This article was first published in 听
While I am not religious, I do enjoy Jewish traditions such as reciting the blessing 鈥渕otzi lechem min Haaretz鈥� before slicing into a challah on a Friday night. I usually don鈥檛 have any specific thoughts in mind while doing this, but I suspect that will not be the case next time. I doubt that I will be able to avoid thinking about 鈥淢OTS-c鈥� (pronounced 鈥渕otzi鈥�), a peptide discovered and named by University of Southern California gerontologist Pinchas Cohen as a nod to his heritage.听
Cohen coined the term 鈥淢itochondrial Open reading frame of the Twelve S RNA type-c鈥� for the peptide so that it would give rise to the clever acronym MOTS-c. Of course, it is beyond our scope here to explain the scientific name, but we can delve into the importance of the peptide鈥檚 discovery, which may turn out to be a springboard for developing drugs with a potential effect on aging and longevity.
Back in 2001, professor Ikuo Nishimoto at Tokyo鈥檚 Keio University made the intriguing observation that not all parts of the brain are damaged to the same extent during the progression of Alzheimer鈥檚 disease. The hippocampus, the small seahorse shaped structure located deep within the brain where memories are consolidated, is damaged to a much greater extent than the occipital lobe at the back of the brain that is responsible for visual processing.听
Nishimoto reasoned that that the occipital lobe must be producing some sort of protective factor that allows it to withstand the accumulation of beta-amyloid proteins that are the hallmark of Alzheimer鈥檚 disease. He went on to examine tissue samples extracted post-mortem from the occipital lobe of an Alzheimer鈥檚 patient from which he eventually isolated a novel peptide.
Peptides are molecules composed of chains of amino acids that are produced extensively in the body and help regulate key processes such as metabolism, immune function and tissue repair. The peptide Nishimoto discovered contained 24 amino acids and was amenable to laboratory synthesis. When added to a culture of healthy nerve cells in a Petri dish, it totally prevented their death upon exposure to toxic beta-amyloid proteins. Nishimoto coined the term 鈥渉umanin鈥� for the peptide, hoping the molecule would eventually be used to restore and preserve the 鈥渉umanity鈥� of patients suffering from the cognitive erosion of Alzheimer鈥檚 disease.
Peptides are produced on instructions from DNA 鈥� but in this case the responsible DNA was not found in the cell鈥檚 nucleus, but rather in the mitochondria, the small structures inside a cell where glucose is 鈥渂urned鈥� to produce energy. This was surprising because it had been believed that mitochondrial DNA only coded for proteins and peptides that were involved in energy production.
It was at this point that Cohen picked up the torch. He had also isolated humanin and discovered that it wasn鈥檛 only found in specific brain cells but was produced in the mitochondria of all cells and released into the circulatory system. This totally flipped the understanding of mitochondria. Clearly, the function of these cellular organelles was not limited to energy production; mitochondria could now be seen as endocrine organs that release peptides with the mission of triggering various actions in the rest of the body.听
Cohen鈥檚 group found that in animal studies humanin reduced arterial plaque, improved insulin sensitivity, enhanced muscle strength and curbed inflammation. Furthermore, another surprise was that these peptides were produced on instructions from what had been assumed to be 鈥渏unk DNA,鈥� large segments of the long DNA molecules that were believed to contain no genes and were therefore useless.
Humanin seemed interesting enough for Cohen to consider developing it as a drug, but the molecule turned out to be so unstable that when administered to people it broke down within minutes. There were also some concerns that since humanin prevents cells from dying, it may also help cancer cells survive and spread.听
That prompted Cohen to give up on humanin and express concern about it still being sold illegally online 鈥� aimed at 鈥渂iohackers鈥� who mistakenly believe that injecting humanin reduces the risk of cognitive impairment. However, whatever they are buying is not likely to be humanin, since the molecule is notoriously unstable.
While Cohen passed on humanin, he did not give up on further exploration of what had been presumed to be junk mitochondrial DNA. Might this 鈥渏unk鈥� not code for other peptides that have biological activity?听
His group began to systematically scan the mitochondrial genome for sequences similar to humanin and turned up a number of peptides with potential physiological activity, with the most interesting one being MOTS-c, a 16 amino acid peptide discovered in 2015. Unlike humanin, it did not prevent cells from dying, so there was no concern about carcinogenicity.
Instead of actively growing, dividing and expending energy, when exposed to the MOTS-c peptide, cells enter a 鈥渟urvival mode鈥� as if they were responding to fasting or intense exercise. Non-essential, energy-intensive processes are shut down and focus is on cellular repair and maintenance. When Cohen injected MOTS-c into mice fed a high-fat diet, the animals gained no weight and showed no accumulation of fat in the liver.听
Even more interesting was the observation that mice treated with MOTS-c were able to run longer on a treadmill and lived longer. Could MOTS-c injections also benefit humans? Thinking this was a possibility, Cohen founded a company but needed evidence before applying to market MOTS-c as a drug.
In a small trial, 20 overweight subjects were injected daily with the peptide for 30 days. Disappointingly they showed no weight loss, but their blood sugar and liver enzymes did decrease, presenting some optimism. However, it was at this point that semaglutide (Ozempic), another peptide, burst on the scene. It required only a weekly, not daily, injection 鈥� and that sounded the death knell for Cohen鈥檚 company. But not for the internet hype extolling the benefits of MOTS-c based on his published mouse study! The banning of the peptide by the World-Anti-Doping Agency claiming that it is an 鈥渆xercise mimetic鈥� and that it increases endurance and fat burning further boosted the demand for MOTS-c. Health Canada and FDA remain unconvinced of benefits and have not approved the peptide for commercial human use.
Cohen鈥檚 group has identified a number of peptides, which have been anointed with scientific names that give rise to Yiddish-sounding acronyms such as SHMOOSE, MENTSH, SCHLEP and most famously MOTS-c.听He believes some of these, or their synthetic analogues, may eventually prove to be of use in the quest for improved health and longevity 鈥� but he cautions that the celebrity wellness gurus, biohackers and alternative medicine physicians who have been known to recommend them as a staple in their 鈥渓ongevity stacks鈥� have way too much chutzpah.
