About

John M Sedivy is the Hermon C. Bumpus Professor of Biology, Associate Dean, and Director of the Center for the Biology of Aging at Brown University. He joined the Brown faculty in 1996 and is a member of the Department of Molecular Biology, Cell Biology and Biochemistry. Sedivy obtained his PhD from Harvard University in 1985 and trained with Nobel Laureate Philip Sharp at the MIT Center for Cancer Research. His independent research career began at Yale University in 1988. His research focuses on cell cycle regulation and signal transduction, initially on the Myc oncogene and later on replicative senescence, which is cellular aging. His work on these topics has been continuously funded by the National Institutes of Health since 1989. Sedivy's research has expanded into genomics, bioinformatics, and systems biology, with significant contributions to understanding cellular senescence through the development of single-cell assays and the study of telomere-initiated senescence. He has also contributed to epigenetics, chromatin regulation, and aging-related genome changes. Sedivy has authored over 140 original articles and has served on numerous study sections and advisory committees at NIH, the American Cancer Society, and the US Army Breast Cancer Initiative. He has also consulted extensively for biotech companies and maintains an active role in aging research as a founding member and current chair of the CMAD study section at NIH, co-Editor-in-Chief of Aging Cell, and chair of the 2015 Gordon Research Conference on the Biology of Aging. His leadership roles at Brown include chairing the Department of Molecular Biology, Cell Biology and Biochemistry and founding an academic center for Genomics and Proteomics.

Research topics

• Biology
• Genetics
• Chemistry
• Computational biology
• Evolutionary biology
• Biochemistry
• Immunology
• Mathematics
• Cell biology
• Gerontology
• Physics
• Mathematical analysis
• Geometry
• Organic chemistry
• Bioinformatics
• Biophysics
• Medicine

Selected publications

• The Translatome of Senescent Cells Revealed by Ribosome Profiling

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-01

  articleOpen accessSenior authorCorresponding

  Abstract Cellular senescence drives aging-related tissue dysfunction in part through the senescence-associated secretory phenotype (SASP), an inflammatory secretome linked to retrotransposable element (RTE) derepression. Transcriptomic and proteomic approaches have characterized the senescent program extensively, but mRNA abundance does not predict protein output well, and limited proteomic depth constrains the detection of low-abundance SASP factors and RTE-derived proteins. To bridge this gap, we used AHARibo, a metabolic labeling–based method that selectively enriches mRNAs associated with actively elongating ribosomes, to generate translatome profiles in human fibroblasts across proliferating, early senescent, and late senescent states. Comparison of total and ribosome-associated mRNA pools reveals marked translational uncoupling in early senescence: transcriptomic changes explain only 34% of translatomic variance, compared to 70% in late senescence, indicating that early senescence is substantially shaped by post-transcriptional regulation. Key senescence programs are actively regulated at the translational level: cell cycle and extracellular matrix remodeling genes are translationally suppressed and enhanced, respectively, while inflammatory SASP components are translationally depleted in early senescence - a depletion relieved in late senescence. Translationally depleted SASP genes are enriched for binding motifs of the ZFP36 family (ZFP36, ZFP36L1, ZFP36L2), implicating these RNA-binding proteins in the post-transcriptional gating of inflammatory signaling. More broadly, translational efficiency is associated with 3’UTR GC content and codon optimality, and translationally depleted mRNAs are enriched for numerous RBP and microRNA target motifs. Finally, we detect robust, locus-resolved translation of evolutionarily young LINE-1 retrotransposons, identifying full-length elements with stage-specific translational activity. Together, these findings establish translational control as a pervasive regulatory layer shaping the senescent phenotype.

  PublisherOA PDFDOI

• LINE1 Inhibition Protects Neurons, Suppresses Inflammation, and Corrects Gait Disturbance in a Mouse Model of Alzheimer's Disease

  Brown Digital Repository · 2026-04-30

  articleOpen access
  PublisherDOI

• Characterization of Cellular Senescence in Primary Human Astrocytes

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-01

  articleOpen accessSenior author

  Senescent astrocytes have been identified in the brains of patients with neurodegenerative disorders, including Alzheimer's disease, yet the molecular characteristics of replicative senescence in human astrocytes remain largely unexplored. Prior work has been hampered by the low proliferative capacity and limited telomere shortening of primary human astrocytes in culture. Here, we describe a culture system in which primary human astrocytes propagated under physiological (3%) oxygen reach canonical telomeric replicative senescence after extensive expansion (up to ~76 population doublings). Senescence was confirmed through multiple biomarkers, including reduced EdU incorporation, elevated senescence-associated beta-galactosidase (SA-β-gal) activity, persistent DNA damage foci (γH2AX and 53BP1) predominantly localized to telomeres, and nuclear accumulation of p53. RNA sequencing across a 12-week time course revealed early upregulation of young LINE-1 (L1HS) retrotransposon transcripts, type-I interferon (IFN-I) and senescence-associated secretory phenotype (SASP) pathway genes, alongside downregulation of cell-cycle and DNA repair programs. To resolve L1HS expression at individual locus resolution, we performed Nanopore DNA sequencing to generate a custom reference genome incorporating non-reference LINE-1 insertions. Applying our TE-Seq pipeline, we identified two full-length intergenic L1HS elements consistently upregulated across the replicative senescence time course, one of which, L1HS_9q22.32_2, retained intact ORF1 and ORF2 open reading frames, indicating potential retrotransposition competence. To contextualize the astrocyte replicative senescence program, we compared it to three additional conditions. First, parallel astrocyte cultures maintained under normoxic (20%) oxygen entered senescence earlier and showed stronger SASP upregulation. Second, DNA damage-induced senescence (DDIS) triggered by etoposide treatment produced a stronger pro-inflammatory transcriptional signature than replicative senescence, including elevated IL6, IL1A, and IL1B expression. DDIS also upregulated L1HS_9q22.32_2 as well as a second intact element, L1HS_14q23.2_3, which we have previously identified among the small number of intact L1HS loci activated during replicative senescence in fibroblasts. The convergent activation of these intact elements across cell types and senescence modalities reinforces L1HS-driven IFN-I signaling as a conserved feature of the senescent program. Third, comparison with replicatively senescent fibroblasts revealed cell-type-specific SASP regulation: the pro-inflammatory cytokines IL6 and CCL2 were downregulated in senescent astrocytes relative to proliferating cells, opposite to their behavior in fibroblasts. Together, these data establish the first comprehensive transcriptomic profile of replicative senescence in human astrocytes, offering a resource for understanding brain aging and senescence-associated neurodegeneration.

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• RNA transcripts in salivary extracellular vesicle cargo isolated from aged populations

  Frontiers in Aging · 2026-01-12 · 1 citations

  articleOpen access

  Introduction: Human saliva contains numerous factors, including DNA, RNA, and protein, that may reflect the health status of the individual. Many of these factors are contained within extracellular vesicles (EVs). The contents of EVs are thought to mirror the cytoplasm of the cell of origin, providing insight into the health of the cell. We investigated the RNA content from EVs isolated from saliva (salEVs) to determine if we could detect transcripts associated with neurodegenerative conditions. Methods: We characterized the RNA cargo of salEVs isolated from individuals over the age of 65 with normal cognition. The salEV RNA content was analyzed by RNA-seq and NanoString miRNA analysis. Results: We found approximately 48.4% of the reads mapped to the human genome, with the remainder mapping to prokaryotic genomes. The transcripts included protein-coding RNA, long non-coding RNA, retrotransposons, and miRNAs. A significant number of the protein-coding transcripts were associated with pathways involved in neurodegenerative conditions. In addition, there was an enrichment of transcripts containing AP-2ε, HEYL, HES4, and TCFL5 transcription factor binding sites. We found that the lncRNA content was similar between samples, with PCBP1-AS1, TEX41, and PVT1 being the top represented transcripts. There were 286 miRNAs found in the salEV samples. The pathways predicted to be affected by the top represented miRNAs include Hippo signaling, TGF-β signaling, Wnt signaling, FoxO signaling, ErbB signaling, axon guidance, and mTOR signaling. We could detect retrotransposon transcripts from LINE, SINE, and LTR elements in salEVs. When compared to blood-derived EVs, salEVs showed greater representation of transcripts associated with neurodegenerative pathways. Discussion: Our results indicate that salEVs contain transcripts that are associated with pathways involved in neurodegeneration. The presence of these transcripts in salEVs suggest that saliva may be used to screen for biomarkers of neurodegenerative diseases.

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• Senolytic reduction of senescent cells mitigates atrial arrhythmia vulnerability in aging rabbits

  Heart Rhythm · 2026-01-08 · 1 citations

  articleOpen access

  BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia among the elderly and a major contributor to morbidity and mortality. Inflammation plays a central role in AF pathogenesis, and aging is a key independent risk factor. Cellular senescence is a hallmark of aging and contributes to age-related disease through the senescence-associated secretory phenotype (SASP), characterized by proinflammatory and profibrotic factors. OBJECTIVE: This study aimed to determine whether senescent atrial cells contribute to age-related AF risk and whether senolytic therapy can mitigate this phenotype. METHODS: Young (≤1 year) and aged (≥4 years) New Zealand White rabbits were evaluated using optical mapping, patch-clamp electrophysiology, and histologic and molecular analyses. Senescence markers were assessed using senescence-associated β-galactosidase staining, immunofluorescence, and RNA sequencing. Human atrial specimens from patients with and without AF were examined to assess translational relevance. Aged rabbits received the senolytic compound fisetin to evaluate its effects on atrial senescence and arrhythmia susceptibility. RESULTS: Aged rabbits displayed electrophysiological heterogeneity, prolonged action potentials, and increased AF inducibility, recapitulating clinical features of elderly human atria. Atrial tissue from aged rabbits and patients with AF showed an increase in senescent myocytes and myofibroblasts with upregulation of inflammatory SASP genes. SASP factor expression correlated with left atrial diameter in human samples, an AF risk factor. Short-term fisetin treatment eliminated most senescent atrial cells, reduced inducible AF, and decreased reentry activity without impairing atrial function. CONCLUSION: Senescent atrial cells promote a proinflammatory, proarrhythmic substrate predisposing to AF. Senolytic therapy with fisetin alleviates this phenotype, suggesting a potential strategy to prevent age-related AF.

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• Retrotransposon Activation in the Aged and Alzheimer’s Disease Brain Examined by Nanopore Long-read DNA Sequencing

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-15

  articleOpen accessSenior authorCorresponding

  Background: Cellular defenses against retrotransposable elements (RTEs) weaken with age and RTEs have been reported to contribute to Alzheimer's disease (AD) pathogenesis by promoting neuroinflammation. The mechanisms implicated include DNA damage promoted by retrotransposition and interferon system activation by RTE-derived cDNA intermediates. LINE-1 (L1) retrotransposons are of particular interest because they are the only autonomously active RTEs in the human genome. Results: To investigate L1 activation and retrotransposition in AD, we performed Nanopore long-read DNA sequencing on six late-onset AD (LOAD) and six age-matched control human prefrontal cortex (PFC) samples. We developed and validated a stringent RTE insertion calling pipeline and identified two high-confidence somatic insertions, one AluY and one L1HS. We estimate that ∼1% of cells in the aged PFC have a somatic RTE insertion. AD samples were hypomethylated, and genome-wide analysis of differentially methylated regions (DMRs) supports a process of epigenetic drift in AD. DMR-associated gene sets primarily related to brain function and inflammation. To investigate L1 activation we used CpG methylation as a proxy for L1 expression. We observed decreased methylation at young L1 elements. While most reads overlapping the L1HS promoter were highly methylated (>80% methylated), 7% were <50% methylated, 1% were <25%, and the highly demethylated read fraction increased in AD. L1HS 5' UTR methylation was strongly correlated with RNA expression. Conclusions: CpG methylation-mediated repression of young RTEs is compromised in old age - our findings indicate that this is further exacerbated in AD. Amid these failing defenses, we report somatic retrotransposition events in the aging and demented brain.

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• Senescence-Associated Chromatin Rewiring Promotes Inflammation and Transposable Element Activation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-17 · 3 citations

  preprintOpen access

  Cellular senescence is a stable form of cell cycle arrest that contributes to aging and age-associated diseases through the secretion of inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). While senescence is driven by transcriptional and epigenetic changes, the contribution of higher-order genome organization remains poorly defined. Here, we present the highest-resolution Hi-C maps (~3 kb) to date of proliferating, quiescent, and replicative senescent (RS) human fibroblasts, enabling a comprehensive analysis of 3D genome architecture during senescence. Our analyses reveal widespread senescence-associated remodeling of chromatin architecture, including extensive compartment and subcompartment switching toward transcriptionally active states, and a dramatic increase in unique chromatin loops. These structural features correlate with local DNA hypomethylation and are largely independent of canonical CTCF binding. The altered 3D genome landscape supports expression of SASP genes, inflammation-related pathways, and neuronal gene signatures consistent with age-associated epigenetic drift. We further demonstrate that architectural changes at multiple levels, including compartments, subcompartments, and loops, facilitate the derepression of LINE-1 retrotransposons, linking 3D chromatin structure to activation of proinflammatory transposable elements. Interestingly, quiescent cells, commonly used as senescence controls, exhibited substantial overlap in inflammatory gene expression with senescent cells, raising important considerations for experimental design. Structural analysis of cell cycle genes showed distinct chromatin configurations in senescence versus quiescence, despite similar transcriptional repression. Together, our results establish a high-resolution framework for understanding how genome architecture contributes to the senescent state.

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• Rapid DNA cleavage by the LINE-1 endonuclease proximal to DNA ends and at mismatches

  Journal of Biological Chemistry · 2025-11-29 · 3 citations

  articleOpen access

  Long interspersed element 1 (LINE-1, L1) is a eukaryotic retrotransposon that propagates through an RNA intermediate. Its mutagenic insertion mechanism, target-primed reverse transcription (TPRT), requires coordinated activities of the encoded ORF2 protein (ORF2p) endonuclease (EN) and reverse transcriptase (RT) domains. EN initiates TPRT by nicking target genomic DNA, creating a 3'-OH that primes ORF2p RT for complementary DNA synthesis using the bound L1 RNA template. L1 insertions occur preferentially at 5'-TTTTT↓AA consensus motifs; this bias could reflect site-specific EN cleavage or sequence requirements in the subsequent RT priming step, in which the cut genomic DNA flap must base pair with the poly(A) RNA template. We find that, in vitro, EN is promiscuous, cutting linear DNA oligonucleotides and plasmids at many non-consensus sites. We discovered a cleavage activity on a mismatched substrate that was nicked ∼40-fold faster than duplex DNA containing the consensus site and identify three features promoting rapid cutting. First, EN cleaves two nucleotides downstream of mismatches, favoring A-G mismatches or T•G/U•G wobble pairs. Second, both mismatch and consensus sequences are cleaved >2-fold faster when proximal to a DNA end. Third, end-proximal EN cutting depends on end composition: 5' overhangs cut fastest, followed by 3' overhangs, followed by blunt ends. Together, these results indicate that EN cleavage is based primarily on DNA structure rather than sequence, that many L1 insertion attempts likely fail after cleavage at the priming step , and that mismatches and possibly other DNA conformational alterations promote EN cleavage, broadening our understanding of the genomic impact of L1.

  PublisherDOI

• Cytosolic DNA crosstalk in senescence: a new axis of inflammatory signaling?

  The EMBO Journal · 2025-08-29 · 7 citations

  articleOpen access

  Cellular senescence is a form of stable growth arrest that contributes to aging and age-related diseases, in part through the senescence-associated secretory phenotype (SASP). Recent studies show that senescent cells accumulate several species of cytosolic DNAs, including mitochondrial DNA (mtDNA), cytoplasmic chromatin fragments (CCFs), and retrotransposable element cDNAs, which collectively activate the cGAS–STING pathway and drive SASP expression. Surprisingly, downregulating any one of these DNA species is often enough to suppress the SASP, raising key questions about their functional interactions. We propose that these cytosolic DNA species do not act in isolation but instead either follow a coordinated sequence or engage in synergistic crosstalk to amplify and sustain inflammatory signaling. While therapeutic approaches directly targeting the cGAS–STING pathway are being developed, we argue that blocking the sources of cytosolic DNA might be a more specific and safer strategy to target the deleterious effects of senescent cells. In particular, this approach should enable reducing chronic inflammation without impairing important immune functions, offering a new direction for therapies aimed at promoting healthy aging.

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• A transcriptomic score to classify the inflammation-dysplasia-cancer sequence lesions in inflammatory bowel disease

  Journal of Crohn s and Colitis · 2025-02-13 · 2 citations

  articleOpen access

  BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is associated with a higher risk of developing colorectal cancer, according to the inflammation-dysplasia-cancer (IDC) sequence from inflammation to colitis-associated colorectal cancer (CAC). The objective of this study was to identify and generate a transcriptomic signature and score, related to the IDC sequence, that could ultimately classify dysplasia and cancer in IBD. METHODS: Demographics, clinical parameters, histological characteristics, and RNA-sequencing data were evaluated on 134 formalin-fixed paraffin-embedded lesions from 2 independent cohorts of IBD patients with low- or high-grade dysplasia (LGD, HGD) and/or CAC. An ordinal logistic regression screened for significant IDC sequence-associated genes that were computed in a transcriptomic signature score. RESULTS: Principal component analysis and unsupervised clustering on 1% of the most variable genes showed a good clustering between the 4 lesion groups (Normal Mucosa, Inflamed Mucosa, LGD/HGD, and CAC). A gene signature was identified on 27 genes that correlated with the lesion groups in the exploratory cohort. The most weighted gene in this transcriptomic signature was the long non-coding regulatory RNA KCNQ1OT1, a gatekeeper against genomic instability and transposon activation. Based on the expression of these 27 genes, we built and validated a transcriptomic signature score to classify dysplasia and CAC. The overall accuracy of the transcriptomic signature score was 85.71% in the exploratory cohort and 90.91% in the validation cohort. CONCLUSION: We identified a tissue-based transcriptomic score to classify IDC lesions in IBD patients and uncovered some of the pivotal genes in carcinogenesis related to inflammation in IBD.

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Recent grants

• NIH Grant R01AG035328

  NIH · $952k · 2013

• NIH Grant R21AG049608

  NIH · $250k · 2017

• The Role of Somatic Transposition in Age-associated Genomic Instability

  NIH · $2.2M · 2017–2024

• NIH Grant R01GM055435

  NIH · $376k · 1999

• Project 3: Inhibition of L1 to Alleviate Alzheimer's Disease Pathogenosis in Mouse Models

  NIH · $53.0M · 2016–2026

Frequent coauthors

• Nicola Neretti

  Providence College

  87 shared

• Wenyi Wei

  Beth Israel Deaconess Medical Center

  58 shared

• Marco De Cecco

  Brown University

  57 shared

• Jill A. Kreiling

  Brown University

  52 shared

• Wendy A. Jobling

  University of Florida

  48 shared

• William C. Hahn

  Dana-Farber Cancer Institute

  38 shared

• Stephen L. Helfand

  Brown University

  33 shared

• Utz Herbig

  Rutgers, The State University of New Jersey

  33 shared

Education

• Ph.D.

  Harvard

  1985

• Other

  MIT Center for Cancer Research

Awards & honors

• Founding member and current chair of the CMAD study section…
• Co-Editor-in-Chief of the journal Aging Cell
• Chair of the 2015 Gordon Research Conference on the Biology…