How do Klotho levels change throughout a person's life?

Klotho levels are highest at birth and decline significantly throughout lifespan, decreasing by about half from age 40 onwards. There's also a daily rhythm, with levels being higher in the morning and declining by late afternoon.

What causes Klotho levels to decrease with age?

A primary known mechanism is hypermethylation around the Klotho promoter with aging, which inhibits its transcription and production. Other possibilities include reduced efficiency of organs like the kidney.

Can chronic stress affect Klotho levels?

Yes, chronic stress is associated with lower Klotho levels. One study found that mothers experiencing high stress levels also had significantly lower Klotho and shorter telomeres.

How can I increase my Klotho levels?

Exercise is one of the most effective known interventions for increasing Klotho levels. Studies show significant increases after 12 weeks of chronic exercise, and even acute increases after a single treadmill run in mice.

Is there a connection between Klotho and BDNF for brain health?

The exact relationship is still being researched, but both Klotho and BDNF are associated with positive brain health and are increased by factors like exercise. It's an important question whether Klotho might influence BDNF levels.

Does Klotho enhance cognition?

Yes, research in both mice and old monkeys has shown that Klotho overexpression enhances cognition, learning, and memory. In mice studies, this effect was significant even in normal mice, not just disease models.

What is the breakthrough potential of Klotho for brain health?

Klotho administration has shown remarkable positive effects on cognition in animal models, suggesting it could be a key factor in maintaining or improving brain health, potentially offering a breakthrough for cognitive decline and neurodegenerative diseases.

Key Moments

Klotho: what it is and why it could have breakthrough potential for brain health

Peter Attia MD

Science & Technology3 min read25 min video

Oct 9, 2024|13,183 views|373|43

Peter Attia MD Dr. Peter Attia Early Medical The Drive Podcast The Drive Longevity Zone 2

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Key Moments

TL;DR

Klotho, a hormone, enhances brain health and cognition, declining with age and stress but boosted by exercise.

Key Insights

Klotho is a large transmembrane protein primarily produced in the kidney and choroid plexus, with a soluble, hormonal form released into the blood and CSF.

Klotho levels naturally decline with age, starting from high levels at birth, and exhibit a daily circadian rhythm with higher levels in the morning.

Chronic stress is associated with lower klotho levels, shortening telomeres and potentially impacting aging markers, though the exact mechanism is unclear.

Exercise is a robust intervention for increasing klotho levels, showing significant increases after regular exercise and even acute boosts from a single session.

Overexpression of klotho in mice significantly enhances cognition, improving learning, memory, and performance in maze tasks, independent of disease models.

Klotho also shows positive effects on cognition and memory in old monkeys, suggesting conserved benefits across species and brain complexity.

UNDERSTANDING THE KLOTHO PROTEIN

Klotho is a substantial protein, approximately 1000 amino acids long, functioning as a type I transmembrane protein. Its extracellular portion, containing K1 and K2 domains with homology across species, is cleaved by enzymes like ADAM10 and ADAM17. This cleavage releases a soluble, hormonal form of klotho that circulates in the blood and cerebrospinal fluid, allowing it to act as a hormone influencing multiple organs.

KLOTHO LEVELS ACROSS THE LIFESPAN

Circulating klotho levels are significantly higher at birth, about six times current levels, and decline throughout life. By age 40 and onward, levels can decrease by half during aging. Additionally, klotho exhibits a daily rhythm, with higher concentrations in the morning and a significant drop by mid-afternoon, although the precise mechanisms regulating this daily variation, such as degradation or sequestration, remain unknown.

FACTORS INFLUENCING KLOTHO PRODUCTION AND LEVELS

The decline in klotho levels with aging is partly attributed to hypermethylation around the klotho promoter, which inhibits transcription and translation. Chronic stress is another significant factor associated with lower klotho levels; studies show reduced klotho in mothers with high stress and children with autism spectrum disorder. This stress-induced reduction may converge with other aging markers like telomere length, though the exact interplay requires further investigation.

EXERCISE AS A KLOTHO BOOSTER

Exercise is identified as one of the most effective interventions for increasing klotho levels. Meta-analyses of multiple studies indicate that approximately 12 weeks of chronic exercise can boost klotho levels by around 30%. Preliminary data in mice even suggest that a single 45-minute treadmill run can acutely double klotho levels, highlighting exercise's potent and rapid impact on this crucial hormone.

KLOTHO'S IMPACT ON BRAIN HEALTH AND COGNITION

Research has demonstrated klotho's significant benefits for brain health. In mice, overexpression of klotho enhances cognition, including learning, memory, and performance in complex tasks like mazes. These improvements are observed across different ages and in models of Alzheimer's and Parkinson's disease. Notably, older monkeys also show similar cognitive enhancements from klotho, indicating conserved therapeutic potential in more complex brains.

KLOTHO VERSUS BDNF AND FUTURE THERAPEUTIC POTENTIAL

Klotho's effects on the brain share similarities with Brain-Derived Neurotrophic Factor (BDNF), another important factor for neural function, which is also increased by exercise and intermittent fasting. While the direct relationship between klotho and BDNF is still being explored, klotho's profound cognitive enhancements, observed in both mice and monkeys, suggest it could be a significant therapeutic target for age-related cognitive decline and neurodegenerative diseases, potentially offering breakthrough potential.

Mentioned in This Episode

●Supplements

●Software & Apps

●Tools

●Companies

●Organizations

●Concepts

●People Referenced

Maximizing Klotho for Brain Health

Practical takeaways from this episode

Do This

Engage in regular exercise, as it's a robust intervention shown to increase Klotho levels.

Monitor Klotho levels, as they naturally decline with age.

Consider how lifestyle factors like chronic stress might impact your Klotho levels.

Avoid This

Do not assume that mouse study results directly translate to humans without caution.

Do not rely solely on specific behaviors like skipping breakfast to boost BDNF or Klotho without considering overall health.

Do not ignore the potential impact of age on Klotho production and effectiveness.

Common Questions

Klotho is a protein primarily produced in the kidney and brain that plays a crucial role in various bodily functions, including brain health and cognition. It circulates in the blood and cerebrospinal fluid as a soluble hormone.

Topics

Klotho Animal Models

Mentioned in this video

Concepts

Exercise

BDNF

type 1 transmembrane protein

Klotho functions as a type 1 transmembrane protein, with its N-terminus in the extracellular space and C-terminus inside the cell.

hippocampi

Neural circuits in the hippocampus are fundamental for memory and are studied in mice to understand human cognition.

Klotho

A protein that plays a significant role in brain health and cognition. Its levels decline with age and can be influenced by factors like stress and exercise.

cerebrospinal fluid (CSF)

The soluble form of Klotho can be released into the CSF in the brain.

hormonal form of Klotho

The soluble form of Klotho, referred to as a hormone because it's released at one site and acts at multiple organs.

soluble Klotho

The form of Klotho released into the blood or CSF after being clipped by enzymes.

amino acids

Klotho is approximately 1000 amino acids long and weighs about 130 kilodaltons.

cord blood

Newborns have approximately six times the Klotho levels found later in life, as measured in cord blood.

brain-derived neurotrophic Factor

BDNF is a crucial trophic factor for the brain, promoting neuron function and associated with positive brain health.

prefrontal cortices

Neural circuits in the prefrontal cortex are studied in mice to understand human cognition.

People

Alissa Eel

A researcher at UCSF who collaborated on a study looking at Klotho levels and telomere length in mothers with children with autism spectrum disorder.

Eric Pray

A researcher at UCSF who collaborated on a study looking at Klotho levels and telomere length in mothers with children with autism spectrum disorder.

Ryan Brown

A researcher at UCSF involved in a study examining the relationship between Klotho levels and telomere length.

Products

mouse

Used extensively in research for Klotho studies, though extrapolating findings to humans requires caution due to differences in lifespan and metabolism.

Companies

biotech

Collaborated on a study with Yale University that found Klotho enhances learning, memory, and cognition in old monkeys.

Software & Apps

ADAM10 and ADAM17

Enzymes that clip the extracellular portion of Klotho, releasing it into the blood or CSF.

Organizations

Alzheimer's conference

A conference where the connection between Klotho and BDNF was discussed.

Locations

kidney

Klotho is primarily produced in the kidney and then transported into the membrane.

choroid plexus

Klotho is also produced in the choroid plexus of the brain.

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