Klotho is the queen of anti-aging proteins. There are no close contenders at this time. While it is predominantly produced in the kidneys and brain, its soluble form circulates throughout the body.

Klotho is a caloric restriction mimetic, meaning that it can yield the same benefits as fasting – without the unwanted side effects!

Because it induces autophagy, it has a wide range of effects. By reducing oxidative stress, Klotho can protect telomeres.

Many investigations into Klotho were conducted by nephrologists interested in its role in Chronic Kidney Disease (CKD), yet over the last twenty years its multifaceted role in the aging process has become a topic of intense research – and for good reason. 

Klotho deficient mice, for example, show premature aging in multiple organs. 

Inducing KL overexpression with gene therapy not only reverses this premature aging, but also enhances their resistance to oxidative and ischemic damage. 

More impressive, KL outright extends the lifespans of mice, likely by inhibiting IGF and insulin signaling. 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 “if 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. By tackling them through elevating Klotho expression, we can attack one thing that causes us to age and encourages the development of the diseases associated with aging. 

Human studies are limited right now, but there is an inverse relationship between chronological age and plasma KL levels. In other words, KL decreases as we get older – that’s probably not a good thing.

In a study with human dementia patients, Klotho and telomerase improved scores on the Folstein exam. This is monumental, as scores predictably fall for those with Alzheimer’s and other forms of dementia. To maintain them is good, to observe increases is a triumph.

Mice that have had their KL gene “knocked out” not only show signs of accelerated aging, but also dangerously high levels of Vitamin D. Over the last four years Vitamin D has received a great deal of attention and, once again, for good reason. 

When the body cannot absorb Vitamin D properly, as when KL becomes too low, this poses a problem for many things, including hematopoietic and red blood cell production. Although this cannot, the researchers caution, be chalked up entirely to VD 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 mentioned earlier. 

KL is especially abundant in the choroid plexus, a structure in the brain that mediates the production of cerebrospinal fluid, facilitates the removal of metabolic waste, and manages the transit of foreign molecules into and out of the brain.

The overlap in gene expression profiles between the two structures have compelled researchers to dub the CP the “kidney” of the brain. 

It has been hypothesized by this same group that KL made by, or that has not been made by, the choroid plexus, can lead to the sorts of mineral imbalances mentioned earlier. Yet it has another much more dramatic impact on inflammaging. As Lei Zu puts it:

“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 only target one of the hallmarks of aging.

Works Cited and Suggested Reading

1. 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.

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

3. 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]

4. 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]

5. 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]

6. 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/

7. 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]

8. 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.

9. 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.

10. Madathil, Sangeetha Vadakke, et al. “Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis.” The American journal of pathology 184.3 (2014): 827–841.

11. Kuro-o, Makoto. “A potential link between phosphate and aging — lessons from Klotho-deficient mice.” Mechanisms of ageing and development 131.4 (2010): 270–275. 827–841.

[11] Kuro-o, Makoto. “A potential link between phosphate and aging — lessons from Klotho-deficient mice.” Mechanisms of ageing and development 131.4 (2010): 270–275.

[12] Lanske, Beate, and M. Shawkat Razzaque. “Premature aging in klotho mutant mice: cause or consequence?.” Ageing research reviews 6.1 (2007): 73–79.

[13] Sewell, P. E., et al. “Safety Study of AAV hTert and Klotho Gene Transfer Therapy for Dementia.” J Regen Biol Med 3.6 (2021): 1-15.

[14] 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.

[15] 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.

[15] 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.

[16] Sathyanesan, M., et al. “A molecular characterization of the choroid plexus and stress-induced gene regulation.” Translational psychiatry 2.7 (2012): e139.

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