Applications of Klotho Human Protein
LIVE WELL LONGER™
Aging is a complex biological process regulated by multiple intrinsic and extrinsic factors such as genetics, epigenetics, environment, lifestyle, and immune response. Aging is often defined as an age-related deterioration of physiological and cognitive functions necessary for survival and reproduction.
During aging, the brain undergoes various morphological, cellular, molecular, and functional changes leading to the occurrence of age-related cognitive decline. Healthy elderly people show significant decreases in brain volume and experience mild cognitive impairment (i.e. working memory & executive function) compared with younger adults. In patients with Alzheimer’s disease or other types of age-related dementia, the cognitive impairment is significantly more severe affecting daily life activities and requiring medical/professional assistance.
The idea of aging is something that is commonly feared by many, but what if it didn’t hurt to grow old? Imagine living independently longer. Less severe dementia. Later onset of cancer. Healthier heart and kidneys for longer. Klotho, a natural human protein has great potential to delay these diseases of aging. Loss of cognition, kidney failure, diabetes, and cancer are all things that are believed to be associated with the body’s production of this Klotho protein. Klotho Therapeutics™ (KTI) is using biotechnology to mimic the human protein.
KLOTHO HUMAN PROTEIN
Klotho is a naturally occurring human protein discovered in 1997. The name comes from the mythological Greek goddess, Klotho, who was one of the three Fates responsible for spinning the thread of life. It’s an appropriate name as Klotho protein is involved in many biological pathways in both humans and animals and appears to have major effects throughout our lifespan. Klotho influences longevity, cognition, and kidney function and slows the progression of diabetes and cancer.
Klotho deficient animals exhibit a premature aging phenotype characterized by a short lifespan, vascular and kidney disease, reduced body weight, osteoporosis, age-related skin changes, ectopic calcification, hypoglycemia, infertility, and cognitive and memory impairment1.
Exogenous administration of Klotho in Klotho deficient or aged animals has proven to significantly improve their aging phenotype, increase lifespan, promote cell survival and neurogenesis, and enhance cognitive and memory function2. Genetic overexpression of Klotho in hAPP mice, which is a model of Alzheimer’s disease, and in the SAMP8 model of premature aging can improve cognitive function and prevent cell loss in the brain3.
In humans, the Klotho gene (KL) exists in three different forms that are associated with different lifespans, intelligence, and health status4. About 75% of the population has the standard KL form. A much smaller group has one copy of the genetic variant KL-VS, which increases Klotho levels1. This is associated with a longer lifespan, good heart and kidney function, larger brain size, and better cognition in healthy adults3. A very small group of people have two copies of KL-VS, resulting in lower Klotho levels and an increase risk of disease.
TEDX AND KLOTHO
NEW ERA IN BIOTECH
Multiple clinical and preclinical studies have implicated Klotho as an important anti-aging molecule regulating lifespan, health, and cognitive function. As discussed above, studies have proven that an absence of Klotho protein in laboratory animals led to a shorter lifespan and cognitive impairment. Inversely, higher circulating Klotho levels in Klotho overexpressing mice and in people carrying the KL-VS allele are associated with longer lifespan and enhanced cognitive and memory function.
There is firm evidence to support that treatment with Klotho protein or an adenovirus increases lifespan and promotes cognitive and memory function in Klotho deficient mice as well as in animal models of Alzheimer’s disease and premature aging. The cellular and molecular mechanisms of action underlying the Klotho beneficial effects on longevity and age-related cognitive decline are related to increases in cell survival, neurogenesis, neuronal maturation, modulation of glutamate signaling and LTP. Future development of Klotho therapies can revolutionize the treatment of aging and age-related cognitive decline.
Unlike traditional biotech companies in this space, KTI is minimizing the standard risks of development to reduce the cost and time of getting Klotho to human trials. Klotho Therapeutics is well positioned to enter human trials within 2 years focused on its first indication: to slow the progression of kidney disease, which affects up to 40 million patients per year in the US, 600,000 of whom are currently on dialysis. It is through this final research that true advancements in Klotho reproduction can be made.
- Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kumek, E., Iwasakik, H., Iida, A., Shiraki-Iida, T., Nishikawa, S., Nagai, R., Nabeshima, Y. (1997). Mutation of the mouse klotho gene leads to a syndrome resembling aging. Nature: 390, 45-51.
- Chen, T-H., Kuro-o, M., Chen, C-H., Sue, Y-M., Chen, Y-C., Wu, H-H., Cheng, C-Y. (2012). The secreted Klotho protein restores phosphate retention and suppresses accelerated aging in Klotho mutant mice. Eur J Pharmacol: 698, 67–73.
- Dubal, D.B., Yokoyama, J.S., Zhu, L., Broestl, L., Worden, K., Wang, D., Sturm, V.E., Kim, D., Klein, E., Yu, G-Q., Ho, K., Eilertson, K.E., Yu, L., Kuro-o, M. De Jager, P.L., Coppola, G., Small, G.W., Bennett, D.A., Kramer, J.H., Abraham, C.R., Miller, B.L., Mucke, L. (2014). Life extension factor Klotho enhances cognition. Cell Reports: 7, 1065-1076.
- Yokoyama, J.S., Sturm, V.E., Bonham, L.W., Klein, E., Arfanakis, K., Yu, L., Coppola, G., Kramer, J.H., Bennett, D.A., Miller, B.L., Dubal, D.B. (2015). Variation in longevity gene KLOTHO is associated with greater cortical volumes. Ann Clin Transl Neurol: 2, 215–230.
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