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

KEYPOINTS

• 01

  Klotho was discovered by accident and behaves like a true longevity factor.

  In 1997, Japanese scientist Makoto Kuro-o was studying hypertension. A transgene insertion disrupted a gene in one mouse line, and those mice aged prematurely from about two weeks old (osteoporosis, atherosclerosis, emphysema) and lived about three months instead of about 30. He mapped the disrupted gene and named it after Clotho, the Fate who spins the thread of life. The decisive test was the reverse: mice engineered to overexpress klotho lived about 30% longer.

• 02

  Most klotho circulates as a hormone cut from a membrane protein.

  Klotho is a roughly 1,000-amino-acid (about 130 kDa) transmembrane protein, made mainly in the kidney and also in the brain's choroid plexus. Enzymes (ADAM10/17) clip off most of its outer portion into the blood or spinal fluid, where it acts on many organs. Dubal calls this the 'klotho hormone.'

• 03

  Levels fall with age, through the day, and with chronic stress; exercise raises them.

  Cord blood has about six times adult levels, and levels can halve from age 40 onward. Fabrisia Ambrosio's lab linked the age-related decline to methylation of the klotho promoter. Levels also fall up to about 40% from morning to midnight. In Dubal's study with Elissa Epel and Aric Prather, highly stressed mothers of children with autism had lower klotho, which tracked shorter telomeres. Across about 12 studies, 12 weeks of regular exercise raised klotho about 30%. Rapamycin raises it in mice, and in mouse data a 45-minute treadmill run may nearly double it acutely.

• 04

  Extra klotho made mice smarter, which surprised Dubal.

  Her lab crossed Alzheimer's-model mice with klotho overexpressers. The biggest surprise was in normal mice: those with more klotho learned and remembered better across many tasks and ages, with nearly non-overlapping data, not because they swam faster or saw better. The effect replicated in aging mice and Alzheimer's models. In a Parkinson's model (alpha-synuclein), klotho improved cognition by about 70% but did nothing for motor deficits.

• 05

  Klotho appears to protect brains despite Alzheimer's pathology.

  In aggressive J20 amyloid mice, three- to fourfold klotho overexpression extended lifespan and normalized cognition, even though amyloid-beta and tau levels didn't change. Synapses were preserved, in work with Lennart Mucke and Eliezer Masliah. A colleague's analogy is 'a helmet for neurons' against amyloid, tau, alpha-synuclein and aging.

• 06

  It works through the GluN2B subunit of NMDA receptors.

  Klotho mice looked like the 'Doogie Howser' GluN2B-overexpressing smart mouse. Klotho increased synaptic GluN2B and plasticity, and blocking GluN2B with drugs abolished the cognitive benefit.

• 07

  Klotho doesn't cross the blood–brain barrier, so a blood messenger was proposed—and platelets turned up.

  Klotho injected into the belly or arm enhances cognition within 4 hours, and the effect lasts weeks. Plasma profiling after injection showed a surprising rise in platelet factors. A persistent postdoc showed klotho mildly activates platelets to release platelet factor 4 (PF4). PF4 crosses into the brain, acts via GluN2B in hippocampal slices, and enhances cognition in young and aging mice. Saul Villeda (young blood) and Tara Walker (exercise) found PF4 independently, and the three groups published together in Nature-family journals on the same day. Yet klotho still worked fully in PF4-knockout mice, so PF4 is 'sufficient but not necessary,' and other messengers are being sought.

• 08

  In old monkeys, one low physiological dose improved working memory for weeks; high doses didn't help.

  With Unity Biotechnology and Yale (Graham Williams, Stacy Castner), 18 aged rhesus macaques did a largely blinded spatial delayed-response task: remembering which covered well held a treat. One subcutaneous low dose (within natural range) improved performance within 4 hours, lasting 14–21 days and in some cases tested to 28. Gains were largest on the harder, many-well version. Doses 10–20 times higher neither harmed nor helped, unlike in mice, where even far higher doses worked. Dubal concludes humans likely have a therapeutic window. She calls the study a 'burn your ships' risk she was willing to take.

• 09

  In humans, the KL-VS variant links higher klotho to better cognition and blunts APOE4 risk.

  About 1 in 4–5 people carry one copy, with about 15–20% higher levels (for example, about 950 vs 800 pg/mL). Dubal and Jennifer Yokoyama found carriers scored better cognitively, by about as much as APOE4 carriers score worse. Michael Belloy and Michael Greicius analysed 22 cohorts and over 20,000 people: APOE4 carriers with KL-VS had near-normal Alzheimer's risk, less MCI-to-Alzheimer's conversion and less amyloid. Dubal says, from personal communication, protection also held for APOE4 homozygotes. Carriers also show less stroke and cardiovascular risk, but a worse prognosis in BRCA1-positive breast cancer. Rare KL-VS homozygotes have about 30% lower klotho and shorter lives.