Klotho: Queen of Anti-Aging Proteins

05 October 2019

Klotho, named after one of the Fates of Greek mythology, is the queen of anti-aging proteins. There are no close contenders at this time. Klotho gene therapy, like the one offered by Integrated Health Systems, has tremendous benefits. While it is produced primarily in the kidneys and brain, its soluble form circulates throughout the body. Many of the investigations so far have been done nephrologists interested in its prominent role in Chronic Kidney Disease (CKD), yet over the last decade its multifaceted role in the aging process has become a topic of intense research. 

Klotho deficient mice show premature aging in multiple organs. 

Inducing KL overexpression with a viral vector, like AAV, not only reverses this premature aging, but also enhances resistance to oxidative and ischemic damage. More impressive, KL outright extends the lifespans of mice, likely be inhibiting IGF and insulin signalling. Dubbed an “aging suppressor gene,” it can yield results similar to caloric restriction – what is, at this time, the most tried and true method of extending the lifespans of a variety of model organisms. 

Along with their more familiar filtration duties, our kidneys also maintain calcium and phosphate homeostasis. Makoto Kur-o, a leading expert on KL, has noted that “phosphate retention not only increases mortality of CKD patients but also accelerates aging processes in general, several important hypotheses may be drawn. First, CKD may be viewed as a state of accelerated aging or a segmental progeroid syndrome caused by phosphate retention.”  

In other words, issues with mineral metabolism are likely both a cause and an effect of the aging process. It looks like elevating Klotho can combat this aspect of aging. In humans there is an inverse relationship between chronological age and plasma KL levels. In other words, KL decreases as we get older, which is not a good thing.

Mice that have had their KL gene “knocked out” not only show signs of accelerated aging, but also dangerously high levels of Vitamin D. When they body cannot absorb Vitamin D properly, as when KL becomes too low, this poses a few problems, including a decline in hematopoietic stem cell and red blood cell production. Although this cannot, researchers caution, be chalked up entirely to Vitamin D accumulation, the groups concluded that KL is crucial to stem cell production in the womb and in life. Because of this, it can alleviate age-related stem cell decline.

Brain functions and cell populations in the brain, including neural progenitors in the hippocampus, the brain’s memory palace, require healthy Klotho levels. Dubal’s group showed KL is a neuroprotectant and that it improves cognition in mice. They also showed that injecting the protein directly into the bloodstream of the animals had the same effect as genetically engineering elevated KL expression. The mice treated “showed improved brain function within just four hours, and this treatment worked in young mice, old mice, and an Alzheimer’s mouse model.” 

Repeatedly injecting a protein is somewhat tedious compared to a single injection of gene therapy…  

The choroid plexus is rich in KL. The choroid plexus is a structure in the brain involved in the production of cerebrospinal fluid, assists in the removal of metabolic waste, and manages the movement of foreign molecules in and out of the brain. The overlap in the gene expression profiles of the two has led researchers to dub the CP the “kidney of the brain.” It has been hypothesized that a lack of production of KL in the CP can also lead to mineral imbalances. 

“The barrier between the brain and the immune system seems to break down with low levels of klotho. Our findings indicate that klotho helps keep that barrier closed. When levels of this molecule are depleted in the choroid plexus, the barrier becomes more porous and allows immune cells and inflammatory molecules to get through more easily.”

The lion’s share of attention in the popular media has gone towards methods of curtailing aging that are either unrefined, unlikely to ever yield significant results in extending healthspan or lifespan, or only target one of the hallmarks of aging. Klotho, despite having a large and growing body of evidence behind it, has been largely ignored. It is versatile and powerful. Klotho gene therapy is here. Want to learn more? Visit Integrated Health Systems. 

 

Works Cited and Suggested Reading

Bernheim, Jacques, and Sydney Benchetrit. “The potential roles of FGF23 and Klotho in the prognosis of renal and cardiovascular diseases.” Nephrology Dialysis Transplantation 26.8 (2011): 2433-2438.

Dubal, D. B., Yokoyama, J. S., Zhu, L., Broestl, L., Worden, K., Wang, D., … & Ho, K. (2014). Life extension factor klotho enhances cognition. Cell reports, 7(4), 1065-1076.

Dubal, D. B., Zhu, L., Sanchez, P. E., Worden, K., Broestl, L., Johnson, E., … & Kuro-o, M. (2015). Life extension factor klotho prevents mortality and enhances cognition in hAPP transgenic mice. Journal of Neuroscience, 35(6), 2358-2371.

Dubal, D. B., Yokoyama, J. S., Zhu, L., Broestl, L., Worden, K., Wang, D., … & Ho, K. (2014). Life extension factor klotho enhances cognition. Cell reports, 7(4), 1065-1076.

Hill, Steve. “Could Klotho Treat Dementia by Targeting Aging Itself? |.” LEAF, Life Extension Advocacy Foundation, 14 Feb. 2018, www.leafscience.org/could-klotho-treat-dementia-by-targeting-aging-itself/. 

Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45–51.

Kurosu, Hiroshi, et al. “Suppression of aging in mice by the hormone Klotho.” Science 309.5742 (2005): 1829-1833.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2536606/

Kuro-o, Makoto. “Klotho and the aging process.” The Korean journal of internal medicine 26.2 (2011): 113.

Lau, Wei Ling, et al. “Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet.” Kidney international 82.12 (2012): 1261-1270.

Mitani H, Ishizaka N, Aizawa T, et al. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension. 2002;39(4):838–843. [PubMed]

Mitobe M, Yoshida T, Sugiura H, et al. Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron Exp Nephrol. 2005;101(2):e67–e74. [PubMed]

Sugiura H, Yoshida T, Tsuchiya K, et al. Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol Dial Transplant. 2005;20(12):2636–2645. [PubMed]

 

Yamazaki Y, Imura A, Urakawa I, et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun. 2010;398(3):513–518. [PMC free article] [PubMed]

 

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