Highlights:
This review explores ferroptosis, an iron-dependent, non-apoptotic form of programmed cell death, as a promising strategy for eliminating senescent cells, which accumulate with age and contribute to tissue dysfunction and age-related diseases such as fibrosis, atherosclerosis, osteoarthritis, and neurodegeneration. The molecular mechanisms of ferroptosis, including iron overload, lipid peroxidation, and oxidative damage, can be leveraged to overcome limitations of traditional senolytic approaches that rely on apoptosis.
Key takeaway:
Ferroptosis-based therapies may offer a next-generation senolytic approach with the potential to selectively target and eliminate senescent cells and mitigate a range of age-associated pathologies.
Dr. Kureel is a postdoctoral fellow in the lab of Blake Rasmussen, PhD, at the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Targeting Ferroptosis to Eliminate Senescent Cells: Mechanisms and Therapeutic Potential
Sanjay Kumar Kureel, Blake B Rasmussen
Aging Dis. 2025 Jul 19. doi: 10.14336/AD.2025.0141. Online ahead of print.
Abstract:
Cellular senescence is involved in early development, wound healing, and tumor suppression. However, the accumulation of senescent cells (SCs) drives tissue dysfunction and many age associated pathologies such as cancer and neurodegeneration. SCs demonstrate irreversible cessation of cell cycle, overexpression of anti-apodotic proteins, and senescence associated secretory phenotype (SASP), cause tissue dysfunction. Traditional senolytics induces apoptosis but have poor selectivity, uncertain long-term efficacy, and resistant SCs, limiting their use. Ferroptosis, an iron-dependent, non-apoptotic form of programmed cell death, has emerged as a promising alternative. SCs bypass the apoptosis by overexpression of an anti-apoptotic pathway, but ferroptosis uses oxidative damage to overcome these defenses, thus, making it effective for eliminating SCs. This review critically evaluates ferroptosis-mediated processes such as elevated level of iron, polyunsaturated fatty acids (PUFAs) and oxidative damages in elimination of SCs and its therapeutic potential for age related pathologies including fibrosis, cancer and neurodegenerative diseases. This review highlights the molecular mechanisms underlying ferroptosis and its potential for treating age-related diseases such as fibrosis, atherosclerosis, osteoarthritis, and neurodegeneration. By addressing the translational challenges of ferroptosis-based therapies, we emphasize its potential as a next generation senolytic for targeting senescence and aging-related pathologies.