Aging at the Crossroads of Cuproptosis and Ferroptosis - From Molecular Pathways to Age-Related Pathologies and Therapeutic Perspectives

Sep 30, 2026

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Aging is a multifactorial process marked by progressive functional decline and increasing vulnerability to diseases including neurodegeneration, cancer, cardiovascular disorders, and infections. A core feature is inflammaging, driven by cellular senescence, mitochondrial dysfunction, and oxidative stress. Ferroptosis and cuproptosis are regulated non-apoptotic cell-death programs connecting redox imbalance, mitochondrial stress, and disrupted metal homeostasis to age-related pathology. The review integrates their roles across metal–redox–metabolic networks, highlighting how iron/copper dysregulation, GSH/GPX4 defects, Fe–S compromise, and lipid peroxidation converge to worsen survival thresholds, immune dysfunction, and tissue degeneration. It further outlines therapeutic potential via nutritional, pharmacological, and lifestyle interventions.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages53

Reading Time2 h 14 min

AccessFree to download

Introduction

Inflammaging and aging hallmarks

Ferroptosis and cuproptosis as regulated cell death

Metal homeostasis and mitochondrial/metabolic links

Integrated therapeutic perspectives

Review Aging at the Crossroads of Cuproptosis and Ferroptosis: From Molecular Pathways to Age-Related Pathologies and Therapeutic Perspectives Grayna Gromadzka 1,*, Beata Tarnacka 2,3 and Magdalena Cie´slik 4, * Academic Editor: Maria Scuto Received: 27 October 2025 Revised: 17 December 2025 Accepted: 18 December 2025 Published: 4 January 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Department of Biomedical Sciences, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, Wóycickiego Street 1/3, 01-938 Warsaw, Poland 2 Department of Rehabilitation, Eleonora Reicher National Institute of Geriatrics, Rheumatology and Rehabilitation, Sparta ´nska 1, 02-637 Warsaw, Poland 3 Department of Rehabilitation Medicine, Faculty of Medicine, Warsaw Medical University, Sparta ´nska 1, 02-637 Warsaw, Poland 4 Department of Cellular Signalling, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawi ´nskiego 5, 02-106 Warsaw, Poland * Correspondence: [g.gromadzka@uksw.edu.pl](g.gromadzka@uksw.edu.pl) (G.G.); [mcieslik@imdik.pan.pl](mcieslik@imdik.pan.pl) (M.C.) Abstract Aging is a multifactorial process marked by a progressive decline in physiological function and increased vulnerability to diseases such as neurodegeneration, cancer, cardiovascular disorders, and infections. A central feature of aging is inflammaging, a state of chronic low-grade inflammation driven by cellular senescence, mitochondrial dysfunction, and oxidative stress. Recently, two regulated forms of non-apoptotic cell death—ferroptosisand cuproptosis—have emerged as critical mechanisms linking redox imbalance, mitochondrial stress, and disrupted metal homeostasis to age-related pathology. Ferroptosis, an iron-dependent process characterized by lipid peroxidation and impaired glutathione peroxidase 4 (GPX4) activity, and cuproptosis, a copper-dependent mechanism associated with protein lipoylation stress, both intersect with aging-related changes in mitochondrial and metabolic function. Importantly, these two forms of cell death should not be viewed as entirely separate pathways but rather as interconnected axes within a broader metal–redox–metabolic network. Disturbances in copper or iron homeostasis, glutathione (GSH)/GPX4 dysfunction, mitochondrial and iron-sulfur (Fe–S) cluster compromise, and enhanced lipid peroxidation may converge to lower cellular survival thresholds, thereby exacerbating oxidative damage, immune dysfunction, and tissue degeneration and ultimately fueling aging and inflammaging. This review offers a unique integrated perspective that situates ferroptosis and cuproptosis within a unified framework of aging biology, emphasizing their roles in age-related diseases and the therapeutic potential of targeting these pathways through nutritional, pharmacological, and lifestyle interventions. Keywords: aging; Alzheimer’s disease; cuproptosis; cardiovascular disease; cancer; curcumin; diet; ferroptosis; hormesis; infection; inflammaging; neurodegeneration; oxidative stress; Parkinson’s disease; polyphenols; polyunsaturated fatty acids (PUFAs) 1. Introduction Aging is a complex and multifactorial biological process characterized by a progressive decline in physiological functions and increased susceptibility to a wide range of diseases, including neurodegeneration, cancer, cardiovascular disorders, and infections [1,2] . One of the hallmarks of aging is the chronic, low-grade systemic inflammation that develops in the absence of overt infection—a phenomenon termed inflammaging [3,4] . Although the exact triggers of inflammaging are still being elucidated, cellular senescence, mitochondrial dysfunction, and oxidative stress are considered major contributors [5] . In recent years, two distinct and regulated for

FAQs

What is inflammaging and what drives it during aging?

Inflammaging refers to chronic low-grade systemic inflammation that arises without overt infection. Cellular senescence, mitochondrial dysfunction, and oxidative stress are major contributors.

How do ferroptosis and cuproptosis relate to metal homeostasis and redox imbalance?

Ferroptosis is iron-dependent and involves lipid peroxidation and impaired GPX4 activity. Cuproptosis is copper-dependent, triggered by intracellular copper accumulation and dysregulated mitochondrial protein lipoylation, leading to proteotoxic stress.

Why does the review treat ferroptosis and cuproptosis as interconnected rather than separate pathways?

It emphasizes shared redox and metabolic features within a unified metal–redox–metabolic network. Copper or iron disturbances, GSH/GPX4 dysfunction, Fe–S compromise, and enhanced lipid peroxidation can converge to lower cellular survival thresholds and amplify aging-related pathology.

Sep 30, 2026

Uploaded by Cipher