8.A.49.1.1
The Klotho (KL; α-Klotho; alpha-Klotho) protein of 1012 aas and 2 (or more) TMSs, N- and C-terminal.  Activates several transporters including the creatine transporter, CreaT or SLC6A8 (TC# 2.A.22.3.11; Almilaji et al. 2014) and the TRP6 cation channel (Smith et al. 2017).  Klotho also regulates diverse calcium and potassium ion channels as well as several carriers including the Na⁺-coupled excitatory amino acid transporters EAAT3 and EAAT4, the Na⁺-coupled phosphate cotransporters, NaP_i-IIa and NaP_i-IIb, and a Na⁺/K⁺-ATPase. All these cellular transport regulations contribute in the aging suppressor role of Klotho (Sopjani et al. 2014). α-Klotho is associated with phosphate, vitamin D, and calcium homeostasis. The calcium imbalance in α-Klotho-negative mice may induce calpain overactivation, leading to cell death and tissue destruction. α-Klotho has glycosidase activity, capable of modifying the N-glycans of channels and transporters and regulating transmembrane movement of several ions, including calcium (Akasaka-Manya et al. 2016). It regulates diacylglycerol-stimulated exocytotic insertion of pre-docked TRPC6 vesicles (Xie et al. 2020). The aging-protective gene alpha-Klotho (KL) produces two main transcripts. The full-length mRNA generates a transmembrane protein that after proteolytic ectodomain shedding can be detected in serum as processed Klotho (p-KL), and a shorter transcript which codes for a putatively secreted protein (s-KL). Both isoforms exhibit potent pleiotropic beneficial properties (Roig-Soriano et al. 2023). s-KL (but not p-KL) is a safe therapeutic strategy to exploit KL anti-aging protective effects, presenting no apparent negative effects over mineral metabolism and bone microstructure (Roig-Soriano et al. 2023).