Aging
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
Abstract
With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immune aging. Here we show that naive T cells from older individuals as well as miR-181ab1–deficient murine T cells develop excessive replication stress after activation, due to reduced histone expression and delayed S-phase cell cycle progression. Reduced histone expression was caused by the miR-181a target SIRT1 that directly repressed transcription of histone genes by binding to their promoters and reducing histone acetylation. Inhibition of SIRT1 activity or SIRT1 silencing increased histone expression, restored cell cycle progression, diminished the replication-stress response, and reduced the production of inflammatory mediators in replicating T cells from old individuals. Correspondingly, treatment with SIRT1 inhibitors improved viral clearance in mice with miR-181a–deficient T cells after LCMV infection. In conclusion, SIRT1 inhibition may be beneficial to treat systemic viral infection in older individuals by targeting antigen-specific T cells that develop replication stress due to miR-181a deficiency.
Authors
Chulwoo Kim, Jun Jin, Zhongde Ye, Rohit R. Jadhav, Claire E. Gustafson, Bin Hu, Wenqiang Cao, Lu Tian, Cornelia M. Weyand, Jörg J. Goronzy
Abstract
Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow–derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.
Authors
Alexandra C. McQuattie-Pimentel, Ziyou Ren, Nikita Joshi, Satoshi Watanabe, Thomas Stoeger, Monica Chi, Ziyan Lu, Lango Sichizya, Raul Piseaux Aillon, Ching-I Chen, Saul Soberanes, Zhangying Chen, Paul A. Reyfman, James M. Walter, Kishore R. Anekalla, Jennifer M. Davis, Kathryn A. Helmin, Constance E. Runyan, Hiam Abdala-Valencia, Kiwon Nam, Angelo Y. Meliton, Deborah R. Winter, Richard I. Morimoto, Gökhan M. Mutlu, Ankit Bharat, Harris Perlman, Cara J. Gottardi, Karen M. Ridge, Navdeep S. Chandel, Jacob I. Sznajder, William E. Balch, Benjamin D. Singer, Alexander V. Misharin, G.R. Scott Budinger
Abstract
Bone marrow (BM) hematopoietic stem cells (HSCs) become dysfunctional during aging (i.e., they are increased in number but have an overall reduction in long-term repopulation potential and increased myeloid differentiation) compared with young HSCs, suggesting limited use of old donor BM cells for hematopoietic cell transplantation (HCT). BM cells reside in an in vivo hypoxic environment yet are evaluated after collection and processing in ambient air. We detected an increase in the number of both young and aged mouse BM HSCs collected and processed in 3% O2 compared with the number of young BM HSCs collected and processed in ambient air (~21% O2). Aged BM collected and processed under hypoxic conditions demonstrated enhanced engraftment capability during competitive transplantation analysis and contained more functional HSCs as determined by limiting dilution analysis. Importantly, the myeloid-to-lymphoid differentiation ratio of aged BM collected in 3% O2 was similar to that detected in young BM collected in ambient air or hypoxic conditions, consistent with the increased number of common lymphoid progenitors following collection under hypoxia. Enhanced functional activity and differentiation of old BM collected and processed in hypoxia correlated with reduced “stress” associated with ambient air BM collection and suggests that aged BM may be better and more efficiently used for HCT if collected and processed under hypoxia so that it is never exposed to ambient air O2.
Authors
Maegan L. Capitano, Safa F. Mohamad, Scott Cooper, Bin Guo, Xinxin Huang, Andrea M. Gunawan, Carol Sampson, James Ropa, Edward F. Srour, Christie M. Orschell, Hal E. Broxmeyer
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ISSN: 0021-9738 (print), 1558-8238 (online)