Biology subjects

Castro, J. P.

Publications and source records attributed to Castro, J. P..

9 recordsLinked to original sources

bioRxiv2026

An inflammatory gene set driven epigenetic clock tracks down disease progression and rejuvenation

Chronic, low-level inflammation, characterized by elevated pro-inflammatory programs, including epigenetic changes, in the absence of infection, is a major driver of aging and age-related diseases. On the other side of the spectrum, aging interventions work, at least in part, by decreasing inflammation. However, the molecular connection between epigenetic aging and inflammatory profiles in chronic diseases and rejuvenation has not been established yet. This study aimed to investigate the role of a newly described inflammatory signature gene set (ISig) in aging, previously associated with accelerated aging, in the progression of chronic diseases and rejuvenation. To achieve this, we developed inflammation-derived epigenetic aging clocks using ElasticNet regression models trained on CpG sites from ISig promoter regions. The newly developed inflammation aging clocks were validated on healthy samples and tested for their capacity to detect accelerated aging in diseased samples and rejuvenation during cellular reprogramming. The data demonstrate that the ISig inflammatory clocks accurately predict age, detect rejuvenation, and identify accelerated aging in disease contexts. Furthermore, we have demonstrated that it is possible to use a curated inflammatory gene-set with biological relevance to estimate biological age acceleration. We also developed a web application, the GeneClock Studio (available at https://ilab.sztaki.hu/geneclockstudio/), that allows researchers to apply the inflammatory aging clocks to their own DNA methylation datasets without requiring any programming expertise. Furthermore, the GeneClockStudio supports the training of new aging clocks based on an arbitrarily selected gene set in a similar way as in the case of the ISig inflammatory clocks.

bioinformatics↗

bioRxiv2026

Modafinil Modulation of Oscillatory and Aperiodic Brain Activity in Rats Across Wakefulness and Subsequent Sleep

Cortical states shape sensory processing, decision-making, and behavior, and are characterized by distinct patterns of neuronal oscillatory activity. Pharmacological agents can modulate these states and their underlying electrophysiological signatures. Modafinil is a widely used wake-promoting agent and cognitive enhancer, but its effects on cortical oscillations are not fully understood. In this study, we evaluated the effect of modafinil on cortical activity during wakefulness and subsequent sleep. Ten male Wistar rats were implanted with electrocorticographic electrodes and recorded following oral administration of modafinil or its vehicle. Our results show that modafinil increased wakefulness in a dose-dependent manner, with doses of 200 and 300 mg/kg producing prolonged wake episodes and reducing hypnogram complexity. During wakefulness, modafinil enhanced gamma-band power in anterior cortices, an effect primarily driven by increases in the aperiodic rather than oscillatory components. Although no sleep rebound was observed, subsequent NREM sleep exhibited increased delta power, particularly in anterior regions, indicating heightened sleep pressure. In conclusion, our findings demonstrate that modafinil-induced wakefulness is associated with an enhanced aperiodic gamma band component at the anterior cortices in the EEG. Furthermore, modafinil modulates sleep homeostasis by enhancing NREM sleep intensity rather than extending its duration.

neuroscience↗

bioRxiv2025

FOXM1 enhances DNA repair in aged cells to maintain the peripheral heterochromatin barrier to senescence enhancers

DNA damage is a key driver of aging, contributing to epigenetic erosion, senescence, and chronic inflammation. However, genoprotective strategies to counteract aging remain intangible. Here we show that FOXM1 repression during aging accounts for a global transcriptional shutdown of DNA repair genes and the accrual of DNA damage. Restored FOXM1 activity in aged cells reduces DNA damage and epigenetic alterations driving senescence. Mechanistically, FOXM1 drives the transcription of DNA repair genes, which prevents the DNA damage-driven degradation of the G9a methyltransferase and subsequent loss of H3K9me2 at the nuclear periphery. Remarkably, we show that amendment of the H3K9me2 guidepost for peripheral heterochromatin by FOXM1 induction in aged cells inactivates enhancers of the AP-1-driven senescence and inflammation program. These findings establish FOXM1 as an age-reversal factor capable of restoring (epi)genetic integrity to inhibit the senescence enhancer landscape, offering a promising therapeutic avenue to address the fundamental causes of aging.

cell biology↗

bioRxiv2025

Differential effects of postpartum sleep restriction on maternal and offspring immunity in the rat

Backgroundsleep disturbances can trigger a wide range of physiological consequences, affecting hormonal regulation, metabolism, cognitive function, and immune responses. Human mothers worldwide frequently experience sleep restriction and fragmentation, a pattern also observed in other mammalian mothers, such as rats. These alterations may add to sleep disturbances unrelated to motherhood. Considering this, we wondered about the impact of sleep restriction in postpartum mother rats on their immunological status. Furthermore, given that early-life experiences can shape the immune system and that even subtle parental changes can influence offspring development, we hypothesized that maternal sleep loss might also exert detrimental effects on the pups. In this study, we investigated the effects of acute and chronic maternal sleep restriction during the postpartum period on immune parameters in both mother rats and their offspring by analyzing antibody titers and systemic inflammation. Methodsmother rats were surgically implanted with electrodes for polysomnographic recordings and for sleep deprivation (deep electrodes targeting the mesopontine wake-promoting area). From postpartum day 5 to day 9, lactating dams were randomly assigned to one of three groups: chronic sleep restriction (CSR; 6 h of sleep deprivation per day for five consecutive days), acute sleep restriction (ASR; 6 h of sleep deprivation only on postpartum day 9), or control (undisturbed). On postpartum day 9, mothers were milked, and blood samples from both mothers and pups were subsequently collected. ELISA assays quantified IL-17A, IL-6, IgG, and IgG2a in maternal serum; IgG and IgG2a in milk; and IgG in pup serum. Hematological parameters, including leukocyte profiles, were also assessed in peripheral blood of dams and pups. Resultsmaternal immune parameters analyzed remained unaffected by sleep restriction. IgG levels were lower in male pups from mothers subjected to ASR (5560 {+/-} 734 {micro}g/mL) compared with the control group (8666 {+/-} 463 {micro}g/mL; p = 0.025), whereas female pups showed no significant changes. Additionally, both female (4.10 {+/-} 0.58) and male (3.81 {+/-} 0.42) pups from dams subjected to CSR exhibited higher absolute lymphocytes counts relative to the control group (females: 2.28 {+/-} 0.25, p = 0.004; males: 2.44 {+/-} 0.25; p = 0.029). ConclusionsChronic and acute maternal sleep restriction had distinct impacts on offspring immunity, altering serum antibody and leukocyte profiles, while leaving maternal parameters unaffected. These results indicate that maternal sleep loss can influence the offspring even in the absence of detectable maternal immune alterations, with male pups being especially susceptible.

immunology↗

bioRxiv2025

Transcriptomic entropy reveals tissue-specific patterns in aging and predicts cancer progression

ABSTRACTAging and cancer share complex molecular mechanisms, yet distinguishing between causative factors and byproducts remains challenging. Here, we investigated the role of transcriptomic entropy in aging and cancer processes by analyzing RNA-sequencing data from thousands of human and mouse samples. We found that entropy changes during aging are highly tissue-specific, with some tissues showing increased entropy while others exhibit decreased or stable entropy levels. Transcriptomic entropy strongly correlates with age-related processes, showing positive associations with proliferation, cellular senescence, and somatic mutation burden, while negatively correlating with stemness. Surprisingly, cellular reprogramming also increases transcriptomic entropy. In cancer, we observed that primary tumors generally display higher entropy than normal tissue, with entropy levels further increasing in metastatic stages. Notably, treatment-resistant tumors showed distinct entropy patterns, with acquired resistance associated with increased entropy, while primary resistance and immediate post-treatment responses showed decreased entropy. Higher entropy levels predicted poor survival outcomes in multiple cancer types, suggesting its potential as a prognostic marker. Furthermore, differential expression analysis revealed that entropy-associated genes are enriched in developmental processes and depleted in metabolic pathways, indicating a possible link to cellular dedifferentiation. Finally, we found increased entropy in various age-related diseases beyond cancer, suggesting that transcriptomic disorder may be a common feature in age-related pathologies. Our findings establish transcriptomic entropy as a fundamental parameter in aging and cancer progression, offering new insights into disease mechanisms and challenging the current view that increased disorder is always detrimental.

genomics↗

bioRxiv2025

Molecular signatures of longevity identify compounds that extendmouse lifespan and healthspan

Longevity interventions in mammals are typically discovered on a case-by-case basis, hindering systematic geroprotector development. We developed a platform for the identification of longevity interventions integrating longevity gene expression biomarkers within and across species, in silico chemical screening, analyses of selected compounds in cell culture, short-term dietary interventions coupled with omics profiling, and ultimately lifespan studies in mice. This approach identified compounds (selumetinib, vorinostat, celastrol, AZD-8055, LY-294002) that extended lifespan and/or healthspan in aged C57BL/6JN male mice, with limited effects in females. In addition, selumetinib and vorinostat increased lifespan when administered to young, genetically heterogeneous UM-HET3 mice. Our biomarker-driven platform accelerates geroprotector discovery, offering a scalable approach to target conserved longevity pathways.

systems biology↗

bioRxiv2024

A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer's disease and aging research

Since its first description in 1906 by Dr. Alois Alzheimer, Alzheimers disease (AD) has been the most common type of dementia. Initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated AD with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of AD by using transcriptomic data from congenital diseases known to increase AD risk, namely Down Syndrome, Niemann Pick Disease Type C (NPC), and Mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of AD pathology, many of which have never been associated with AD. We then investigated common molecular alterations in brain samples from an NPC disease mouse model by juxtaposing them with brain samples of both human and mouse models of AD. Detailed phenotypic and molecular analyses revealed that the NPCmut mouse model can serve as a potential short-lived in vivo model for AD research and for understanding molecular factors affecting brain aging. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on AD research while highlighting shortcomings and lack of correlation in diverse in vitro models. Considering the lack of an AD mouse model that recapitulates the physiological hallmarks of brain aging, the characterization of a short-lived NPC mouse model will further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of AD from a perspective of accelerated brain aging.

genetics↗

bioRxiv2022

Rapamycin treatment during development extends lifespan and healthspan

The possibility that pace of development is tightly connected to aging is supported by the fact that the onset of reproduction is associated with lifespan and that many longevity interventions target growth and development. However, it has been unknown whether targeting development with pharmacological intervention can lead to a longer lifespan. To test this possibility, we subjected genetically diverse UMHET3 mice to the mTOR inhibitor rapamycin for the first 45 days of life and followed them up until death. Treated mice grew slower, with most of the deceleration occurring in the first week, and remained smaller for their entire lives. Their reproductive age was delayed but without affecting offspring numbers. The treatment was sufficient to extend the median lifespan by 10%, with the most effect in males, and to preserve better health as measured by frailty index, gait speed, and glucose and insulin tolerance tests. Mechanistically, the liver transcriptome of treated mice was younger at the completion of treatment and stayed younger into the old ages in males. Rapamycin initially reduced DNA methylation age of livers, however, that effect was lost with aging. Analogous to mice, rapamycin exposure only during development robustly extended the lifespan of Daphnia magna as well as reduced their body size, suggesting evolutionary conserved mechanisms of this early life effect. Overall, the results demonstrate that short-term rapamycin treatment during early life is a novel longevity intervention that establishes causality between pace of development and longevity in evolutionary distant organisms.

developmental biology↗

bioRxiv2021

Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome

While cancer is an age-related disease, many cancer studies utilize younger animal models. Here, we uncover how a cancer, B-cell lymphoma, develops as a consequence of a naturally aged system. We show that this malignancy is associated with increased cell size, splenomegaly, and a newly discovered age-associated clonal B-cell (ACBC) population. Driven by exogenous c-Myc activation, hypermethylated promoters and somatic mutations, ACBC cells clonally expand independent of germinal centers (IgM+) and show increased biological age and hypomethylation in partially methylated domains related to mitotic solo-CpGs. Epigenetic changes in transformed mouse B cells are enriched for changes observed in human B-cell lymphomas. Mechanistically, the data suggest that cancerous ACBC cells originate from age-associated B cells, in part involving CD22 protein signaling fostered by the aging microenvironment. Transplantation assays demonstrate that ACBC evolve to become self-sufficient and support malignancy when transferred into young recipients. Inhibition of mTOR or c-Myc in old mice attenuates premalignant changes in B cells during aging and emerges as a therapeutic strategy to delay the onset of age-related lymphoma. Together, we show how aging contributes to B-cell lymphoma through a previously unrecognized mechanism involving cell-intrinsic changes and the aged microenvironment, characterize a model that captures the origin and progression of spontaneous cancer during aging and identify candidate interventions against age-associated lymphoma.

cancer biology↗