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Molecular Insights into Genetic and Epigenetic Alterations in Age-Related Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 1065

Special Issue Editors


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Guest Editor
Department of Clinical Medicine, Life, Health and Environmental Sciences—MESVA, University of L’Aquila, 67100 Coppito, AQ, Italy
Interests: epigenetics; genomics; metabolic disorders; complex diseases; DNA methylation
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Departmental Faculty of Medicine, Saint Camillus International University of Health Sciences, Via di Sant’Alessandro, 8-00131 Rome, Italy
Interests: genetics; epigenetics; pharmacogenomics; multifactorial diseases; autoimmune diseases; microRNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging represents a major risk factor for the development of chronic and degenerative diseases, including neurodegenerative disorders, metabolic diseases, and cancer. Increasing evidence highlights the central role of molecular mechanisms at the (epi)genomic level in driving the onset and progression of age-related diseases. Individual genetic make-up, genomic instability, high-order chromatin interactions, telomere (dys)regulation, and mitochondrial DNA alterations intersect with epigenetic modifications, such as DNA methylation changes, histone modifications, and dysregulation of non-coding RNAs. These processes contribute to altered gene expression, impaired cellular homeostasis, and tissue dysfunction. Recent advances in high-throughput technologies and integrative/spatial omics have provided unprecedented opportunities to map molecular alterations in aging and identify novel biomarkers of disease susceptibility, progression, and therapeutic response. This Special Issue aims to collect original research and comprehensive reviews broadly exploring the molecular, genetic, and epigenetic landscape in age-related diseases, with a focus on mechanistic insights, translational implications, and novel therapeutic strategies.

Dr. Valerio Caputo
Dr. Andrea Latini
Guest Editors

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Keywords

  • genomics
  • epigenetic modifications
  • age-related pathologies
  • neurodegeneration
  • dysmetabolism
  • spatial omics
  • 3D genome
  • genetic variants
  • telomere length
  • mitochondrial DNA
  • biomarkers

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Published Papers (1 paper)

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Research

26 pages, 4731 KB  
Article
Brain Single-Cell Transcriptional Responses to Bexarotene-Activated RXR in an Alzheimer’s Disease Model
by Carolina Saibro-Girardi, Yi Lu, Nicholas F. Fitz, Daniel P. Gelain, Iliya Lefterov and Radosveta Koldamova
Int. J. Mol. Sci. 2026, 27(5), 2435; https://doi.org/10.3390/ijms27052435 - 6 Mar 2026
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Abstract
Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects [...] Read more.
Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting Aβ-responsive signatures in disease-associated microglia and reactive astrocytes while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell–cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the molecular complexity of RXR-mediated regulation, revealing the cellular origins of bexarotene’s known effects as well as novel, cell-type-specific responses. This study provides mechanistic insights into RXR-targeted interventions and supports APOE-associated pathways as promising therapeutic targets in AD. Full article
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