Humanin

What humanin is and where the name comes from

In 2001, a Japanese research group examined brain tissue from a person with Alzheimer’s disease. Not the destroyed regions, but a region that had been spared, the occipital lobe. The question: why did this part survive? What they found there was a tiny protein of 24 amino acids that protected nerve cells from dying. It was given the name humanin.

What is special is where it comes from. Almost all of our proteins are encoded in the cell nucleus; humanin is not. Its blueprint lies in the DNA of the mitochondria, more precisely in a tiny reading frame within the gene for 16S ribosomal RNA. This showed that mitochondria are not only power plants but also transmitters. This peptide family is therefore called mitochondrially encoded peptides, and humanin, together with MOTS-c, is among the best known.

Four observations that fit together

In humans and in comparisons across species, there is a series of findings that form a very coherent picture. First, the humanin level in the blood falls with age, in humans as in mice. Second, in a small study with 18 versus 19 people, children of centenarians had markedly higher levels than comparison subjects of the same age; a larger Italian cohort with 102 versus 92 people, by contrast, found no difference and, in healthy people, even an increase in the level with age. Third, the level in the cerebrospinal fluid is lower in people with Alzheimer’s disease than in controls, and likewise in a mitochondrial disorder called MELAS.

Fourth, the species comparison: in the roundworm, mouse, rhesus monkey and human, humanin falls with age; in the naked mole-rat it does not. It stays stable. The naked mole-rat is the standard example of negligible senescence; it lives absurdly long for a rodent and shows hardly any age-dependent rise in mortality. Of all animals, it is the one in which the humanin level stays constant.

Why this is still not proof

All four findings have one thing in common: they are correlations. None of them says which way the arrow points. Children of centenarians have much more in common than their humanin level: a different genome, different mitochondria, often different habits. Humanin could be the cause of their robustness. It could just as well be the indicator.

The difference matters. If healthy mitochondria release more humanin, then a high level is simply the signal that the power plants are in order. Injecting humanin would then be about as effective as turning up the fuel gauge.

The test in worm and mouse

This question can be tested, and it has been tested. In the roundworm, a permanent genetic overproduction of humanin led to a small but significant extension of lifespan. The effect depended on a specific gene, daf-16, the worm counterpart of FOXO, that is, on the insulin signaling pathway through which caloric restriction and rapamycin also act. A finding that is mechanistically well classified, but in a worm and with lifelong genetic overproduction.

In mice there are two experiments. Mice that genetically produce more humanin permanently are smaller and lighter than normal mice and better protected against toxins. The second experiment comes closest to what people actually do: middle-aged mice were given a humanin analogue, injected twice a week. Metabolic values improved, with less abdominal fat and more lean mass. Exactly what every advertisement would say. Lifespan remained unchanged.

The half-life problem

The authors themselves explain this with the half-life. Humanin has a half-life in the blood of about 30 minutes. Something of which half has already been broken down after half an hour is injected twice a week. The research group writes that an optimized dosing regimen might perhaps lead to an extension after all. That is fair self-criticism, especially since the finding comes from the same group that researches humanin and could have left it out.

At the same time, it is the argument against any self-experiment. If a research group with laboratory animals, a controlled dose and analytics has not solved the dosing problem, nobody will solve it with a vial from the internet.

What the studies show

Overproduction in the roundworm

Worms that permanently produce humanin in excess live somewhat longer; the difference is small but significant. The effect depends on daf-16, the worm counterpart of FOXO, and thus on the same signaling pathway through which caloric restriction and rapamycin also act. This is only transferable to a limited extent, because the overproduction was genetic and lifelong.

Humanin analogue in middle-aged mice

The experiment that comes closest to an application: injected twice a week, in middle-aged mice. Metabolic values improved, abdominal fat decreased and lean mass increased. Lifespan remained unchanged. The authors attribute this to the half-life of about 30 minutes and note that an optimized dosing regimen might perhaps lead to an extension after all.

Species comparison with the naked mole-rat

In the roundworm, mouse, rhesus monkey and human, the humanin level falls with age. In the naked mole-rat, the standard example of negligible senescence, it stays constant. A nice finding, but an observation, not an intervention.

What is missing in humans

There is no human study on humanin. Not a few: none. The current review of this peptide family names exactly one substance that has made it into clinical testing at all, and that is not humanin but a MOTS-c analogue that was studied in fatty liver inflammation and obesity. For humanin there is not even phase 1.

Status, approval and legal

Humanin is not approved anywhere and is not in any clinical trial. Humanin and an analogue of it are sold as injectable products, exclusively via the gray market: no pharmacopoeia, no purity standard, no manufacturer who is liable. Anyone who buys it anyway can at least check the laboratory report for the batch. However, that only says that what is on the label is in the vial, and nothing about whether it works.

Safety

There are no safety data in humans, and that is a statement about the state of knowledge. Without human studies, there are no side effect statistics either. From animal experiments comes a warning signal: in a mouse model of an aggressive, triple-negative breast cancer, administered humanin accelerated tumor growth and weakened the effect of chemotherapy; the authors explicitly advise caution with therapeutic administration. If nobody looks, nobody finds anything, and exactly that is regularly sold as well tolerated. On top of that come the risks of the source, because a gray-market product guarantees neither purity nor identity. For a substance without a single human study, the rule is: nobody can say what it will do in you.

Sources

• Hashimoto et al., Proc Natl Acad Sci U S A 2001 (discovery of humanin in a brain region spared by Alzheimer’s disease)
• Yen et al., Aging (Albany NY) 2020 (humanin levels in old age, in children of centenarians and in Alzheimer’s disease)
• Yen et al., Aging (Albany NY) 2020 (species comparison of humanin levels including the naked mole-rat)
• Yen et al., Aging (Albany NY) 2020 (humanin overproduction in the roundworm, dependence on daf-16)
• Yen et al., Aging (Albany NY) 2020 (humanin analogue in middle-aged mice, metabolism and lifespan)
• Review of mitochondrially encoded peptides with a MOTS-c analogue in clinical testing
• Conte et al., GeroScience 2021 (humanin levels in children of centenarians and in healthy aging)
• Moreno Ayala et al., Sci Rep 2020 (humanin in a mouse model of triple-negative breast cancer)
• Gidlund et al., Physiol Rep 2016 (humanin in muscle after strength training)
• Woodhead et al., J Appl Physiol 2020 (humanin after high-intensity interval training)