bims-senagi 2021-11-07 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2021–11–07
25 papers selected by
Maria Grazia Vizioli, Mayo Clinic

Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging.
Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection.
Homologous recombination-mediated irreversible genome damage underlies telomere-induced senescence.
NAD+, Senolytics, or Pyruvate for Healthy Aging?
Role of mTOR in the development of asthma in mice with cigarette smoke-induced cellular senescence.
Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1.
Precise Diabetic Wound Therapy: PLS Nanospheres Eliminate Senescent Cells via DPP4 Targeting and PARP1 Activation.
Molecular programs of fibrotic change in aging human lung.
Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases.
CAMSAP3 depletion induces lung cancer cell senescence-associated phenotypes through extracellular signal-regulated kinase inactivation.
Predicting physiological aging rates from a range of quantitative traits using machine learning.
Microbiota Signals Suppress B Lymphopoiesis With Aging in Mice.
Immunosenescence, Inflammaging and Resilience: An Evolutionary Perspective of Adaptation in the Light of COVID-19 Pandemic.
Stress and Telomere Shortening: Insights from Cellular Mechanisms.
TGF-β1 is involved in senescence-related pathways in glomerular endothelial cells via p16 translocation and p21 induction.
Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence.
Application of Machine Learning and Weighted Gene Co-expression Network Algorithm to Explore the Hub Genes in the Aging Brain.
Glial AP1 is activated with aging and accelerated by traumatic brain injury.
Mediterranean Diet In Healthy Aging.
Integrated Single-Cell Bioinformatics Analysis Reveals Intrinsic and Extrinsic Biological Characteristics of Hematopoietic Stem Cell Aging.
Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice.
Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis.
Insights into T-cell dysfunction in Alzheimer's disease.
Non-genomic rewiring of vitamin D receptor to p53 as a key to Alzheimer's disease.
Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.

Aging Cell. 2021 Nov 03. e13486

Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging.

Lei Zhang, Jing Zhao, Xiaodong Mu, Sara J McGowan, Luise Angelini, Ryan D O'Kelly, Matthew J Yousefzadeh, Ayumi Sakamoto, Zaira Aversa, Nathan K LeBrasseur, Yousin Suh, Johnny Huard, Theodore M Kamenecka, Laura J Niedernhofer, Paul D Robbins.

  Constitutive NF-κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF-κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF-κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence-associated beta-galactosidase (SA-β-gal) activity in oxidative stress-induced senescent mouse embryonic fibroblasts as well as in etoposide-induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1-/ ∆ and Zmpste24-/- mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2-year-old WT mice. Taken together, these results demonstrate that IKK/NF-κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age-related diseases.

Keywords:  NEMO; NF-κB; SR12343; aging; senescence

DOI:  https://doi.org/10.1111/acel.13486
Signal Transduct Target Ther. 2021 11 03. 6(1): 382

Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection.

Zhuo Zhou, Xinyi Zhang, Xiaobo Lei, Xia Xiao, Tao Jiao, Ruiyi Ma, Xiaojing Dong, Qi Jiang, Wenjing Wang, Yujin Shi, Tian Zheng, Jian Rao, Zichun Xiang, Lili Ren, Tao Deng, Zhengfan Jiang, Zhixun Dou, Wensheng Wei, Jianwei Wang.

The global coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense RNA virus. How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved. Here, we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway. SARS-CoV-2 infection induces the cellular level of 2'3'-cGAMP associated with STING activation. cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection. We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion. Furthermore, cytoplasmic chromatin-cGAS-STING pathway, but not MAVS-mediated viral RNA sensing pathway, contributes to interferon and pro-inflammatory gene expression upon cell fusion. Finally, we show that cGAS is required for host antiviral responses against SARS-CoV-2, and a STING-activating compound potently inhibits viral replication. Together, our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection, mediated by cytoplasmic chromatin from the infected cells. Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19. In addition, these findings extend our knowledge in host defense against viral infection by showing that host cells' self-nucleic acids can be employed as a "danger signal" to alarm the immune system.

DOI: https://doi.org/10.1038/s41392-021-00800-3
Nucleic Acids Res. 2021 Nov 02. pii: gkab965. [Epub ahead of print]

Homologous recombination-mediated irreversible genome damage underlies telomere-induced senescence.

Sabrina Ghadaouia, Marc-Alexandre Olivier, Aurélie Martinez, Tibila Kientega, Jian Qin, Patrick Lambert-Lanteigne, Guillaume B Cardin, Chantal Autexier, Nicolas Malaquin, Francis Rodier.

Loss of telomeric DNA leads to telomere uncapping, which triggers a persistent, p53-centric DNA damage response that sustains a stable senescence-associated proliferation arrest. Here, we show that in normal cells telomere uncapping triggers a focal telomeric DNA damage response accompanied by a transient cell cycle arrest. Subsequent cell division with dysfunctional telomeres resulted in sporadic telomeric sister chromatid fusions that gave rise to next-mitosis genome instability, including non-telomeric DNA lesions responsible for a stable, p53-mediated, senescence-associated proliferation arrest. Unexpectedly, the blocking of Rad51/RPA-mediated homologous recombination, but not non-homologous end joining (NHEJ), prevented senescence despite multiple dysfunctional telomeres. When cells approached natural replicative senescence, interphase senescent cells displayed genome instability, whereas near-senescent cells that underwent mitosis despite the presence of uncapped telomeres did not. This suggests that these near-senescent cells had not yet acquired irreversible telomeric fusions. We propose a new model for telomere-initiated senescence where tolerance of telomere uncapping eventually results in irreversible non-telomeric DNA lesions leading to stable senescence. Paradoxically, our work reveals that senescence-associated tumor suppression from telomere shortening requires irreversible genome instability at the single-cell level, which suggests that interventions to repair telomeres in the pre-senescent state could prevent senescence and genome instability.

DOI: https://doi.org/10.1093/nar/gkab965
Nutr Metab Insights. 2021 ;14 11786388211053407

NAD+, Senolytics, or Pyruvate for Healthy Aging?

Fang-Qiang Zhou.

  In last decades, healthy aging has become one of research hotspots in life science. It is well known that the nicotinamide adenine dinucleotide oxidized form (NAD+) level in cells decreases with aging and aging-related diseases. Several years ago, one of NAD+ precursors was first demonstrated with its new role in DNA damage repairing in mice, restoring old mice to their physical state at young ones. The finding encourages extensive studies in animal models and patients. NAD+ and its precursors have been popular products in nutrition markets. Alternatively, it was also evidenced that clearance of cellular senescence by senolytics preserved multiorgan (kidney and heart) function and extended healthy lifespan in mice. Subsequent studies confirmed findings in elderly patients subjected with idiopathic pulmonary fibrosis. The senolytic therapy is now focused on various diseases in animal and clinical studies. However, pyruvate, as both a NAD+ substitute and a new senolytic, may be advantageous, on the equimolar basis, over current products above in preventing and treating diseases and aging. Pyruvate-enriched fluids, particularly pyruvate oral rehydration salt, may be a novel intervention for diseases and aging besides critical care. Albeit the direct evidence that benefits healthy aging is still limited to date, pyruvate, as both NAD+ provider and senolytic agent, warrants intensive research to compare NAD+ or senolytics for healthy aging, specifically on the equimolar basis, in effective blood levels. This review briefly discussed the recognition of healthy aging by comparing NAD+ and Senolytics with sodium pyruvate from the clinical point of view.

Keywords:  Healthy aging; NAD+; pyruvate; senescence; senolytics

DOI:  https://doi.org/10.1177/11786388211053407
J Gerontol A Biol Sci Med Sci. 2021 Nov 01. pii: glab303. [Epub ahead of print]

Role of mTOR in the development of asthma in mice with cigarette smoke-induced cellular senescence.

Hyun Seung Lee, Heung-Woo Park.

  The role of cellular senescence in the development of asthma is not well known. We aimed to evaluate the susceptibility of mice with cellular senescence to asthma development and determine whether the mTOR pathway played an important role in this process. Cellular senescence was induced in mice by intranasal instillation of 2% cigarette smoke extract (CSE). Subsequently, a low dose (0.1 μg) of house dust mite (HDM) allergens, which causes no inflammation and airway hyperresponsiveness (AHR) in mice without cellular senescence, was administered intranasally. To evaluate the role of mTOR pathway in this model, rapamycin (TORC1 inhibitor) was injected intraperitoneally before CSE instillation. CSE significantly increased senescence-associated β-gal (SA-β-gal) activity in lung homogenate and S100A8/9+p-mTOR+ population in lung cells. Moreover, S100A8/9+ or HMGB1+ populations in airway epithelial cells with phospho-mTOR activity increased remarkably. Rapamycin attenuated all changes. Subsequent administration of low-dose HDM allergen induced murine asthma characterized by increased AHR, serum HDM-specific immunoglobulin E, and eosinophilic airway inflammation; these asthma characteristics disappeared after rapamycin injection. In vitro experiments showed significant activation of bone marrow-derived cells co-cultured with S100A9 or HMGB1 overexpressing MLE-12 cells treated with HDM allergen, compared to those treated with HDM allergen only. CSE increased the levels of senescence markers (S100A8/9 and HMGB1) in airway epithelial cells, making the mice susceptible to asthma development due to low-dose HDM allergens by activating dendritic cells. Since rapamycin significantly attenuated asthma characteristics, the mTOR pathway may be important in this murine model.

Keywords:  Animal model; Asthma; Cellular senescence; Cigarette smoking; HMGB1; S100A9; Sirolimus; mTOR protein

DOI:  https://doi.org/10.1093/gerona/glab303
EMBO Mol Med. 2021 Nov 02. e14146

Glomerular endothelial cell senescence drives age-related kidney disease through PAI-1.

Camille Cohen, Océane Le Goff, Frédéric Soysouvanh, Florence Vasseur, Marine Tanou, Clément Nguyen, Lucile Amrouche, Julien Le Guen, Oriana Saltel-Fulero, Tanguy Meunier, Thao Nguyen-Khoa, Marion Rabant, Dominique Nochy, Christophe Legendre, Gérard Friedlander, Bennett G Childs, Daren J Baker, Bertrand Knebelmann, Dany Anglicheau, Fabien Milliat, Fabiola Terzi.

  The mechanisms underlying the development of glomerular lesions during aging are largely unknown. It has been suggested that senescence might play a role, but the pathophysiological link between senescence and lesion development remains unexplained. Here, we uncovered an unexpected role for glomerular endothelial cells during aging. In fact, we discovered a detrimental cross-talk between senescent endothelial cells and podocytes, through PAI-1. In vivo, selective inactivation of PAI-1 in endothelial cells protected glomeruli from lesion development and podocyte loss in aged mice. In vitro, blocking PAI-1 in supernatants from senescent endothelial cells prevented podocyte apoptosis. Consistently, depletion of senescent cells prevented podocyte loss in old p16 INK-ATTAC transgenic mice. Importantly, these experimental findings are relevant to humans. We showed that glomerular PAI-1 expression was predictive of poor outcomes in transplanted kidneys from elderly donors. In addition, we observed that in elderly patients, urinary PAI-1 was associated with age-related chronic kidney disease. Altogether, these results uncover a novel mechanism of kidney disease and identify PAI-1 as a promising biomarker of kidney dysfunction in allografts from elderly donors.

Keywords:  PAI-1; aging nephropathy; endothelial-podocyte cross-talk; kidney transplantation; senescence

DOI:  https://doi.org/10.15252/emmm.202114146
Adv Sci (Weinh). 2021 Nov 05. e2104128

Precise Diabetic Wound Therapy: PLS Nanospheres Eliminate Senescent Cells via DPP4 Targeting and PARP1 Activation.

Renliang Zhao, Xiangyun Jin, Ang Li, Bitong Xu, Yifan Shen, Wei Wang, Jinghuan Huang, Yadong Zhang, Xiaolin Li.

  Diabetic ulcers, a difficult problem faced by clinicians, are strongly associated with an increase in cellular senescence. Few empirical studies have focused on exploring a targeted strategy to cure diabetic wounds by eliminating senescent fibroblasts (SFs) and reducing side effects. In this study, poly-l-lysine/sodium alginate (PLS) is modified with talabostat (PT100) and encapsulates a PARP1 plasmid (PARP1@PLS-PT100) for delivery to target the dipeptidyl peptidase 4 (DPP4) receptor and eliminate SFs. PARP1@PLS-PT100 releases encapsulated plasmids, displaying high selectivity for SFs over normal fibroblasts by targeting the DPP4 receptor, decreasing senescence-associated secretory phenotypes (SASPs), and stimulating the secretion of anti-inflammatory factors. Furthermore, the increased apoptosis of SFs and the disappearance of cellular senescence alleviates SASPs, accelerates re-epithelialization and collagen deposition, and significantly induces macrophage M2 polarization, which mediates tissue repair and the inflammatory response. This innovative strategy has revealed the previously undefined role of PARP1@PLS-PT100 in promoting diabetic wound healing, suggesting its therapeutic potential in refractory wound repair.

Keywords:  DPP4 receptor; diabetic wound healing; nanospheres; selective targeting; senescence

DOI:  https://doi.org/10.1002/advs.202104128
Nat Commun. 2021 Nov 02. 12(1): 6309

Molecular programs of fibrotic change in aging human lung.

Seoyeon Lee, Mohammad Naimul Islam, Kaveh Boostanpour, Dvir Aran, Guangchun Jin, Stephanie Christenson, Michael A Matthay, Walter L Eckalbar, Daryle J DePianto, Joseph R Arron, Liam Magee, Sunita Bhattacharya, Rei Matsumoto, Masaru Kubota, Donna L Farber, Jahar Bhattacharya, Paul J Wolters, Mallar Bhattacharya.

Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging.

DOI: https://doi.org/10.1038/s41467-021-26603-2
Cell Biosci. 2021 Nov 02. 11(1): 188

Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases.

Shuqi Du, Hui Zheng.

  Aging happens to all of us as we live. Thanks to the improved living standard and discovery of life-saving medicines, our life expectancy has increased substantially across the world in the past century. However, the rise in lifespan leads to unprecedented increases in both the number and the percentage of individuals 65 years and older, accompanied by the increased incidences of age-related diseases such as type 2 diabetes mellitus and Alzheimer's disease. FoxO transcription factors are evolutionarily conserved molecules that play critical roles in diverse biological processes, in particular aging and metabolism. Their dysfunction is often found in the pathogenesis of many age-related diseases. Here, we summarize the signaling pathways and cellular functions of FoxO proteins. We also review the complex role of FoxO in aging and age-related diseases, with focus on type 2 diabetes and Alzheimer's disease and discuss the possibility of FoxO as a molecular link between aging and disease risks.

Keywords:  Age-related disease; Aging; Alzheimer’s disease; FoxO; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1186/s13578-021-00700-7
Cancer Med. 2021 Nov 01.

CAMSAP3 depletion induces lung cancer cell senescence-associated phenotypes through extracellular signal-regulated kinase inactivation.

Onsurang Wattanathamsan, Paninee Chetprayoon, Naphat Chantaravisoot, Piriya Wongkongkathep, Pithi Chanvorachote, Varisa Pongrakhananon.

   BACKGROUND: Cellular senescence is an aging-related process found in cancer cells that contributes to irreversible growth arrest and tumor aggressiveness. Recently, calmodulin-regulated spectrin-associated protein 3 (CAMSAP3), a minus-end microtubule-stabilizing protein, has received increasing attention in cancer cell biology. However, the biological role of CAMSAP3 on senescence in human lung cancer remains incompletely understood.
METHODS: The function of CAMSAP3 on the regulation of cellular senescence-associated phenotypes in human non-small cell lung cancer H460 cells were determined in CAMSAP3 deletion (H460/C3ko) cells. The effects of CAMSAP3 on cell proliferation were investigated using MTT and colony formation assays. The cell cycle activity was evaluated by flow cytometry and the senescence-associated phenotypes were observed by SA-β-Gal staining. Quantitative RT-PCR and westen blot were used to evaluate the expression of cell cycle and senescence markers. Moreover, the interaction of CAMSAP3-ERK1/2 and possible partner protein was quantified using immunoprecipitation/mass spectrometry and immunofluorescence. Lastly, an xenograft model were performed.
RESULTS: CAMSAP3 knockout promotes lung cancer cell senescence-associated phenotypes and induces G1 cell cycle arrest. Mechanistic investigation revealed that phosphorylated ERK (p-ERK) was markedly downregulated in CAMSAP3-deleted cells, suppressing cyclin D1 expression levels, and full-length CAMSAP3 abrogated these phenotypes. Proteomic analysis demonstrated that vimentin, an intermediate filament protein, is required as a scaffold for CAMSAP3-modulating ERK signaling. Furthermore, an in vivo tumor xenograft experiment showed that tumor initiation is potentially delayed in CAMSAP3 knockout tumors with the downregulation of p-ERK and cyclin D1, resulting in a senescence-like phenotype.
CONCLUSION: This study is the first to report an intriguing role of CAMSAP3 in lung carcinoma cell senescence-associated phenotypes via the modulation of p-ERK/cyclin D1 signaling.

Keywords:  CAMSAP3; cellular senescence-associated phenotypes; cyclin D1; extracellular signal-regulated kinase 1/2 (ERK1/2); lung cancer

DOI:  https://doi.org/10.1002/cam4.4380
Aging (Albany NY). 2021 Oct 29. 13(20): 23471-23516

Predicting physiological aging rates from a range of quantitative traits using machine learning.

Eric D Sun, Yong Qian, Richard Oppong, Thomas J Butler, Jesse Zhao, Brian H Chen, Toshiko Tanaka, Jian Kang, Carlo Sidore, Francesco Cucca, Stefania Bandinelli, Gonçalo R Abecasis, Myriam Gorospe, Luigi Ferrucci, David Schlessinger, Ilya Goldberg, Jun Ding.

  It is widely thought that individuals age at different rates. A method that measures "physiological age" or physiological aging rate independent of chronological age could therefore help elucidate mechanisms of aging and inform an individual's risk of morbidity and mortality. Here we present machine learning frameworks for inferring individual physiological age from a broad range of biochemical and physiological traits including blood phenotypes (e.g., high-density lipoprotein), cardiovascular functions (e.g., pulse wave velocity) and psychological traits (e.g., neuroticism) as main groups in two population cohorts SardiNIA (~6,100 participants) and InCHIANTI (~1,400 participants). The inferred physiological age was highly correlated with chronological age (R2 > 0.8). We further defined an individual's physiological aging rate (PAR) as the ratio of the predicted physiological age to the chronological age. Notably, PAR was a significant predictor of survival, indicating an effect of aging rate on mortality. Our trait-based PAR was correlated with DNA methylation-based epigenetic aging score (r = 0.6), suggesting that both scores capture a common aging process. PAR was also substantially heritable (h2~0.3), and a subsequent genome-wide association study of PAR identified significant associations with two genetic loci, one of which is implicated in telomerase activity. Our findings support PAR as a proxy for an underlying whole-body aging mechanism. PAR may thus be useful to evaluate the efficacy of treatments that target aging-related deficits and controllable epidemiological factors.

Keywords:  aging clock; machine learning; mortality; personalized medicine; physiological aging rate; quantitative trait

DOI:  https://doi.org/10.18632/aging.203660
Front Immunol. 2021 ;12 767267

Microbiota Signals Suppress B Lymphopoiesis With Aging in Mice.

Joseph R Krambs, Darlene A Monlish, Feng Gao, Laura G Schuettpelz, Daniel C Link.

  Aging is associated with significant changes in hematopoiesis that include a shift from lymphopoiesis to myelopoiesis and an expansion of phenotypic hematopoietic stem cells (HSCs) with impaired self-renewal capacity and myeloid-skewed lineage differentiation. Signals from commensal flora support basal myelopoiesis in young mice; however, their contribution to hematopoietic aging is largely unknown. Here, we characterize hematopoiesis in young and middle-aged mice housed under specific pathogen free (SPF) and germ-free (GF) conditions. The marked shift from lymphopoiesis to myelopoiesis that develops during aging of SPF mice is mostly abrogated in GF mice. Compared with aged SPF mice, there is a marked expansion of B lymphopoiesis in aged GF mice, which is evident at the earliest stages of B cell development. The expansion of phenotypic and functional HSCs that occurs with aging is similar in SPF and GF mice. However, HSCs from young GF mice have increased lymphoid lineage output, and the aging-associated expansion of myeloid-biased HSCs is significantly attenuated in GF mice. Consistent with these data, RNA expression profiling of phenotypic HSCs from aged GF mice show enrichment for non-myeloid biased HSCs. Surprisingly, the RNA expression profiling data also suggest that inflammatory signaling is increased in aged GF HSCs compared with aged SPF HSCs. Collectively, these data suggest that microbiota-related signals suppress B lymphopoiesis at multiple stages of development and contribute to the expansion of myeloid-biased HSCs that occurs with aging.

Keywords:  B lymphopoiesis; HSC transplantation; aging; hematopoiesis; hematopoietic stem cell; inflammation; microbiome; myeloid skewing

DOI:  https://doi.org/10.3389/fimmu.2021.767267
Psychiatr Danub. 2021 Spring-Summer;33(Suppl 4):33(Suppl 4): 427-431

Immunosenescence, Inflammaging and Resilience: An Evolutionary Perspective of Adaptation in the Light of COVID-19 Pandemic.

Marko Banić, Sanja Pleško, Marija Urek, Žarko Babić, Duško Kardum.

The evolution of immunology enabled the study of role of innate and adaptive immunity in systems biology network of immunosenescence and inflammaging. Due to global reduction in birth rates and reduced mortality, in year 2025 there will be about 1.2 billion of people over age of sixty, worldwide. The notion that the real age is not chronological, but the biological one led to the concept of "bioage", defining the biologic reactivity and resilience, including the immune competence of an individual. A competent immune network, systemic and mucosal is intrinsic to resilience and homeostasis of the human holobiont as the unit of evolution. In elderly, the immunosenescence could be associated with higher levels of proinflammatory mediators (such as IL-6), frialty and mortality. Proi-inflammatory state in elderly is denoted as inflammaging, characterized with low-grade (sterile) inflammation, as a physiologic response to life-long antigenic stimuli. When under control, inflammaging could be regarded as an efficient defense mechanism, oposed and regulated by anti-inflammatory pathways and molecules. Immunosensecence. The emerging concepts of "individual immunobiography" and "trained immunity" speak in favour that the immunological experience during the life would shape the ability of each individual to respond to various stimuli, strongly influencing the elements of innate and adaptive immunity, including macrophages and innate lymphoid cells. Older age is one of the main risk factors for the severe clinical picture and adverse outcome of COVID-19 infection, due to immunosenscence and chronic low-grade inflammation (inflammaging), both characterizing the immune reactioin in elderly. The senescent immune system, along with the advanced process of inflammaging is prone to react with uncontrolled activation of innate immune response that leads to cytokine release syndrome, tissue damage and adverse outcome of infection. Further research is aimed to nutritional and pharmacologic (immunomodulatory) interventions to influence the process of bioaging and immunosenscence, and to modulate the reaction of elderly to infection, including the COVID-19.
Ageing Res Rev. 2021 Nov 01. pii: S1568-1637(21)00254-3. [Epub ahead of print] 101507

Stress and Telomere Shortening: Insights from Cellular Mechanisms.

Jue Lin, Elissa Epel.

  Short telomeres confer risk of degenerative diseases. Chronic psychological stress can lead to disease through many pathways, and research from in vitro studies to human longitudinal studies has pointed to stress-induced telomere damage as an important pathway. However, there has not been a comprehensive model to describe how changes in stress physiology and neuroendocrine pathways can lead to changes in telomere biology. Critically short telomeres or the collapse of the telomere structure caused by displacement of telomere binding protein complex shelterin elicit a DNA damage response and lead to senescence or apoptosis. In this narrative review, we summarize the key roles glucocorticoids, reactive oxygen species (ROS) and mitochondria, and inflammation play in mediating the relationship between psychological stress and telomere maintenance. We emphasis that these mediators are inter-connected and reinforce each other in positive feedback loops. Telomere length has not been studied across the lifespan yet, but the initial setting point at birth appears to be the most influential point, as it sets the lifetime trajectory, and is influenced by stress. We describe two types of intergenerational stress effects on telomeres - prenatal stress effects on telomeres during fetal development, and 'telotype transmission" -the directly inherited transmission of short telomeres from parental germline. It is clear that the initial simplistic view of telomere length as a mitotic clock has evolved into a far more complex picture of both transgenerational telomere influences, and of interconnected molecular and cellular pathways and networks, as hallmarks of aging where telomere maintenance is a key player interacting with mitochondria. Further mechanistic investigations, testing this comprehensive model of stress mediators shaping telomere biology and the telomere-mitochondrial nexus will lead to better understanding from cell to human lifespan aging, and could lead to anti-aging interventions.

Keywords:  glucocorticoid; inflammation; reactive oxidative species; shelterin complex; stress; telomerase; telomeres

DOI:  https://doi.org/10.1016/j.arr.2021.101507
Sci Rep. 2021 Nov 04. 11(1): 21643

TGF-β1 is involved in senescence-related pathways in glomerular endothelial cells via p16 translocation and p21 induction.

Sayo Ueda, Tatsuya Tominaga, Arisa Ochi, Akiko Sakurai, Kenji Nishimura, Eriko Shibata, Shu Wakino, Masanori Tamaki, Kojiro Nagai.

p16 inhibits cyclin-dependent kinases and regulates senescence-mediated arrest as well as p21. Nuclear p16 promotes G1 cell cycle arrest and cellular senescence. In various glomerular diseases, nuclear p16 expression is associated with disease progression. Therefore, the location of p16 is important. However, the mechanism of p16 trafficking between the nucleus and cytoplasm is yet to be fully investigated. TGF-β1, a major cytokine involved in the development of kidney diseases, can upregulate p21 expression. However, the relationship between TGF-β1 and p16 is poorly understood. Here, we report the role of podocyte TGF-β1 in regulating the p16 behavior in glomerular endothelial cells. We analyzed podocyte-specific TGF-β1 overexpression mice. Although p16 was found in the nuclei of glomerular endothelial cells and led to endothelial cellular senescence, the expression of p16 did not increase in glomeruli. In cultured endothelial cells, TGF-β1 induced nuclear translocation of p16 without increasing its expression. Among human glomerular diseases, p16 was detected in the nuclei of glomerular endothelial cells. In summary, we demonstrated the novel role of podocyte TGF-β1 in managing p16 behavior and cellular senescence in glomeruli, which has clinical relevance for the progression of human glomerular diseases.

DOI: https://doi.org/10.1038/s41598-021-01150-4
Sci Rep. 2021 Nov 02. 11(1): 21506

Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence.

Ruchi Kumari, Holger Hummerich, Xu Shen, Martin Fischer, Larisa Litovchick, Sibylle Mittnacht, James A DeCaprio, Parmjit S Jat.

Cellular senescence is a stable cell cycle arrest that normal cells undergo after a finite number of divisions, in response to a variety of intrinsic and extrinsic stimuli. Although senescence is largely established and maintained by the p53/p21WAF1/CIP1 and pRB/p16INK4A tumour suppressor pathways, the downstream targets responsible for the stability of the growth arrest are not known. We have employed a stable senescence bypass assay in conditionally immortalised human breast fibroblasts (CL3EcoR) to investigate the role of the DREAM complex and its associated components in senescence. DREAM is a multi-subunit complex comprised of the MuvB core, containing LIN9, LIN37, LIN52, LIN54, and RBBP4, that when bound to p130, an RB1 like protein, and E2F4 inhibits cell cycle-dependent gene expression thereby arresting cell division. Phosphorylation of LIN52 at Serine 28 is required for DREAM assembly. Re-entry into the cell cycle upon phosphorylation of p130 leads to disruption of the DREAM complex and the MuvB core, associating initially to B-MYB and later to FOXM1 to form MMB and MMB-FOXM1 complexes respectively. Here we report that simultaneous expression of MMB-FOXM1 complex components efficiently bypasses senescence with LIN52, B-MYB, and FOXM1 as the crucial components. Moreover, bypass of senescence requires non-phosphorylated LIN52 that disrupts the DREAM complex, thereby indicating a central role for assembly of the DREAM complex in senescence.

DOI: https://doi.org/10.1038/s41598-021-01012-z
Front Aging Neurosci. 2021 ;13 707165

Application of Machine Learning and Weighted Gene Co-expression Network Algorithm to Explore the Hub Genes in the Aging Brain.

Keping Chai, Jiawei Liang, Xiaolin Zhang, Panlong Cao, Shufang Chen, Huaqian Gu, Weiping Ye, Rong Liu, Wenjun Hu, Caixia Peng, Gang Logan Liu, Daojiang Shen.

  Aging is a major risk factor contributing to neurodegeneration and dementia. However, it remains unclarified how aging promotes these diseases. Here, we use machine learning and weighted gene co-expression network (WGCNA) to explore the relationship between aging and gene expression in the human frontal cortex and reveal potential biomarkers and therapeutic targets of neurodegeneration and dementia related to aging. The transcriptional profiling data of the human frontal cortex from individuals ranging from 26 to 106 years old was obtained from the GEO database in NCBI. Self-Organizing Feature Map (SOM) was conducted to find the clusters in which gene expressions downregulate with aging. For WGCNA analysis, first, co-expressed genes were clustered into different modules, and modules of interest were identified through calculating the correlation coefficient between the module and phenotypic trait (age). Next, the overlapping genes between differentially expressed genes (DEG, between young and aged group) and genes in the module of interest were discovered. Random Forest classifier was performed to obtain the most significant genes in the overlapping genes. The disclosed significant genes were further identified through network analysis. Through WGCNA analysis, the greenyellow module is found to be highly negatively correlated with age, and functions mainly in long-term potentiation and calcium signaling pathways. Through step-by-step filtering of the module genes by overlapping with downregulated DEGs in aged group and Random Forest classifier analysis, we found that MAPT, KLHDC3, RAP2A, RAP2B, ELAVL2, and SYN1 were co-expressed and highly correlated with aging.

Keywords:  SOM (self-organization map); WGCNA (weighted gene co-expression network analyses); aging brain; machine learning; random forest

DOI:  https://doi.org/10.3389/fnagi.2021.707165
Nat Aging. 2021 Jul;1(7): 585-597

Glial AP1 is activated with aging and accelerated by traumatic brain injury.

China N Byrns, Janani Saikumar, Nancy M Bonini.

The emergence of degenerative disease after traumatic brain injury is often described as an acceleration of normal age-related processes. Whether similar molecular processes occur after injury and in age is unclear. Here we identify a functionally dynamic and lasting transcriptional response in glia, mediated by the conserved transcription factor AP1. In the early post-TBI period, glial AP1 is essential for recovery, ensuring brain integrity and animal survival. In sharp contrast, chronic AP1 activation promotes human tau pathology, tissue loss, and mortality. We show a similar process activates in healthy fly brains with age. In humans, AP1 activity is detected after moderate TBI and correlates with microglial activation and tau pathology. Our data provide key molecular insight into glia, highlighting that the same molecular process drives dynamic and contradictory glia behavior in TBI, and possibly age, first acting to protect but chronically promoting disease.

DOI: https://doi.org/10.1038/s43587-021-00072-0
J Nutr Health Aging. 2021 ;25(9): 1076-1083

Mediterranean Diet In Healthy Aging.

E Mazza, Y Ferro, R Pujia, R Mare, S Maurotti, T Montalcini, A Pujia.

  The World elderly population is expected to double before 2050. Unhealthy habits and unhealthy lifestyles are commonly associated with age-related diseases or their worsening. Modification in daily lifestyle and diet may help preventing age-related diseases onset and efficiently affecting their evolution, thus promoting the Healthy Aging process, concept recently coined to describe the disease-free aging process. This review highlights the role of nutrition science in promoting healthy aging. Since the Mediterranean Model demonstrated to be a useful style in supporting healthy aging, promotion of this correct lifestyle by health policies seems to be the best approach to achieve this target.

Keywords:  Healthy Aging; Mediterranean diet; food intake; lifestyle; nutrition; prevention

DOI:  https://doi.org/10.1007/s12603-021-1675-6
Front Genet. 2021 ;12 745786

Integrated Single-Cell Bioinformatics Analysis Reveals Intrinsic and Extrinsic Biological Characteristics of Hematopoietic Stem Cell Aging.

Xiangjun Zeng, Xia Li, Mi Shao, Yulin Xu, Wei Shan, Cong Wei, Xiaoqing Li, Limengmeng Wang, Yongxian Hu, Yanmin Zhao, Pengxu Qian, He Huang.

  Hematopoietic stem cell (HSC) aging, which is accompanied by loss of self-renewal capacity, myeloid-biased differentiation and increased risks of hematopoietic malignancies, is an important focus in stem cell research. However, the mechanisms underlying HSC aging have not been fully elucidated. In the present study, we integrated 3 independent single-cell transcriptome datasets of HSCs together and identified Stat3 and Ifngr1 as two markers of apoptosis-biased and inflammatory aged HSCs. Besides, common differentially expressed genes (DEGs) between young and aged HSCs were identified and further validated by quantitative RT-PCR. Functional enrichment analysis revealed that these DEGs were predominantly involved in the cell cycle and the tumor necrosis factor (TNF) signaling pathway. We further found that the Skp2-induced signaling pathway (Skp2→Cip1→CycA/CDK2→DP-1) contributed to a rapid transition through G1 phase in aged HSCs. In addition, analysis of the extrinsic alterations on HSC aging revealed the increased expression levels of inflammatory genes in bone marrow microenvironment. Colony formation unit assays showed that inflammatory cytokines promoted cellular senescence and that blockade of inflammatory pathway markedly rejuvenated aged HSC functions and increased B cell output. Collectively, our study elucidated the biological characteristics of HSC aging, and the genes and pathways we identified could be potential biomarkers and targets for the identification and rejuvenation of aged HSCs.

Keywords:  aging; cell cycle; hematopoietic stem cells; inflammation; single cell integrated analysis

DOI:  https://doi.org/10.3389/fgene.2021.745786
Immun Ageing. 2021 Nov 05. 18(1): 42

Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice.

Huan Liu, Shujuan Chu, Zhilin Wu.

BACKGROUND: Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system. TLR4 contributes to many aging-related chronic diseases. However, whether TLR4 is involved in cardiovascular injury during the aging process has not been investigated.
METHODS: The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4-/- mice. An intraperitoneal glucose tolerance test (IPGTT) and insulin sensitivity test (IST) were conducted to evaluate global insulin sensitivity. Echocardiography was used to measure cardiac structure and performance. An isolated artery ring assay was used to measure the vasodilator function of the thoracic aorta. The inflammatory response was reflected by the serum concentration of cytokines.
RESULTS: TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency.
CONCLUSION: In summary, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.

DOI: https://doi.org/10.1186/s12979-021-00251-y
Aging Cell. 2021 Oct 31. e13510

Dietary citrate supplementation enhances longevity, metabolic health, and memory performance through promoting ketogenesis.

Shou-Zen Fan, Cheng-Sheng Lin, Yu-Wen Wei, Sheng-Rong Yeh, Yi-Hsuan Tsai, Andrew Chengyu Lee, Wei-Sheng Lin, Pei-Yu Wang.

  Citrate is an essential substrate for energy metabolism that plays critical roles in regulating cell growth and survival. However, the action of citrate in regulating metabolism, cognition, and aging at the organismal level remains poorly understood. Here, we report that dietary supplementation with citrate significantly reduces energy status and extends lifespan in Drosophila melanogaster. Our genetic studies in fruit flies implicate a molecular mechanism associated with AMP-activated protein kinase (AMPK), target of rapamycin (TOR), and ketogenesis. Mice fed a high-fat diet that supplemented with citrate or the ketone body β-hydroxybutyrate (βOHB) also display improved metabolic health and memory. These results suggest that dietary citrate supplementation may prove to be a useful intervention in the future treatment of age-related dysfunction.

Keywords:  dendritic spine; hippocampus; insulin; lifespan

DOI:  https://doi.org/10.1111/acel.13510
Aging Cell. 2021 Nov 01. e13511

Insights into T-cell dysfunction in Alzheimer's disease.

Linbin Dai, Yong Shen.

  T cells, the critical immune cells of the adaptive immune system, are often dysfunctional in Alzheimer's disease (AD) and are involved in AD pathology. Reports highlight neuroinflammation as a crucial modulator of AD pathogenesis, and aberrant T cells indirectly contribute to neuroinflammation by secreting proinflammatory mediators via direct crosstalk with glial cells infiltrating the brain. However, the mechanisms underlying T-cell abnormalities in AD appear multifactorial. Risk factors for AD and pathological hallmarks of AD have been tightly linked with immune responses, implying the potential regulatory effects of these factors on T cells. In this review, we discuss how the risk factors for AD, particularly Apolipoprotein E (ApoE), Aβ, α-secretase, β-secretase, γ-secretase, Tau, and neuroinflammation, modulate T-cell activation and the association between T cells and pathological AD hallmarks. Understanding these associations is critical to provide a comprehensive view of appropriate therapeutic strategies for AD.

Keywords:  Alzheimer's disease; T cells; hallmarks; neuroinflammation; risk factors

DOI:  https://doi.org/10.1111/acel.13511
Aging Cell. 2021 Nov 02. e13509

Non-genomic rewiring of vitamin D receptor to p53 as a key to Alzheimer's disease.

Rai-Hua Lai, Yueh-Ying Hsu, Feng-Shiun Shie, Che-Ching Huang, Mei-Hsin Chen, Jyh-Lyh Juang.

  Observational epidemiological studies have associated vitamin D deficiency with Alzheimer's disease (AD). However, whether vitamin D deficiency would result in some impacts on the vitamin D binding receptor (VDR) remains to be characterized in AD. Vitamin D helps maintain adult brain health genomically through binding with and activating a VDR/retinoid X receptor (RXR) transcriptional complex. Thus, we investigated the role of VDR in AD using postmortem human brains, APP/PS1 mice, and cell cultures. Intriguingly, although vitamin D was decreased in AD patients and mice, hippocampal VDR levels were inversely increased. The abnormally increased levels of VDR were found to be colocalized with Aβ plaques, gliosis and autophagosomes, implicating a non-genomic activation of VDR in AD pathogenesis. Mechanistic investigation revealed that Aβ upregulated VDR without its canonical ligand vitamin D and switched its heterodimer binding-partner from RXR to p53. The VDR/p53 complex localized mostly in the cytosol, increased neuronal autophagy and apoptosis. Chemically inhibiting p53 switched VDR back to RXR, reversing amyloidosis and cognitive impairment in AD mice. These results suggest a non-genomic rewiring of VDR to p53 is key for the progression of AD, and thus VDR/p53 pathway might be targeted to treat people with AD.

Keywords:  Alzheimer's disease; autophagy; non-genomic vitamin D receptor; p53; vitamin D

DOI:  https://doi.org/10.1111/acel.13509
Cell Prolif. 2021 Nov 01. e13155

Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.

Jiachen Sun, Xinzhu Liu, Chuan'an Shen, Wen Zhang, Yuezeng Niu.

   INTRODUCTION: Skin is susceptible to senescence-associated secretory phenotype (SASP) and inflamm-ageing partly owing to the degeneration of mitochondria. AdipoRon (AR) has protective effects on mitochondria in metabolic diseases such as diabetes. We explored the role of AR on mitochondria damage induced by skin inflamm-ageing and its underlying mechanism.
METHODS: Western blot, immunofluorescence and TUNEL staining were used to detect inflammatory factors and apoptosis during skin ageing. Transmission electron microscopy, ATP determination kit, CellLight Mitochondria GFP (Mito-GFP), mitochondrial stress test, MitoSOX and JC-1 staining were used to detect mitochondrial changes. Western blot was applied to explore the underlying mechanism. Flow cytometry, scratch test, Sulforhodamine B assay and wound healing test were used to detect the effects of AR on cell apoptosis, migration and proliferation.
RESULTS: AR attenuated inflammatory factors and apoptosis that increased in aged skin, and improved mitochondrial morphology and function. This process at least partly depended on the suppression of dynamin-related protein 1 (Drp1)-mediated excessive mitochondrial division. More specifically, AR up-regulated the phosphorylation of Drp1 at Serine 637 by activating AMP-activated protein kinase (AMPK), thereby inhibiting the mitochondrial translocation of Drp1. Moreover, AR reduced mitochondrial fragmentation and the production of superoxide, preserved the membrane potential and permeability of mitochondria and accelerated wound healing in aged skin.
CONCLUSION: AR rescues the mitochondria in aged skin by suppressing its excessive division mediated by Drp1.

Keywords:  AdipoRon; Dynamin-related protein 1 (Drp1); SASP; inflamm-ageing; mitochondria; skin

DOI:  https://doi.org/10.1111/cpr.13155