The role of GDF15 in aging and age-related diseases (ARDs): studies on ex vivo and in vitro models

Aging is a complex phenomenon and the main risk factor for various age-related diseases (ARDs), which share common molecular mechanisms with aging. Among these mechanisms, two are of particular interest for our group: chronic inflammation (inflammaging) and mitochondrial dysfunction, both of which are present in several ARDs. In this context, the role of Growth Differentiation Factor 15 (GDF15), one of the most upregulated protein during aging and in ARDs, was studied. GDF15 is a stress-responsive protein involved in inflammation and mitochondrial dysfunction, with protective effects on mitochondria and anti-inflammatory properties. However, its precise role in aging and ARDs is still unclear. The study focused on two typical ARDs: Alzheimer’s disease (AD) and sarcopenia, both of which are characterized by mitochondrial dysfunction and inflammation. Brain samples and cerebrospinal fluid (CSF) from AD patients were analyzed, alongside skeletal muscle biopsies and plasma from patients with lower limb mobility impairment. In AD, no significant differences in CSF GDF15 levels were found, but GDF15 expression was observed in various brain regions, mainly in neurons, with higher levels of the mature form in AD patients and centenarians compared to non-demented subjects. In sarcopenia, patients with muscle atrophy had higher plasma GDF15 levels but lower intramuscular GDF15 expression (SM-GDF15) compared to healthy subjects. In vitro experiments showed that GDF15 knockdown in dermal fibroblasts led to increased inflammation and mitochondrial alterations, while in tumor cell lines, it appeared to affect cell cycle regulation. These findings suggest that GDF15 in brain could be part of a stress response aimed at counteract mitochondrial stress and inflammation. GDF15 expression in muscle appears to be stimulated by muscle contraction and may be crucial for maintaining mitochondrial function in healthy, active individuals. In vitro data on dermal fibroblasts confirmed the role of GDF15 in protecting cells from mitochondrial stress and inflammation.