Ferro-Aging as a Contribution to Age-Related Disease, Distinct from Ferroptosis
The only viable way to definitively establish the importance of any given mechanism of action is to create a therapy that selectively prevents or repairs that mechanism without touching the other mechanisms of aging, and then observe the outcomes in aged animals. This is a challenge, and typically the results are a surprise; until the development of senolytic therapies, no-one expected clearance of senescent cells to be so very effective at reversing age-related disease in animal models, for example. Because it is hard to determine the relative importance of mechanisms of aging, much of the aging research community often resembles a collection of small fiefdoms, each advocating for the importance of their small portion of degenerative aging, in the absence of concrete proof of that importance. This is worth bearing in mind when looking at new viewpoints, such as the concept of ferro-aging advanced here.
In recent years, with increasing research on ferroptosis, abnormal iron metabolism has gradually been recognized as an important pathological basis for aging-related diseases. Iron is an essential trace element for oxygen transport, energy metabolism, and DNA synthesis. However, excess free iron can generate large amounts of reactive oxygen species (ROS) through the Fenton reaction. This induces lipid peroxidation, DNA damage, and cellular dysfunction.
Traditionally, iron overload has been thought to promote tissue damage primarily by triggering ferroptosis; Nevertheless, recent studies have proposed a new concept distinct from ferroptosis - ferro-aging. Ferro-aging is not an acute form of cell death but rather a chronic pre-pathological state characterized by persistent lipid peroxidation and progressive cellular dysfunction. Although cells in the ferro-aging state retain membrane integrity, they can sustain irreversible damage and continuously affect the local microenvironment through the formation of the senescence-associated secretory phenotype (SASP), ultimately contributing to tissue functional decline and systemic aging,
This review systematically summarizes the molecular basis of ferro-aging, with a focus on the central role of ACSL4 in promoting membrane lipid remodeling and sustaining chronic lipid peroxidation. We discuss how ACSL4-associated ferro-aging contributes to the pathogenesis of osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD) by disrupting local microenvironmental homeostasis, driving metabolic reprogramming, amplifying inflammatory SASP signaling, and impairing the function of key cell types such as osteoblasts, chondrocytes, and nucleus pulposus cells.