Klotho and The Thread of Life
Klotho is named after one of the three Fates from Greek mythology.
She spins the thread of life.
Appropriately, this protein is pivotal to the aging process.
Aging’s causes are manifold, but some, like sinking Klotho levels, are low-hanging fruit for regenerative modalities like gene therapy.
Makoto Kuro-o discovered Klotho when he found that mice without this gene died young — about 20% earlier than those with it.
They didn’t die of a particular ailment, but something akin to accelerated aging (Kuro-o, 1997).
He later found excessive phosphate retention produces these phenotypes (Kuro-o, 2011). Although, this is just one way Klotho depletion hastens the sands of time.
Klotho is an obligate co-receptor for fibroblast growth factor 23 (FGF-23), a hormone involved in calcium and phosphate metabolism. Defects in either result in what Kuro-o calls “phosphatopathies.”
Of course, other mineral imbalances can be just as deadly.
Hardy chunks of calcium belong in your bones, not your bloodstream, so Klotho’s knack for preventing arterial calcification should be cause for celebration (Lee, 2022).
Its help to heart health don’t stop here; higher levels lower blood pressure sensitivity to salt intake (Kawarazaki, 2020).
It’s not surprising that vascular calcification is a common complication of Chronic Kidney Disease.
In mouse models Klotho ameliorates CKD. It achieves this, in part, by promoting autophagy (Li, 2022).
Autophagy is how cellular waste is recycled or otherwise disposed of; this necessary maintenance function declines with age and is intimately intertwined with the hallmarks of aging (Barbosa, 2019).
Enhanced autophagy is one of the advantages of fasting (Bagherniya, 2018). Klotho, along with its litany of other virtues, is a way to deliver the benefits of caloric restriction without the unpleasantness or drawbacks of nutritional deprivation.
Over 850 million people have CKD. As the global population ages, this number will continue to surge.
Produced predominantly in the kidneys, Klotho is paramount to renal health. Lower levels are strongly associated with CKD, especially among those most susceptible to developing it — the elderly, obese, and diabetic (Zhang, 2022).
By reducing oxidative stress, inflammation, and fibrosis, Klotho shows immense promise for acute and chronic kidney disease (Franco, 2021).
This research can claim a nearly thirty-year pedigree, yet no interventions — the most straightforward being Klotho gene therapy — have been approved for CKD…
Or any other medical condition.
This is a sobering reminder of the need for expedited therapeutic approval routes, like the one proposed by Best Choice Medicine.
More attention is being paid to Klotho’s formidable nootropic properties–its importance to cognition and neuroprotection.
Klotho levels don’t just influence how long you’ll live, they also play a substantial role — in fact, more significant than any single gene yet studied — in determining intelligence and how long you’ll keep your faculties (Deary, 2005; Dubal, 2014).
It not only protects the brain, but significantly reverses damage.
Deena Dubal’s mouse studies brought these properties to the forefront.
Klotho not only improved brain function, but did so within four hours. This was observed in both young and old mice, as well as a mouse model of Alzheimer’s (Dubal, 2014; Dubal, 2015).
A recent Nature article showed long-term benefits for aged nonhuman primates. The macaques were approximately 65 in human years; the veritas group scored 10% higher on difficult memory tasks, and 5% higher on less demanding ones (Castner, 2023).
For those suffering from a neurodegenerative disease, or “ordinary” cognitive decline, this lift could make a tremendous difference.
For many of the same reasons it is a strong candidate for addressing renal diseases, Klotho gives hope for treating neurodegenerative diseases, including what is considered “normal” cognitive decline.
A human study, analyzed by BioViva in this video, tested the efficacy of telomerase and Klotho gene therapy for Alzheimer’s (Sewell, 2022).
The findings, though preliminary, are astonishing.
Scores on the Folstein exam inexorably drop for those with dementia. Those given these gene therapies not only maintained their scores, they improved.
Klotho gene therapy shows immense promise as a preventative and therapeutic intervention for a litany of issues, including aging itself.
There is no doubt it will continue to play a prominent role in regenerative medicine for centuries to come.
Authored by Adam Alonzi
Adam is a writer, independent researcher, and video maker. He is the Marketing Director for BioViva Science. Visit adamalonzi.com for more.
References and Suggested Reading
Bagherniya, Mohammad, et al. “The effect of fasting or calorie restriction on autophagy induction: A review of the literature.” Ageing research reviews 47 (2018): 183–197.
Bian, Ao, et al. “Klotho, stem cells, and aging.” Clinical Interventions in Aging (2015): 1233–1243.
Castner, Stacy A., et al. “Longevity factor klotho enhances cognition in aged nonhuman primates.” Nature Aging (2023): 1–7.
Deary, Ian J., et al. “KLOTHO genotype and cognitive ability in childhood and old age in the same individuals.” Neuroscience letters 378.1 (2005): 22–27.
Dubal, Dena B., et al. “Life extension factor klotho enhances cognition.” Cell reports 7.4 (2014): 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.
Franco, Marcella Liciani, Stephany Beyerstedt, and Érika Bevilaqua Rangel. “Klotho and mesenchymal stem cells: a review on cell and gene therapy for chronic kidney disease and acute kidney disease.” Pharmaceutics 14.1 (2021): 11.
Kawarazaki, W., et al. (2020) Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency. Journal of Clinical Investigation. doi.org/10.1172/JCI134431.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. (November 1997). “Mutation of the mouse klotho gene leads to a syndrome resembling ageing”. Nature. 390 (6655): 45–51. Bibcode:1997Natur.390…45K. doi:10.1038/36285. PMID 9363890. S2CID 4428141.
Kuro-o, Makoto. “Klotho and the aging process.” The Korean journal of internal medicine 26.2 (2011): 113.
Lee, Jaeho, et al. “Association between serum klotho levels and cardiovascular disease risk factors in older adults.” BMC cardiovascular disorders 22.1 (2022): 442.
Li, L., Liu, W., Mao, Q., Zhou, D., Ai, K., Zheng, W., … & Zhao, X. (2022). Klotho Ameliorates Vascular Calcification via Promoting Autophagy. Oxidative Medicine and Cellular Longevity, 2022.
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.
Zhang, Zilong, et al. “The association between serum soluble Klotho and chronic kidney disease among us adults ages 40 to 79 years: Cross-sectional study.” Frontiers in Public Health 10 (2022): 995314.
