Agings
Abstract
Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage, and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease.
Authors
Allison B. Herman, Dimitrios Tsitsipatis, Carlos Anerillas, Krystyna Mazan-Mamczarz, Angelica E. Carr, Jordan M. Gregg, Mingyi Wang, Jing Zhang, Marc Michel, Charnae' Henry-Smith, Sophia C. Harris, Rachel Munk, Jennifer L Martindale, Yulan Piao, Jinshui Fan, Julie A. Mattison, Supriyo De, Kotb Abdelmohsen, Robert W. Maul, Toshiko Tanaka, Ann Z. Moore, Megan E. DeMouth, Simone Sidoli, Luigi Ferrucci, Yie Liu, Rafael de Cabo, Edward G. Lakatta, Myriam Gorospe
Abstract
Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allows for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclasts and marrow adipocytes. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide the first proof-of-concept evidence that local senolysis has health benefits in the context of aging, but importantly, local senolysis only partially replicates the benefits of systemic senolysis. Further, we establish that SnCs, through their SASP, lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging.
Authors
Joshua N. Farr, Dominik Saul, Madison L. Doolittle, Japneet Kaur, Jennifer L. Rowsey, Stephanie J. Vos, Mitchell N. Froemming, Anthony B. Lagnado, Yi Zhu, Megan M. Weivoda, Yuji Ikeno, Robert J. Pignolo, Laura J. Niedernhofer, Paul D. Robbins, Diana Jurk, João F. Passos, Nathan K. LeBrasseur, Tamara Tchkonia, James L. Kirkland, David G. Monroe, Sundeep Khosla
Abstract
Obesity is a risk factor for neurodegenerative disease associated with cognitive dysfunction, including Alzheimer’s disease. Low-grade inflammation is common in obesity, but the mechanism between inflammation and cognitive impairment in obesity is unclear. Accumulative evidence shows that quinolinic acid (QA), a neuroinflammatory neurotoxin, is involved in the pathogenesis of neurodegenerative processes. We investigated the role of QA in obesity-induced cognitive impairment and the beneficial effect of butyrate in counteracting impairments of cognition, neural morphology, and signaling. We show that in human obesity, there was a negative relationship between serum QA levels and cognitive function and decreased cortical gray matter. Diet-induced obese mice had increased QA levels in the cortex associated with cognitive impairment. At single-cell resolution, we confirmed that QA impaired neurons, altered the dendritic spine’s intracellular signal, and reduced brain-derived neurotrophic factor (BDNF) levels. Using Caenorhabditis elegans models, QA induced dopaminergic and glutamatergic neuron lesions. Importantly, the gut microbiota metabolite butyrate was able to counteract those alterations, including cognitive impairment, neuronal spine loss, and BDNF reduction in both in vivo and in vitro studies. Finally, we show that butyrate prevented QA-induced BDNF reductions by epigenetic enhancement of H3K18ac at BDNF promoters. These findings suggest that increased QA is associated with cognitive decline in obesity and that butyrate alleviates neurodegeneration.
Authors
Xing Ge, Mingxuan Zheng, Minmin Hu, Xiaoli Fang, Deqin Geng, Sha Liu, Li Wang, Jun Zhang, Li Guan, Peng Zheng, Yuanyi Xie, Wei Pan, Menglu Zhou, Limian Zhou, Renxian Tang, Kuiyang Zheng, Yinghua Yu, Xu-Feng Huang
Abstract
As representatives for our entire team, we thank Jhaveri et al. (1) for their insightful comments on our recent study investigating the increased expression of programmed cell death protein-1 (PD1) in kidneys during aging and FSGS.(2) In our manuscript we showed that PD1 was predominantly increased in podocytes and kidney tubular epithelial cells in both mice and humans. Moreover, in humans, age-elevated glomerular PCDC1 (gene encoding human PD1) levels were associated with a lower eGFR, increased segmental glomerulosclerosis, and reduced arterial intima-to-lumen ratio. We also demonstrated a mechanistic link between increased PD1 levels in podocytes and their shortened lifespan. Finally, specifically antagonizing the PD1 pathway with a specific anti-PD1 antibody (similar to humanized Pembrolizumab or Nivolumab) in aged mice and mice with experimental FSGS had major benefits on kidney histology, podocyte life- and health-span, and tubular epithelial injury.(2) In their response, Jhaveri and colleagues, experts in onco-nephrology, eloquently discuss the clinical kidney-specific adverse events (AEs) when using immune checkpoint inhibitors (ICI) in cancer patients.(1) They provide important clinical insights and an up-to-date summary of the incidence and types of glomerular lesions, acute kidney injury and acute interstitial nephritis observed in patients receiving ICI for cancer treatment.(3,4) Importantly, complete or partial remission of kidney-specific AEs upon discontinuation of ICI treatment in a subset of patients suggests a causal link.(3, 4) We unreservedly agree with Jhaveri et al. that caution is warranted when using ICI clinically. In fact, we have not advocated the clinical use of anti-PD1 treatment to limit or reverse kidney aging, nor to be used as a therapy for FSGS. The clinical data highlighted by Jhaveri et al. underscore the importance of gaining a better understanding of the mechanism(s) underlying kidney complications in patients. While T cell activation, proliferation and subsequent kidney infiltration is the leading hypothesis,(3, 4) how this cumulates into kidney dysfunction is unknown. ICIs block the CTLA-4 and/or PD1 pathways. CTLA-4 acts early in tolerance induction, stopping potentially autoreactive T cells at the initial stage of naive T-cell activation, while PD1 acts late to maintain long-term tolerance, primarily in peripheral tissues.(5) Typically a lower incidence of AEs is associated with PD1 blockade compared with CTLA-4 blockade.(3, 4) Interestingly, in our study mice Ctla4 mRNA levels in contrast to PD1 were not elevated in podocytes with age. There are also several differences between humans and mice that may influence the response to anti-PD1 treatments. To reconcile these, one needs to experimentally align the animal studies with the therapeutic scenario in human cancer patients. Possible considerations include: (i) the duration of therapy - in our study mice received 8 weeks of treatment, while human patients typically receive a 13-week median drug exposure before glomerular disease is first detected; (ii) the presence of comorbid conditions is oftentimes present in humans (e.g., patients receiving additional medications or already exhibiting altered kidney function before receiving ICI agents), but was absent in our mice; (iii) sex and age – the median age of patients developing glomerular disease after ICI treatment is 63 years and 75% thereof are male,(4) while our mouse study was based on males only; (iv) drug dosing – the therapeutic doses of ICIs used in humans might be much higher than the doses of the mouse-specific anti-PD1 antibody yielding beneficial effects in mouse podocytes; (v) finally, genetic variation in humans may influence the response to anti-PD1 treatments, while mice strains are genetically very homogenous. We believe that our study has provided some exciting new considerations that has moved us ahead scientifically. First, the PD1 signaling is a new pathway contributing to the aging of podocytes and other kidney epithelial cells, as well as the response of podocytes in disease. Second, podocyte aging and diseased-induced podocyte injury share a new common pathway – PD1. This raises the possibility that PD1 signaling is one of the pathways responsible for the more severe kidney injury when FSGS is superimposed on an aged kidney. Third, the effects of the anti-PD1 antibody treatment are not restricted to the kidney, but also reduced some aspects of liver aging. This suggests that it might be a common aging pathway, that needs to be studied further. Fourth, the unexpected discovery of PD1 signaling in aging leads us to predict that there will be additional surprises in new pathways contributing to kidney aging and disease that will translate into new druggable targets.
Authors
Stuart J. Shankland, Jeffrey W. Pippin, Oliver Wessely
Abstract
With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti–PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti–PD-1 antibody treatment improved the health span of podocytes. Administering the same anti–PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.
Authors
Jeffrey W. Pippin, Natalya Kaverina, Yuliang Wang, Diana G. Eng, Yuting Zeng, Uyen Tran, Carol J. Loretz, Anthony Chang, Shreeram Akilesh, Chetan Poudel, Hannah S. Perry, Christopher O’Connor, Joshua C. Vaughan, Markus Bitzer, Oliver Wessely, Stuart J. Shankland
Abstract
A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens and T cell repertoire size is believed to decline with age. However, the precise size of human TCR repertoire in total and subsets of T cells, and their changes with age are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier (UMI) based RNAseq method. Thorough analysis of 1.9 x 108 T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 x 108. Alterations of TCR repertoire with age were observed in all four subsets of T cells. The greatest reduction was observed in naïve CD8+ T cells; the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting aging has a more profound impact on the cytotoxic than on the helper T cell functions. This may explain the increased susceptibility of older adults to the novel infections.
Authors
Xiaoping Sun, Thomas Nguyen, Achouak Achour, Annette Ko, Jeffrey Cifello, Chen Ling, Jay Sharma, Toyoko Hiroi, Yongqing Zhang, Chee W. Chia, William Wood III, Wells W. Wu, Linda Zukley, Je-Nie Phue, Kevin G. Becker, Rong-Fong Shen, Luigi Ferrucci, Nan-ping Weng
Abstract
Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF-β1. TGF-β–neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF-β1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF-β1 signaling is a molecular mechanism for fractures in the elderly via SCs.
Authors
Jiatong Liu, Jun Zhang, Xi Lin, Brendan F. Boyce, Hengwei Zhang, Lianping Xing
Abstract
As life expectancy continues to increase, clinicians are challenged by age-related renal impairment that involves podocyte senescence and glomerulosclerosis. There is now compelling evidence that lithium has a potent antiaging activity that ameliorates brain aging and increases longevity in Drosophila and Caenorhabditis elegans. As the major molecular target of lithium action and a multitasking protein kinase recently implicated in a variety of renal diseases, glycogen synthase kinase 3β (GSK3β) is overexpressed and hyperactive with age in glomerular podocytes, correlating with functional and histological signs of kidney aging. Moreover, podocyte-specific ablation of GSK3β substantially attenuated podocyte senescence and glomerular aging in mice. Mechanistically, key mediators of senescence signaling, such as p16INK4A and p53, contain high numbers of GSK3β consensus motifs, physically interact with GSK3β, and act as its putative substrates. In addition, therapeutic targeting of GSK3β by microdose lithium later in life reduced senescence signaling and delayed kidney aging in mice. Furthermore, in psychiatric patients, lithium carbonate therapy inhibited GSK3β activity and mitigated senescence signaling in urinary exfoliated podocytes and was associated with preservation of kidney function. Thus, GSK3β appears to play a key role in podocyte senescence by modulating senescence signaling and may be an actionable senostatic target to delay kidney aging.
Authors
Yudong Fang, Bohan Chen, Zhangsuo Liu, Athena Y. Gong, William T. Gunning, Yan Ge, Deepak Malhotra, Amira F. Gohara, Lance D. Dworkin, Rujun Gong
Abstract
BACKGROUND. Presbyosmia, or aging related olfactory loss, occurs in a majority of humans over age 65 years, yet remains poorly understood, with no specific treatment options. The olfactory epithelium (OE) is the peripheral organ for olfaction, and is subject to acquired damage, suggesting a likely site of pathology in aging. Adult stem cells reconstitute the neuroepithelium in response to cell loss under normal conditions. In aged OE, patches of respiratory-like metaplasia have been observed histologically, consistent with a failure in normal neuroepithelial homeostasis. METHODS. Accordingly, we have focused on identifying cellular and molecular changes in presbyosmic OE. The study combined psychophysical testing with olfactory mucosa biopsy analysis, single cell RNA-sequencing (scRNA-seq), and culture studies. RESULTS. We identified evidence for inflammation-associated changes in the OE stem cells of presbyosmic patients. The presbyosmic basal stem cells exhibited increased expression of genes involved in response to cytokines or stress, or the regulation of proliferation and differentiation. Using a culture model, cytokine exposure drove increased TP63, a transcription factor acting to prevent OE stem cell differentiation. CONCLUSIONS. Our data suggest aging-related inflammatory changes in OE stem cells may contribute to presbyosmia, via the disruption of normal epithelial homeostasis. OE stem cells may represent a therapeutic target for restoration of olfaction. TRIAL REGISTRATION. Not applicable FUNDING. National Institutes of Health grants DC018371 (BJG), NS121067 (EAM), DC016224 (HM);Office of Physician-Scientist Development, Burroughs-Wellcome Fund Research Fellowship for Medical Students Award, Duke University School of Medicine (AO).
Authors
Allison D. Oliva, Rupali Gupta, Khalil Issa, Ralph Abi Hachem, David W. Jang, Sebastian A. Wellford, E. Ashley Moseman, Hiroaki Matsunami, Bradley J. Goldstein
Abstract
Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer’s disease (AD), however neither disease- nor brain region-specificity of these transcriptome alterations have been explored. Using RNA sequencing data from 231 temporal cortex and 224 cerebellum samples of patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identify a striking correlation in the directionality and magnitude of gene expression changes between these two neurodegenerative proteinopathies. Further, the transcriptome changes in AD and PSP are highly conserved between the temporal and cerebellar cortices, indicating highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or down-regulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of two distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex and ubiquitous molecular alterations in neurodegenerative diseases.
Authors
Xue Wang, Mariet Allen, Özkan İş, Joseph S. Reddy, Frederick Q. Tutor-New, Monica Castanedes Casey, Minerva M. Carrasquillo, Stephanie R. Oatman, Yuhao Min, Yan W. Asmann, Cory Funk, Thuy Nguyen, Charlotte C.G. Ho, Kimberly G. Malphrus, Nicholas T. Seyfried, Allan I. Levey, Steven G. Younkin, Melissa E. Murray, Dennis W. Dickson, Nathan D. Price, Todd E. Golde, Nilufer Ertekin-Taner
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