Last March, I wrote a column entitled Reality Check, featuring the work of Stephen Spindler. Spindler is a veteran researcher at UCRiverside, and perhaps the world’s foremost expert in the design and execution of longevity studies in mice. But Steve is a glass-half-empty kind of guy. And ever since I wrote that column, I’ve been thinking that I need to write about Spindler’s opposite number in Russia: Vladimir Anisimov is a veteran gerontologist at the Petrov Institute in St Petersburg, who has also been testing longevity potions on mice through a long career. Anisimov is a glass-half-full kind of guy. His best contribution to anti-aging medicine may be epithalamin, a treatment that has been hiding in plain sight for over thirty years.
An innovator with a deep knowledge of biochemistry, Anisimov has published theoretical as well as practical science. His lab has tested biochemical ideas about aging, as well as doing many studies on genetics and longevity in rodents and flies. He has reported and summarized results of other Russian labs in English-language journals.
Some of Anisimov’s findings are well-known to me, and therefore to followers of this blog and of my Aging Advice web site. Metformin reduces mortality and slashes cancer risk in people who take it as a medication for diabetes. Metformin increases life span of ordinary non-diabetic mice. Anisimov thinks it will do the same for non-diabetic humans, and I agree it’s a good bet. Melatonin, the hormone that regulates our daily cycle, is also found to prolong life span in mice. Melatonin in the blood is very sensitive to light exposure, and melatonin disappears with the dawn’s early light Anisimov found that sleeping in total darkness is better for longevity than exposure to light during the night. Here are two reviews by Anisimov of mostly Russian work on life extension with melatonin [2003, 2006].
(Unrelated to melatonin and to Anisimov: A recent study also suggests sleeping in the cold helps preserve insulin sensitivity.)
Another of Anisimov’s lines of research is less well-known to me, and I report here my first impressions. He has worked with “short peptides”, strings of less than 10 amino acids, that can act as signals or switches that control body chemistry globally. Short peptides are small enough to pass easily through the skin or through the blood-brain barrier. Unlike full-size proteins, short peptides tend to resist dismemberment by stomach enzymes. Carnosine and carnitine are familiar examples of di-peptides, consisting of 2 amino acids.
Here’s the theory: We know that gene expression is quite different in old and young people. In the literature, you find various interpretations and explanations why this might be true. But my interpretation is clear and simple: The body times its life cycle using gene expression. When we’re young, we express genes that make us grow. When we’re middle-aged, we express genes that keep us healthy. When we’re old, we express genes that destroy us.
“Gene expression” is the translation of DNA into proteins. Proteins are the signals and the workhorses of body chemistry. The translation is well understood since Francis Crick discovered the Genetic Code in the 1960s. But the language for determining which gene gets expressed when is apparently much more complicated, and it is just beginning to be decoded in the 21st Century. This is the science of epigenetics.
Among the signals that can locate a particular stretch of DNA, and turn it ON or OFF are short stretches of RNA called pi-RNAs, methyl transferases and histone de-acetylases. (I’m sorry to throw biochem jargon at you, but I’m excited to have just barely begun to educate myself about the fundamentals of epigenetics with a Coursera course this spring.) But the point is that these short peptides that Anisimov has been studying for 20 years work also as gene promoters and repressors – epigenetic signals that are more specific than the methyl transferases and less specific than pi-RNAs. Apparently they can affect whole categories of genes [ref].
Here’s a paper in which Anisimov summarizes 35 years’ experience with animal experiments, and some tantalizing human results as well. (One of the differences in Russian bio-medicine, for better and for worse, is that regulations about experiments on humans are more relaxed than in the US.) Here’s a table summarizing results in mice and rats. (As usual, life extension in flies is more dramatic, but less indicative of human benefits.) As you can see, this is a science that goes back to the 1970s, when the top two preparations were purified from epithalamus and thymus glands.
The thymus is a gland in the upper chest that trains the immune cells in our blood to attack invading cells, but to lay off our own body’s cells. As we get older, the thymus shrinks, and I believe this to be a basic cause of aging immune function, auto-immune disease, and increased susceptibility to infection. Thymalin was found to stimulate thymus re-growth and to rejuvenate immune function.
Epithalamin is also called epitalon or epithalon, and was discovered in extacts from a region of the brain called the epithalamus. This region contains the pineal gland, or “third eye”, which controls wake/sleep cycles and is the body’s source of melatonin. Like thymalin, epithalamin is a string of four amino acids. Thymalin generated excitement in the 1980s, until epithalamin stole its thunder. Not only did it extend life more consistently, but its effect on thymic growth was found to be superior to thymalin.
In the table, epithalamin has been the best-studied short peptide, and it has the best record for life extension in rodents. In a separate table, the same paper shows that epithalamin and thymalin suppress cancer in rodents. There is also evidence of large reductions in mortality when epithalamin was given to older human subjects:
In addition, it has recenty been reported (2003, 2004) that epithalamin is a telomerase activator. Skeptics (Spindler in particular) point out that caloric restriction is such a strong influence on life span that many treatments will appear to show benefit only because they affect appetite. Some of the studies do measure food intake, and find that epithalamin is able to increase lifespan without decreasing food consumption.
(Epitalon is available commercially, but not from most supplement sources. Recommended dosage is usually less than 10mg, but experience with different dosages is very limited.)
Reference: a crash course in mid-brain anatomy
Here’s a picture of the human brain, courtesy of Wikipedia. The mid-brain is the endocrine function, where computations made with neurons are translated into prescriptions for internal secretion.
The epithalamus is shown in cherry. It includes the pineal gland, the so-called “third eye” which is responsible for the body’s light-sensitive clock, and where melatonin comes from. The hypothalamus is shown in lime. It includes various “nuclei”, notably the suprachiasmatic nucleus, which is the closest thing science has found to a developmental clock. The pituitary is also part of the hypothalamus, and secretes hormones involved in the life cycle and the menstrual cycle: HGH, LH, FSH, TSH and sex hormones.
All of this looks so promising that I wonder why there hasn’t been more follow-up, and why American researchers haven’t built on the Russian results. Russian science tends to be more adventurous than American science. That doesn’t mean they make more mistakes. The problem with American science is that it is too rigidly institutionalized and controlled within an establishment. It is usually not possible to get funding to ask a question to which you do not already know the answer. So the mistakes of American science are more likely to be under the header “confirmation bias”, while Russian science is more likely to be offering results that may not pan out. This seems to be a well-established field, with positive results that have been affirmed over decades in different labs with flies, rodents, and humans. My web search identified no dangers or reports of toxicity. I’d say it’s high time the American and European gerontology communities picked up this thread. In the mean time, please comment if you have any experience with epitalon or other short peptides.
Very interesting – more so if we know how it works. Thymic involution is one way in which the immune system is made incompetent with age – another is the proclivity of hematopoietic stem cells (blood-cell forming) to differentiate mostly to myleloid lineage cells (which produce the red blood cells, white blood cells and platelets- except for lymphocytes which are lymphoid lineage cells, both b and t -lymphocytes), disturbing the normal balance lymphoid to myeloid cells. So the thymus normally ‘trains’ t-lymphocytes (they aren’t functional without such training), but without enough lymphocytes to bring to maturity it’s not that important that the thymus involutes – there aren’t enough trainees to worry about. It’s already been learned that factors carried in the blood are responsible for the change in HSC potency.
I remember some experiments where they gave mice I think..melatonin and zinc…and they had no thymic involution
Curr Aging Sci. 2013 Feb;6(1):99-107.
Is there a possible single mediator in modulating neuroendocrine-thymus interaction in ageing?
Mocchegiani E1, Malavolta M, Costarelli L, Giacconi R, Piacenza F, Lattanzio F, Basso A.
The restoration of the thymic functions and the thymic re-growth may be achieved in old mice by some endocrinological (melatonin) or nutritional interventions (arginine or zinc), suggesting that the thymic involution in old age is a phenomenon secondary to age-related alterations occurring in neuroendocrine-thymus interactions. The targets for the thymic restoration may be hormone receptors and cytokines, strictly related to the presence of two nutritional factors, such as arginine and zinc, which are in turn essential for the efficiency of neuroendocrine-immune network both in ontogeny and ageing. The effect of melatonin is largely due to the presence of its specific receptors on cell membrane of thymocytes and Thymic Epithelial Cells (TECs). TECs synthesize thymulin peptide that is required for T-cell differentiation and maturation within the thymus gland. In this context, the role of zinc is pivotal because it is involved, through “zinc finger motifs”, in the gene expression of melatonin receptors, in cell proliferation, apoptosis and thymulin reactivation. Zinc is also required for the biological action of arginine, via Nitric Oxide pathway. Therefore, the beneficial effect of melatonin or arginine on neuroendocrine-thymus interaction in ageing can also occur via a better zinc pool redistribution within the body where the capability of the zinc-binding proteins Metallothioneins (MT) in zinc release has a key role. These findings suggest that zinc, via MT buffering, can be a single mediator in modulating neuroendocrine-thymus interaction in ageing.
PMID: 23895527 [PubMed – indexed for MEDLINE]
This study shows that the Thymus can be regenerated with Tamoxifen. In male rats anyway
Is there an effective/active oral form of epithalamin or does it only come in vials for injection?
I think it’s a question of absorption. You can hold it under your tongue and get a little bioavailability or you can inject it and get more, and the stuff is so expensive that most people inject it.
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What is chemical structure Epithalamin? I can not find any publication on bio-assay guided isolation, purification and elucidation of the structure of this peptide. How identity of synthetic and natural peptides was demonstrated?
chemical structure Epithalamin is new to me and I’ve found it interesting to learn. I have heard before about claims that sleeping in the cold preserves insulin. Is there any further proof of that? I read about it here https://hi-peptide.com/
NL-Epithalon as a arginine salt – how does it compare to orginal infusion epithalon form?