bims-senagi 2022-08-07 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–08–07
thirty-one papers selected by
Maria Grazia Vizioli, Mayo Clinic

Cellular senescence: a key therapeutic target in aging and diseases.
Extracellular Nicotinamide Phosphoribosyltransferase Is a Component of the Senescence-Associated Secretory Phenotype.
Cellular senescence: the good, the bad and the unknown.
Ganoderic acid D prevents oxidative stress-induced senescence by targeting 14-3-3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells.
Intersection of Inflammation and Senescence in the Aging Lung Stem Cell Niche.
Role of Mitochondria in Retinal Pigment Epithelial Aging and Degeneration.
Cyclin-Dependent Kinase 1 Inhibition Potentiates the Proliferation of Tonsil-Derived Mesenchymal Stem Cells by Delaying Cellular Senescence.
Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression.
Transformed cells after senescence give rise to more severe tumor phenotypes than transformed non-senescent cells.
The motor neuron disease mouse model hSOD1-G93A shows a non-canonical profile of senescence biomarkers.
Elimination of senescent cells inhibits epithelial-mesenchymal transition of retinal pigment epithelial cells.
MyMD-1 improves health span and prolongs lifespan in old mice: A non-inferiority study to rapamycin.
Suppression of AGTR1 Induces Cellular Senescence in Hepatocellular Carcinoma Through Inactivating ERK Signaling.
Cap-independent translation of GPLD1 enhances markers of brain health in long-lived mutant and drug-treated mice.
Small RNA sequencing of small extracellular vesicles secreted by umbilical cord mesenchymal stem cells following replicative senescence.
Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.
Plasma proteome profiling of healthy individuals across the life span in a Sicilian cohort with long-lived individuals.
Tieing together loose ends: telomere instability in cancer and aging.
TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging.
Quantitative acetylomics reveals dynamics of protein lysine acetylation in mouse livers during aging and upon the treatment of nicotinamide mononucleotide.
Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway.
Cellular communication network 2 (connective tissue growth factor) aggravates acute DNA damage and subsequent DNA damage response-senescence-fibrosis following kidney ischemia reperfusion injury.
Living in endemic area for infectious diseases accelerates epigenetic age.
Hippocampal DNA Methylation, Epigenetic Age and Spatial Memory Performance in Young And Old Rats.
p300 arrests intervertebral disc degeneration by regulating the FOXO3/Sirt1/Wnt/β-catenin axis.
New horizons in life extension, healthspan extension and exceptional longevity.
Astragaloside IV alleviates senescence of vascular smooth muscle cells through activating Parkin-mediated mitophagy.
Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells.
p38α-MAPK-deficient myeloid cells ameliorate symptoms and pathology of APP-transgenic Alzheimer's disease mice.
Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men.
Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation.

J Clin Invest. 2022 Aug 01. pii: e158450. [Epub ahead of print]132(15):

Cellular senescence: a key therapeutic target in aging and diseases.

Lei Zhang, Louise E Pitcher, Matthew J Yousefzadeh, Laura J Niedernhofer, Paul D Robbins, Yi Zhu.

Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.

DOI: https://doi.org/10.1172/JCI158450
Front Endocrinol (Lausanne). 2022 ;13 935106

Extracellular Nicotinamide Phosphoribosyltransferase Is a Component of the Senescence-Associated Secretory Phenotype.

Chisaka Kuehnemann, Kang-Quan Hu, Kayla Butera, Sandip K Patel, Joanna Bons, Birgit Schilling, Cristina Aguayo-Mazzucato, Christopher D Wiley.

  Cellular senescence is a stress or damage response by which a cell adopts of state of essentially permanent proliferative arrest, coupled to the secretion of a number of biologically active molecules. This senescence-associated secretory phenotype (SASP) underlies many of the degenerative and regenerative aspects of cellular senescence - including promoting wound healing and development, but also driving diabetes and multiple age-associated diseases. We find that nicotinamide phosphoribosyltransferase (NAMPT), which catalyzes the rate-limiting step in nicotinamide adenine dinucleotide (NAD) biosynthesis, is elevated in senescent cells without a commensurate increase in NAD levels. This elevation is distinct from the acute DNA damage response, in which NAD is depleted, and recovery of NAD by NAMPT elevation is AMPK-activated protein kinase (AMPK)-dependent. Instead, we find that senescent cells release extracellular NAMPT (eNAMPT) as part of the SASP. eNAMPT has been reported to be released as a catalytically active extracellular vesicle-contained dimer that promotes NAD increases in other cells and extends lifespan, and also as free monomer that acts as a damage-associated molecular pattern and promotes conditions such as diabetes and fibrosis. Senescent cells released eNAMPT as dimer, but surprisingly eNAMPT appeared in the soluble secretome while being depleted from exosomes. Finally, diabetic mice showed elevated levels of eNAMPT, and this was lowered by treatment with the senolytic drug, ABT-263. Together, these data reveal a new SASP factor with implications for NAD metabolism.

Keywords:  NAD; NAMPT; SASP; aging; cellular senescence; diabetes; eNAMPT; senescence

DOI:  https://doi.org/10.3389/fendo.2022.935106
Nat Rev Nephrol. 2022 Aug 03.

Cellular senescence: the good, the bad and the unknown.

Weijun Huang, LaTonya J Hickson, Alfonso Eirin, James L Kirkland, Lilach O Lerman.

Cellular senescence is a ubiquitous process with roles in tissue remodelling, including wound repair and embryogenesis. However, prolonged senescence can be maladaptive, leading to cancer development and age-related diseases. Cellular senescence involves cell-cycle arrest and the release of inflammatory cytokines with autocrine, paracrine and endocrine activities. Senescent cells also exhibit morphological alterations, including flattened cell bodies, vacuolization and granularity in the cytoplasm and abnormal organelles. Several biomarkers of cellular senescence have been identified, including SA-βgal, p16 and p21; however, few markers have high sensitivity and specificity. In addition to driving ageing, senescence of immune and parenchymal cells contributes to the development of a variety of diseases and metabolic disorders. In the kidney, senescence might have beneficial roles during development and recovery from injury, but can also contribute to the progression of acute kidney injury and chronic kidney disease. Therapies that target senescence, including senolytic and senomorphic drugs, stem cell therapies and other interventions, have been shown to extend lifespan and reduce tissue injury in various animal models. Early clinical trials confirm that senotherapeutic approaches could be beneficial in human disease. However, larger clinical trials are needed to translate these approaches to patient care.

DOI: https://doi.org/10.1038/s41581-022-00601-z
Aging Cell. 2022 Aug 05. e13686

Ganoderic acid D prevents oxidative stress-induced senescence by targeting 14-3-3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells.

Huan Yuan, Yan Xu, Yi Luo, Jia-Rong Zhang, Xin-Xin Zhu, Jian-Hui Xiao.

  Stem cell senescence is an important cause of aging. Delaying senescence may present a novel way to combat aging and age-associated diseases. This study provided a mechanistic insight into the protective effect of ganoderic acid D (GA-D) against human amniotic mesenchymal stem cell (hAMSCs) senescence. GA-D, a Ganoderma lucidum-derived triterpenoid, markedly prevented hAMSCs senescence via activating the Ca2+ calmodulin (CaM)/CaM-dependent protein kinase II (CaMKII)/nuclear erythroid 2-related factor 2 (Nrf2) axis, and 14-3-3ε was identified as a target of GA-D. 14-3-3ε-encoding gene (YWHAE) knockdown in hAMSCs reversed the activation of the CaM/CaMKII/Nrf2 signals to attenuate the GA-D anti-aging effect and increase senescence-associated β-galactosidase (SA-β-gal), p16 and p21 expression levels, including reactive oxygen species (ROS) production, thereby promoting cell cycle arrest and decreasing differentiation potential. YWHAE overexpression maintained or slightly enhanced the GA-D anti-aging effect. GA-D prevented d-galactose-caused aging in mice by significantly increasing the total antioxidant capacity, as well as superoxide dismutase and glutathione peroxidase activity, and reducing the formation of malondialdehyde, advanced glycation end products, and receptor of advanced glycation end products. Consistent with the protective mechanism of GA-D against hAMSCs senescence, GA-D delayed the senescence of bone-marrow mesenchymal stem cells in this aging model in vivo, reduced SA-β-gal and ROS production, alleviated cell cycle arrest, and enhanced cell viability and differentiation via regulating 14-3-3ε and CaM/CaMKII/Nrf2 axis. Therefore, GA-D retards hAMSCs senescence by targeting 14-3-3ε to activate the CaM/CaMKII/Nrf2 signaling pathway. Furthermore, the in vivo GA-D anti-aging effect may involve the regulation of stem cell senescence via the same signal axis.

Keywords:  14-3-3ε; CaM/CaMKII/Nrf2 signaling; aging mouse model; anti-aging; bone-marrow mesenchymal stem cells; ganoderic acid D; human amniotic mesenchymal stem cells

DOI:  https://doi.org/10.1111/acel.13686
Front Cell Dev Biol. 2022 ;10 932723

Intersection of Inflammation and Senescence in the Aging Lung Stem Cell Niche.

Nancy C Allen, Nabora S Reyes, Jin Young Lee, Tien Peng.

  Aging is the final stage of development with stereotyped changes in tissue morphology. These age-related changes are risk factors for a multitude of chronic lung diseases, transcending the diverse pathogenic mechanisms that have been studied in disease-specific contexts. Two of the hallmarks of aging include inflammation and cellular senescence, which have been attributed as drivers of age-related organ decline. While these two age-related processes are often studied independently in the same tissue, there appears to be a reciprocal relationship between inflammation and senescence, which remodels the aging tissue architecture to increase susceptibility to chronic diseases. This review will attempt to address the "chicken or the egg" question as to whether senescence drives inflammation in the aging lung, or vice versa, and whether the causality of this relationship has therapeutic implications for age-related lung diseases.

Keywords:  SASP; aging; inflammation; senescence; stem cell niche

DOI:  https://doi.org/10.3389/fcell.2022.932723
Front Aging. 2022 ;3 926627

Role of Mitochondria in Retinal Pigment Epithelial Aging and Degeneration.

Yao Tong, Zunyi Zhang, Shusheng Wang.

  Retinal pigment epithelial (RPE) cells form a monolayer between the neuroretina and choroid. It has multiple important functions, including acting as outer blood-retina barrier, maintaining the function of neuroretina and photoreceptors, participating in the visual cycle and regulating retinal immune response. Due to high oxidative stress environment, RPE cells are vulnerable to dysfunction, cellular senescence, and cell death, which underlies RPE aging and age-related diseases, including age-related macular degeneration (AMD). Mitochondria are the powerhouse of cells and a major source of cellular reactive oxygen species (ROS) that contribute to mitochondrial DNA damage, cell death, senescence, and age-related diseases. Mitochondria also undergo dynamic changes including fission/fusion, biogenesis and mitophagy for quality control in response to stresses. The role of mitochondria, especially mitochondrial dynamics, in RPE aging and age-related diseases, is still unclear. In this review, we summarize the current understanding of mitochondrial function, biogenesis and especially dynamics such as morphological changes and mitophagy in RPE aging and age-related RPE diseases, as well as in the biological processes of RPE cellular senescence and cell death. We also discuss the current preclinical and clinical research efforts to prevent or treat RPE degeneration by restoring mitochondrial function and dynamics.

Keywords:  RPE; age-related macula degeneration; aging; cell death; degeneration; mitochondria; senescense

DOI:  https://doi.org/10.3389/fragi.2022.926627
Stem Cells Int. 2022 ;2022 4302992

Cyclin-Dependent Kinase 1 Inhibition Potentiates the Proliferation of Tonsil-Derived Mesenchymal Stem Cells by Delaying Cellular Senescence.

Da Hyeon Choi, Kyeong Eun Lee, Yoon Shin Park.

Mesenchymal stem cells (MSCs) have been widely used in tissue regeneration and stem cell therapy and are currently being tested in numerous clinical trials. Senescence-related changes in MSC properties have attracted considerable attention. Senescent MSCs exhibit a compromised potential for proliferation; senescence acts as a stress response that prevents the proliferation of dysfunctional cells by inducing an irreversible cell cycle arrest. Here, we established a senescent MSC model using senescence-associated β-galactosidase, proliferation, and cell cycle assays. We further identified novel biomarker candidates for old, senescent tonsil-derived MSCs (TMSCs) using transcriptomics. A plot of the cellular senescence pathway showed cyclin-dependent kinase 1 (CDK1; +8-fold) and CDK2 (+2-fold), and transforming growth factor beta 2 (TGFB2; +2-fold) showed significantly higher expression in old TMSCs than in young TMSCs. The CDK family was shown to be related to cell cycle and proliferation, as confirmed by quantitative RT-PCR. As replicative senescence of TMSCs, the gene and protein expression of CDK1 was significantly increased, which was further validated by inhibiting CDK1 using an inhibitor and siRNA. Taken together, we suggest that the CDK1 can be used as a selective senescence biomarker of MSCs and broaden the research criteria for senescent mechanisms.

DOI: https://doi.org/10.1155/2022/4302992
Cell Death Dis. 2022 Aug 05. 13(8): 681

Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression.

Marta Varela-Eirín, Paula Carpintero-Fernández, Amanda Guitián-Caamaño, Adrián Varela-Vázquez, Alejandro García-Yuste, Agustín Sánchez-Temprano, Susana B Bravo-López, José Yañez-Cabanas, Eduardo Fonseca, Raquel Largo, Ali Mobasheri, José Ramón Caeiro, María D Mayán.

The accumulation of senescent cells is a key characteristic of aging, leading to the progression of age-related diseases such as osteoarthritis (OA). Previous data from our laboratory has demonstrated that high levels of the transmembrane protein connexin 43 (Cx43) are associated with a senescent phenotype in chondrocytes from osteoarthritic cartilage. OA has been reclassified as a musculoskeletal disease characterized by the breakdown of the articular cartilage affecting the whole joint, subchondral bone, synovium, ligaments, tendons and muscles. However, the mechanisms that contribute to the spread of pathogenic factors throughout the joint tissues are still unknown. Here, we show for the first time that small extracellular vesicles (sEVs) released by human OA-derived chondrocytes contain high levels of Cx43 and induce a senescent phenotype in targeted chondrocytes, synovial and bone cells contributing to the formation of an inflammatory and degenerative joint environment by the secretion of senescence-associated secretory associated phenotype (SASP) molecules, including IL-1ß and IL-6 and MMPs. The enrichment of Cx43 changes the protein profile and activity of the secreted sEVs. Our results indicate a dual role for sEVs containing Cx43 inducing senescence and activating cellular plasticity in target cells mediated by NF-kß and the extracellular signal-regulated kinase 1/2 (ERK1/2), inducing epithelial-to-mesenchymal transition (EMT) signalling programme and contributing to the loss of the fully differentiated phenotype. Our results demonstrated that Cx43-sEVs released by OA-derived chondrocytes spread senescence, inflammation and reprogramming factors involved in wound healing failure to neighbouring tissues, contributing to the progression of the disease among cartilage, synovium, and bone and probably from one joint to another. These results highlight the importance for future studies to consider sEVs positive for Cx43 as a new biomarker of disease progression and new target to treat OA.

DOI: https://doi.org/10.1038/s41419-022-05089-w
Cancer Lett. 2022 Aug 01. pii: S0304-3835(22)00334-2. [Epub ahead of print] 215850

Transformed cells after senescence give rise to more severe tumor phenotypes than transformed non-senescent cells.

Alberta Palazzo, Hector Hernandez-Vargas, Delphine Goehrig, Jean-Jacques Médard, David Vindrieux, Jean-Michel Flaman, David Bernard.

  Oncogenic stress-induced senescence initially inhibits tumor initiation by blocking proliferation and by attracting immune cells to clear potentially harmful cells. If these cells are not eliminated they may resume proliferation upon loss-of-tumor suppressors, and be at risk of transformation. During tumor formation, depending on the sequence of events of gain-of-oncogenes and/or loss-of-tumor suppressors, cancer cells may emerge from senescent cells. Here, we show that these transformed cells after senescence (TS) display more aggressive tumorigenic features, with a greater capacity to migrate and a higher resistance to anti-tumoral drugs than cells having undergone transformation without senescence. Bulk transcriptomic analysis and single cell RNA sequencing revealed a signature unique to TS cells. A score of this signature was then generated and a high score was correlated with decreased survival of patients with lung adenocarcinoma, head-neck squamous cell carcinoma, adrenocortical carcinoma, liver hepatocellular carcinoma, skin cutaneous melanoma and low-grade glioma. Together, these findings strongly support that cancer cells arising from senescent cells are more dangerous, and that a molecular signature of these cells may be of prognostic value for some human cancers. It also raises questions about modeling human tumors, using cells or mice, without regards to the sequence of events leading to transformation.

Keywords:  Cellular senescence; RAS oncogene; Tumor aggressiveness; p53 tumor suppressor

DOI:  https://doi.org/10.1016/j.canlet.2022.215850
Dis Model Mech. 2022 Aug 02. pii: dmm.049059. [Epub ahead of print]

The motor neuron disease mouse model hSOD1-G93A shows a non-canonical profile of senescence biomarkers.

Pascual Torres, Carlos Anerillas, Omar Ramírez-Núñez, Anna Fernàndez, Mario Encinas, Mònica Povedano, Pol Andrés-Benito, Isidre Ferrer, Victòria Ayala, Reinald Pamplona, Manuel Portero-Otín.

  To evaluate senescence mechanisms, including senescence-associated secretory phenotype (SASP), in the motor-neuron disease model hSOD1-G93A, we quantified the expression of p16 and p21 and the senescence-associated β galactosidase (SA-β-gal) in nervous tissue. As SASP markers, we measured the mRNA levels of Il1a, Il6, Ifna, and Ifnb. Furthermore, we explored if an alteration of alternative splicing is associated with senescence by measuring the Adipor2 cryptic exon inclusion levels, a specific splicing variant repressed by TAR-DNA binding of 43 kDa (Tdp-43). Transgenic mice show an atypical senescence profile with high p16 and p21 mRNA and protein in glia, without the canonical increase in SA-β-gal activity. Consistent with SASP, there is an increase in Il1a and Il6 expression, associated with increased TNFR and M-CSF protein levels, with females being partially protected. TDP-43 splicing activity is compromised in this model. Senolytic drug Navitoclax does not alter the present 'model's disease progression. This lack of effect is reproduced in vitro, in contrast with Dasatinib and quercetin, which diminish p16 and p21. Our findings show a non-canonical profile of senescence biomarkers in the model hSOD1-G93A.

Keywords:  Amyotrophic lateral sclerosis; Cryptic exon; Neuroinflammation; Senolysis

DOI:  https://doi.org/10.1242/dmm.049059
Exp Eye Res. 2022 Aug 01. pii: S0014-4835(22)00287-1. [Epub ahead of print] 109207

Elimination of senescent cells inhibits epithelial-mesenchymal transition of retinal pigment epithelial cells.

Furong Gao, Lei Wang, Binxin Wu, Qingjian Ou, Haibin Tian, Jingying Xu, Caixia Jin, Jieping Zhang, Juan Wang, Lixia Lu, Guo-Tong Xu.

  Age-related macular degeneration (AMD) is one of the most common leading causes of irreversible blindness, and there is no effective treatment for it. It has been reported that aging is the greatest risk factor for AMD, and epithelial-mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells plays an important role in the pathogenesis of AMD. To clarify the relationship between senescence and EMT in RPE cells, we used the replicative senescence model, H2O2- and/or Nutlin3a-induced senescence model, and low-density and/or TGF-β-induced EMT model to detect the expression of senescence-, RPE- and EMT-related genes, and assessed the motility of cells by using a scratch wound migration assay. The results showed that replicative senescence of RPE cells was accompanied by increased expression of EMT markers. However, senescent RPE cells themselves did not undergo EMT, as the H2O2-and Nutlin3a treated cells showed no increase in EMT characteristics, including unchanged or decreased expression of EMT markers and decreased motility. Furthermore, conditioned medium (CM) from senescent cells induced EMT in presenescent RPE cells, and EMT accelerated the process of senescence. Importantly, dasatinib plus quercetin, which selectively eliminates senescent cells, inhibited low-density-induced EMT in RPE cells. These findings provide a better understanding of the interconnection between senescence and EMT in RPE cells. Removal of senescent cells by certain methods such as senolytics, might be a promising potential approach to prevent or delay the progression of RPE-EMT-related retinal diseases such as AMD.

Keywords:  Age-related macular degeneration; Epithelial-mesenchymal transition; Retinal pigment epithelium; Senescence

DOI:  https://doi.org/10.1016/j.exer.2022.109207
J Gerontol A Biol Sci Med Sci. 2022 Aug 02. pii: glac142. [Epub ahead of print]

MyMD-1 improves health span and prolongs lifespan in old mice: A non-inferiority study to rapamycin.

Elena Sabini, Alison O'Mahony, Patrizio Caturegli.

  Aging and age-related diseases represent a compelling therapeutic goal for senolytics and drugs targeting inflammatory or metabolic pathways. We compared MyMD-1, a synthetic derivative of the alkaloid myosmine capable of suppressing TNF-α production, to rapamycin, the best characterized drug endowed with anti-aging properties. In vivo, a longitudinal cohort of 54 C57BL/6 mice, 19-month-old at the start, was randomized to receive MyMD-1, high-dose (126 ppm) rapamycin, or low-dose (14 ppm) rapamycin plus metformin. Each treatment arm included 18 mice (10 females and 8 males) and was followed for 16 months or until death. Lifespan was significantly longer in MyMD-1 than rapamycin (P= 0.019 versus high-dose and 0.01 versus low-dose) in a Cox survival model that accounted for sex and serum levels of IL-6, TNF-α, and IL-17A. MyMD-1 also improved several health span characteristics, resulting in milder body weight loss, greater muscle strength, and slower progression to frailty. In vitro, MyMD-1 and rapamycin were compared using a panel of 12 human primary cell systems (BioMAP Diversity PLUS™) where a total of 148 biomarkers are measured. MyMD-1 possessed anti-proliferative, anti-inflammatory, and anti-fibrotic properties. Many were shared with rapamycin, but MyMD-1 was more active in the inhibition of pro-inflammatory and pro-fibrotic biomarkers. Overall, MyMD-1 emerges as a new compound that, even when begun at an advanced age, induces beneficial effects on health and lifespan by modulating inflammation and tissue remodeling.

Keywords:  MyMD-1; aging; health span; inflammaging; lifespan; rapamycin

DOI:  https://doi.org/10.1093/gerona/glac142
Front Bioeng Biotechnol. 2022 ;10 929979

Suppression of AGTR1 Induces Cellular Senescence in Hepatocellular Carcinoma Through Inactivating ERK Signaling.

Houhong Wang, Yayun Cui, Huihui Gong, Jianguo Xu, Shuqin Huang, Amao Tang.

  Objective: Cellular senescence is an effective barrier against tumorigenesis. Hence, it is of significance to characterize key features of cellular senescence and the induction of senescence in hepatocellular carcinoma (HCC) cells via pharmacological interventions. Our study determined the biological roles as well as mechanisms of angiotensin II type I receptor (AGTR1) on cellular senescence in HCC. Methods: Lentivirus vector-mediated overexpression or knockdown of AGTR1 was conducted in HCC cells, respectively. A volume of 8 μM sorafenib was used to induce cellular senescence, and ERK was activated by 30 ng/ml ERK agonist EGF. Proliferation was evaluated via clone formation assay. HCC cell senescence was examined by flow cytometry for cell cycle, senescence-associated β-galactosidase (SA-β-gal) staining, and senescence-associated heterochromatin foci (SAHF) analysis. AGTR1, p53, p21, extracellular signal-regulated kinase (ERK), and p-ERK expression were assessed through Western blot or immunofluorescence. Results: AGTR1-knockout HCC cells displayed the attenuated proliferative capacity, G2-M phase arrest, increased expression of p53 and p21, and elevated percentages of SA-β-gal- and SAHF-positive cells. In sorafenib-exposed HCC cells, overexpressed AGTR1 enhanced the proliferative capacity and alleviated G2-M phase arrest as well as decreased p53 and p21 expression and the proportions of SA-β-gal- and SAHF-positive cells. Moreover, AGTR1 knockdown attenuated the activity of p-ERK in HCC cells, and ERK agonist ameliorated AGTR1 knockdown-induced cellular senescence. Conclusion: This study demonstrates that suppression of AGTR1 induces cellular senescence in HCC through inactivating ERK signaling. The significant synergistic effect of AGTR1 suppression and sorafenib might represent a potential combination therapy for HCC.

Keywords:  AGTR1; ERK signaling; cellular senescence; hepatocellular carcinoma; sorafenib

DOI:  https://doi.org/10.3389/fbioe.2022.929979
Aging Cell. 2022 Aug 05. e13685

Cap-independent translation of GPLD1 enhances markers of brain health in long-lived mutant and drug-treated mice.

Xinna Li, Xiaofang Shi, Madaline McPherson, Mary Hager, Gonzalo G Garcia, Richard A Miller.

  Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) hydrolyzes inositol phosphate linkages in proteins anchored to the cell membrane. Mice overexpressing GPLD1 show enhanced neurogenesis and cognition. Snell dwarf (DW) and growth hormone receptor knockout (GKO) mice show delays in age-dependent cognitive decline. We hypothesized that augmented GPLD1 might contribute to retained cognitive function in these mice. We report that DW and GKO show higher GPLD1 levels in the liver and plasma. These mice also have elevated levels of hippocampal brain-derived neurotrophic factor (BDNF) and of doublecortin (DCX), suggesting a mechanism for maintenance of cognitive function at older ages. GPLD1 was not increased in the hippocampus of DW or GKO mice, suggesting that plasma GPLD1 increases elevated these brain proteins. Alteration of the liver and plasma GPLD1 was unaltered in mice with liver-specific GHR deletion, suggesting that the GH effect was not intrinsic to the liver. GPLD1 was also induced by caloric restriction and by each of four drugs that extend lifespan. The proteome of DW and GKO mice is molded by selective translation of mRNAs, involving cap-independent translation (CIT) of mRNAs marked by N6 methyladenosine. Because GPLD1 protein increases were independent of the mRNA level, we tested the idea that GPLD1 might be regulated by CIT. 4EGI-1, which enhances CIT, increased GPLD1 protein without changes in GPLD1 mRNA in cultured fibroblasts and mice. Furthermore, transgenic overexpression of YTHDF1, which promotes CIT by reading m6A signals, also led to increased GPLD1 protein, showing that elevation of GPLD1 reflects selective mRNA translation.

Keywords:  aging; cap-independent translation; glycosylphosphatidylinositol specific phospholipase D1; growth hormone

DOI:  https://doi.org/10.1111/acel.13685
Genes Genomics. 2022 Aug 02.

Small RNA sequencing of small extracellular vesicles secreted by umbilical cord mesenchymal stem cells following replicative senescence.

Chris Gunwoo Kim, Jae Kyung Lee, Geum-Joon Cho, Ok Sarah Shin, Jeong-An Gim.

   BACKGROUND: Umbilical cord mesenchymal stem cells (UCMSC) are subsets of multipotent stem cells involved in immune modulation, tissue regeneration, and antimicrobial defense. Cellular senescence is associated with the onset of aging-related diseases and small extracellular vesicles (sEVs) are important mediators of senescence and aging.
OBJECTIVE: However, little is known about the role and function of microRNAs (miRNAs) carried by UCMSC-derived sEVs. To analyze the expression profiles of miRNAs secreted by senescent UCMSC, small RNA sequencing of the miRNAs within the sEVs was performed in this study.
METHODS: UCMSC cultures underwent serial passaging beyond passage number 20 to achieve replicative senescence, which was confirmed by various methods, including increased senescence-associated β-gal staining and cytokine secretion levels. sEVs derived from non-senescent and senescent UCMSC were isolated and characterized by nanoparticle tracking analysis, transmission electron microscopy, and immunoblot analysis.
RESULTS: Small RNA sequencing of the miRNAs within the sEVs revealed senescence-associated differences in the miRNA composition, as shown by the upregulation of miR-122-5p and miR-146a-5p, and downregulation of miR-125b-5p and miR-29-3p. In addition, total RNA sequencing analysis showed that PENK, ITGA8, and TSIX were upregulated, whereas AKR1B10, UNC13D, and IL21R were downregulated by replicative senescence in UCMSC. In sEVs, upregulated genes were linked to downregulated miRNAs, and vice versa. In the gene-concept network analysis, five gynecologic terms were retrieved.
CONCLUSIONS: The study provides an insight into the cellular characteristics of UCMSC following replicative senescence and emphasizes the importance of monitoring passage numbers of UCMSC for further therapeutic use.

Keywords:  Senescence; Small extracellular vesicles; UCMSC; microRNA

DOI:  https://doi.org/10.1007/s13258-022-01297-y
Eur Heart J. 2022 Aug 04. pii: ehac431. [Epub ahead of print]

Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.

Chen Chi, Hui Fu, Yong-Hua Li, Guo-Yan Zhang, Fei-Yan Zeng, Qing-Xin Ji, Qi-Rui Shen, Xu-Jie Wang, Zi-Chen Li, Can-Can Zhou, Di-Yang Sun, Jiang-Tao Fu, Wen-Bin Wu, Ping-Ping Zhang, Jia-Bao Zhang, Jian Liu, Fu-Ming Shen, Dong-Jie Li, Pei Wang.

   AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored.
METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study.
CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

Keywords:  Exercise; Extracellular vesicles; FNDC5; SIRT6; Senescence; Vascular ageing

DOI:  https://doi.org/10.1093/eurheartj/ehac431
Aging Cell. 2022 Aug 06. e13684

Plasma proteome profiling of healthy individuals across the life span in a Sicilian cohort with long-lived individuals.

Valentina Siino, Ashfaq Ali, Giulia Accardi, Anna Aiello, Mattia E Ligotti, Sergio Mosquim Junior, Giuseppina Candore, Calogero Caruso, Fredrik Levander, Sonya Vasto.

  The study of healthy human aging is important for shedding light on the molecular mechanisms behind aging to promote well-being and to possibly predict and/or avoid the development of age-related disorders such as atherosclerosis and diabetes. Herein, we have employed an untargeted mass spectrometry-based approach to study age-related protein changes in a healthy Sicilian plasma cohort including long-lived individuals. This approach confirmed some of the previously known proteins correlated with age including fibulin-1, dystroglycan, and gamma-glutamyl hydrolase. Furthermore, our findings include novel proteins that correlate with age and/or with location and uric acid, which could represent a unique signature for healthy aging.

Keywords:  aging; longevity; plasma proteome

DOI:  https://doi.org/10.1111/acel.13684
Mol Oncol. 2022 Aug 03.

Tieing together loose ends: telomere instability in cancer and aging.

Gustavo Borges, Mélanie Criqui, Lea Harrington.

  Telomere maintenance is essential for maintaining genome integrity in both normal and cancer cells. Without functional telomeres, chromosomes lose their protective structure, and undergo fusion and breakage events that drive further genome instability, including cell arrest or death. One means by which this loss can be overcome in stem cells and cancer cells is via re-addition of G-rich telomeric repeats by the telomerase reverse transcriptase (TERT). During aging of somatic tissues, however, insufficient telomerase expression leads to a proliferative arrest called replicative senescence, which is triggered when telomeres reach a critically short threshold that induces a DNA damage response. Cancer cells express telomerase but do not entirely escape telomere instability as they often possess short telomeres; hence there is often selection for genetic alterations in the TERT promoter that result in increased telomerase expression. In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for preserving genome stability.

Keywords:  Telomeres; aging; cancer; genome instability; senescence; telomerase reverse transcriptase

DOI:  https://doi.org/10.1002/1878-0261.13299
J Dent Res. 2022 Aug 02. 220345221110108

TLR9 Mediates Periodontal Aging by Fostering Senescence and Inflammaging.

E Albuquerque-Souza, K E Crump, K Rattanaprukskul, Y Li, B Shelling, X Xia-Juan, M Jiang, S E Sahingur.

  TLR9 is a critical nucleic acid sensing receptor in mediating periodontitis and periodontitis-associated comorbidities. Emerging evidence implicates TLR9 as a key sensor during aging, although its participation in periodontal aging is unexplored. Here, we investigated whether TLR9-mediated host responses can promote key hallmarks of aging, inflammaging, and senescence, in the course of periodontitis using a multipronged approach comprising clinical and preclinical studies. In a case-control model, we found increased TLR9 gene expression in gingival tissues of older (≥55 y) subjects with periodontitis compared to older healthy subjects as well as those who are younger (<55 y old) with and without the disease. Mechanistically, this finding was supported by an in vivo model in which wild-type (WT) and TLR9-/- mice were followed for 8 to 10 wk (young) and 18 to 22 mo (aged). In this longitudinal model, aged WT mice developed severe alveolar bone resorption when compared to their younger counterpart, whereas aged TLR9-/- animals presented insignificant bone loss when compared to the younger groups. In parallel, a boosted inflammaging milieu exhibiting higher expression of inflammatory/osteoclast mediators (Il-6, Rankl, Cxcl8) and danger signals (S100A8, S100A9) was noted in gingival tissues of aged WT mice compared to the those of aged TLR9-/- mice. Consistently, WT aged mice displayed an increase in prosenescence balance as measured by p16INK4a/p19ARF ratio compared to the younger groups and aged TLR9-/- animals. Ex vivo experiments with bone marrow-derived macrophages primed by TLR9 ligand (ODN 1668) further corroborated in vivo and clinical data and showed enhanced inflammatory-senescence circuit followed by increased osteoclast differentiation. Together, these findings reveal first systematic evidence implicating TLR9 as one of the drivers of periodontitis during aging and functioning by boosting a deleterious inflammaging/senescence environment. This finding calls for further investigations to determine whether targeting TLR9 will improve periodontal health in an aging population.

Keywords:  S100 proteins; cellular senescence; macrophages; nucleic acids; periodontitis; toll-like receptor 9

DOI:  https://doi.org/10.1177/00220345221110108
Mol Cell Proteomics. 2022 Aug 03. pii: S1535-9476(22)00084-6. [Epub ahead of print] 100276

Quantitative acetylomics reveals dynamics of protein lysine acetylation in mouse livers during aging and upon the treatment of nicotinamide mononucleotide.

Jingshu Li, Ye Cao, Kongyan Niu, Jiaqian Qiu, Han Wang, Yingnan You, Dean Li, Yu Luo, Zhengjiang Zhu, Yaoyang Zhang, Nan Liu.

Lysine acetylation is a reversible and dynamic post-translational modiﬁcation that play vital roles in regulating multiple cellular processes including aging. However, acetylome-wide analysis in the aging process remains poorly studied in mammalian tissues. Nicotinamide adenine dinucleotide (NAD+), a hub metabolite, benefits healthspan at least in part due to the activation of Sirtuins, a family of NAD+-consuming deacetylases, indicating changes in acetylome. Here, we combine two antibodies for the enrichment of acetylated peptides and perform label-free quantitative acetylomic analysis of mouse livers during natural aging and upon the treatment of beta-nicotinamide mononucleotide (NMN), a NAD+ booster. Our study describes previously unknown acetylation sites and reveals the acetylome-wide dynamics with age as well as upon the treatment of NMN. We discover protein acetylation events as potential aging biomarkers. We demonstrate that the life-beneficial effect of NMN could be partially reflected by the changes in age-related protein acetylation. Our quantitative assessment indicates that NMN has mild effects on acetylation sites previously reported as substrates of Sirtuins. Collectively, our data analyzes protein acetylation with age, laying critical foundation for the functional study of protein post-translational modification essential for healthy aging and perhaps disease conditions.

DOI: https://doi.org/10.1016/j.mcpro.2022.100276
Inflamm Res. 2022 Aug 01.

Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway.

Hang Yang, Yong-Yan Luo, Lue-Tao Zhang, Kai-Ran He, Xiao-Jun Lin.

   BACKGROUND: Sepsis is an abnormal immune-inflammatory response that is mainly caused by infection. It can lead to life-threatening organ dysfunction and death. Severely damaged tissue cells will release intracellular histones into the circulation as damage-related molecular patterns (DAMPs) to accelerate the systemic immune response. Although various histone-related cytotoxicity mechanisms have been explored, those that affect extracellular histones involved in vascular smooth muscle cell (VSMC) dysfunction are yet to be determined.
METHODS: Mouse aortic vascular smooth muscle cells (VSMCs) were stimulated with different concentrations of histones, and cell viability was detected by CCK-8 assay. Cellular senescence was assessed by SA β-gal staining. C57BL/6 mice were treated with histones with or without BML-275 treatment. RT-qPCR was performed to determine the expression of inflammatory cytokines. Western blotting was used to analyze the expression of NLRP3, ASC and caspase-1 inflammasome proteins. The interaction of NLRP3 and ASC was detected by CoIP and immunofluorescence staining.
RESULTS: In this study, we found that extracellular histones induced senescence and inflammatory response in a dose-dependent manner in cultured VSMCs. Histone treatment significantly promoted apoptosis-associated speck-like protein containing CARD (ASC) as well as NACHT, LRR and PYD domains-containing protein 3 (NLRP3) interaction of inflammasomes in VSMCs. Forkhead box protein O4 (FOXO4), which is a downstream effector molecule of extracellular histones, was found to be involved in histone-regulated VSMC inflammatory response and senescence. Furthermore, the 5'-AMP-activated protein kinase (AMPK) signaling pathway was confirmed to mediate extracellular histone-induced FOXO4 expression, and blocking this signaling pathway with an inhibitor can suppress vascular inflammation induced by extracellular histones in vivo and in vitro.
CONCLUSION: Extracellular histones induce inflammation and senescence in VSMCs, and blocking the AMPK/FOXO4 pathway is a potential target for the treatment of histonemediated organ injury.

Keywords:  Extracellular histones; Inflammatory response; Organ injury; Senescence; VSMC

DOI:  https://doi.org/10.1007/s00011-022-01618-7
Kidney Int. 2022 Jul 31. pii: S0085-2538(22)00553-1. [Epub ahead of print]

Cellular communication network 2 (connective tissue growth factor) aggravates acute DNA damage and subsequent DNA damage response-senescence-fibrosis following kidney ischemia reperfusion injury.

Floris A Valentijn, Sebastiaan N Knoppert, Laura Marquez-Exposito, Raúl R Rodrigues-Diez, Georgios Pissas, Jiaqi Tang, Lucia Tejedor-Santamaria, Roel Broekhuizen, Rohan Samarakoon, Theodoros Eleftheriadis, Roel Goldschmeding, Tri Q Nguyen, Marta Ruiz-Ortega, Lucas L Falke.

  Chronic allograft dysfunction with progressive fibrosis of unknown cause remains a major issue after kidney transplantation, characterized by ischemia-reperfusion injury (IRI). One hypothesis to account for this is that spontaneous progressive tubulointerstitial fibrosis following IRI is driven by cellular senescence evolving from a prolonged, unresolved DNA damage response (DDR). Since cellular communication network factor 2 ((CCN2), formerly called connective tissue growth factor), an established mediator of kidney fibrosis, is also involved in senescence associated pathways, we investigated the relation between CCN2 and cellular senescence following kidney transplantation. Tubular CCN2 overexpression was found to be associated with DDR, loss of kidney function and tubulointerstitial fibrosis in both the early and the late phase in human kidney allograft biopsies. Consistently, CCN2 deficient mice developed reduced senescence and tubulointerstitial fibrosis in the late phase; six weeks after experimental IRI. Moreover, tubular DDR markers and plasma urea were less elevated in CCN2 knockout than in wild type mice. Finally, CCN2 administration or overexpression in epithelial cells induced upregulation of tubular senescence-associated genes including p21, while silencing of CCN2 alleviated DDR induced by anoxia-reoxygenation injury in cultured proximal tubule epithelial cells. Thus, our observations indicate that inhibition of CCN2 can mitigate IRI-induced acute kidney injury, DNA damage, and the subsequent DDR-senescence-fibrosis sequence. Hence, targeting CCN2 might help to protect the kidney from transplantation associated post-IRI chronic kidney dysfunction.

Keywords:  DNA damage response; Ischemia-reperfusion injury; cellular communication network factor 2; cellular senescence; chronic kidney disease; tubulointerstitial fibrosis

DOI:  https://doi.org/10.1016/j.kint.2022.06.030
Mech Ageing Dev. 2022 Aug 02. pii: S0047-6374(22)00095-1. [Epub ahead of print] 111713

Living in endemic area for infectious diseases accelerates epigenetic age.

D F Durso, G Silveira-Nunes, M M Coelho, G C Camatta, L H Ventura, L S Nascimento, F Caixeta, E H M Cunha, A Castelo-Branco, D M Fonseca, T U Maioli, A Teixeira-Carvalho, C Sala, M J Bacalini, P Garagnani, C Nardini, C Franceschi, A M C Faria.

  Inflammaging is a low-grade inflammatory state generated by the aging process that can contribute to frailty and age-related diseases in the elderly. However, it can have distinct effects in the elderly living in endemic areas for infectious diseases. An increased inflammatory response may confer protection against infectious agents in these areas, although this advantage can cause accelerating epigenetic aging. In this study, we evaluated the inflammatory profile and the epigenetic age of infected and noninfected individuals from an endemic area in Brazil. The profile of cytokines, chemokines and growth factors analyzed in the sera of the two groups of individuals showed similarities, although infected individuals had a higher concentration of these mediators. A significant increase in IL-1ra, CXCL8, CCL2, CCL3 and CCL4 production was associated with leprosy infection. Notably, elderly individuals displayed distinct immune responses associated with their infection status when compared to adults suggesting an adaptive remodelling of their immune responses. Epigenetic analysis also showed that there was no difference in epigenetic age between the two groups of individuals. However, individuals from the endemic area had a significant accelerated aging when compared to individuals from São Paulo, a non-endemic area in Brazil. Moreover, the latter cohort was also epigenetically aged in relation to an Italian cohort. Our data shows that living in endemic areas for chronic infectious diseases results in remodelling of inflammaging and acceleration of epigenetic aging in individuals regardless of their infectious status. It also highlights that geographical, genetic and environmental factors influence aging and immunosenescence in their pace and profile.

Keywords:  endemic area; epigenetic age; infectious diseases; inflammaging; leprosy

DOI:  https://doi.org/10.1016/j.mad.2022.111713
J Gerontol A Biol Sci Med Sci. 2022 Aug 02. pii: glac153. [Epub ahead of print]

Hippocampal DNA Methylation, Epigenetic Age and Spatial Memory Performance in Young And Old Rats.

Priscila Chiavellini, Marianne Lehmann, Martina Canatelli Mallat, Joseph A Zoller, Claudia B Herenu, Gustavo R Morel, Steve Horvath, Rodolfo G Goya.

  In humans and rats, aging is associated with a progressive deterioration of spatial learning and memory. These functional alterations are correlated with morphological and molecular changes in the hippocampus. Here, we assessed age-related changes in DNA methylation (DNAm) landscape in the rat hippocampus and the correlation of spatial memory with hippocampal DNAm age in 2.6 months and 26.6 months old rats. Spatial memory performance was assessed with the Barnes maze test. In order to evaluate learning ability as well as spatial memory retention, we assessed the time spent by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. The rat pan-tissue clock was applied to DNA methylation data from hippocampal tissue. An enrichment pathway analysis revealed that neuron fate commitment, brain development, and central nervous system development were processes whose underlying genes were enriched in hypermethylated CpGs in the old rats. In the old rat hippocampi, the methylation levels of CpGs proximal to transcription factors associated with genes Pax5, Lbx1, Nr2f2, Hnf1b, Zic1, Zic4, Hoxd9; Hoxd10, Gli3, Gsx1 and Lmx1b, and Nipbl showed a significant regression with spatial memory performance. Regression analysis of different memory performance indices with hippocampal DNAm age was significant These results suggest that age-related hypermethylation of transcription factors related to certain gene families, like Zic and Gli, may play a causal role in the decline in spatial memory in old rats. Hippocampal DNAm age seems to be a reliable index of spatial memory performance in young and old rats.

Keywords:  Aging; DNAm age; Hippocampus; Methylation landscape; Spatial memory

DOI:  https://doi.org/10.1093/gerona/glac153
Aging Cell. 2022 Jul 30. e13677

p300 arrests intervertebral disc degeneration by regulating the FOXO3/Sirt1/Wnt/β-catenin axis.

Yingjie Hao, Zhinan Ren, Lei Yu, Guangduo Zhu, Panke Zhang, Jian Zhu, Shuyan Cao.

  The transcription factor p300 is reportedly involved in age-associated human diseases, including intervertebral disc degeneration (IDD). In this study, we investigate the potential role and pathophysiological mechanism of p300 in IDD. Clinical tissue samples were collected from patients with lumbar disc herniation (LDH), in which the expression of p300, forkhead box O3 (FOXO3), and sirtuin 1 (Sirt1) was determined. Nucleus pulposus cells (NPCs) isolated from clinical degenerative intervertebral disc (IVD) tissues were introduced with oe-p300, oe-FOXO3, Wnt/β-catenin agonist 1, C646 (p300/CBP inhibitor), or si-p300 to explore the functional role of p300 in IDD and to characterize the relationship between p300 and the FOXO3/Sirt1/Wnt/β-catenin pathway. Also, we established a rat IDD model by inducing needle puncture injuries in the caudal IVDs for further verification of p300 functional role. We found that p300 was downregulated in the clinical tissues and NPCs of IDD. Overexpression of p300 promoted the proliferation and autophagy of NPCs while inhibiting cell apoptosis, which was associated with FOXO3 upregulation. p300 could increase the expression of FOXO3 by binding to the Sirt1 promoter, and thus, contributed to inactivation of the Wnt/β-catenin pathway. In vivo results further displayed that p300 slowed down the progression of IDD by disrupting the Wnt/β-catenin pathway through the FOXO3/Sirt1 axis. Taken together, we suggest that p300 can act to suppress IDD via a FOXO3-dependent mechanism, highlighting a potential novel target for treatment of IDD.

Keywords:  Autophagy; FOXO3; Intervertebral disc degeneration; Nucleus pulposus cells; Sirt1; Wnt/β-catenin pathway; p300

DOI:  https://doi.org/10.1111/acel.13677
Age Ageing. 2022 Aug 02. pii: afac156. [Epub ahead of print]51(8):

New horizons in life extension, healthspan extension and exceptional longevity.

David G Le Couteur, Nir Barzilai.

  Many common chronic diseases and syndromes are ageing-related. This raises the prospect that therapeutic agents that target the biological changes of ageing will prevent or delay multiple diseases with a single therapy. Gerotherapeutic drugs are those that target pathways involved in ageing, with the aims of reducing the burden of ageing-related diseases and increasing lifespan and healthspan. The approach to discovering gerotherapeutic drugs is similar to that used to discover drugs for diseases. This includes screening for novel compounds that act on receptors or pathways that influence ageing or repurposing of drugs currently available for other indications. A novel approach involves studying populations with exceptional longevity, in order to identify genes variants linked with longer lifespan and could be targeted by drugs. Metformin, rapamycin and precursors of nicotinamide adenine dinucleotide are amongst the frontrunners of gerotherapeutics that are moving into human clinical trials to evaluate their effects on ageing. There are also increasing numbers of potential gerotherapeutic drugs in the pipeline or being studied in animal models. A key hurdle is designing clinical trials that are both feasible and can provide sufficient clinical evidence to support licencing and marketing of gerotherapeutic drugs.

Keywords:  ageing; ageing biology; exceptional longevity; gerotherapeutic; metformin; nicotinamide adenine dinucleotide; older people; rapamycin

DOI:  https://doi.org/10.1093/ageing/afac156
Hum Cell. 2022 Aug 04.

Astragaloside IV alleviates senescence of vascular smooth muscle cells through activating Parkin-mediated mitophagy.

Huijun Li, Jialin Xu, Yanan Zhang, Lei Hong, Zhijian He, Zhiheng Zeng, Li Zhang.

  Astragaloside IV (AS-IV), as one of the main active components of Astragalus membranaceus, has been reported to have cardiovascular protective effects. However, the role and molecular mechanism of AS-IV in vascular senescence have not been clearly stated. The in vitro aging model was constructed using bleomycin (BLM) in vascular smooth muscle cells (VSMCs). Cell senescence were assessed through Western blotting analysis of aging markers, flow cytometry, and the β-galactosidase (SA-β-Gal) kit. Mitophagy was determined through transmission electron microscopy, TMRM staining, and Western blotting analysis of p62. A model of aging blood vessels was induced by D-gal. The vascular wall thickness of mice was also evaluated by H&E staining. Our data proved that AS-IV plays an anti-senescent role in vitro and in vivo. Results showed that AS-IV effectively improved mitochondrial injury, raised MMP, and mediated mitophagy in BLM-induced senescent VSMCs and D-gal induced aging mice. Parkin expression strengthened AS-IV's anti-senescent function. In conclusions, AS-IV attenuated BLM-induced VSMC senescence via Parkin to regulate mitophagy. Therefore, AS-IV-mediated Parkin might be a latent therapeutic agent and target for VSMC senescence.

Keywords:  Astragaloside IV; Mitophagy; Parkin; Senescence; Vascular smooth muscle cells

DOI:  https://doi.org/10.1007/s13577-022-00758-6
Cell Stem Cell. 2022 Aug 04. pii: S1934-5909(22)00297-1. [Epub ahead of print]29(8): 1156-1158

Turning the clock forward: Inflammation accelerates the aging of hematopoietic stem cells.

Sarah S Burns, Reuben Kapur.

In the current issue of Cell Stem Cell, Bogeska et al. demonstrate that repeated exposures to inflammation cause indelible and specific functional compromise and accelerated aging of long-term hematopoietic stem cells (LT-HSCs). This study proposes the notion that the cumulative inflammatory events over the course of an organism's lifespan may irreversibly damage LT-HSCs.

DOI: https://doi.org/10.1016/j.stem.2022.07.002
Aging Cell. 2022 Jul 31.

p38α-MAPK-deficient myeloid cells ameliorate symptoms and pathology of APP-transgenic Alzheimer's disease mice.

Qinghua Luo, Laura Schnöder, Wenlin Hao, Kathrin Litzenburger, Yann Decker, Inge Tomic, Michael D Menger, Yang Liu, Klaus Fassbender.

  Alzheimer's disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by extracellular deposition of amyloid-β peptides (Aβ) and microglia-dominated inflammatory activation in the brain. p38α-MAPK is activated in both neurons and microglia. How p38α-MAPK in microglia contributes to AD pathogenesis remains unclear. In this study, we conditionally knocked out p38α-MAPK in all myeloid cells or specifically in microglia of APP-transgenic mice, and examined animals for AD-associated pathologies (i.e., cognitive deficits, Aβ pathology, and neuroinflammation) and individual microglia for their inflammatory activation and Aβ internalization at different disease stages (e.g., at 4 and 9 months of age). Our experiments showed that p38α-MAPK-deficient myeloid cells were more effective than p38α-MAPK-deficient microglia in reducing cerebral Aβ and neuronal impairment in APP-transgenic mice. Deficiency of p38α-MAPK in myeloid cells inhibited inflammatory activation of individual microglia at 4 months but enhanced it at 9 months. Inflammatory activation promoted microglial internalization of Aβ. Interestingly, p38α-MAPK-deficient myeloid cells reduced IL-17a-expressing CD4-positive lymphocytes in 9 but not 4-month-old APP-transgenic mice. By cross-breeding APP-transgenic mice with Il-17a-knockout mice, we observed that IL-17a deficiency potentially activated microglia and reduced Aβ deposition in the brain as shown in 9-month-old myeloid p38α-MAPK-deficient AD mice. Thus, p38α-MAPK deficiency in all myeloid cells, but not only in microglia, prevents AD progression. IL-17a-expressing lymphocytes may partially mediate the pathogenic role of p38α-MAPK in peripheral myeloid cells. Our study supports p38α-MAPK as a therapeutic target for AD patients.

Keywords:  Alzheimer's disease; amyloid-beta (Aβ); microglia; neurodegeneration; p38α-MAPK

DOI:  https://doi.org/10.1111/acel.13679
NPJ Aging. 2022 May 01. 8(1): 5

Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men.

Masaki Igarashi, Yoshiko Nakagawa-Nagahama, Masaomi Miura, Kosuke Kashiwabara, Keisuke Yaku, Mika Sawada, Rie Sekine, Yuichiro Fukamizu, Toshiya Sato, Takanobu Sakurai, Jiro Sato, Kenji Ino, Naoto Kubota, Takashi Nakagawa, Takashi Kadowaki, Toshimasa Yamauchi.

Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD + ) upon the administration of nicotinamide mononucleotide (NMN), an NAD + precursor, can mitigate aging-related disorders; however, human data on this are limited. We investigated whether the chronic oral supplementation of NMN can elevate blood NAD + levels and alter physiological dysfunctions in healthy older participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test, which should be validated in larger studies; however, NMN exerted no significant effect on body composition. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

DOI: https://doi.org/10.1038/s41514-022-00084-z
Proc Natl Acad Sci U S A. 2022 Aug 09. 119(32): e2114758119

Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation.

Desi C Alexander, Tanya Corman, Mariel Mendoza, Andrew Glass, Tal Belity, Ranran Wu, Rianne R Campbell, Joseph Han, Ashley A Keiser, Jeffrey Winkler, Marcelo A Wood, Thomas Kim, Benjamin A Garcia, Hagit Cohen, Philipp Mews, Gabor Egervari, Shelley L Berger.

  Histone acetylation is a key component in the consolidation of long-term fear memories. Histone acetylation is fueled by acetyl-coenzyme A (acetyl-CoA), and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of chromatin. In particular, acetyl-CoA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well tolerated in mice, yet the Acss2-null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Furthermore, systemic administration of blood-brain barrier-permeable Acss2 inhibitors during the consolidation window reduces fear-memory formation in mice and rats and reduces anxiety in a predator-scent stress paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated, role in the formation of fear memories.

Keywords:  epigenetics; fear conditioning; histone acetylation; learning and memory; mass spectrometry

DOI:  https://doi.org/10.1073/pnas.2114758119