I came across a recent podcast by Peter Attia M.D. where he interviews Dena Dubal M.D. Ph.D. on a potential “breakthrough in Alzheimer’s disease” in the form of α-klotho supplementation. α-klotho, often referred to as just “klotho,” is a transmembrane protein expressed in the brain, liver, and kidney. Klotho seems to have several mechanisms of control over different metabolic pathways, including insulin sensitivity, maintaining calcium homeostasis, mitigating oxidative stress and endothelial dysfunction, facilitating oligodendrocyte maturation, myelin integrity, and a host of other functions. 1

Klotho was originally discovered by accident in 1997, when a researcher noticed accelerated aging in mice with a mutated gene for the klotho protein. 2 (The name “klotho” is in reference to the Greek mythological figure Clotho, who “spins the thread of human life.” 3) Since then, observational studies have shown klotho expression to somehow protect against aging and cognitive decline.

Interestingly, klotho has been shown to be closely associated with physical exercise, such that it has been referred to as an “exerkine,” or a signaling molecule released in response to exercise. 4 There is also a human genetic variant of the klotho gene called “KL-VS” that is associated with “enhanced cognition in heterozygous carriers,” 5 further establishing klotho’s role in aging.

Dr. Dubal has been involved in research on the effects of klotho for many years, but only recently published a study of the effects of klotho supplementation in rhesus monkeys in Nature Aging (2023) 6. In the podcast, she reports the results of that study, and how it has led to the formation of Jocasta Neuroscience, Inc., a drug discovery startup that aims to explore klotho supplementation as a treatment for Alzheimer’s dementia and other forms of age-related neurocognitive disease.

To Good to Be True?

Here are some of the takeaways from the paper:

  1. Low dose (10 µg/kg) of rhesus klotho (each species has its own variant) significantly boosted cognitive function in aged rhesus macacques (see chart for high memory load task in figure labeled c below).

  2. Higher doses (20 and 30 µg/kg) didn’t show enhancement versus vehicle (placebo), suggesting that the effect has a relatively narrow window of efficacy with supratherapeutic doses showing no benefit (see figures labeled g and h below).

  3. A single administration of 10 µg/kg enhanced performance in both normal memory load (NML) and high memory load (HML) tasks, and the effect lasted for at least two weeks (see charts for HML persistence in figure labeled d below).

Castner et al. (2023)

Castner et al. (2023)

This combination of cognitive effect size and persistence of effect is very exciting because it suggests a potential biologic therapy for humans that could meaningfully improve cognition but wouldn’t require daily injections.

Exercise in a Bottle?

Given that klotho is known to be expressed by exercise, and given the strong meta-analysis support for the beneficial effect of exercise on Alzheimer’s dementia 7, could klotho be the “exerkine” mediating the beneficial effect of exercise?

The benefits of exercise on human health have been known for years. Exercise is sometimes not used by patients presumably because exercise can be uncomfortable and requires discipline and consistency to implement. Is it “too good to be true,” or simply “true,” that a drug therapy could deliver all or most of the benefits of exercise?

I think it’s unlikely that we can hack our biology so easily with a single protein such that the myriad benefits of exercise are completely reproduced. But even if a fraction of the benefit can be delivered to patients who are unable or unwilling to start an exercise regimen, the beneficial effect could be massive.

I think this an important space to watch in understanding ways to mitigate aging and meaningfully extend human longevity.

  1. Wikipedia contributors. (2024, February 13). Klotho (biology). Wikipedia. https://en.wikipedia.org/wiki/Klotho_(biology) ↩︎

  2. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997 Nov 6;390(6655):45-51. doi: 10.1038/36285. PMID: 9363890. ↩︎

  3. Wikipedia contributors. (2024, February 22). Clotho. Wikipedia. https://en.wikipedia.org/wiki/Clotho ↩︎

  4. De Luca Corrêa, H., Raab, A. T. O., Araújo, T. M., Deus, L. A., Reis, A. L., Honorato, F. S., Rodrigues-Silva, P. L., Neves, R. V. P., Brunetta, H. S., Da Silva Mori, M. A., Franco, O. L., & Rosa, T. D. S. (2022). A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-22123-1 ↩︎

  5. Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. Life extension factor klotho enhances cognition. Cell Rep. 2014 May 22;7(4):1065-76. doi: 10.1016/j.celrep.2014.03.076. Epub 2014 May 10. PMID: 24813892; PMCID: PMC4176932. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176932/ ↩︎

  6. Castner, S. A., Gupta, S., Wang, D., Moreno, A. J., Park, C., Chen, C., Poon, Y., Groen, A., Greenberg, K., David, N., Boone, T., Baxter, M. G., Williams, G. V., & Dubal, D. B. (2023). Longevity factor klotho enhances cognition in aged nonhuman primates. Nature Aging, 3(8), 931–937. https://doi.org/10.1038/s43587-023-00441-x ↩︎

  7. Liu, W., Zhang, J., Wang, Y., Li, J., Chang, J., & Jia, Q. (2022). Effect of Physical exercise on Cognitive Function of Alzheimer’s Disease Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trial. Frontiers in Psychiatry, 13. https://doi.org/10.3389/fpsyt.2022.927128 ↩︎