Peter Attia MD303-A breakthrough in Alzheimer’s disease: potential of klotho for brain health & as a therapeutic
CHAPTERS
- 0:00 – 7:03
Dena Dubal's path into aging research and klotho
Peter Attia introduces his guest, and Dena Dubal traces her interest in brain aging from her undergraduate days through her MD PhD and neurology training. She describes a mentor's advice to pursue work that is big and important, and why she chose to study klotho as a longevity factor that might help the brain.
- •Dubal is a neurologist and neuroscientist who directs a lab focused on klotho
- •Her interest in aging began in college with a medical anthropology project and a physiology of aging class
- •Steven Hauser told her to do big and important work rather than incremental work
- •Cynthia Kenyon's worm work showed aging is malleable, which motivated her to ask whether klotho could affect the brain
- •Little was known about klotho in the brain when she started, so the project was risky
- 7:03 – 11:02
The accidental discovery of klotho
Dubal recounts how Makoto Kuro-o accidentally discovered klotho in 1997 while engineering mice for hypertension research. Disrupting the gene caused premature aging, and overexpressing it extended mouse lifespan by 30%.
- •Mice carrying the accidental mutation lived about three months instead of about 30 months
- •They developed osteoporosis, atherosclerosis and emphysema, and moved slowly
- •The gene was named after the Greek fate Clotho, with a K as a nod to Kuro-o's name
- •Overexpression of klotho extended lifespan by 30%, which made it a true longevity factor
- •Attia and Dubal note the role of serendipity and curiosity in the finding
- 11:02 – 21:53
Klotho biology: structure, production, and decline with age
Dubal explains that klotho is a large transmembrane protein made mainly in the kidney and the choroid plexus, and that enzymes cleave it into a soluble hormonal form. She covers how levels fall with age, follow a daily rhythm, and are influenced by promoter methylation and chronic stress.
- •Klotho is about 1,000 amino acids, and ADAM10 and ADAM17 cleave the extracellular portion into a soluble hormone
- •Levels are about six times higher in cord blood and can fall by half from around age 40 onward
- •Klotho is high on waking and falls by roughly 40% by midnight, for reasons that are not known
- •Hypermethylation of the klotho promoter with aging may shut down its expression
- •Chronic stress is linked to lower klotho and shorter telomeres in mothers of children with autism
- 21:53 – 30:12
Exercise, BDNF, fasting, and the relevance of mouse models
Dubal says exercise is one of the most robust ways to raise klotho, and the discussion turns to BDNF and whether the two are related. Attia and Dubal then debate how far fasting results in mice translate to humans, and Dubal defends mouse work for studying memory circuits.
- •Chronic exercise raises klotho by about 30% over 12 weeks, and a mouse study suggests an acute run can double it
- •Dubal doesn't know whether klotho and BDNF are related or whether one mediates the other
- •A 24-hour fast in mice raised both klotho and BDNF, and Attia cautions against extrapolating that to humans
- •Dubal argues mouse memory and navigation circuits are fundamental and preserved up to primates
- •She previews that klotho enhances cognition in mice and in old monkeys
- 30:12 – 37:09
Klotho enhances cognition in mice, including Alzheimer's models
Dubal describes the surprising finding that mice overexpressing klotho were smarter even without disease. Attia stresses the size and reproducibility of the effect. The cognitive benefit held in young, aging, Alzheimer's and Parkinson's model mice.
- •The starting hypothesis was that klotho-overexpressing mice would resist Alzheimer's toxins
- •Normal mice with extra klotho learned and remembered better across several tasks and ages
- •Attia says the effect is large enough that statistics are almost a formality, and Dubal agrees
- •Replication across tasks and ages convinced Dubal this may be one of her most important findings
- •Attia compares the consistency of the effect to the case for rapamycin
- 37:09 – 45:40
The blood-brain barrier puzzle and the platelet factor discovery
Dubal explains that klotho engages GluN2B in NMDA receptors but does not cross the blood-brain barrier, yet a peripheral injection improves cognition within hours. Profiling plasma after injection revealed increased platelet factors, which led to platelet factor 4 as a possible messenger.
- •Klotho raises GluN2B at the synapse, and blocking GluN2B abolished klotho's cognitive benefit
- •A peripheral klotho shot enhances cognition within four hours, for at least a couple of weeks
- •Klotho activates platelets, which release PF4
- •PF4 given to mice enhanced cognition and reversed cognitive deficits
- •Attia calls the barrier question the jugular question
- 45:40 – 52:31
Converging labs on PF4: young blood, exercise, and klotho
Dubal describes how her lab, Saul Villeda's young blood work, and Tara Walker's exercise work each found that PF4 enhances the aging brain. The three groups published together in the Nature family of journals on the same day.
- •Villeda found young blood is enriched in PF4, which declines with age, and that PF4 rejuvenates old brains
- •Walker's group found exercise activates platelets and releases PF4, which reaches the brain
- •The three groups chose to cooperate and published the papers on the same day
- •Dubal initially dismissed the platelet signal and her postdoc persisted
- •Platelets were unexpected messengers of brain health
- 52:31 – 1:02:51
How PF4 acts on GluN2B, and why other messengers must exist
Dubal shows that PF4 reaches the brain and acts through GluN2B in hippocampal slices. However, klotho still enhanced cognition in PF4-knockout mice to the same extent, so PF4 is sufficient but not necessary. Her lab is searching for other messengers and using screening assays.
- •PF4 given peripherally ended up near or inside neural cells
- •In hippocampal slices PF4 changed membrane potential and let in calcium, and GluN2B inhibitors blocked this
- •Klotho enhanced cognition equally in mice lacking PF4, so other messengers must exist
- •Her lab is profiling proteins and metabolites, including cell-type-specific secretion with TurboID
- •Attia suggests the slice assay as a screen, and Dubal says they are doing this with synaptic plasticity and neurite outgrowth
- 1:02:51 – 1:11:13
Klotho in a Parkinson's mouse model and the neuronal helmet idea
Dubal reports that klotho improved cognition in alpha-synuclein Parkinson's model mice but did nothing for motor deficits. She uses the image of a helmet for neurons and sets out her hope for a klotho and anti-amyloid cocktail.
- •Klotho improved cognition by roughly 70% but did not help the motor deficits
- •Parkinson's colleagues have told Dubal their patients complain about executive function problems
- •A colleague's analogy likens klotho to a helmet that protects neurons from multiple toxicities
- •Dubal argues Alzheimer's is a multi-proteinopathy and imagines klotho added to lecanemab or donanemab
- •The effect seems to be on cognition circuits rather than motor function
- 1:11:13 – 1:18:16
Klotho in the J20 Alzheimer's mouse: resilience despite plaques
Attia asks whether klotho prevents Alzheimer's-type decline in mice genetically prone to the disease. Dubal describes the J20 APP mouse crossed with klotho overexpression, which lived longer and kept normal cognition with preserved synapses despite amyloid and tau.
- •The J20 model loses synapses before three months and shows cognitive deficits at three to four months
- •Klotho overexpression by about three to fourfold normalized cognition and extended lifespan
- •Amyloid beta and tau levels in the brain were unchanged
- •Synapses were preserved, which Dubal calls resilience
- •Attia wonders whether a klotho drug would be given only at MCI or earlier
- 1:18:16 – 1:39:35
Testing klotho in aged monkeys and the therapeutic window
Dubal explains why she pursued a risky primate study with Unity Biotechnology and Yale. A low, physiologic klotho dose improved working memory in 18 aged rhesus macaques within four hours, with effects lasting at least three weeks, while much higher doses did not help.
- •Rhesus macaques are genetically diverse and have brain circuits similar to ours, so success would help bridge the valley of death
- •Attia praises Dubal's willingness to risk her research program for a meaningful answer
- •A spatial delayed response test measured working and spatial memory in 18 monkeys
- •A low dose roughly four to fivefold above baseline improved cognition within four hours, with benefit lasting at least 14 to 28 days
- •Doses ten to twenty times higher were not harmful but did not help, unlike in mice, which suggests a therapeutic window
- 1:39:35 – 1:43:03
Why a single klotho injection lasts so long
Attia asks why one injection yields weeks of benefit when klotho's natural levels fluctuate daily. Dubal speculates that klotho has an organizational effect at the synapse, such as remodeling it and trafficking GluN2B, and notes this could allow dosing about monthly or every three months.
- •The long duration is counterintuitive given daily klotho variation and the short-lived effects of exercise
- •Dubal does not know the answer but speculates about an organizational or structural effect at the synapse
- •GluN2B trafficking to the synapse is one possible mechanism
- •The durability could allow a shot once a month or every three months
- 1:43:03 – 2:04:48
KL-VS variant: better cognition and protection against APOE4
The conversation turns to humans and the KL-VS variant, carried heterozygously by about one in four people and linked to roughly 15–20% higher klotho. Dubal describes studies tying it to better cognition and a large meta-analysis suggesting it blunts APOE4-related Alzheimer's risk.
- •Heterozygous KL-VS carriers had better cognition, with an effect comparable in size to APOE4's harm in the opposite direction
- •The Stanford meta-analysis of over 20,000 people found KL-VS carriers with APOE4 had Alzheimer's risk near the normal population and lower amyloid
- •Homozygotes exist in about 1–2% and have lower klotho and shorter lifespans
- •Dubal speculates the wild-type allele overcompensates for a mutant protein in heterozygotes
- •KL-VS heterozygosity is associated with protection against stroke and cardiovascular and metabolic disease, but with poorer prognosis in BRCA1 breast cancer
- 2:04:48 – 2:11:50
Klotho levels, mortality, and organ health
Dubal discusses NHANES and InCHIANTI data linking lower klotho to higher five-year mortality, mostly from cancer and cardiovascular disease. She adds that klotho has a large literature on organ health, including cancer models and kidney disease biomarkers.
- •In NHANES, levels below about 666 pg/mL were associated with roughly 30% higher mortality over five years
- •InCHIANTI replicated the finding, and the deaths were mainly from cancer and cardiovascular disease
- •Soluble klotho stopped and reversed cancers such as pancreatic cancer in mouse models
- •Klotho falls early in kidney disease, so kidney specialists are developing it as a biomarker
- •Dubal imagines klotho checked routinely like blood pressure or cholesterol
- 2:11:50 – 2:18:31
Measuring klotho and KL-VS status in practice
Attia and Dubal discuss practical issues: the diurnal rhythm, fasting morning draws, and the lack of a standardized clinical assay. They also cover exercise effects on measured levels and the difficulty of getting KL-VS genotype commercially.
- •Dubal recommends morning fasting samples for the most accurate level, drawn alongside cholesterol
- •No CLIA-based klotho assay exists yet, and levels differ between labs
- •Dubal has not seen human data on acute exercise effects, and Attia offers to help run such an experiment
- •Attia's practice cannot easily get KL-VS status, and 23andMe has not worked for him
- •Dubal's collaborators use fully genotyped cohorts, and she will circle back on commercial options
- 2:18:31 – 2:23:23
Looking ahead: clinical trials, Alzheimer's need, and philanthropy
Attia and Dubal close by stressing the unmet need in Alzheimer's and the importance of moving klotho into human trials. Dubal thanks her funders, and Attia argues philanthropy suits high-risk, high-upside science like klotho.
- •Attia says anti-amyloid therapies have barely dented Alzheimer's and that klotho must go into clinical trials
- •Dubal says the whole world is aging rapidly and effective therapies are lacking
- •She hopes klotho could join anti-amyloid therapy as a resilience cocktail
- •Dubal credits NIH, foundations, biotech, and philanthropy for enabling risky science
- •Attia says philanthropy should fund work too risky for NIH or industry but with strong biologic plausibility
