The Epigenetic Aging-Cancer Continuum: Biomarkers, Metabolism, and Therapy.

Abstract

Aging and cancer form a biological continuum influenced by epigenomic changes, metabolic dysfunction, inflammation, cellular senescence, and loss of tissue homeostasis. Age-related epigenetic alterations can promote cancer, which exploits plasticity for evolution, immune evasion, metastasis, and resistance. Nutrition and metabolism affect this process through one-carbon metabolism, methyl-donor availability, acetyl-CoA and NAD⁺ balance, redox status, microbiome metabolites, and chromatin enzyme activity. Circulating biomarkers such as cell-free DNA methylation, mutation-based ctDNA, fragmentomic features, and non-coding RNAs can detect tumor and host changes linked to aging, inflammation, nutrition, and treatment with minimal invasiveness. This review explores the epigenetic aging-cancer link, how nutrition and metabolism modify pathways, and the potential of circulating biomarkers for diagnosis, prognosis, prediction, and monitoring. The focus is on epigenetic plasticity, drug-tolerant states, resistance, epigenetic drugs, metabolic targeting, and nutritional interventions. New technologies, including single-cell and spatial epigenomics, long-read sequencing, and multimodal computational approaches, aid biomarker discovery and clinical use. Challenges include variability, misclassification, heterogeneity, confounding, reverse causality, overfitting, and limited validation. Clinical applications need standard workflows, representative cohorts, transparent models, and proof that biomarker-guided strategies improve outcomes.