Biological roles of aging suppressor gene klotho

Klotho is an aging regulator gene that is linked to the risk of age-related diseases. The klotho protein is produced mainly by the kidneys and circulating levels of this protein decrease with age. In the laboratory, klotho-deficient mice demonstrate accelerated aging. On the contrary, overexpression of the gene leads to an extended lifespan. Klotho is, therefore, an aging-suppressor gene. The name comes from Greek mythology, where klotho (clotho), which means “spinner,” was the daughter of Greek God Zeus and was one of the Moirai (three fates) responsible for spinning the thread of life. The klotho gene is located on chromosome 13 and encodes a transmembrane protein. Besides the kidneys, klotho is expressed in the choroid plexus of the brain as well as the aorta, parathyroid glands, and sex organs. What are the physiological roles of klotho that make it an important player in aging suppression? The klotho protein occurs in three forms – membrane-bound, intracellular, and secreted – and each has a different role. Membrane-bound klotho binds to fibroblasts growth factor receptors (FGFRs) which are involved in aging and the development of chronic diseases. Intracellular klotho stimulates sodium-potassium-ATPase and suppresses inflammation-mediated cell senescence and mineral metabolism. Secreted klotho acts like a humoral factor and targets cytokines and growth factors with protective effects through the regulation of oxidative stress. Now, let’s take a look at some of the physiological roles of klotho in more detail. Insulin/IGF-1 Pathway Inhibition: Klotho indirectly inhibits IGFRs (insulin-like growth factor receptors) and IRS (insulin receptor substrate). Activation of the IRS is responsible for phosphorylation of FOXOs which are involved in the regulation of glucose production. In laboratory experiments, klotho knockout mice (mice in whom the klotho gene is knocked out or turned off) demonstrate decreased insulin production and increased insulin sensitivity. Compared to controls, null (knockout) mice have less energy storage and expenditure. WNT Glycoprotein Signaling Suppression: Klotho suppresses WNT signals by binding to WNT ligands. This is demonstrated in the lab where klotho null mice exhibit enhanced WNT signaling. The WNT signaling pathway arrests and prolongs the cell cycle. Klotho treated cells can bypass this phase of the cell cycle. Under hypoxic conditions in the kidney, there is inhibition of klotho and upregulation of beta-catenin. Klotho, therefore, acts as a natural antagonist and its loss may lead to kidney disease. On the other hand, the expression of klotho decreases activation of beta-catenin with consequent improvement in kidney function. Calcium and Phosphate Homeostasis: Klotho in the soluble form increases the expression of a calcium channel and stabilization of the plasma membrane, leading to improved insulin secretion from the pancreatic beta cells. Another physiological role performed by klotho is to bind to TRPC1 and maintain endothelial integrity. TRPC1 is a nonspecific channel on the plasma membrane that allows both sodium and calcium ions to pass through. Klotho also increases the expression of sodium-potassium ATPase. The gene linked to rickets, FGF23, regulates phosphate levels. Phosphate absorption causes increased secretion of FGF23. Klotho increases the binding affinity of FGF23 and inhibits phosphate reabsorption in the kidneys. This is demonstrated in the laboratory where klotho knockout mice exhibit high serum levels of phosphate. Hyperphosphatemia (high levels of phosphate) are associated with aging in mammals. Suppression of Oxidative Stress: Various environmental stressors can lead to the excessive production of reactive oxygen species (ROS) in the body, ultimately progressing to oxidative damage and cell death. Klotho upregulates manganese superoxide dismutase (MnSOD), an antioxidant enzyme that lowers the production of reactive oxygen species. In the laboratory, mice with overexpression of klotho demonstrate higher levels of MnSOD and less oxidative stress and DNA damage. Klotho-based therapies are promising antiaging strategies for the future. For now, however, the mechanisms of action and effects of klotho are poorly understood and a great deal of further research is needed before klotho can be used to slow down aging and extend lifespan.