Most of us have been affected by someone in our lives suffering from dementia or Alzheimer's. These diseases are debilitating and terrifying, taking away the essence of who a person is. The thought of not being able to recognize my family sends chills down my spine. Because of the emotional toll cognitive diseases have on all of us, society has often been overly optimistic about potential "cures" or solutions. I remember when beta-amyloid plaques were all the rage, and the belief was that once we figured out how to treat these plaques, we would have a cure. A decade later, that isn't the case. So it's with modest optimism that I write this article. I do my best to let the science guide my excitement. I have to say, I'm still quite excited to see where this leads!

What is Klotho?

Klotho is a protein that plays a crucial role in various physiological processes, including the regulation of aging. Discovered in 1997 by Japanese scientist Makoto Kuro-o, Klotho was initially found while studying hypertension in mice. The absence of Klotho resulted in mice exhibiting symptoms of premature aging, while over-expression extended their lifespan by about 30%. This finding highlighted Klotho as a significant longevity factor.

The Science Behind Klotho and Cognitive Decline

Understanding how Klotho works might sound complicated, but let’s break it down into simple terms:

Gatekeeper of Aging: Think of Klotho as a gatekeeper for your body's aging process. It helps manage how your body handles aging by controlling important functions such as:

Calcium and Phosphate Regulation: Klotho helps balance calcium and phosphate levels in the body, crucial for maintaining healthy bones and preventing calcification in tissues.

Oxidative Stress Reduction: Klotho reduces oxidative stress, which is the damage caused by free radicals. This helps protect cells from damage and supports overall cellular health.

Growth Factor Signaling: Klotho modulates the signaling of growth factors, which are essential for various cellular processes including cell growth, differentiation, and survival.

Two Forms: Klotho exists in two forms—one that's attached to cells and one that floats around in your bloodstream. Both forms help keep your body’s systems in check.

Protects Your Brain: The floating form of Klotho acts like a guardian for your brain, helping reduce stress on brain cells and keeping them healthy. This is crucial for maintaining good brain function as we age.

Animal Studies Highlighting Klotho's Benefits

Several studies have highlighted the positive impact of Klotho on cognitive function in animals. For example:

Rodent Studies: Research on mice has demonstrated that overexpression of Klotho can lead to improved cognitive abilities and extended lifespan. Mice with higher levels of Klotho perform better in memory and learning tasks, suggesting a protective effect against cognitive decline. Even more impressive, mice that were genetically predisposed to develop Alzheimer’s showed significant improvements. When these mice were given high doses of Klotho, their risk of developing the disease dropped to levels similar to those of mice without a genetic predisposition.

Primate Studies: More recently, studies on primates have shown similarly promising results. Primates administered with Klotho exhibited enhanced cognitive performance and neural resilience. These studies are particularly significant as they offer a closer approximation to human physiology compared to rodent models.

Klotho and Neurodegenerative Diseases

The implications of these findings for neurodegenerative diseases like Alzheimer's and dementia are profound. Higher levels of Klotho have been associated with a reduced risk of developing these conditions. By enhancing cognitive function and protecting neurons, Klotho could potentially slow the progression of these diseases, offering a new avenue for treatment and prevention.

Dena Dubal, a leading researcher in this field, has explored Klotho's effects extensively. Her work at the University of California San Francisco has shown that Klotho enhances learning and memory in both mice and primates. Dubal's studies indicate that Klotho could be a critical factor in brain resilience, potentially offering protection against Alzheimer's and other neurodegenerative diseases.

Exercise: A Natural Booster of Klotho

While direct Klotho supplements or treatments are not yet available, there is compelling evidence that lifestyle choices can influence Klotho levels. Among these, exercise stands out as a particularly effective method. As if you needed another reason to exercise!?

The Link Between Exercise and Klotho

Regular physical activity has been directly linked to increased levels of Klotho. Here’s how exercise influences Klotho:

Stimulates Production: Exercise has been shown to stimulate the production of Klotho in the body. When you engage in physical activity, your body responds by producing more Klotho, which then circulates through your bloodstream and exerts its beneficial effects on the brain.

Promotes Healthy Aging: The increased Klotho levels from regular exercise help protect brain cells from damage and promote the growth of new neurons. This leads to better cognitive function and reduced risk of cognitive decline.

Enhances Brain Resilience: Higher Klotho levels associated with exercise make the brain more resilient to stress and injury, which is particularly important in preventing neurodegenerative diseases.

Studies have shown that chronic exercise can increase Klotho levels by about 30%. In mice, even a single bout of exercise can double Klotho levels. This positions exercise as one of the most potent natural ways to boost Klotho and, by extension, protect against cognitive decline.

Exercise: The Closest Thing to a Fountain of Youth

Given its profound impact on Klotho levels and, by extension, cognitive health, exercise can be viewed as one of the most effective strategies for combating cognitive decline. Regular physical activity not only supports overall health but also appears to offer significant protection against the ravages of aging on the brain. Get your ass to the gym friends!

Conclusion

While the research on Klotho is still evolving, its potential to impact cognitive decline and neurodegenerative diseases is incredibly promising. By understanding the role of Klotho and making lifestyle choices that support its expression—especially through regular exercise—we can take proactive steps to protect our brain health and enhance our longevity.

If you want to listen to an amazing podcast on Klotho, I highly recommend checking out episode 303 of Dr. Peter Attia’s The Drive here: Click here.

See you next time,

Jake Louro

Louro Training

References:

Brombo, G., Bonetti, F., Ortolani, B., Morieri, M., Bosi, C., Passaro, A., ... & Zuliani, G. (2018). Lower Plasma Klotho Concentrations Are Associated with Vascular Dementia but Not Late-Onset Alzheimer’s Disease. Gerontology, 64, 414-421. (Click here to read)

Deng, L., Yu, S., Zhang, Z., Li, Y., Qiu, S., & Birong, D. (2023). The relationship between serum klotho and cognitive performance in a nationally representative sample of US adults. Frontiers in Aging Neuroscience, 15. (Click here to read)

Linghui, D., Simin, Y., Zilong, Z., Yuxiao, L., Shi, Q., & Birong, D. (2023). The relationship between serum klotho and cognitive performance in a nationally representative sample of US adults. Frontiers in Aging Neuroscience, 15. (Click here to read)

Mengel-From, J., Soerensen, M., Nygaard, M., McGue, M., Christensen, K., & Christiansen, L. (2016). Genetic Variants in KLOTHO Associate With Cognitive Function in the Oldest Old Group. The journals of gerontology. Series A, Biological sciences and medical sciences, 71(9), 1151-1159. (Click here to read)

Shardell, M., Semba, R., Rosano, C., Kalyani, R., Bandinelli, S., Chia, C., & Ferrucci, L. (2016). Plasma Klotho and Cognitive Decline in Older Adults: Findings From the InCHIANTI Study. The journals of gerontology. Series A, Biological sciences and medical sciences, 71(5), 677-682. (Click here to read)

Yokoyama, J., Marx, G., Brown, J. A., Bonham, L., Wang, D., Coppola, G., ... & Dubal, D. (2016). Systemic klotho is associated with KLOTHO variation and predicts intrinsic cortical connectivity in healthy human aging. Brain Imaging and Behavior, 11, 391-400. (Click here to read)