Nancy A. Melville

September 30, 2015

CHICAGO — Klotho, an aging regulator and pleiotropic hormone, continues to show remarkable improvements in human and mice studies in countering the effects of aging and disease, such as Parkinson's disease and Alzheimer's disease, on the brain, sparking cautious optimism that the klotho gene may represent an important target for therapeutic intervention.

"We have found that genetic variants that increase klotho levels associate with enhanced cognition in humans and elevation of klotho in mice enhances normal cognition, independent of age," said Dena Dubal, MD, PhD, from the University of California, San Francisco, in presenting the research here at the American Neurological Association (ANA) 2015 Annual Meeting.

"There is furthermore evidence in mice that elevation of klotho may confer resilience to counter the effects of diseases such as Alzheimer's and Parkinson's disease," she added.

Klotho, as reported by Medscape Medical News in 2014, was discovered in 1997 and got its name from the mythological Greek goddess of fate, who spins the "thread of life."

Previous research in humans has shown that carriers of a single copy of the KL-VS variant of the klotho gene was associated with longer lifespan and lower rates of age-related disease, such as cardiovascular disease.

Various studies have further shown carriers of the gene variant to have improvements in cognitive function after controlling for age, sex, and the presence of the APOE ε4 allele, the primary genetic risk factor for Alzheimer's disease. Additional evidence has shown that having the genetic variant or elevated klotho is also associated with resilience against age-related changes in biomarkers of neurodegenerative stress.

"This was a compelling association seen in multiple populations and we are looking at people at risk of Alzheimer's disease and seeing similar results," Dr Dubal said in her talk.

Among the latest research is a study published in Translational Psychiatry in June showing significantly lower levels of the klotho hormone among 90 women experiencing high chronic stress as maternal caregivers for a child with autism spectrum disorder compared with 88 low-stress control mothers of a typically developing child (P = .004).

"These findings provide the first evidence that klotho levels are sensitive to psychosocial stressors and raise the possibility that klotho may serve as a novel biological link connecting stress, depression and risk for accelerated disease development," Dr Dubal and her colleagues wrote.

Studies involving overexpression of klotho in mice with Alzheimer's disease have also been impressive. In one study, mice with Alzheimer's predictably struggled with cognitive challenges, but when klotho was overexpressed, the same mice showed remarkably normal cognition and ease in the challenges, despite having significant levels of plaque and tau.

"The studies showed elevation of klotho in mice boosts brain resistance despite high levels of pathogenic proteins, enhancing normal cognition, independent of age."

Dr Dubal told Medscape Medical News the effects have been robust and enduring across age spans, in young mice as well as old.

"With transgenic overexpression of klotho, the effect of cognitive enhancement has been observed in mice even into the old life stage. We've found the effect is enduring and robust in every cohort we've looked at," Dr Dubal said.

In addition, while noting that much more research is needed, the klotho safety profile so far looks promising.

"We have not yet observed deleterious consequences of modest lifetime overexpression of klotho, even in older mice," Dr Dubal said.

"But it will be important to continue to study and look for limitations. Interestingly, the hormone is endogenously produced and tolerated over a wide range within our own bodies, suggesting a low risk of toxicity."

As the research continues, Dr Dubal and her team are looking further into the prospect of klotho elevation potentially reversing cognitive impairment — in mice as well as humans.

"There is overall strong biologic evidence to support movement of klotho studies into a therapeutic space, hopefully soon into human populations," she said.

"This movement will include continued rigorous studies in mice, particularly to demonstrate that increasing klotho, or klotho-based molecules, in adulthood shows similar effects compared to transgenic overexpression in mice."

"It is possible that individuals with varied conditions could benefit since elevating klotho may boost cognition across the lifespan, and in many neurologic and psychiatric disorders. Let's see what the next studies show us."

The findings are intriguing on many levels, David M. Holtzman, MD, Andrew B. and Gretchen P. Jones Professor and chairman of neurology, Washington University, St. Louis, Missouri, told Medscape Medical News.

"I think it is very interesting that this protein has hormone-like effects on many tissue to prevent aging-like changes," he said.

Among potential limitations are the suggestion of klotho being "antiaging," Dr Holtzman noted.

"The effects on brain may or not be 'antiaging,'" he said. "The effects in the brain may be related to the effects of the protein on improving efficacy of synaptic function."

"I think it is exciting, [however], that the protein may be improving normal synaptic function such that even in normal brain, function is potentially better than normal."

Thomas Sutula, MD, PhD, professor and chair of the Department of Neurology at the University of Wisconsin School of Medicine and Public Health, Madison, who chaired the session, also expressed interest in the research while underscoring its preliminary nature.

"[The research] is interesting and represents a potentially promising approach, but as it is still relatively preliminary I am not sure about how to regard its significance at this point," he told Medscape Medical News.

"If the work advances, there could be potential for development of a way to modify adverse aging and degenerative processes, which would certainly be a major advance."

Dr Dubal, Dr Holtzman, and Dr Sutula have disclosed no relevant financial relationships. Portions of the Translational Psychiatry study are the subject of a provisional patent application held by the Regents of the University of California. Dr Dubal's research has also received support from grants from the National Institutes of Health and from the Coulter-Weeks Foundation, the Bakar Family Foundation, the Glenn Foundation for Medical Research, the American Federation for Aging Research, and the UCSF Research Office of Development.

American Neurological Association (ANA) 2015 Annual Meeting. Abstract S255WIP. Presented September 27, 2015.


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