Understanding Klotho Protein: The Key to Longevity and Health
While listening to an orthopaedics podcast, I encountered a term that piqued my interest: Klotho protein.Â
Known as a potential "key to longevity," this protein's role in aging and health is becoming increasingly recognized.Â
Intrigued, I decided to dig into what Klotho is and how it might help us live longer and healthier lives.
 What is Klotho Protein?
Named after Clotho, one of the three Fates in Greek mythology who spun the thread of life, Klotho was first identified in mutant mice lacking the Klotho gene. These mice developed age-related disorders and had a significantly shorter lifespan (1).
How Does Klotho Appear in the Body?
The Klotho gene produces a secreted form of the protein, which was first described in 1998. By 2004, researchers demonstrated that Klotho protein is present in human serum and cerebrospinal fluid.Â
However, until recently, the lack of a sensitive and reliable assay hindered the study of circulating Klotho in relation to aging and human health. A breakthrough assay now allows precise measurement of soluble Klotho in the blood, enabling further research into its role in aging (1).
 Can Low Klotho Levels Affect Lifespan?
Yes, studies have shown that older adults with low plasma Klotho levels are at a higher risk of mortality. Low plasma Klotho is an independent predictor of death, highlighting its crucial role in longevity (1).
Is Klotho Relevant Only to Humans?
No, much of the research on Klotho has been conducted in mice, suggesting its relevance to all mammals. This means findings related to Klotho could also benefit our pets, potentially enhancing their longevity and combating age-related diseases. Additionally, I’m going to reveal some information about research in dogs.
Diseases Related to Klotho
Research indicates that increased Klotho levels in mice enhance synaptic plasticity, cognition, and resistance to age-related diseases like Alzheimer’s and Parkinson’s.Â
Additionally, understanding the crystal structure of Klotho could aid in developing treatments for chronic kidney disease and other age-related conditions (2, 3, 4). Recent studies also show that Klotho expression in cardiomyocytes increases in response to heart stress, linking it to heart health (5).
How Can Klotho Levels Be Increased?
Exercise and muscle growth are effective in elevating Klotho levels. In mice, high-intensity interval training (HIIT) increased Klotho expression in muscles. This response was further amplified in mice with a Klotho transgene, leading to higher numbers of muscle stem cells and enhanced muscle regeneration. Interestingly, the Klotho transgene also modulated muscle cell differentiation, showing that Klotho influences how muscles respond to mechanical stress (6).
Chronic exercise training, regardless of the individual's health or the type of exercise, also boosts circulating Klotho levels. The effect of exercise on Klotho can vary based on training duration, volume, and intensity, suggesting that Klotho could be considered an "exerkine" – a protein influenced by exercise (7).
Research in Pets
Studies have shown that Klotho levels are reduced in dogs with chronic kidney disease (CKD), correlating with markers of kidney function and mineral metabolism. Additionally, Klotho expression in canine tumors is associated with prognosis, with negative Klotho expression linked to poorer survival rates in dogs with malignant tumors (8, 9).
In summary, Klotho protein plays a pivotal role in aging and health across species. While research continues to uncover its full potential, the evidence so far suggests that boosting Klotho levels through lifestyle choices like exercise could be key to enhancing longevity and quality of life for both humans and animals.
If you want to read more:Â
Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, Guralnik JM, Ferrucci L. Plasma klotho and mortality risk in older community-dwelling adults. J Gerontol A Biol Sci Med Sci. 2011 Jul;66(7):794-800. doi: 10.1093/gerona/glr058. Epub 2011 Apr 7. PMID: 21474560; PMCID: PMC3143348.
Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, Hasegawa H, Yamashita T, Nakatani K, Saito Y, Okamoto N, Kurumatani N, Namba N, Kitaoka T, Ozono K, Sakai T, Hataya H, Ichikawa S, Imel EA, Econs MJ, Nabeshima Y. 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 Jul 30;398(3):513-8. doi: 10.1016/j.bbrc.2010.06.110. Epub 2010 Jul 1. PMID: 20599764; PMCID: PMC4130489.
Castner, S.A., Gupta, S., Wang, D. et al. Longevity factor klotho enhances cognition in aged nonhuman primates. Nat Aging 3, 931–937 (2023). https://doi.org/10.1038/s43587-023-00441-x
Kuro-o, M. The Klotho proteins in health and disease. Nat Rev Nephrol 15, 27–44 (2019). https://doi.org/10.1038/s41581-018-0078-3
Olejnik, Agnieszka, Franczak, Aleksandra, Krzywonos-Zawadzka, Anna, Kałużna-Oleksy, Marta, Bil-Lula, Iwona, The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases, BioMed Research International, 2018, 5171945, 17 pages, 2018. https://doi.org/10.1155/2018/5171945
Ochi E, Barrington A, Wehling-Henricks M, Avila M, Kuro-O M, Tidball JG. Klotho regulates the myogenic response of muscle to mechanical loading and exercise. Exp Physiol. 2023 Dec;108(12):1531-1547. doi: 10.1113/EP091263. Epub 2023 Oct 20. PMID: 37864311; PMCID: PMC10841225.
Corrêa, H.d., Raab, A.T.O., Araújo, T.M. et al. A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine. Sci Rep 12, 17587 (2022). https://doi.org/10.1038/s41598-022-22123-1
Yi, H.j., Lee, J.b., Lee, K.p. et al. Investigation on urinary and serum alpha klotho in dogs with chronic kidney disease. BMC Vet Res 16, 246 (2020). https://doi.org/10.1186/s12917-020-02458-5
Chung H, Lee S, Kim GA, Kim WH. Down-expression of klotho in canine mammary gland tumors and its prognostic significance. PLoS One. 2022 Jun 6;17(6):e0265248. doi: 10.1371/journal.pone.0265248. PMID: 35666743; PMCID: PMC9170104.