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Klotho: Spinning the Thread of Life


Greek goddesses threading Klotho

Klotho (pronounced “cloth-o”) is likely the most promising longevity-enhancing hormone that most people have never heard of. Given the excitement it’s been generating in aging research circles recently, that’s likely to change. Consider that when a Japanese scientist accidentally discovered it in 1997, in a mouse genetic experiment gone wrong, he quickly grew so enamored with its anti-aging potential, he gave Klotho its unusual name. He borrowed it from one of the three Fates in Greek mythology, whose job it was to spin the thread of human life.

Klotho Protein Structure

 

Putting its potential aside for a moment, getting a handle on what exactly Klotho is requires a bit of explanation. Found throughout the animal world, it’s a gene that codes for a specific protein that in humans and other species is produced mostly in cells in the kidneys and, secondarily, in the brain. That protein assumes two basic forms. It exists as a “trans-membrane” protein which sits attached to the cell membrane. Other Klotho proteins cleave off from the cell to travel the bloodstream in soluble form where, functioning like a hormone, they help regulate physiological processes up and down the system.


The trans-membrane form of Klotho helps the kidneys excrete phosphorus, essential if unglamorous work. But it’s the hormone-like Klotho,  interacting with a surprisingly large number of aging pathways, which helps tamp down inflammation and reduce oxidative stress and seems to strongly influence how long our bodies can last. It’s something like the Zelig of anti-aging hormones, a background player, and yet, all the available evidence suggests, when there’s more of it in circulation we age better, when there’s less, worse.

 

The mouse research was our first strong clue. When the Klotho gene was knocked out, the mice aged in fast-motion, and survived for only 20% of their normal lifespans. When the mice were genetically manipulated to over-express the gene, their normal lifespan expanded by a third. Further research found that injecting an extra dose of Klotho into mice genetically engineered to be vulnerable to the mouse form of Alzheimer’s (“mouse-heimer’s”) protected them from the ravages of the disease. The prospect of a desperately-needed Alzheimer’s drug, for humans, is tantalizing.

 

But researchers sometimes talk about “the valley of death” that separates exciting rodent results from the abject failures that too often follow in human trials. However, the “mouse-heimer” researcher, USCF neurologist Dena Dubal, put together a Silicon Valley-academic collaboration to see if Klotho injections could enhance the cognitive performance of aging rhesus macaque monkeys, among our closest primate relatives. (The NIH generally steers clear of funding pure aging research; they see themselves as being in the disease business.)

 

The results were published last year. A single Klotho injection significantly improved the monkeys’ performance on a spatial memory test, and the improvement sustained for about three weeks, suggesting that the hormone had, in some way, optimized their synaptic architecture. Interestingly, unlike with the mice, boosting Klotho beyond youthful “physiologic” levels (Klotho levels decline by about a third over the course of the human lifespan) did not confer any performance lift, nor, for that matter, cause any worrisome side-effects.

 

So, when will we see human trials? Some experts think we’re only a few years away. Currently, at least one player, Klotho Therapeutics, a small biotech company in San Diego, is working on bringing a recombinant Klotho protein-based therapy to the clinical trial stage, the first disease target, kidney disease.

 

But even before any such trials materialize, we do have strong indirect evidence that human Klotho therapies stand a good chance of success. Several studies have analyzed Klotho levels in blood serum collected in large health data bases and found a correlation between more Klotho and less disease. (In one such study, people whose levels were 30% lower than average for their age had a 30% higher all-cause mortality, deaths mostly attributed to cardiovascular disease and cancer.) Other research has looked at people with a common variant of the Klotho gene, found in about a quarter of the population, that seems to boost Klotho levels by 15-20%. And this group does better, on average, on tests measuring cognitive performance in seniors than people who don’t share the mutation.

 

Before you go running out to see whether you are in the lucky quartile with the KLVS “allele” (private labs are beginning to do this test), know that anyone can raise their levels with exercise. The data, according to Dr. Dubal, show that 12 weeks of aerobic exercise can lift levels by about 30%. Smaller increases have been measured in people taking certain medications, including metformin and rapamycin (which we know engage with longevity pathways), as well as the GLP-1 agonist/incretin weight-loss drugs and losartan, a popular blood pressure drug. This increase in Klotho may be the reason these medications have an additional dividend in longevity,

 

Given the protection that therapeutic Klotho may provide against neurodegenerative diseases, cardiovascular disease, kidney disease, diabetes, cancer and sarcopenia, it is entirely possible that the string of life spun by the Greek Fate will reach that much longer.


 

Low Serum Klotho Associated With All-cause Mortality Among a Nationally Representative Sample of American Adults

 

Association between soluble α-klotho and mortality risk in middle-aged and older adults


Longevity factor klotho enhances cognition in aged nonhuman primates

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