**Structure of Klotho Protein**:
– The α-klotho gene on chromosome 13 encodes a membrane protein with short intracellular and long extracellular portions.
– The extracellular portion contains KL1 and KL2 repeat sequences.
– Proteolytic cleavage of the transmembrane protein leads to a soluble form.
– The β-Klotho gene on chromosome 4 shares homology with α-klotho.
– Differentiation between alpha-cut and beta-cut of α-klotho.
**Function and Clinical Significance**:
– Klotho influences insulin sensitivity, aging, and cellular calcium homeostasis.
– Interaction with FGFs via β-klotho has physiological effects.
– α-klotho reduces oxidative stress and inflammation.
– Reduced klotho expression is linked to various health issues such as lung problems, muscle loss, and potential implications in cancer detection and treatment.
– β-klotho activation of FGF21 protects heart muscle cells and klotho is vital for brain health and neuron protection.
**Effects on Aging**:
– Low levels of α-klotho or FGF23 impair phosphate excretion.
– Mice lacking these proteins exhibit premature aging symptoms.
– Plasma α-klotho decreases with age and is associated with frailty.
– Physical activity can boost plasma α-klotho levels.
– Over-expression of klotho in mice extends lifespan and cognition.
**Miscellaneous Effects and Research Findings**:
– Klotho deficiency in mice leads to accelerated aging symptoms.
– Klotho may have protective effects in Alzheimer’s disease.
– Research shows cognitive benefits of α-klotho in primates.
– Reduced klotho is linked to methylation changes in oral tissues and may protect the cardiovascular system through nitric oxide production.
– Klotho protein may have implications in various disorders like cardiovascular diseases and neurodegenerative disorders.
**Therapeutic Potential and Gene Regulation**:
– Klotho has therapeutic potential as an autophagy regulator and a target for various conditions.
– Gene regulation of Klotho involves transcriptional activation influenced by epidermal growth factor and regulatory SNPs in the promoter.
– Senolytic drugs boost proteins that protect against aging effects, and Klotho is an antiaging protein involved in mineral and vitamin D metabolism.
– Klotho gene variants are associated with lipid metabolism, glucose metabolism, essential hypertension, and potential breast cancer risk modification.
– Research findings suggest Klotho’s role in calcium and phosphate metabolism, survival in dialysis patients, and genetic variation in health conditions.
Klotho is an enzyme that in humans is encoded by the KL gene. The three subfamilies of klotho are α-klotho, β-klotho, and γ-klotho. α-klotho activates FGF23, and β-klotho activates FGF19 and FGF21. When the subfamily is not specified, the word "klotho" typically refers to the α-klotho subfamily, because α-klotho was discovered before the other members.
α-klotho is highly expressed in the brain, liver and kidney. β-klotho is predominantly expressed in the liver. γ-klotho is expressed in the skin.
Klotho can exist in a membrane-bound form or a (hormonal) soluble, circulating form. Proteases can convert the membrane-bound form into the circulating form.
The KL gene encodes a type-I single-pass transmembrane protein that is related to β-glucuronidases. Reduced production of this protein has been observed in patients with chronic kidney failure (CKF), and this may be one of the factors underlying degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CKF. Mutations within the family have been associated with ageing, bone loss and alcohol consumption. Transgenic mice that overexpress Klotho live longer than wild-type mice.