Fig. 2: Klotho mitigates the phosphorylation of Forkhead box O3 (FOXO3a), primarily through the inhibition of Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT).

This action prevents the displacement of this central transcription factor from the nucleus, resulting in elevated expression of antioxidative enzymes such as Superoxide Dismutase II (SODII) and human Catalase (CAT) through the activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ). Possible outcomes include reduced production of interleukins, Major Histocompatibility Complex - II (MHC-II), Tumour Necrosis Factor α (TNF-α), and Reactive Oxygen Species (ROS), coupled with an increase in mitochondrial biogenesis and autophagy²⁵. Similar effects can be induced by modifying lifestyle factors, including physical intervention, the application of substances such as ginseng, curcumin, or polyamines like spermidine, and caloric restriction, which has been associated with an extension in life expectancy⁴⁰. These protective effects are hypothetically diminished by SERPIN E1 stabilising the Insulin-like Growth Factor 1 (IGF1) receptor and reducing telomere length²⁹. Created with BioRender.com.