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An illustration of DNA helices within a circle on a pale blue background. "Klotho" is written to the right in capital letters, echoing the mystique of the Emperor's New Klotho. In the bottom right corner, there's an icon of 10 almonds.

The Emperor’s New Klotho, Or Something More?

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Unzipping The Genes Of Aging?

Klotho is an enzyme encoded in humans’ genes—specifically, in the KL gene.

It’s found throughout all living parts of the human body (and can even circulate about in its hormonal form, or come to rest in its membranaceous form), and its subgroups are especially found:

  • α-klotho: in the brain
  • β-klotho: in the liver
  • γ-klotho: in the kidneys

Great! Why do we care?

Klotho, its varieties and variants, its presence or absence, are very important in aging.

Almost every biological manifestation of aging in humans has some klotho-related indicator; usually the decrease or mutation of some kind of klotho.

Which way around the cause and effect go has been the subject of much debate and research: do we get old because we don’t have enough klotho, or do we make less klotho because we’re getting old?

Of course, everything has to be tested per variant and per system, so that can take a while (punctuated by research scientists begging for more grants to do the next one). Given that it’s about aging, testing in humans would take an incredibly long while, so most studies so far have been rodent studies.

The general gist of the results of rodent studies is “reduced klotho hastens aging; increased klotho slows it”.

(this can be known by artificially increasing or decreasing the level of klotho expression, again something easier in mice as it is harder to arrange transgenic humans for the studies)

Here’s one example of many, of that vast set of rodent studies:

Suppression of Aging in Mice by the Hormone Klotho

Relevance for Alzheimer’s, and a science-based advice

A few years ago (2020), an Alzheimer’s study was undertaken; they noted that the famous apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor for Alzheimer’s, and that klotho may be another. FGF21 (secreted by the liver, mostly during fasting) binds to its own receptor (FGFR1) and its co-receptor β-klotho. Since this is a known neuroprotective factor, they wondered whether klotho itself may interact with β-amyloid (Aβ), and found:

❝Aβ can enhance the ability of klotho to draw FGF21 to regions of incipient neurodegeneration in AD❞

~ Dr. Lehrer & Dr. Rheinstein

In other words: β-amyloid, the substance whose accumulation is associated with neurodegeneration in Alzheimer’s disease, is a mediator in klotho bringing a known neuroprotective factor, FGF21, to the areas of neurodegeneration

In fewer words: klotho calls the firefighters to the scene of the fire

Read more: Alignment of Alzheimer’s disease amyloid β-peptide and klotho

The advice based on this? Consider practicing intermittent fasting, if that is viable for you, as it will give your liver more FGF21-secreting time, and the more FGF21, the more firefighters arrive when klotho sounds the alarm.

See also: Intermittent Fasting: What’s the truth?

…and while you’re at it:

Does intermittent fasting have benefits for our brain?

A more recent (2023) study with a slightly different (but connected) purpose, found results consistent with this:

Longevity factor klotho enhances cognition in aged nonhuman primates

…and, for that matter this (2023) study that found:

Associations between klotho and telomere biology in high stress caregivers

…which looks promising, but we’d like to see it repeated with a sounder method (they sorted caregiving into “high-stress” and “low-stress” depending on whether a child was diagnosed with ASD or not, which is by no means a reliable way of sorting this). They did ask for reported subjective stress levels, but to be more objective, we’d like to see clinical markers of stress (e.g. cortisol levels, blood pressure, heart rate changes, etc).

A very recent (April 2024) study found that it has implications for more aspects of aging—and this time, in humans (but using a population-based cohort study, rather than lab conditions):

The prognostic value of serum α-klotho in age-related diseases among the US population: A prospective population-based cohort study

Can I get it as a supplement?

Not with today’s technology and today’s paucity of clinical trials, you can’t. Maybe in the future!

However… The presence of senescent (old, badly copied, stumbling and staggering onwards when they should have been killed and eaten and recycled already) cells actively reduces klotho levels, which means that taking supplements that are senolytic (i.e., that kill those senescent cells) can increase serum klotho levels:

Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans

Ok, what can I take for that?

We wrote about a senolytic supplement that you might enjoy, recently:

Fisetin: The Anti-Aging Assassin

Want to know more?

If you have the time, Dr. Peter Attia interviews Dr. Dena Dubal (researcher in several of the above studies) here:

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