What Is Epithalon?

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Epithalon is a short peptide consisting of just four amino acids (Alanine-Glutamate-Asparagine-Glycine). In animal studies, epithalon has been shown to affect melatonin secretion as well as telomerase activity. The molecule is sometimes referred to as epithalone, epitalon, LS-72251, and CID2192042. Epithalon was developed in Russia (isolated from the bovine (cow) pineal gland) and has received attention for its anti-aging and anti-carcinogenic properties as well as for its ability to regulate melatonin secretion.


The Anti-Cancer Effects of Epithalon


A 2002 study on transgenic mice prone to cancer produced surprising results. Epithalon prolonged the average lifetime of the cancer-prone her2/neu mice by 13.5% when administered subcutaneously 5 times per week. The molecule appeared to suppress the development of cancer and reduce metastasis (spread) of existing cancers. Overall, cancer rates in mice that were provided epithalon were 3.7 times lower than in mice who did not receive the peptide. The mice that did develop cancer lived 1.7 times longer if they received epithalon compared to mice that did not. Epithalon also extended the life of mice without cancer substantially1 .


The Anti-Aging Effects of Epithalon


The anti-aging effects of epithalon appear to be a result of its ability to activate telomerase. Telomerase is an enzyme, found in all cells, that maintains the length of telomeres. Telomeres are specialized sequences of the DNA that protect chromosomes from damage, but shorten over time as an organism ages. Maintenance of telomere length has been associated with longevity, disease-free survival, and a reduction in the physical manifestations of aging.


Two studies in birds, published in 2012 and 2013, found that epithalon can impact thymus health and function. The thymus is a gland that functions in the development of T-lymphocytes (T-cells). By improving thymus function, epithalon improves lymphocyte function and boosts T-cell proliferation. The result is increased levels of interferon gamma, a molecule important in immune fucntion2,3 .


Epithalon and Melatonin


Catecholamines, like norepinephrine and dopamine, are critical in regulating the hypothalamus, a small region of the brain responsible for much of the hormone secretion in mammalian and avian organisms. The pineal gland, found in another region of the brain, is responsible for melatonin release, which regulates the normal day/night cycle of most living things. Inappropriate melatonin release leads to fluctuations in catecholamine release, which in turn affects the hypothalamus.


A 2012 study found that epithalon is capable of influencing melatonin release and can diurnal rhythms in female rats. Epithalon proved to be more effective than melatonin supplementation in correcting experimentally induced disturbances in circadian rhythm, thereby lessening impact on normal reproductive function and even reducing the risk of premature aging in female rats4 .


What Is Epithalon, Really?


Epithalon is a small peptide consisting of just four amino acids. It was developed from isolates of bovine pineal gland extract. It has shown promise as a potential anti-cancer agent. It is also being investigated as a means of controlling circadian rhythm disturbances and as a potential anti-aging treatment.


A Note on Naming


While epithalon is sometimes referred to as AGAG because of its amino acid sequence, such an abbreviation violates scientific convention and is incorrect. The appropriate shorthand for epithalon is AERG. The abbreviation AGAG would refer to a peptide with the sequence Alanine-Glycine-Alanine-Glycine rather than to epithalon, which is Alanine-Glutamate-Asparagine-Glycine.




  1. Anisimov, V. N., Khavinson, V. K., Alimova, I. N., Semchenko, A. V. & Yashin, A. I. Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice. Bull. Exp. Biol. Med.134, 187-190 (2002).


  1. Pateyk, A. V., Baranchugova, L. M., Rusaeva, N. S., Obydenko, V. I. & Kuznik, B. I. Effect of peptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly on the morphology of the thymus in hypophysectomized young and old birds. Bull. Exp. Biol. Med.154, 681-685 (2013).


  1. Lin’kova, N. S., Kuznik, B. I. & Khavinson, V. K. [Peptide Ala-Glu-Asp-Gly and interferon gamma: their role in immune response during aging]. Adv. Gerontol. Uspekhi Gerontol. Ross. Akad. Nauk Gerontol. Obshchestvo25, 478-482 (2012).


  1. Arutjunyan, A. et al. Melatonin and pineal gland peptides are able to correct the impairment of reproductive cycles in rats. Curr. Aging Sci.5, 178-185 (2012).

The Biochemistry of TB-500 (Thymosin Beta-4)

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TB-500 is a synthetic analog of the active region of thymosin beta-4 (TB4). TB4 is a protein that is active in the sequestration of actin and thus plays a role in actin polymerization. Actin is a globular protein that, when polymerized, forms microfilaments. Microfilaments are fundamental components of cell structure and make up a number of different proteins. These filaments play active roles in cell growth, cell division, cell proliferation, muscle function, and cell longevity.

The Genetics of TB4

TB4 is an interesting protein because the gene that encodes it is found in two variations. The main variation is found on the X chromosome, which is found in both males and females. A variant, known as thymosin beta-4 Y-chromosomal, is found on the male-specific region of the Y chromosome and thus is only found in males. This means that males have an additional thymosin beta gene that is not found in females and which escapes X inactivation1. Though the significance of this additional TB4-like gene has not yet been elucidated, it does appear to play a role in the increased muscle growth seen in male as opposed to female mammals.

TB-500 and Sarcomere Function

The primary components of muscle sarcomeres, the proteins responsible for muscle contraction and thus strength, are actin and myosin. Myosin provides the active component of contraction while active provides the structural component against which myosin acts. Sarcomeres are found primarily in skeletal and cardiac (heart) muscle. Actin is found in smooth muscle, but in a less organized form not associated with sarcomeres.

The most basic role of TB4 is in maintaining a pool of monomeric actin within cells2. This suggests that TB4 is like a storage system for actin. It ensures that actin monomers, the smallest units of actin, are available within cells that will eventually need them to construct larger actin polymers. This, however, is not the only known role of TB4.

During development of myocytes (muscle cells), a particular type of actin known as gamma-actin, plays an important role in the organization and assembly of sarcomeres. In other words, gamma-actin is necessary for sarcomeres to form and develop properly. Gamma-actin is encoded by the ACTG1 gene, a gene that TB4 interacts with. By activating ACTG1, TB4 sets off a chain reaction that helps to ensure proper gamma-actin production and thus proper sarcomere development.

TB4 is also associated with activation of another actin gene known as ACTA1. This gene handles the production of alpha-actin, the primary component of microfilaments in sarcomeres. In sarcomere development, gamma-actin sets up the organization of a sarcomere and then is replaced over time by alpha-actin.

While the exact role of TB4 in actin development is unclear, research in mouse models has found that TB4 administration can reactivate cardiac progenitor cells and aid in the repair of damaged heart tissue3,4. Very recent studies have also suggested that TB4 may inhibit certain cell processes known to interfere with actin arrangement and lead to actin dysfunction5. It appears that TB4 may play roles in both promoting actin arrangement and in preventing other processes from interfering with actin. The end result is increased actin polymerization and thus sarcomere development in both cardiac and skeletal muscle cells.


1. Lahn, B. T. & Page, D. C. Functional Coherence of the Human Y Chromosome. Science278, 675-680 (1997).

2. Xue, B., Leyrat, C., Grimes, J. M. & Robinson, R. C. Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization. Proc. Natl. Acad. Sci. U. S. A.111, E4596-4605 (2014).

3. Smart, N. et al. De novo cardiomyocytes from within the activated adult heart after injury. Nature474, 640-644 (2011).

4. Rui, L. et al. Extending the time window of mammalian heart regeneration by thymosin beta 4. J. Cell. Mol. Med.18, 2417-2424 (2014).

5. Kim, S. & Kwon, J. Actin cytoskeletal rearrangement and dysfunction due to activation of the receptor for advanced glycation end products is inhibited by thymosin beta 4. J. Physiol.593, 1873-1886 (2015).

How Does Ipamorelin Affect Growth Hormone?

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Ipamorelin is a synthetic agonist of the ghrelin receptor and ghrelin is often referred to as the hunger hormone. Higher levels of ghrelin receptor activation lead to increased appetite, but they also lead to increased growth and changes in energy metabolism. How does ipamorelin create its effects?

Ipamorelin and Ghrelin

Ipamorelin is a five-amino-acid protein (Aib-His-D-2-Nal-D-Phe-Lys-NH2) derived from growth hormone releasing peptide-1 (another agonist of the ghrelin receptor). It was originally developed to aid in treatment of postoperative ileus (slow movement of food through the intestine after surgery), but has since been investigated as a potential growth hormone stimulant and for its beneficial effects on cardiovascular and cognitive function.

Ipamorelin can be thought of as a synthetic form of ghrelin. Ghrelin (lenomorlin) is a naturally occurring protein produced by specific cells in the gastrointestinal (GI) tract. Though produced in the GI tract, ghrelin activates receptors in the central nervous system to stimulate hunger and regulate the distribution and rate of use of energy throughout the body. When the stomach is empty, ghrelin is secreted, reaching its highest levels just before eating. The best way to think of ghrelin is as a preparatory hormone. It gets the body ready for food intake and part of that function is to increase release of growth hormone so that the body is prepared to make use of the energy that will be consumed in the form of food.

Ipamorelin and Growth Hormone

Ipamorelin causes growth hormone release, but unlike ghrelin it does not have a massive effect on hunger. In fact, ipamorelin is almost exclusively a growth-hormone secretagogue1 . Synthetic molecules like ipamorelin (e.g. pralmorelin, GHRP-6) have been developed in the past. Studies have shown them to have a diverse range of effects that include
. Increasing hunger,
. Increasing prolactin release,
. Increasing follicle-stimulating hormone levels,
. Increasing luteinizing hormone levels, and
. Increasing thyroid-stimulating hormone levels.

The problem with producing such diverse effects is that synthetic analogues of ghrelin can have a profound impact on sex hormones and secondary sex characteristics as well as deleterious effects on cortisol levels, cardiovascular health, and immune function. Because ipamorelin is so selective, it has none of the above side effects. In fact, it may improve cardiovascular function along with other physiologic parameters.

Ipamorelin and other growth hormone secretagogues do not act on the growth hormone secreting hormone receptor, which means they have a very distinct functional difference from growth hormone releasing hormone (GHRH) and its synthetic analogues (i.e. GRF (1-29), CJC-1295, etc.). This is important because it means that growth hormone secretagogues are synergistic with GHRH analogues. When taken together, the effect is a massive increase in growth hormone release2.

Ipamorelin also shows less response to standard growth hormone regulation. The effects of GHRH can be almost abolished by somatostatin, a natural inhibitor of growth hormone release, as well as by increased glucose levels, increased fatty acid levels, glucocorticoids, and increased levels of growth hormone itself. While there is a small effect of these substances on GH release secondary to ipamorelin, it orders of magnitude smaller than the inhibitory effect that they have on GHRH3.

Ipamorelin Administration

One of the interesting benefits of ipamorelin and other growth hormone secretagogues is that they easily cross both intestinal and blood-brain barriers. This means that these peptides can be administered orally, reducing the need for injections and the risks (primarily infection) associated with them4. Human and animal studies show that orally administered GHRP-6, which is similar to ipamorelin, causes growth hormone levels to start to rise after just fifteen minutes and leads to peak activity in just sixty minutes5. Investigations into intravenous, subcutaneous, oral, and intranasal administration of ipamorelin are ongoing.


1. Raun, K. et al. Ipamorelin, the first selective growth hormone secretagogue. Eur. J. Endocrinol. Eur. Fed. Endocr. Soc.139, 552-561 (1998).

2. Camanni, F., Ghigo, E. & Arvat, E. Growth hormone-releasing peptides and their analogs. Front. Neuroendocrinol.19, 47-72 (1998).

3. Ghigo, E., Arvat, E., Muccioli, G. & Camanni, F. Growth hormone-releasing peptides. Eur. J. Endocrinol. Eur. Fed. Endocr. Soc.136, 445-460 (1997).

4. Ghigo, E., Arvat, E. & Camanni, F. Orally active growth hormone secretagogues: state of the art and clinical perspectives. Ann. Med.30, 159-168 (1998).

5. Argente, J., García-Segura, L. M., Pozo, J. & Chowen, J. A. Growth hormone-releasing peptides: clinical and basic aspects. Horm. Res.46, 155-159 (1996).

The Effects of Epithalon

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Epithalon is a synthetic peptide that is just four amino acids long (Alanine-Glutamate-Asparagine-Glycine) and was originally isolated from cow pineal gland. Despite its small size, epithalon has been found to have some amazing effects. It is being widely tested for its anti-cancer, anti-aging, and sleep-regulating effects.

Epithalon as Cancer Therapy.

Studies suggest that even small doses of epithalon are effective in prolonging the lives of mice suffering from certain forms of cancer. It has also been found to suppress cancer formation in mice that are genetically prone to certain tumors. In particular, epithalon is being developed as a potential treatment for breast cancers that express the HER-2/neu gene mutation1. More recent research suggests that epithalon may also prevent the development of spontaneous tumors in the testicle as well as leukemias2,3.

Eipthalon as Fountain of Youth

Epithalon has been shown to activate the enzyme telomerase, which is responsible for maintaining the integrity of telomeres. Telomeres cap the ends of chromosomes and because chromosomes shorten each time they are replicated for cell division, eventually disappear. To prevent DNA damage from occurring, cells with telomeres that are too short are killed off. This process, known as apoptosis, occurs in most human and mammalian cells and is part of the reason that organisms age. Telomerase repairs telomeres and thus prevents apoptosis and its aging effects from occurring. By activating telomerase, epithalon can ward off at least some of the effects of aging such as loss of skin tone, loss of muscle mass, vision changes, etc.

Another way in which epithalon wards of aging is through stimulation of the immune system. In normal aging, the thymus, the gland responsible for T-cell production, losses function. Without new T-cells, the body has difficulty fighting off new infections, particularly infections that it has never encountered before. By protecting the thymus and boosting its function, epithalon helps the body to maintain a healthy immune system.

Epithalon as Sleep Aid

Epithalon can influence melatonin release in rats, thus affecting sleep quality, the rate of onset of sleep, and sleep duration. Epithalon is so effective in improving sleep that it produces better results than direct melatonin supplementation in tests on rats. By improving sleep, epithalon helps to improve hormone profiles and even fight off premature aging4.


1. Anisimov, V. N., Khavinson, V. K., Alimova, I. N., Semchenko, A. V. & Yashin, A. I. Epithalon decelerates aging and suppresses the development of breast adenocarcinomas in transgenic her-2/neu mice. Bull. Exp. Biol. Med.134, 187-190 (2002).

2. Vinogradova, I. A. et al. Geroprotective effect of ala-glu-asp-gly peptide in male rats exposed to different illumination regimens. Bull. Exp. Biol. Med.145, 472-477 (2008).

3. Vinogradova, I. A. et al. Effect of Ala-Glu-Asp-Gly peptide on life span and development of spontaneous tumors in female rats exposed to different illumination regimes. Bull. Exp. Biol. Med.144, 825-830 (2007).

4. Arutjunyan, A. et al. Melatonin and pineal gland peptides are able to correct the impairment of reproductive cycles in rats. Curr. Aging Sci.5, 178-185 (2012).