Below is a concise, source‑based picture of José Pedro Castro’s research direction, followed by a compact physical‑chemistry (“p‑chem”) explainer on why carbamylation of long‑lived proteins promotes degenerative change.
José Pedro Castro — research direction (high‑level)
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Overall focus. Aging biology and its interface with cancer: how aging trajectories in cells and tissues predispose to malignancy; cross‑species longevity signatures; and interventions that shift those trajectories. Trained in proteostasis/oxidative damage, now combining in vivo mouse work with large‑scale multi‑omics and computational analyses.
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Aging → B‑cell malignancy (clonal evolution in old mice). Seminal work showed that aging drives clonal expansion of B cells, marked by c‑Myc activation, recurrent somatic mutations, and promoter hypermethylation, culminating in B‑cell lymphoma; inhibiting mTOR or c‑Myc in old mice attenuates these premalignant changes. A 2024 paper extended this line, characterizing age‑associated clonal B cells (ACBCs) as drivers of lymphoma.
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Cross‑species longevity mechanisms & biomarkers. Multi‑tissue RNA‑seq across mammals revealed signatures linked to lifespan (e.g., downregulated IGF1, upregulated mitochondrial translation), clarified what’s shared vs. species‑specific, and used the signatures to nominate geroprotectors.
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Interventions that reprogram aging. Transient early‑life rapamycin lengthens lifespan and preserves healthspan in genetically diverse mice (and Daphnia), with “younger” transcriptome/epigenome readouts—work Castro co‑authored within the Gladyshev lab program.
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Genetics of human longevity. Depletion of rare loss‑of‑function germline variants in centenarians highlights putative longevity genes.
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Tissue‑specific aging programs. (Preprint) “Transcriptomic entropy” captures how aging patterns differ across tissues and helps predict cancer progression, expanding Castro’s computational toolkit for aging/cancer inference.
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Other recent themes. Aging skeletal muscle: down‑regulated mitochondrial metabolism as a driver of fast‑fiber loss; disease‑similarity models linking lysosomal storage disease to accelerated brain aging and Alzheimer’s research.
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Early training (proteostasis/oxidative damage). Prior work characterized protein carbonylation (e.g., actin) and chaperone‑assisted proteasomal removal of oxidatively damaged proteins—background that foreshadowed his later focus on age‑linked proteome damage and its systemic consequences.
Where he is/was based. Harvard Medical School, Gladyshev Lab (BWH/HMS); publications and “skills” on aging, clonality, cell size, and transcriptomics are listed on his ResearchGate profile.
P‑chem explainer: why carbamylation of long‑lived proteins (LLPs) promotes degeneration
What carbamylation is. A non‑enzymatic post‑translational modification (NEPTM) in which isocyanic acid (HNCO) or cyanate (OCN⁻) reacts with amino groups on proteins—most prominently the ε‑amine of lysine—to form homocitrulline (ε‑carbamyl‑lysine); N‑terminal α‑amines can also be carbamylated. Key in vivo sources of HNCO are urea decomposition (augmented in CKD) and myeloperoxidase (MPO) oxidation of thiocyanate (SCN⁻) at inflammatory sites.
Kinetics & pH dependence (why it happens in physiological conditions).
- Amine carbamylation by HNCO proceeds largely between neutral species (HNCO + R–NH₂) with second‑order kinetics; pKₐ(HNCO) ≈ 3.5, so reactive HNCO is available across physiological pH. Rates are relatively pH‑insensitive above ~pH 5 until ~1.5 units below the amine pKₐ; microenvironments that lower lysine pKₐ (buried/basic pockets) increase reactivity. Classic kinetic work also showed large site‑to‑site rate differences (e.g., N‑terminal valines of hemoglobin carbamylate far faster than lysyl α‑amines at pH 7.4), illustrating strong microenvironmental control.
Why long‑lived proteins are preferential targets.
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Time × exposure: LLPs (e.g., type I collagen, elastin, lens crystallins) turn over very slowly; cumulative exposure to low levels of HNCO/OCN⁻ yields age‑dependent accumulation of homocitrulline. Across species, tissue carbamylation tracks aging and even life expectancy.
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Inflammation & uremia contexts: MPO‑rich inflammatory foci and elevated urea (CKD) boost carbamylation in plasma/tissues, accelerating modification of LLPs.
What carbamylation does to proteins (first principles → phenotype).
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Electrostatics & hydrogen bonding. Converting Lys–NH₃⁺ to neutral homocitrulline removes positive charge and alters hydrogen‑bond networks and salt bridges. This destabilizes native folds, shifts solubility, and can promote aggregation, especially in dense protein matrices like the lens. (Classic work links lens‑protein carbamylation to crystallin conformational changes and high‑molecular‑weight aggregates, a cataract mechanism.)
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Protease recognition. Lysine carbamylation blocks Lys‑dependent cleavage (e.g., trypsin sites), reducing normal proteolysis/turnover of damaged proteins—contributing to persistence/accumulation of dysfunctional species. (This principle is well‑documented in proteomics, where carbamyl‑Lys prevents tryptic cleavage.)
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Cross‑link chemistry in ECM. In collagen, carbamylation (including hydroxylysine → hydroxy‑homocitrulline) competes with or disrupts lysyl‑oxidase–mediated cross‑links, thereby altering fibril cross‑link density and mechanics (stiffness, resilience). That shift in ECM biomechanics underlies arterial stiffening, skin changes, and other degenerative phenotypes.
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Pathologic particle remodeling. Carbamylation of lipoproteins (e.g., cHDL, cLDL) impairs HDL function and promotes atherogenesis, linking local MPO activity and systemic uremia to vascular degeneration.
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Competition with other NEPTMs. In matrices, carbamylation can compete with glycation; in some settings it predominates, further biasing ECM chemistry toward dysfunction with age/disease.
Empirical anchors.
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Aging hallmark: Multiple mammalian species show age‑progressive tissue carbamylation, particularly in ECM LLPs (collagen, elastin).
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Uremia amplifies it: Chronically high urea increases tissue and plasma carbamylation rates.
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Lens as a case study: Carbamylation of crystallins induces conformational shifts and aggregation, long linked to cataractogenesis; carbamylation is detectable in vivo at specific crystallin sites.
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Vascular elastic fibers: Direct elastic‑fiber carbamylation stiffens fibers (AFM measurements), contributing to vascular wall mechanical changes with age.
Why this leads to degenerative phenotypes in LLP‑rich tissues (mechanistic chain):
Slow turnover (+ persistent HNCO exposure) → cumulative Lys → homocitrulline conversions → loss of charge, misfolding/aggregation (lens) and impaired protease clearance → disrupted cross‑linking & stiffer ECM (collagen/elastin) → altered cell‑matrix signaling and hemodynamics → macroscopic functional decline (opacity, stiffness, fragility), i.e., degeneration.
Practical readouts / levers.
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Biomarker: Homocitrulline (LC–MS/MS or immunoassay) as a load marker of carbamylation.
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Contextual modifiers: Reducing uremic load and MPO‑driven inflammation can lower HNCO exposure; these are active areas in CKD and cardiovascular medicine research.
How carbamylation relates to Castro’s trajectory
While Castro’s own early bench work centered on oxidative protein damage (carbonylation) and proteostasis, his current research addresses systemic aging programs and age‑driven malignancy, where non‑enzymatic protein damage in LLPs (carbamylation among them) is one of several upstream molecular‑aging forces that reshape tissues over time, biasing them toward dysfunction and disease. His portfolio bridges that molecular aging layer (earlier training) with organismal aging signatures, clonal evolution, and interventions that may shift trajectories.
Representative publications (selection)
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Aging predisposes B cells to malignancy by activating c‑Myc and perturbing the genome & epigenome. Mechanistic link from aging to lymphoma via clonal expansions in B cells.
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Age‑associated clonal B cells drive B‑cell lymphoma in mice. Defines ACBCs as disease‑driving population in old mice.
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Distinct longevity mechanisms across and within species. Cross‑species transcriptomics yields actionable longevity signatures.
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Rapamycin during development extends lifespan & healthspan. Transient early‑life mTOR inhibition reprograms aging.
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Depletion of loss‑of‑function germline mutations in centenarians reveals longevity genes. Human genetics of exceptional longevity.
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Actin carbonylation & Hsp70‑proteasome removal of oxidized proteins. Proteome damage and quality control in aging.
Key background on carbamylation (for deeper reading)
- Carbamylation as an aging hallmark in mammals; ECM LLPs as prime targets.
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MPO/SCN⁻ pathway to HNCO (inflammation) and uremia‑driven carbamylation (CKD).
- Reaction kinetics/pH features of amine carbamylation.
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Collagen/elastin mechanics under carbamylation; lens crystallin aggregation and cataract.
If you want, I can turn this into a one‑page research brief (with figure sketches of the carbamylation reaction and a quick “Castro lab themes” diagram) or expand any one topic into a deeper technical note.