Epitalon Research Article – Part 4

This is the Epitalon Research Article – Part 4

Part 4 – Discussion

The results of our study show that the long-term administration of Epitalon slows down demographic aging rate, increases survival and maximum life span and decreases the development of spontaneous leukemias in female SHR mice.

Treatment with Epitalon increased the food consumption in comparison to the controls between the 5th and 16th months of their life, but the body weight was similar in both the control and Epitalon treated group.

Epithalon

Administration of Epitalon to female CBA mice failed to influence the body weight, and increased food consumption at the age of 12 months (Anisimov et al. 2001a). No significant differences in the age-related dynamics of body temperature between both groups were observed in SHR mice. In CBA mice a slight decrease in the body temperature under the influence of Epitalon has been observed (Anisimov et al. 2001a).

Thus, it could be suggested that increased food consumption induced by Epitalon was not followed by an increase in the basal metabolic rate, because both the body weight and the body temperature were not different from the controls.

The administration of Epitalon was followed by a slowing down of the age-related disturbances in estrous function in female SHR mice. These observations are in agreement with data obtained with Epitalon in other strains of mice – CBA and FVB/N (Anisimov et al. 2001a, 2002b).

It is worth nothing that long-term administration of melatoninor pineal peptide preparation Epithalamin was also followed by a slowdown of age-related switching-off of reproductive function in SHR, C3H/Sn and CBA mice and rats (Anisimov et al. 1989, 1998, 2001a, b; Meredith et al. 2000).

The aging process predisposes cells to accumulate mutations, some of which are necessary for initiation of tumor growth in target tissues (Vijg 2000; Bodyak et al. 2002). The incidence of chromosome aberrations increases with age in different strains of mice (Crowley and Curtis 1963; Sato et al. 1995).

Previously we found age-related increases in chromosome aberrations in bone marrow cells and in primary spermatocytes in male SHR mice (Rosenfeld et al. 2001). In this study we observed a significant increase in the frequency of chromosome aberrations in the bone marrow cells in 12-month-old female SHR mice compared to 3-month-old specimens.

Long-term treatment with Epitalon significantly decreased the age-associated increase in chromosome aberrations in female SHR mice. It was shown earlier that Epitalon also inhibited the incidence of chromosome aberration in one-year-old senescence-accelerated mice (Rosenfeld et al. 2002).

The long-term administration of Epitalon failed to influence total spontaneous tumor incidence in female SHR mice, but it significantly inhibited the development of leukemias (P<0.001) (Table 7).

Treatment with Epitalon inhibited the growth of transplanted sarcoma M-1 (Khavinson et al. 2001b), decreased spontaneous tumor incidence in female CBA mice (mainly lung adenomas) (Anisimov et al. 2001a) and inHER-2/neutransgenic mice (Anisimov et al. 2002b). It also inhibited colon carcinogenesis induced by 1,2-dimethylhydtrazine in rats (Anisimov et al. 2002a).

It possible to suggest that the capacity of Epitalon to prevent the development of spontaneous leukemias in female SHR mice can be related to its antioxidative activity.

It has been shown that Epitalon inhibits free radical processes inD. melanogasterand CBA mice (Anisimov et al. 2001a; Khavinson and Mylnikov 2000).

Our observation of the positive effect of Epitalon on the life span of SHR mice is in agreement with observations of similar activities of Epithalamin in SHR and C3H/Sn mice and rats (Anisimov et al. 1989, 1994) and of Epitalon in female CBA mice (Anisimov et al. 2001a). The effective concentration of Epitalon was 1000–5000 times less than that of Epithalamin.

In experiments with two strains of D. melanogaster, Epithalon treatment was followed by an increase in their mean life span (Khavinson and Mylnikov 2000). It is noteworthy that effective concentrations of the tetrapeptide were 1000 times less than of Epithalamin and 16,000–80 ×106 times less than that of melatonin (Khavinson and Mylnikov 2000).

Epithalon increased catalase activity and decreased the level of conjugated hydroperoxides in fruit flies (Mylnikov and Lyubimova 2000). The results of this investigation agree with data obtained in previous observations on the safety of long-term administration of peptide preparations isolated from the pineal gland on their geroprotective and anti-tumour effects (Anisimov et al. 1994; Khavinson et al. 2001c; Khavinson 2002).

Thus, the results obtained confirm a geroprotective potential of the peptide preparation Epithalon (AlaGlu-Asp-Gly). In the heart of CBA mice, the expression of 15,247 transcripts from the cDNA library was studied by the microarray technique (Anisimov S et al. 2002).

The analysis of the results of hybridizing the cDNA clone containing microarrays with the heart samples of the control and Epitalon-exposed mice revealed intensified expression of 194 clones and reduced expression of 48 clones. The analysis identified the multiple genes involved in cell division (14 genes), cell signaling/communication (14), cell structure/motility (6), cell/organism defense (13), gene/protein expression (17), metabolism (11), and genes encoded by mitochondrial DNA (5). These subgroups may include gene products that can explain some of the physiological effects described above, and form a molecular basis for the geroprotective effects of these peptides.

Acknowledgements

This study was supported by grants 99-04-48023 and 02-04-07573 from the Russian Foundation for Basic Research. The authors are very grateful to James W. Vaupel for the opportunityto use the facilities of the Max Planck Institute for Demographic Researchto complete this paper, and to I. I. Mikhailova and O.V. Novikova for their excellent technical assistance.

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