Klotho now turns up in supplement ads, longevity panels and podcast episodes faster than anyone has managed to explain what it actually does.
That is why I wanted Dr. Joe Cleaver back for the January webinar in the series. About eleven minutes in, he stopped and said that in twenty-five years of speaking, he had never told a room this: the DNA that fails first in an aging stem cell may not be the DNA the field has been watching. From there, he walked through the role of mitochondrial DNA and alpha-Klotho, the Klotho range he tracks in his own patients, and what he says actually moves it.
Cleaver is board certified in internal medicine and did his training in rheumatology and immunology at the University of Miami Jackson Memorial. He has spent fifteen years in clinical practice with stem cells, secretomes and exosomes, and the last ten on Klotho specifically, work that led to The Anti-Aging Power of Klotho a couple of years ago and a fourth book, The Klotho Effect, that he is finishing now with a gene therapy physician.
Why mitochondrial DNA fails first in aging stem cells
The usual account of stem cell aging starts with double-stranded breaks in nuclear DNA, followed by senescence and then failure. Cleaver argues that mitochondrial DNA gives out well before any of that and is where the sequence actually begins. It sits next to the source of the oxidative stress, it has nothing like the repair capacity of the DNA in the nucleus, and once it is damaged, the mitochondria leak more oxidative stress and damage it further, which is the loop he wants clinicians to interrupt.
The fragments the damaged mitochondria release are what he calls DAMPs, damage-associated molecular patterns, and the immune system reads them as inflammatory, which is what kicks off the nuclear damage everyone was watching for in the first place. His conclusion is that the place to intervene moves accordingly, because the work is not reversing senescence after the fact but keeping mitochondrial DNA intact for long enough that the cascade never starts.
What alpha-Klotho does for stem cell mitochondria
Klotho was identified in 1997 by Makoto Kuro-o and colleagues, who traced an aging-like syndrome in a line of transgenic mice to the disruption of a single gene. Disrupting it produced a syndrome resembling human aging, including a shortened lifespan, arteriosclerosis and osteoporosis [1]. It codes for a protein of roughly 1,012 amino acids, produced mainly in the distal nephron of the kidney and the choroid plexus of the brain, and the circulating soluble form is the one Cleaver tracks in his patients.
He described it as a master upstream regulator of mitochondrial resilience in stem cells, and the diagram he has built for it puts Klotho in the middle, pushing on SIRT1, AMPK, PGC-1 alpha and PINK1, with oxidative stress falling and mitochondrial biogenesis rising on the other side of it. The published work runs in the same direction. Sahu and colleagues, writing in Nature Communications in 2018, showed that age-related declines in alpha-Klotho drive mitochondrial dysfunction in muscle progenitor cells and impair regeneration, and that in mice carrying a single working copy of the gene, restoring mitochondrial ultrastructure with the peptide SS-31 brought DNA damage and cellular energetics back to wild-type levels [2]. That work is in animals, and the human evidence is still observational.
That is where the peptides came in. Cleaver said SS-31 tracks closely with Klotho in the literature, and he walked through three he described as acting on the mitochondria directly, SS-31, MOTS-c and humanin, explaining where each one sits in the sequence. He built a single comparison slide for them.
The Klotho range he works with
Cleaver tracks Klotho in his own patients, and he was specific about the range and about how unsettled the top of it still is.
He looks for a floor around 600 pg/mL and a working band up to roughly 1,200. Below about 700, he pointed to increased all-cause mortality in the NHANES cohort [3] and similar findings in InCHIANTI, where plasma klotho measured in 804 adults aged 65 and over was an independent predictor of all-cause mortality [4]. The ceiling is the part nobody has settled. What used to be quoted as 2,200 has come down to around 1,700, and he was direct that it is a moving target because very high readings turn up in patient groups where nobody yet understands why. The NHANES analysis supports caution at the top, reporting a U-shaped curve in which both the lowest and the highest readings carried raised risk, with the highest group starting at about 1,030 pg/mL [3].
He was equally direct about the measurement problem. As he described it, one laboratory currently runs the assay for clinical use, and it has only done so for about five years, after he went to them and argued that Klotho needed to be measured in humans at all.
What raises and lowers Klotho
Most of what lowers it is unglamorous, and his list runs through sedentary living, muscle loss, obesity, excess alcohol, vitamin D deficiency and declining kidney function. He singled out grip strength adjusted for age as one of the best predictors of a low reading that a physician can measure in their own office. The same InCHIANTI cohort supports him on it, with grip strength positively associated with plasma klotho below a threshold of 681 pg/mL [5], which sits close to the floor he works from.
Stress is the one he pushed hardest. In his account, Klotho responds sharply to cortisol and can fall a long way, and he showed one caregiver’s levels falling through a long stretch of looking after her mother. He called stress one of the most important things any of us can change to move the number.
Which is where he ended. It is worth keeping the order he put it in. The purest form of medicine, in his words, is lifestyle and prevention, and if those two are not addressed, a longevity program does not make much headway regardless of what else is in it. In his view, exercise does more for lifespan and healthspan than anything he or any other longevity physician can prescribe, and the figure he still uses is around 150 minutes a week of moderate cardiovascular work. He described Klotho as an exerkine, raised by exactly that kind of exercise. Which means the cheapest intervention on his list is also the one he rates highest, and it is the one nobody sells.
Watch the full session
The hour has what is not written up here, including the slide comparing SS-31, MOTS-c and humanin that he told the room to put on the wall, and the plasma membrane work that sits underneath all of it. It also has the question the audience put to him at the end, which was simply what turns Klotho off. Recorded January 2026.
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The series is how we keep working through this between editions. The next time the room is in one place is the Winter Edition at the Omni Fort Lauderdale. The Regenerative Clinical Cadaver Lab runs Thursday, February 4, 2027, with limited seats, followed by two days of lectures on February 5 and 6, all CME-accredited. Registration is open:
Register for the Winter Edition
References
- Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390(6655):45-51. doi:10.1038/36285
- Sahu A, Mamiya H, Shinde SN, et al. Age-related declines in alpha-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nature Communications. 2018;9:4859. doi:10.1038/s41467-018-07253-3
- Wei K, Chen Q. U-shaped association of alpha-klotho with all and cause-specific mortality in US adults: a second analysis of NHANES. Innovation in Aging. 2023;7(Suppl 1):866. doi:10.1093/geroni/igad104.2789. Conference abstract.
- Semba RD, Cappola AR, Sun K, et al. Plasma klotho and mortality risk in older community-dwelling adults. The Journals of Gerontology Series A. 2011;66(7):794-800.
- Semba RD, Cappola AR, Sun K, et al. Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study. European Journal of Applied Physiology. 2012;112(4):1215-1220. doi:10.1007/s00421-011-2072-3
