The Klotho (KL) gene was identified as an anti-aging gene and has produced insights into how the aging process works. Researchers have uncovered several functions of Klotho, but future research should investigate the location of Klotho receptors and downstream signaling functions.

Known Functions of Klotho

The encoded α-Klotho protein regulates phosphate, Vitamin D, and calcium metabolism resulting in the following functions:

1) Full-length α-Klotho is important in maintaining mineral metabolism. It acts as a coreceptor and signal booster for FGF23, a gene important to regulating phosphate levels.

2) Full-length α-Klotho could inhibit Wnt signaling associated with conditions such as liver cancer.

3) Soluble α-Klotho enhances TRPV5 and ROMK, increasing reabsorption of calcium in the kidneys and impacting the transport of potassium in the kidneys.

4) Full-length α-Klotho impedes the IGF/insulin signaling.

5) Full-length α-Klotho reduces the impact of oxidative stress on the body.

These functions have broad implications in the aging process and the development of certain age-related diseases. However, scientists haven’t identified how α-Klotho extends life span.

Klotho Suppresses the Aging Process, but How?

Although current research has confirmed Klotho as an age-suppressing gene, there are still many questions. If the full-length α-Klotho protein expression takes place in the kidneys and the choroid plexus of the brain, why does klotho have such a huge impact on other organs and tissues throughout the body?

For example, circulating Klotho affects cells and tissues that do not seem to express Klotho. Further, mutations of the KL gene trigger cell characteristics associated with aging. Circulating Klotho could result from alternative RNA splicing conducted by secreted Klotho. Alternatively, it could result from soluble Klotho breaking down the peptide bonds of KL protein (proteolytic cleavage).

It may turn out that Klotho acts as a hormone. However, that will remain a mystery until researchers isolate Klotho’s receptors and binding sites.

Direction of Future Research

Future research must delve into how α-Klotho accomplishes these functions. Currently, research is inhibited by these factors:

  • Lack of inhibitors capable of blocking α-Klotho in in vitro and in vivo
  • Inability to distinguish various forms of α-Klotho.
  • Unknown receptors and binding sites

Research focusing on these gaps will greatly facilitate understanding of this important anti-aging gene.