BRIEF RESEARCH REPORT article
Front. Aging
Sec. Genetics, Genomics and Epigenomics of Aging
This article is part of the Research TopicGenetic and Epigenetic Determinants of LongevityView all articles
Epigenetic Age Acceleration and Neurotrophin Signaling Pathways in Cancer-Related Cognitive Impairment: A Longitudinal, Prospective Cohort Study
Provisionally accepted
Michael Sayer1
Ding Quan Ng1
Julia Trudeau1Raymond J Chan2
Munjal M Acharya1
Kord Kober3
Alexandre Chan1*- 1University of California Irvine, Irvine, United States
- 2Flinders University, Adelaide, Australia
- 3University of California San Francisco, San Francisco, United States
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Abstract: Introduction Biological age acceleration and disruptions in neurotrophin pathway signaling may significantly contribute to cancer-related cognitive impairment (CRCI) etiology. In this study, we evaluated the relationship of epigenetic age acceleration with cognitive function measures and circulating BDNF levels. Furthermore, we evaluated DNA methylation (DNAm) patterns to explore neurotrophin pathway associations with CRCI symptoms. Methods In a longitudinal study, 51 newly diagnosed Adult and Young adult cancer patients and 8 age-matched healthy controls provided blood samples for DNAm and BDNF measurements with concurrent clinical assessments (#NCT03476070). We evaluated the relationship of epigenetic ageing with cancer status, circulating BDNF levels, and measured cognitive function. Next, we identified significant differentially methylated positions (DMPs), regions (DMRs), and significantly enriched pathways associated with BDNF and cognitive function outcomes. Results PhenoAge and GrimAge demonstrated significant age acceleration relative to non-cancer controls and worsening cognitive function symptoms, with accelerated GrimAge associated with decreasing BDNF levels. DMPs associated with 5 different cognitive function outcomes (FactCog Score, Response, Memory, Executive Function, Multi-Tasking) were mapped to genes within KEGG pathway HSA:04722 (Neurotrophin Signaling Pathway). Key enriched pathways relative to both subjective cognitive function and multiple objective cognitive measurement domains were also enriched with respect to BDNF levels, including Synapse (GO:0045202), Glutamatergic Synapse (GO:0098978), and Neuron Projection (GO:0043005). Conclusion Cancer and cancer treatment lead to significant epigenetic age acceleration, which can influence neuronal health and CRCI symptom onset. Furthermore, DNAm patterns corroborate BDNF as a potential biomarker for CRCI and suggest neurotrophin pathways play a meaningful role in CRCI etiology.
Keywords: Cancer related cognitive impairment, epigenetic ageing, Neurotrophin Signaling Pathways, Brain Derived Neuropathic Factor, Differential DNA methylation, Pathway enrichment analysis
Received: 09 Oct 2025; Accepted: 05 Nov 2025.
Copyright: © 2025 Sayer, Ng, Trudeau, Chan, Acharya, Kober and Chan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Alexandre Chan, a.chan@uci.edu
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