Klotho is an anti-aging protein that is predominantly produced in the kidney and brain.
Deficiencies of Klotho have important implications for aging, renal failure, acute cardiac events and neurodegenerative diseases.1 2 Thus, an increase in the serum concentration of Klotho could have a therapeutic effect. Due to the short half-life of Klotho in serum, continuous infusion of Klotho would be necessary to increase Klotho concentrations. This can be avoided by producing Klotho via an MSC.
- Preclinical studies show that mice deficient in Klotho have a shortened life span, while mice overexpressing Klotho have a prolonged life span.3 4
- In the clinic, Klotho is shown to be one of the earliest markers of renal failure. The stages of chronic renal failure (CKD I-V) correlate with the serum level of Klotho.5 Timely elevation of Klotho levels by autologous MSC-Klotho could prevent chronic renal failure requiring dialysis.
- After myocardial infarction (aka “heart attack”), the heart responds to injury and stress signals by pathological growth and remodeling that often progresses to heart failure and sudden death. Soluble klotho protects the heart against these pathological conditions.6 Therefore, the therapy of acute cardiac events with allogeneic MSC-Klotho may arrest the pathological process and prevent permanent cardiac damage.
- Furthermore, clinical data show that patients with neurodegenerative diseases have reduced serum levels of Klotho and, in the context of Amyothrophic Lateral Sclerosis (ALS) and Alzheimer's disease, intracerebral Klotho levels are also reduced.7 8 Since Klotho is predominantly produced in the brain, intracerebral therapy with MSC-Klotho may be a valid therapeutic option in neurodegenerative diseases.
MSC-Klotho represents a therapeutic option both for diseases with orphan drug status, such as amyothrophic lateral sclerosis, for which there is currently no specific therapy as well as for diseases that have a high impact on the health care system such as chronic kidney failure (CKD). Data from the CDC show that around 37 million Americans suffer from impaired kidney function. For over 130,000 each year, this leads to end-stage renal disease (ESRD) with the need for dialysis treatment.
The number of Americans living with Alzheimer's is growing - and growing fast. More than 6 million Americans of all ages have Alzheimer's. One in three seniors dies with Alzheimer's or another form of dementia. It kills more than breast cancer and prostate cancer patients combined. In 2021, Alzheimer's and other dementias will cost the nation $355 billion, including $239 billion in Medicare and Medicaid payments combined.
Both diseases - CKD and Alzheimer's - show a relatively long and slow chronic course. Early detection and then therapy with autologous MSC-Klotho could prevent disease progression.
1 Buchanan S, Combet E, Stenvinkel P, Shiels PG. Klotho, Aging, and the Failing Kidney. Front Endocrinol (Lausanne). 2020 Aug 27;11:560. doi: 10.3389/fendo.2020.00560. PMID: 32982966; PMCID: PMC7481361.
2 Lu X, Hu MC. Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease. Kidney Dis (Basel). 2017 Jul;3(1):15-23. doi: 10.1159/000452880. Epub 2016 Nov 17. PMID: 28785560; PMCID: PMC5527179
3 Xu Y, Sun Z. Molecular basis of Klotho: from gene to function in aging. Endocr Rev. 2015 Apr;36(2):174-93. doi: 10.1210/er.2013-1079. Epub 2015 Feb 19. PMID: 25695404; PMCID: PMC4399270.
4 Kuro-o M. Klotho and aging. Biochim Biophys Acta. 2009 Oct;1790(10):1049-58. doi: 10.1016/j.bbagen.2009.02.005. Epub 2009 Feb 20. PMID: 19230844; PMCID: PMC2743784
5 Neyra JA, Hu MC, Moe OW. Klotho in Clinical Nephrology: Diagnostic and Therapeutic Implications. Clin J Am Soc Nephrol. 2020 Dec 31;16(1):162-176. doi: 10.2215/CJN.02840320. Epub 2020 Jul 22. PMID: 32699047; PMCID: PMC7792642.
6 Olejnik A, Franczak A, Krzywonos-Zawadzka A, Kałużna-Oleksy M, Bil-Lula I. The Biological Role of Klotho Protein in the Development of Cardiovascular Diseases. Biomed Res Int. 2018 Dec 24;2018:5171945. doi: 10.1155/2018/5171945..
7 Paroni G, Panza F, De Cosmo S, Greco A, Seripa D, Mazzoccoli G. Klotho at the Edge of Alzheimer's Disease and Senile Depression. Mol Neurobiol. 2019 Mar;56(3):1908-1920. doi: 10.1007/s12035-018-1200-z. Epub 2018 Jul 5. PMID: 29978424
8 Semba RD, Moghekar AR, Hu J, Sun K, Turner R, Ferrucci L, O'Brien R. Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease. Neurosci Lett. 2014 Jan 13;558:37-40. doi: 10.1016/j.neulet.2013.10.058. Epub 2013 Nov 7. PMID: 24211693; PMCID: PMC4037850.