Anti-Aging Hormone Linked to Blood Calcium Regulation

Lack of klotho may explain osteoporosis and other conditions of aging, study suggests

THURSDAY, Oct. 20, 2005 (HealthDay News) -- Life hangs by a thread, so the saying goes. And in a roundabout way, that may be true. Klotho, a hormone whose name refers to one of the Greek Fates who spun the thread of life, appears to extend life in a unique way.

Using a heretofore unknown mechanism, klotho, which is found in cerebrospinal fluid, urine and blood, helps to control blood calcium concentrations by regulating the amount of calcium that is allowed to enter cells, according to the results of a new study with mice.

"Calcium is an essential ion in all organisms, where it plays a crucial role in processes of the formation and maintenance of the skeleton and also neuronal functions," said lead researcher Joost G.J. Hoenderop, an assistant professor of physiology at Radboud University Nijmegen Medical Center in the Netherlands.

Calcium regulation in the body is tightly maintained within narrow limits, despite variations in daily intake, Hoenderop said. "This is done by the intestine, bone and kidney," he noted.

Previous studies showed that aging is associated with calcium imbalances. "Diseases such as osteoporosis occur when the calcium balance is negative," Hoenderop said. In addition, animal studies have found that when klotho is removed, the animals undergo premature aging, he said.

The Dutch researchers saw this same effect in "klotho-knockout mice" when their calcium balance was disturbed.

In their work, Hoenderop and colleagues found how klotho regulates calcium in the blood.

"We identified a very fascinating mechanism about klotho," Hoenderop said. "We found that the klotho hormone is made in the kidney and secreted into the urine."

Klotho activates the calcium channel TRPV5, which is the gatekeeper in the process of calcium handling in the kidneys. "This channel is involved in absorbing calcium from the urine back to the blood," Hoenderop said.

The way klotho does this is unique, the researcher pointed out. The mechanism involves klotho's ability to remove some sugar from the cell membrane, thus allowing the right amount of calcium to accumulate on the cell membrane, he said. "This is a very new mechanism," Hoenderop noted.

"This is a whole new concept of ion channels," he added. "But I am sure that many more proteins are regulated in the same way. It is possible that other proteins in the urine can affect sugars on cell membranes to regulate ion transport."

This discovery may be related to the anti-aging properties of klotho, Hoenderop explained. "As we age, it is more difficult to absorb calcium," he said. "So this might be due to the fact that these people have less klotho. The finding of the activation of the calcium channel by klotho may form the link between the negative calcium balance observed in the elderly."

The study findings appear in the Oct. 21 issue of Science.

One expert thinks this study breaks new ground in understanding how ion channels are activated.

"This is a very interesting and exciting study," said Dr. Michael Caterina, an associate professor of neuroscience at Johns Hopkins University. "TRPV5 is one of a family of related ion channels that regulate processes as diverse as calcium absorption to pain sensation to taste perception. Therefore, a great deal of effort has gone into identifying the mechanisms that regulate their function."

In the study, Hoenderop's team has identified a completely novel mechanism by which TRPV5 molecules are trapped on the cell surface to increase their activity, Caterina said. "The authors have done an extremely nice job of documenting this novel mechanism, which involves the cleavage of specific sugar residues that are attached to the protein."

"It appears that some sugars must be cleaved and others left behind for the protein to get trapped on the surface," he said. "This finding may have significant implications for a whole family of about 30 proteins that share structural similarities with TRPV5 and whose regulation in various cells of the body is poorly understood."

Hoenderop noted that klotho is only one protein involved in calcium -- and so is only part of the story of aging.

More information

The U.S. National Institute on Aging can tell you more about research into aging.

SOURCES: Joost G.J. Hoenderop, Ph.D., assistant professor, physiology, Radboud University Nijmegen Medical Center, the Netherlands; Michael Caterina, M.D., Ph.D., associate professor, neuroscience, Johns Hopkins University, Baltimore; Oct. 21, 2005, Science
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