How was Klotho discovered?

Klotho was accidentally discovered in 1997 by Japanese scientist Makoto Kuro-o. He engineered mice for hypertension research, but one line developed premature aging. Upon further investigation, he found the Klotho gene had been disrupted, leading to this phenotype. Overexpression of Klotho later extended lifespan by 30% in mice.

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

We are born with about six times the Klotho levels found in adulthood, which then decline throughout life, halving from age 40 onwards. Klotho also exhibits a circadian rhythm, with higher levels in the morning that can decrease by up to 40% by midnight.

What lifestyle factors can influence Klotho levels?

Chronic stress is associated with lower Klotho levels and shorter telomeres. Conversely, exercise is one of the most robust interventions, with chronic exercise (e.g., 12 weeks) increasing Klotho levels by about 30%. Acute exercise in mice can even double Klotho levels.

Can Klotho protect against Alzheimer's disease even when plaques are present?

Remarkably, mouse models that have aggressive Alzheimer's mutations but also overexpress Klotho show normalized cognition and preserved synapses. This suggests that Klotho provides resilience, thwarting the toxic effects of amyloid and tau, even if these Alzheimer's toxins are still present in the brain.

Does Klotho cross the blood-brain barrier?

Surprisingly, Klotho does not cross the blood-brain barrier. Despite this, peripheral injection of Klotho in mice and monkeys leads to cognitive enhancement within hours, suggesting it acts through a peripheral messenger that then signals the brain.

What is Platelet Factor 4 (PF4) and its connection to Klotho and brain health?

PF4 is a bioactive chemical released by activated platelets. Research shows that Klotho activates platelets to release PF4, which then travels to the brain and enhances cognition. PF4 is also increased by exercise and is found to be enriched in 'young blood' that rejuvenates old brains, indicating a convergent biological pathway.

What was discovered about Klotho's effect in non-human primates?

In aging rhesus macaques, a low, physiological dose of Klotho enhanced cognition within four hours, and this improvement lasted for at least three weeks (14-21 days). This effect was particularly pronounced in tasks requiring high memory load, demonstrating Klotho's ability to boost complex brain functions.

How does the KL-VS genetic variant affect Klotho levels and human cognition?

About 20-25% of the population carries the KL-VS variant, which genetically leads to 15-20% higher circulating Klotho levels. Individuals with this variant consistently show better cognitive performance compared to non-carriers, suggesting a direct link between endogenous Klotho levels and brain health in humans.

Does KL-VS offer protection against APOE4's Alzheimer's risk?

Yes, a large meta-analysis found that carrying the KL-VS variant significantly reduces Alzheimer's disease risk in APOE4 carriers. It decreased conversion from mild cognitive impairment (MCI) to Alzheimer's and lowered amyloid-beta biomarkers, effectively abating the toxicity associated with APOE4.

Are there any negative health consequences associated with the KL-VS variant?

While KL-VS heterozygosity is largely protective against stroke, cardiovascular, and metabolic risks, it has been found to be a poor prognostic indicator in BRCA1 positive breast cancer patients, suggesting context-dependent effects.

Could Klotho levels be measured like cholesterol in the future?

Klotho is being developed as a diagnostic biomarker for kidney function, where declining levels signal early kidney trouble. Scientists envision a future where Klotho levels could be routinely checked, similar to blood pressure or cholesterol, preferably in a morning, fasting state due to its circadian rhythm.

What is the future potential of Klotho as a therapeutic?

Klotho holds significant promise as a therapeutic to enhance brain health, combat cognitive decline, and potentially address other aging-related diseases like cancer and cardiovascular and kidney disease. It is seen as a crucial component of future 'cocktail' therapies to provide resilience against multiple protein toxicities in conditions like Alzheimer's.

303-A breakthrough in Alzheimer’s disease: potential of klotho for brain health & as a therapeutic

Peter Attia MD

Science & Technology3 min read144 min video

May 27, 2024|90,931 views|1,622|204

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 longevity hormone, shows promise for brain health promotion and Alzheimer's treatment.

Key Insights

Klotho is a longevity hormone that declines with age and stress, but exercise can increase its levels.

Klotho enhances cognitive function in mice and non-human primates, potentially by increasing GluN2B at synapses.

Peripheral klotho administration improves cognition in primates for weeks, even though it doesn't cross the blood-brain barrier.

Platelet Factor 4 (PF4) is a potential blood-borne messenger that connects klotho, young blood, and exercise to brain health.

A genetic variant (KVs) associated with higher klotho levels shows better cognitive function and may counteract APOE4's risk for Alzheimer's.

Klotho shows promise as a therapeutic agent for age-related cognitive decline and neurodegenerative diseases.

THE DISCOVERY AND NATURE OF KLOTHO

Klotho, named after the Greek fate who spins the thread of life, was serendipitously discovered in 1997. Initially identified through mice exhibiting premature aging when the gene was disrupted, subsequent research showed that overexpressing klotho extended lifespan by 30%. This transmembrane protein, primarily produced in the kidney and choroid plexus, is cleaved into a secreted, hormonal form that circulates in the body. Klotho levels naturally decrease with aging and are influenced by factors like stress. Exercise, notably, has been shown to robustly increase klotho levels, offering a potential pathway to support its beneficial effects.

KLOTHO'S POTENTIAL TO BOOST COGNITION

Research has demonstrated that klotho significantly enhances cognitive function in various animal models. Studies in mice revealed that overexpressing klotho not only extended lifespan but also improved performance in cognitive tasks, such as navigating mazes more efficiently. This cognitive enhancement was observed in young, aging, and even in mouse models of Alzheimer's and Parkinson's disease. These findings suggest klotho may imbue brains with resilience against age-related cognitive decline and neurodegenerative toxins.

MECHANISMS OF KLOTHO ACTION ON THE BRAIN

A key finding is that peripherally administered klotho enhances cognition in mice and primates, despite not readily crossing the blood-brain barrier. Investigating the mechanism, researchers found that klotho increases the expression of GluN2B, a subunit of NMDA receptors crucial for synaptic plasticity and memory formation. This suggests klotho may act indirectly on the brain, possibly through circulating factors. One such factor identified is Platelet Factor 4 (PF4), which is released by activated platelets and has been shown to cross into the brain and improve cognitive function, mirroring klotho's effects.

THE CONVERGENCE OF KLOTHO, EXERCISE, AND YOUNG BLOOD

Remarkably, three distinct interventions—klotho administration, exercise, and young blood transfusion—all converge on activating platelets and increasing PF4 levels, subsequently benefiting brain function. This interconnectedness highlights a shared biological pathway involving platelets as messengers of brain health. The observation that PF4, like klotho, can cross the blood-brain barrier and enhance cognition suggests a critical role for these blood-borne factors in maintaining neural function and resilience, particularly during aging.

GENETIC INSIGHTS: THE KLOTHO KVS VARIANT

Human genetic studies have provided further support for klotho's role in brain health. The KVs genetic variant, present in about 25% of the population, is associated with naturally higher circulating klotho levels. Individuals carrying this variant exhibit better cognitive performance across various tests. Intriguingly, KVs heterozygosity appears to counteract the increased risk of Alzheimer's disease associated with the APOE4 gene, suggesting klotho's protective effects extend to mitigating genetic predispositions for neurodegeneration. Homozygosity for KVs, however, is rare and linked to lower klotho levels and adverse health outcomes.

THERAPEUTIC IMPLICATIONS AND FUTURE DIRECTIONS

The preclinical data strongly suggest klotho's therapeutic potential for Alzheimer's disease and other age-related cognitive deficits. Clinical trials are being considered, potentially exploring klotho as part of a combination therapy to address the multi-factorial nature of Alzheimer's. Even beyond brain health, klotho levels are associated with reduced mortality from cancer and cardiovascular disease, indicating its broader impact on aging and overall health. Standardized assays and further research are crucial to harness klotho's benefits, possibly through periodic injections, to promote longevity and enhance brain resilience.

Mentioned in This Episode

●Software & Apps

●Tools

●Companies

●Organizations

●Books

●Studies Cited

●Concepts

●People Referenced

Common Questions

Klotho is a protein naturally circulating in our bodies, named after the Greek fate who spins the thread of life. It helps with longevity, supports various organ systems, and notably enhances brain function. Its decline with age is associated with increased risk of diseases and mortality.

Topics

Platelet Factor 4 Genetic Polymorphism Therapeutic Development

Mentioned in this video

personLawrence Cohen

A medical anthropologist at UC Berkeley with whom Dr. Dubal worked on the experience of dementia in different cultures.

personMakoto Kuro-o

A Japanese scientist who accidentally discovered Klotho in 1997 while studying hypertension, by engineering a mouse with a premature aging phenotype.

personVillis Wienis

A neuroendocrinologist who studied brain aging and mentored Dr. Dubal during her PhD at the University of Kentucky.

organizationFabia Ambrosio's Lab

Research lab that discovered hypermethylation around the Klotho promoter occurs with aging, leading to decreased Klotho levels.

personKaya Park

A post-doctoral researcher in Dr. Dubal's lab who persistently investigated the link between Klotho, platelets, and PF4, leading to significant discoveries.

personTom Boon

Expert who consulted on relevant dosing strategies in monkeys for the Klotho studies.

personStacy Kastner

Conducted the specialized cognitive tests in monkeys for the Klotho primate studies.

personLeonard Mucke

Collaborator with Dr. Dubal whose work looked at synapses in Klotho-overexpressing mice and their resilience to Alzheimer's toxins.

conceptKL-VS

A genetic variant of the Klotho gene (two single nucleotide polymorphisms) that leads to naturally higher levels of circulating Klotho (15-20% higher) in heterozygotes and is associated with better cognition and reduced risk of Alzheimer's.

bookNature Aging

Scientific journal where Dr. Dubal's lab published their study on Klotho and platelet factors, highlighting the convergence of Klotho, young blood, and exercise.

personJennifer Yokoyama

Geneticist at the UCSF Memory and Aging Center who collaborated with Dr. Dubal to study the KL-VS genetic variant and its association with cognition in humans.

personNed David

Founder of Unity Biotechnology, instrumental in funding and supporting the primate studies on Klotho.

drugDonanemab

A drug that removes amyloid beta from the brain, potentially part of a cocktail therapy for Alzheimer's disease alongside Klotho.

conceptDoogie Houser Mouse

An affectionately named mouse model (GluN2B overexpressing) engineered to be smarter, showing similar cognitive enhancements to Klotho overexpressing mice.

personBruce Miller

Researcher at the UCSF Memory and Aging Center who helped build a population of individuals and patients for genetic and biomarker studies.

conceptAlpha-Synuclein

A pathogenic protein involved in Parkinson's disease; its overexpression in mice models leads to motor and cognitive deficits that Klotho can selectively improve the latter.

companyUnity Biotechnology

Company started by Ned David to attack aging; collaborated with Dr. Dubal's team and Yale to fund and execute primate studies on Klotho.

drugLecanemab

A drug that removes amyloid beta from the brain, potentially part of a cocktail therapy for Alzheimer's disease alongside Klotho.

personStephen Houser

Former chair of UCSF Neurology who encouraged Dr. Dubal to pursue 'big and important' research, influencing her focus on Klotho.

personTara Walker

Australian scientist whose group found that exercise activates platelets to release PF4, which travels to the brain to cause neurogenesis.

personMichael Gracious

Senior PI at Stanford involved in a large genetic population study on KL-VS, APOE4, and Alzheimer's disease.

personEric Prather

Collaborated with Dr. Dubal and Alyssa Epel on a study showing chronic stress associates with lower Klotho levels and shorter telomeres in mothers.

conceptGluN2B

A specific subunit of NMDA receptors, crucial for efficient synaptic connections and memory formation. Klotho increases GluN2B at the synapse.

conceptJ20 Mouse Model

An aggressive mouse model of Alzheimer's disease that expresses human APP with mutant forms, leading to early synaptic loss and cognitive deficits.

personJoel Kramer

Researcher at the UCSF Memory and Aging Center who helped build a population of individuals and patients for genetic and biomarker studies.

personBarbara Shara

A graduate student in Dr. Dubal's lab studying the direct effects of Klotho and other factors on neurons using live cell imaging.

toolTurboID

A system (genetic manipulation technique) that labels proteins as they are secreted from specific organs, enabling higher-resolution studies of Klotho's systemic changes.

personMikel Belloy

Led a remarkable genetic population study at Stanford (now at WashU) on KL-VS, APOE4, and Alzheimer's risk.

personAlyssa Epel

Collaborated with Dr. Dubal and Eric Prather on a study showing chronic stress associates with lower Klotho levels and shorter telomeres in mothers.

personGraham Williams

Conducted the specialized cognitive tests in monkeys for the Klotho primate studies.

studyENHAN Study

A large-scale study (2022) with over 10,000 participants that showed lower Klotho levels correlated with a 30% increase in all-cause mortality over 5 years, primarily due to cancer and cardiovascular disease.

personPrometheus

softwareNMDA receptors