocation in response to TNF-α were similar between young and senescent ECs. We found a higher association of VCAM-1 gene with active histone H3 trimethylated on lysine 4, leading to increased NF-κB accessibility in senescent ECs. Our data revealed that EC cellular senescence causes endothelial hyper-inflammability through epigenetic alteration, which consequently accelerates atherosclerosis. Therefore, EC senescence is a promising therapeutic target for the prevention and/or treatment of atherosclerotic disease in elderly population.

DOI: https://doi.org/10.1038/s41598-021-94097-5
Aging (Albany NY). 2021 Jul 12. 13

The dual distinct role of telomerase in repression of senescence and myofibroblast differentiation.

Masanori Harada, Biao Hu, Jeffrey Lu, Jing Wang, Andrew E Rinke, Zhe Wu, Tianju Liu, Sem H Phan.

  Many aging related diseases such as cancer implicate the myofibroblast in disease progression. Furthermore genesis of the myofibroblast is associated with manifestation of cellular senescence of unclear significance. In this study we investigated the role of a common regulator, namely telomerase reverse transcriptase (TERT), in order to evaluate the potential significance of this association between both processes. We analyzed the effects of TERT overexpression or deficiency on expression of CDKN2A and ACTA2 as indicators of senescence and differentiation, respectively. We assess binding of TERT or YB-1, a repressor of both genes, to their promoters. TERT repressed both CDKN2A and ACTA2 expression, and abolished stress-induced expression of both genes. Conversely, TERT deficiency enhanced their expression. Altering CDKN2A expression had no effect on ACTA2 expression. Both TERT and YB-1 were shown to bind the CDKN2A promoter but only YB-1 was shown to bind the ACTA2 promoter. TERT overexpression inhibited CDKN2A promoter activity while stimulating YB-1 expression and activation to repress ACTA2 gene. TERT repressed myofibroblast differentiation and senescence via distinct mechanisms. The latter was associated with TERT binding to the CDKN2A promoter, but not to the ACTA2 promoter, which may require interaction with co-factors such as YB-1.

Keywords:  cellular senescence; myofibroblast; telomerase

DOI:  https://doi.org/10.18632/aging.203246
J Autoimmun. 2021 Jul 12. pii: S0896-8411(21)00107-4. [Epub ahead of print]123 102699

Telomeres: New players in immune-mediated inflammatory diseases?

Anne-Charlotte Heba, Simon Toupance, Djésia Arnone, Laurent Peyrin-Biroulet, Anthanase Benetos, Ndeye Coumba Ndiaye.

  Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.

Keywords:  Dynamics; Immune-mediated inflammatory diseases; Telomere

DOI:  https://doi.org/10.1016/j.jaut.2021.102699
Eur J Pharmacol. 2021 Jul 13. pii: S0014-2999(21)00470-2. [Epub ahead of print] 174317

Involvement of miR-199a-3p/DDR1 in vascular endothelial cell senescence in diabetes.

Li Yan, Xu Xie, Bing-Xuan Niu, Mei-Ting Wu, Wei-Qiang Tong, Shuang-Yi He, Chu-Yi Huang, Wei-Cheng Zhao, Ge Li, Nian-Sheng Li, Jun-Lin Jiang.

  Endothelial cell dysfunction is a prominent feature of diabetic cardiovascular complications, and endothelial cell senescence is considered to be an important contributor to endothelial dysfunction. Discoidin domain receptor 1 (DDR1) has been reported to be involved in atherogenesis and cerebral ischemia/reperfusion injury. In this study, we aimed to explore the role of DDR1 in endothelial cell senescence under diabetic conditions and elucidate the underlying mechanisms. A diabetic rat model was established by a single intraperitoneal injection of streptozocin (STZ) (60 mg/kg), which showed an increase in senescence-associated β-galactosidase (SA-β-gal) staining signal of thoracic aortic endothelium, impaired vascular structure and function, accompanied by an up-regulation of DDR1. Next, we verified the role of DDR1 in endothelial senescence and the underlying mechanisms in high glucose-treated human umbilical vein endothelial cells (HUVECs). Consistent with the in vivo findings, high glucose induced endothelial senescence, impaired endothelial function and elevated DDR1 expression, accompanied by the elevation of senescence-related genes p53 and p21 expression, and these effects were reversed by DDR1 siRNA. DDR1 has been documented to be a potential target of miR-199a-3p. Here, we found that miR-199a-3p was down-regulated by high glucose in the aorta tissue and HUVECs, while miR-199a-3p mimic significantly suppressed increased endothelial senescence and elevated DDR1 induced by high glucose. In conclusion, our data demonstrated that miR-199a-3p/DDR1/p53/p21 signaling pathway was involved in endothelial senescence under diabetic conditions, and therapeutic targeting DDR1 would be exploited to inhibit endothelial senescence owing to high glucose exposure.

Keywords:  Diabetes; Discoidin domain receptor 1; Vascular endothelial senescence; miR-199a-3p

DOI:  https://doi.org/10.1016/j.ejphar.2021.174317
Aging Cell. 2021 Jul 10. e13428

Single-oocyte transcriptome analysis reveals aging-associated effects influenced by life stage and calorie restriction.

Tappei Mishina, Namine Tabata, Tetsutaro Hayashi, Mika Yoshimura, Mana Umeda, Masashi Mori, Yayoi Ikawa, Hiroshi Hamada, Itoshi Nikaido, Tomoya S Kitajima.

  Chromosome segregation errors in oocytes lead to the production of aneuploid eggs, which are the leading cause of pregnancy loss and of several congenital diseases such as Down syndrome. The frequency of chromosome segregation errors in oocytes increases with maternal age, especially at a late stage of reproductive life. How aging at various life stages affects oocytes differently remains poorly understood. In this study, we describe aging-associated changes in the transcriptome profile of mouse oocytes throughout reproductive life. Our single-oocyte comprehensive RNA sequencing using RamDA-seq revealed that oocytes undergo transcriptome changes at a late reproductive stage, whereas their surrounding cumulus cells exhibit transcriptome changes at an earlier stage. Calorie restriction, a paradigm that reportedly prevents aging-associated egg aneuploidy, promotes a transcriptome shift in oocytes with the up-regulation of genes involved in chromosome segregation. This shift is accompanied by the improved maintenance of chromosomal cohesin, the loss of which is a hallmark of oocyte aging and causes chromosome segregation errors. These findings have implications for understanding how oocytes undergo aging-associated functional decline throughout their reproductive life in a context-dependent manner.

Keywords:  aging; chromosome segregation; cohesin; oocyte; transcriptome

DOI:  https://doi.org/10.1111/acel.13428
Aging (Albany NY). 2021 Jul 14. undefined(undefined):

Senescence in neurons: an open issue.

Jordi Bruna, Aina Calls, Victor J Yuste.



Keywords:  chemotherapy-induced peripheral neuropathy; cisplatin; neuron; neurotoxicity; senescence

DOI:  https://doi.org/10.18632/aging.203329
Aging (Albany NY). 2021 Jul 13. 13(undefined):

Implication of integrin α2β1 in senescence of SK-Mel-147 human melanoma cells.

Nadezhda I Kozlova, Galina E Morozevich, Albert E Berman.

  This investigation addressed the impact of integrin-initiated signaling pathways on senescence of tumor cells. In a model of human SK-Mel-147 melanoma cells, the silencing of integrin α2β1 strongly reduced cell proliferation and enhanced the percentage of SA-β-Gal-positive cells, a phenotypic feature of cellular senescence. These changes were accompanied by a significant increase in the activity of Akt and mTOR protein kinases and also in the expression of p53 and p21 oncosuppressors. Pharmacological inhibition of Akt and mTORC1 and genetic inhibition of p53 and p21 reduced the senescence of α2β1-depleted SK-Mel-147 cells to the level of control cells. Based on our earlier data on the non-canonical functions of Akt isomers in the invasion and anoikis of SK-Mel-147 cells, we investigated the role of Akt isomers in senescence induced by α2β1 suppression. The inhibition of Akt1 strongly reduced the percentage of SA-β-Gal-positive cells in the α2β1-depleted cell population, while the inhibition of Akt2 did not have a noticeable effect. Our data demonstrated for the first time that α2β1 is involved in the protection of tumor cells against senescence and that senescence, which is induced by the downregulation of α2β, is based on a signaling mechanism in which Akt1 performs a non-canonical function.

Keywords:  Akt isoforms; integrins; senescence; signaling; tumor progression

DOI:  https://doi.org/10.18632/aging.203309
J Physiol. 2021 Jul 16.

Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.

Maude Dulac, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marie-Belle Ayoub, Olivier Reynaud, Anwar Shams, Alaa Moamer, Marcos Francisco Nery Ferreira, Sabah Na Hussain, Gilles Gouspillou.

   KEY POINTS: The maintenance of mitochondrial integrity is critical for skeletal muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in the muscle aging process remains unclear. Here we report that both Drp1 knockdown and overexpression late in life in mice is detrimental to skeletal muscle function and mitochondrial health. Drp1 knockdown in 18-month-old mice resulted in severe skeletal muscle atrophy, mitochondrial dysfunction, muscle degeneration/regeneration, oxidative stress, and impaired autophagy. Overexpressing Drp1 in 18-month-old mice resulted in mild skeletal muscle atrophy and decreased mitochondrial quality. Our data indicate that silencing or overexpressing Drp1 late in life is detrimental to skeletal muscle integrity. We conclude that modulating Drp1 expression is unlikely to be a viable approach to counter the muscle aging process.
ABSTRACT: Sarcopenia, the aging-related loss of skeletal muscle mass and function, is a debilitating process negatively impacting s the quality of life of afflicted individuals. Although the mechanisms underlying sarcopenia are still only partly understood, impairments in mitochondrial dynamics, and specifically mitochondrial fission, have been proposed as an underlying mechanism. Importantly, conflicting data exist in the field and both excessive and insufficient mitochondrial fission were proposed to contribute to sarcopenia. In D. Melanogaster, enhancing mitochondrial fission in midlife through overexpression of dynamin-1-like protein (Drp1) extended lifespan and attenuated several key hallmarks of muscle aging. Whether a similar outcome of Drp1 overexpression is observed in mammalian muscles remains unknown. In this study, we investigated the impact of knocking down and overexpressing Drp1 protein for 4 months in skeletal muscles of late middle-aged (18 months) mice using intra-muscular injections of adeno-associated viruses expressing shRNA targeting Drp1 or full Drp1 cDNA. We report that knocking down Drp1 expression late in life triggers severe muscle atrophy, mitochondrial dysfunctions, degeneration/regeneration, oxidative stress and impaired autophagy. Drp1 overexpression late in life triggered mild muscle atrophy and decreased mitochondrial quality. Taken altogether, our results indicate that both overexpression or silencing Drp1 in late middle-aged mice negatively impact skeletal muscle mass and mitochondrial health. These data suggest that Drp1 content must remain within a narrow physiological range to preserve muscle and mitochondrial integrity during aging. Altering Drp1 expression is therefore unlikely to be a viable target to counter sarcopenia. This article is protected by copyright. All rights reserved.

Keywords:  autophagy; mitochondrial dynamics; mitochondrial fission; myopathic phenotype; oxidative stress; skeletal muscle aging; skeletal muscle atrophy

DOI:  https://doi.org/10.1113/JP281752
Proc Natl Acad Sci U S A. 2021 Jul 20. pii: e2024853118. [Epub ahead of print]118(29):

Telomere dysfunction instigates inflammation in inflammatory bowel disease.

Deepavali Chakravarti, Rumi Lee, Asha S Multani, Andrea Santoni, Zachery Keith, Wen-Hao Hsu, Kyle Chang, Laura Reyes, Asif Rashid, Chang-Jiun Wu, Jun Li, Jiexin Zhang, Hong Seok Shim, Krishna Chandra, Pingna Deng, Denise J Spring, Ole Haagen Nielsen, Lene Buhl Riis, Kavya Kelagere Mayigegowda, Sarah E Blutt, Jianhua Zhang, Mamoun Younes, Andrew DuPont, Selvi Thirumurthi, Eduardo Vilar, Mary K Estes, Simona Colla, Noah F Shroyer, Ronald A DePinho.

  Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

Keywords:  DNA damage; Yap1; inflammatory bowel disease; pro-IL-18; telomere dysfunction

DOI:  https://doi.org/10.1073/pnas.2024853118
Sci Rep. 2021 Jul 14. 11(1): 14454

MYCN-induced nucleolar stress drives an early senescence-like transcriptional program in hTERT-immortalized RPE cells.

Sofia Zanotti, Suzanne Vanhauwaert, Christophe Van Neste, Volodimir Olexiouk, Jolien Van Laere, Marlies Verschuuren, Joni Van der Meulen, Liselot M Mus, Kaat Durinck, Laurentijn Tilleman, Dieter Deforce, Filip Van Nieuwerburgh, Michael D Hogarty, Bieke Decaesteker, Winnok H De Vos, Frank Speleman.

MYCN is an oncogenic driver in neural crest-derived neuroblastoma and medulloblastoma. To better understand the early effects of MYCN activation in a neural-crest lineage context, we profiled the transcriptome of immortalized human retina pigment epithelial cells with inducible MYCN activation. Gene signatures associated with elevated MYC/MYCN activity were induced after 24 h of MYCN activation, which attenuated but sustained at later time points. Unexpectedly, MYCN activation was accompanied by reduced cell growth. Gene set enrichment analysis revealed a senescence-like signature with strong induction of p53 and p21 but in the absence of canonical hallmarks of senescence such as β-galactosidase positivity, suggesting incomplete cell fate commitment. When scrutinizing the putative drivers of this growth attenuation, differential gene expression analysis identified several regulators of nucleolar stress. This process was also reflected by phenotypic correlates such as cytoplasmic granule accrual and nucleolar coalescence. Hence, we propose that the induction of MYCN congests the translational machinery, causing nucleolar stress and driving cells into a transient pre-senescent state. Our findings shed new light on the early events induced by MYCN activation and may help unravelling which factors are required for cells to tolerate unscheduled MYCN overexpression during early malignant transformation.

DOI: https://doi.org/10.1038/s41598-021-93863-9
Nature. 2021 Jul 13.

'Inflammation clock' can reveal body's biological age.

Max Kozlov.



Keywords:  Ageing; Health care; Immunology; Machine learning

DOI:  https://doi.org/10.1038/d41586-021-01915-x
Immunity. 2021 Jul 13. pii: S1074-7613(21)00254-5. [Epub ahead of print]54(7): 1369-1371

Aged vasculature drives neutrophils mad.

Marco Di Gioia, Ivan Zanoni.

Inflammaging drives age-related pathologies. In this issue of Immunity, Barkaway et al. illustrate how aged endothelial cells and mast cells promote reverse migration of neutrophils from inflamed tissue back into circulation, causing tissue damage at distal sites.

DOI: https://doi.org/10.1016/j.immuni.2021.06.010
Mol Psychiatry. 2021 Jul 16.

Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing.

Sujeong Yang, Sylvain Gigout, Angelo Molinaro, Yuko Naito-Matsui, Sam Hilton, Simona Foscarin, Bart Nieuwenhuis, Chin Lik Tan, Joost Verhaagen, Tommaso Pizzorusso, Lisa M Saksida, Timothy M Bussey, Hiroshi Kitagawa, Jessica C F Kwok, James W Fawcett.

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

DOI: https://doi.org/10.1038/s41380-021-01208-9
Nat Commun. 2021 07 15. 12(1): 4336

Dietary thiols accelerate aging of C. elegans.

Ivan Gusarov, Ilya Shamovsky, Bibhusita Pani, Laurent Gautier, Svetlana Eremina, Olga Katkova-Zhukotskaya, Alexander Mironov, Alexander А Makarov, Evgeny Nudler.

Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1-mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.

DOI: https://doi.org/10.1038/s41467-021-24634-3
Front Immunol. 2021 ;12 680944

High Fat Diet-Induced CD8+ T Cells in Adipose Tissue Mediate Macrophages to Sustain Low-Grade Chronic Inflammation.

Sonia Kiran, Vijay Kumar, E Angela Murphy, Reilly T Enos, Udai P Singh.

  Obesity in the United States and worldwide reached epidemic proportions within the last 20 years. Obesity is a very powerful health determinant or indicator that facilitates the development and progression of several metabolic diseases, insulin resistance, and low-grade chronic inflammation. Low-grade chronic inflammation in adipose tissue (AT) is marked by the accumulation of T cells, macrophages, and other immune cells and increased production of proinflammatory cytokines. During the onset of obesity but before the influx of macrophages, the AT is infiltrated by T cells that are strongly implicated in the initiation of obesity-associated inflammation. In comparing mice fed a high-fat diet (HFD) with those fed a normal diet (ND), we observed in HFD epididymal AT induction and infiltration of activated T cells, an accumulation and polarization of macrophages, and an increase in populations of activated CD4+ T cells and CD8+ T cells that express CXCR3 or killer cell lectin-like receptor subfamily G member 1 (KLRG1). Levels of inflammatory cytokines and leptin and the results of in vitro co-culture experiments revealed interactions among HFD- and ND-induced CD8+ T cells, macrophages, and adipocytes. Our findings suggest that obese tissues activate and induce both CD4+ and CD8+ CD69+ T cells and augment the expression of CXCR3 receptors, which promotes the recruitment and numbers of pro-inflammatory M1 macrophages to maintain low-grade chronic inflammation. The results support the hypothesis that CXCR3-expressing CD8+T cells play an essential role in the initiation and maintenance of adipose tissue inflammation.

Keywords:  CD8+ T cells; chemokine; inflammation; macrophages; obesity

DOI:  https://doi.org/10.3389/fimmu.2021.680944
Nature. 2021 Jul 14.

Daily briefing: 'Inflammation clock' shows your immune system's age.

Flora Graham.

DOI: https://doi.org/10.1038/d41586-021-01949-1
Aging Cell. 2021 Jul 10. e13429

A high-fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the AppNL-F/NL-F knock-in mouse model.

Guianfranco Mazzei, Ryohei Ikegami, Nona Abolhassani, Naoki Haruyama, Kunihiko Sakumi, Takashi Saito, Takaomi C Saido, Yusaku Nakabeppu.

  Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from transgenes, we used a knock-in mouse model, AppNL-F/NL-F , which accumulates Aβ plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6-month-old male AppNL-F/NL-F and wild-type mice were fed a regular or high-fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild-type and AppNL-F/NL-F mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aβ deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD-fed AppNL-F/NL-F mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8-oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the Aβ binding protein transthyretin (TTR) in AppNL-F/NL-F mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD-fed AppNL-F/NL-F mice.

Keywords:  Alzheimer's disease; gene expression; knock-in mouse model; microgliosis; oxidative stress; transthyretin; type 2 diabetes mellitus; β amyloid

DOI:  https://doi.org/10.1111/acel.13429
Exp Gerontol. 2021 Jul 10. pii: S0531-5565(21)00253-9. [Epub ahead of print] 111471

Gonadotropin-releasing hormone receptor pathway affects the function of human EBV-transformed B lymphocytes in an age-independent way.

Dorota Walkiewicz, Zofia Wicik, Monika Puzianowska-Kuznicka.

  Immune system function changes during aging, but the molecular mechanisms of this phenomenon are not fully understood. The present study identified pathways that are associated with age-associated changes in human B lymphocytes. Initial in silico analysis of 1355 genes involved in aging revealed the strongest association (p = 4.36E-21) with the gonadotropin-releasing hormone receptor (GnRHR) pathway. Extended analysis of 2736 aging-related genes using updated databases confirmed such association (p = 2.41E-16). Genes involved in both aging and the GnRHR pathway were significantly involved in lymphocyte B and T activation and aging-related phenotypes, including hyperinsulinemia and diabetes, arthritis, cerebrovascular disease, and cancers. We, therefore, examined non-tumorigenic Epstein-Barr virus (EBV)-transformed B-lymphocyte cell lines that originated from 12 young subjects (20-31 years old) and 10 centenarians (100-102 years old). Gonadotropin-releasing hormone I (GnRH-I) and GnRHR levels did not depend on the age of the cell donors. Inhibition of the GnRHR pathway age-independently decreased cell proliferation (p < 0.001) and increased apoptosis (p < 0.001). However, the decrease in immunoglobulin G synthesis (p < 0.01) was twice as high in centenarian cells than in young cells. In conclusion, the GnRHR pathway regulated essential properties of B lymphocytes. However, upon EBV transformation, memory class-switched B cells became the dominant cell subpopulation. Therefore, the observed effects of GnRHR inhibition were attributable to this subpopulation.

Keywords:  Aging; B lymphocytes; GnRHR antagonist; Gonadotropin-releasing hormone (GnRH-I); Gonadotropin-releasing hormone receptor (GnRHR); Immune system

DOI:  https://doi.org/10.1016/j.exger.2021.111471
Transl Med Aging. 2021 ;5 17-30

The regulation of healthspan and lifespan by dietary amino acids.

Reji Babygirija, Dudley W Lamming.

  As a key macronutrient and source of essential macromolecules, dietary protein plays a significant role in health. For many years, protein-rich diets have been recommended as healthy due to the satiety-inducing and muscle-building effects of protein, as well as the ability of protein calories to displace allegedly unhealthy calories from fats and carbohydrates. However, clinical studies find that consumption of dietary protein is associated with an increased risk of multiple diseases, especially diabetes, while studies in rodents have demonstrated that protein restriction can promote metabolic health and even lifespan. Emerging evidence suggests that the effects of dietary protein on health and longevity are not mediated simply by protein quantity but are instead mediated by protein quality - the specific amino acid composition of the diet. Here, we discuss how dietary protein and specific amino acids including methionine, the branched chain amino acids (leucine, isoleucine, and valine), tryptophan and glycine regulate metabolic health, healthspan, and aging, with attention to the specific molecular mechanisms that may participate in these effects. Finally, we discuss the potential applicability of these findings to promoting healthy aging in humans.

Keywords:  aging; amino acids; branched-chain amino acids; methionine; protein restriction

DOI:  https://doi.org/10.1016/j.tma.2021.05.001
Curr Oncol Rep. 2021 Jul 16. 23(9): 104

Determination of Biological Age: Geriatric Assessment vs Biological Biomarkers.

Lucas W M Diebel, Kenneth Rockwood.

   PURPOSE OF REVIEW: Biological age is the concept of using biophysiological measures to more accurately determine an individual's age-related risk of adverse outcomes. Grading of the degree of frailty and measuring biomarkers are distinct methods of measuring biological age. This review compares these strategies for estimating biological age for clinical purposes.
RECENT FINDINGS: The degree of frailty predicts susceptibility to adverse outcomes independently of chronological age. The utility of this approach has been demonstrated across a range of clinical contexts. Biomarkers from various levels of the biological aging process are improving in accuracy, with the potential to identify aberrant aging trajectories before the onset of clinically manifest frailty. Grading of frailty is a demonstrably, clinically, and research-relevant proxy estimate of biological age. Emerging biomarkers can supplement this approach by identifying accelerated aging before it is clinically apparent. Some biomarkers may even offer a means by which interventions to reduce the rate of aging can be developed.

Keywords:  Aging; Biomarkers; Comprehensive geriatric assessment; Epigenetics; Frailty; Frailty index; Oncogeriatrics

DOI:  https://doi.org/10.1007/s11912-021-01097-9
J Nutr Biochem. 2021 Jul 13. pii: S0955-2863(21)00237-0. [Epub ahead of print] 108817

Dietary supplementation with sulforaphane ameliorates skin aging through activation of the Keap1-Nrf2 pathway.

Marija Petkovic, Ermelindo C Leal, Ines Alves, Chanda Bose, Philip T Palade, Preeti Singh, Sanjay Awasthi, Elisabet Børsheim, Louise T Dalgaard, Sharda P Singh, Eugenia Carvalho.

  Visible impairments in skin appearance, as well as a subtle decline in its functionality at the molecular level, are hallmarks of skin aging. Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-pathway, which is important in controlling inflammation and oxidative stress that occur during aging, can be triggered by sulforaphane (SFN), an isothiocyanate found in plants from the Brassicaceae family. This study aimed to assess the effects of SFN intake on age-related skin alterations. Male C57BL6 young (2 months) and old (21 months) mice were treated for 3 months with SFN diet (442.5 mg per kg) or control diet. The antioxidant capacities of the skin were increased in old SFN-treated animals as measured by mRNA levels of Nrf2 (p<0.001) and its target genes NQO1 (p<0.001) and HO1 (p<0.001). Protein expression for Nrf2 was also increased in old SFN fed animals (p<0.01), but not the protein expression of NQO1 or HO1. Additionally, ROS and MMP9 protein levels were significantly decreased (p<0.05) in old SFN fed animals. Histopathological analysis confirmed that there was no difference in epidermal thickness in old, when compared to young, SFN treated animals, while the dermal layer thickness was lower in old vs. young, treated animals (p<0.05). Moreover, collagen deposition was improved with SFN treatment in young (p<0.05) and structurally significantly improved in the old mice (p<0.001). SFN dietary supplementation therefore ameliorates skin aging through activation of the Nrf2-pathway.

Keywords:  Cruciferous vegetables; Nrf2 pathway; oxidative stress; skin aging; sulforaphane

DOI:  https://doi.org/10.1016/j.jnutbio.2021.108817
Front Aging Neurosci. 2021 ;13 671142

Gut Microbiota: Critical Controller and Intervention Target in Brain Aging and Cognitive Impairment.

Hui Li, Junjun Ni, Hong Qing.

  The current trend for the rapid growth of the global aging population poses substantial challenges for society. The human aging process has been demonstrated to be closely associated with changes in gut microbiota composition, diversity, and functional features. During the first 2 years of life, the gut microbiota undergoes dramatic changes in composition and metabolic functions as it colonizes and develops in the body. Although the gut microbiota is nearly established by the age of three, it continues to mature until adulthood, when it comprises more stable and diverse microbial species. Meanwhile, as the physiological functions of the human body deteriorated with age, which may be a result of immunosenescence and "inflammaging," the guts of elderly people are generally characterized by an enrichment of pro-inflammatory microbes and a reduced abundance of beneficial species. The gut microbiota affects the development of the brain through a bidirectional communication system, called the brain-gut-microbiota (BGM) axis, and dysregulation of this communication is pivotal in aging-related cognitive impairment. Microbiota-targeted dietary interventions and the intake of probiotics/prebiotics can increase the abundance of beneficial species, boost host immunity, and prevent gut-related diseases. This review summarizes the age-related changes in the human gut microbiota based on recent research developments. Understanding these changes will likely facilitate the design of novel therapeutic strategies to achieve healthy aging.

Keywords:  Alzheimer’s disease; brain aging; cognitive impairment; diet; gut microbiota; machine learning; probiotics

DOI:  https://doi.org/10.3389/fnagi.2021.671142
Nat Cell Biol. 2021 Jul;23(7): 677

cGAS senses translation stress.

Melina Casadio.

DOI: https://doi.org/10.1038/s41556-021-00719-5
Int J Sports Med. 2021 Jul 13.

Telomere Length, SIRT1, and Insulin in Male Master Athletes: The Path to Healthy Longevity?

Samuel S Aguiar, Thiago S Rosa, Rodrigo V P Neves, Patrício L A Leite, Larissa A Maciel, Sara D Gutierrez, Erica C Rosa, Rosângela V Andrade, Hans Degens, Marko T Korhonen, John E Lewis, Herbert G Simões.

Lower SIRT1 and insulin resistance are associated with accelerated telomere shortening. This study investigated whether the lifestyle of master athletes can attenuate these age-related changes and thereby slow aging. We compared insulin, SIRT1, and telomere length in highly trained male master athletes (n=52; aged 49.9±7.2 yrs) and age-matched non-athletes (n=19; aged 47.3±8.9 yrs). This is a cross-sectional study, in which all data were collected in one visit. Overnight fasted SIRT1 and insulin levels in whole blood were assessed using commercial kits. Relative telomere length was determined in leukocytes through qPCR analyses. Master athletes had higher SIRT1, lower insulin, and longer telomere length than age-matched non-athletes (p<0.05 for all). Insulin was inversely associated with SIRT1 (r=-0.38; p=0.001). Telomere length correlated positively with SIRT1 (r=0.65; p=0.001), whereas telomere length and insulin were not correlated (r=0.03; p=0.87). In conclusion, master athletes have higher SIRT1, lower insulin, and longer telomeres than age-matched non-athletes. Furthermore, SIRT1 was negatively associated with insulin and positively associated with telomere length. These findings suggest that in this sample of middle-aged participants reduced insulin, increased SIRT1 activity, and attenuation of biological aging are connected.

DOI: https://doi.org/10.1055/a-1510-9259