Telomeres & EpithalonIntroduction to Telomeres
Telomeres are repeating sequences of nucleotide sequences (TTAGGG) that tag the ends of all chromosomes. They are designed to prevent unpredictable changes in the DNA strand, keeping the genome stable.
Their primary function is to prevent chromosomal “fraying” when a cell replicates, much like the plastic tips on the end of shoelaces. As a cell ages, its telomeres become shorter.
This shortening is thought to be one of several factors that causes cells to age. In actively dividing cells, such as those in the bone marrow, the stem cells of the embryo, and germ cells in the adult, telomere length (TL) is kept constant by the enzyme telomerase.
As the organism grows, this enzyme becomes less active over time. This leads to a slow decrease in telomere length, until a point is reached at which the cell is no longer capable of replication (‘replicative senescence’). A cell can no longer divide when telomeres are too short—once they reach a critical point, the cell becomes inactive (or ‘senescent’), slowly accumulating damage that it can’t repair, or it dies.
Why are Telomeres Important?Telomere length is affected by both genetic and epigenetic contributions. A new study found that DNA methylation is closely linked to TL. The study by researchers at the University of California Los Angeles shows a very significant linkage between two different markers that indicate aging.
Telomeres are an essential part of human cells that affect how our cells age. Telomere length has emerged as an important determinant of replicative senescence and cell fate - an important indicator of the aging process and a wide range of disease states, including cancers,
cardiovascular disease, and age-related disorders.
Shorter telomeres are not only associated with age but with disease too. In fact, shorter telomere length and low telomerase activity are associated with several chronic preventable diseases. These include hypertension, cardiovascular disease, insulin resistance, type 2 diabetes, depression, osteoporosis, and obesity.
Shorter telomeres have also been implicated in genomic instability and oncogenesis. Older people with shorter telomeres have three- and eight-times increased risk to die from heart and infectious diseases, respectively.
The telomerase theory of aging attributes the age-associated decrease of the tissue proliferative potential to critical shortening of telomeres during cell division. Telomerase is a ribonucleic enzyme constructing the telomere repeats TTAGGG, which are lost because of asymmetry in the synthesis of the leading and lagging DNA strands and is encoded by two genes (for RNA component and protein component of the enzyme).
In humans the expression of telomerase protein component and the corresponding enzyme activity are observed in the majority of malignant, sex, early embryonal, and presumably, stem cells. Human somatic cells have no telomerase activity.
What is Epithalon?
Epithalon (aka Epitalon) peptide (Ala- Glu-Asp-Gly) was constructed and synthesized based on amino acid composition of Epithalamine, a complex peptide preparation isolated from animal brain pineal. It was first discovered in the late 1980’s by Prof. Vladimir Khavinson from The Sankt Petersburg University, Russia.
As the most prominent tasks of the pineal gland are to maintain different kind of processes in our body, such as to normalize the activity of anterior pituitary and to maintain the levels of calcium, gonadotropins, and melatonin, its activity is highly regulated by a series of feedback mechanisms. Epithalamin acts as an antioxidant and increases the resistance to stress and lowers the levels of corticosteroids. The life extension and anti-aging properties, amongst a variety of different clinical indications, of epithalon are incredible antioxidant and increases the resistance to stress and lowers the levels of corticosteroids. The life extension and anti-aging properties, amongst a variety of different clinical indications, of epithalon are incredible.
Epithalon in the Literature (Quick Review)Epitalon restores disorder to neuroendocrine regulation in animals by activating ribosomal genes. Addition of the tetrapeptide cultured lymphocytes isolated from elderly and senile humans promoted decondensation of pericentromeric heterochromatin and activation of genes repressed because of age-associated condensation of chromosomal euchromatic regions.
The geroprotective activity of Epitalon was studied in three strains of Drosophila melanogaster (Khavinson et al. 2000; Mylnikov and Lyubimova 2000). Epitalon increased the lifespan of these animals significantly by 11–16% when applied at unprecedentedly low concentrations – from 0.001 × 10−6 to 5 × 10−6 wt% of the culture medium.
A recent study team demonstrated a geroprotective effect of long-term Epitalon administration in female inbred CBA mice (Anisimov et al. 2001a). The bioregulator slowed down aging of the reproductive function, inhibited free radical processes, and decreased total spontaneous tumor incidence in female CBA mice (Anisimov et al. 2001a).
Epitalon inhibited mammary carcinogenesis and metastasis in transgenic HER-2/neu mice (Anisimov et al. 2002b) and colon and small intestine carcinogenesis induced by 1,2-dimethylhydrazine in rats (Anisimov et al. 2002a).
Administration of Epitalon to young (6–8 years old) and senescent (20–26 years old) female monkeys Macaca mulatta restored the evening level of melatonin and the circadian rhythm of cortisol in the blood serum of senescent monkeys (Khavinson et al. 2001a).
Epithalon prolongs the meant lifespan of mice and rates and decreases the incidence of chromosome aberrations in rapidly aging SAM mice. It is also worth mentioning that the peptide prolongs the mean and maximum lifespan without development of malignant tumors in these animals.
What you need to know:Epitalon offers several benefits that can help combat the symptoms of aging. It also helps with mood, and acts as an antioxidant.
Numerous studies have shown the importance of telomerase production and telomere rejuvenation in fighting the symptoms of aging. The research data have proved that Epitalon has a regenerating and life-prolonging effect, as well as a positive effect on the hormonal levels, immune responses and thyroid gland. In addition, Epitalon helps to prevent the early aging process of cells and inhibit tumor development in somatic cells. As Epitalon has been shown to increase the production of telomerase which in turn strengthens and lengthens telomeres, this means that Epitalon can play a vital role in decreasing the aging process and thus extending human longevity.
Epithalon in Telomere Research (Expanded)Research example #1:
Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells
Addition of Epithalon peptide in telomerase-negative human fetal fibroblast culture induced expression of the catalytical subunit, enzymatic activity of telomerase, and telomere elongation, which can be due to reactivation of telomerase gene in somatic cells and indicates the possibility of prolonging life span of a cell population and of the whole organism.
These results indicate that in human somatic cells Epithalon can induce the expression of telomerase enzyme component, telomerase activity, and telomere elongation (by on average 33.3%). Hence, for the first time ever, researchers demonstrated induction of telomerase activity with a peptide. These data largely explain the geroprotective effects of Epithalon in various experimental models]. It is known that critically short telomeres cannot prevent chromosome fusion, which can lead to activation of protooncogenes and malignant transformation, while activation of telomerase and telomere elongation under the effect of the peptide explain the mechanism of antitumor effect of Epithalon in old animals.
Electrophoretic separation and detection of PCR-amplified elongated TS primers in PAAG. 1) 10 b. p., DNA marker; 2) HeLa cells; 3) fibroblasts; 4) fibroblasts treated with Epithalon.
Results of evaluation of telomere length by fluorescent in situ hybridization with flow cytofluorometry (flow-FISH). Fetal fibroblasts in control (a), Epithalon-treated fetal fibroblasts (b). Vertically: telomere staining with PNA-FITC probe (linear scale). Horizontally: cell DNA staining with propidium iodide (linear scale). Cells in the G1 phase of cell cycle are in the frame.
Research example #2:
Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR miceFrom the age of 3 months until their natural deaths, female outbred Swiss-derived SHR mice were subcutaneously injected on 5 consecutive days every month with 0.1 ml of normal saline (control) or with 1.0 microg/mouse (approximately 30-40 microg/kg) of tetrapeptide Epitalon (Ala-Glu-Asp-Gly) dissolved in 0.1 ml saline. There were 54 mice in each group. The results of this study show that treatment with Epitalon did not influence food consumption, body weight or mean life span of mice. However, it slowed down the age-related switching-off of estrous function and decreased the frequency of chromosome aberrations in bone marrow cells (by 17.1%, P<0.05). It also increased by 13.3% the life span of the last 10% of the survivors (P<0.01) and by 12.3% the maximum life span in comparison with the control group. We also found that treatment with Epitalon did not influence total spontaneous tumor incidence, but inhibited the development of leukemia (6.0-fold), as compared with the control group. The data obtained suggest a geroprotector activity of Epitalon and the safety of its long-term administration in mice.
You can view the table below which reviews the parameters of lifespan in female SHR mice treated with Saline or Epitalon.
Research example #3:
Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People: Results of 15-Year Follow-Up
There was a human trial done over a 12-year period with patients treated with epithalon and a placebo group. The results of this study demonstrated a 28% decrease in overall mortality with those treated with epithalon, and a 2-fold decrease in cardiovascular mortality by decreasing the functional age and degree of cardiovascular aging. Another study was done to show that those treated with thymalin and epithalamin over a 6-year period had a mortality rate that was 4.1 times lower than the control group.
In further details, this paper presents the results of a randomized comparative study of the efficiency of peptide geroprotector from the pituitary gland in elderly patients with rapidly aging cardiovascular system. Over three years 39 coronary patients received, in addition to basic therapy, regular courses of epithalamin (peptide drug), while 40 coronary patients (control group) received basic therapy alone. Long-term treatment with epithalamin (6 courses over 3 years) decelerated aging of the cardiovascular system, prevented age-associated impairment of physical endurance, normalized circadian rhythm of melatonin production and carbohydrate and lipid metabolism. A significantly lower mortality in the group of patients treated with epithalamin in parallel with basic therapy also indicated a geroprotective effect of the peptide preparation from the pineal gland.
Cumulative survival curves of elderly coronary patients with rapidly aging CVS treated by different protocols. 1) basic therapy; 2) basic therapy+epithalamin. *p<0.05 compared to the parameters in the basic therapy group throughout the entire period of observation