Gender Specificity of the Effect of Neonatal Melatonin Administration on Lifespan and Age-Associated Pathology in 129/Sv Mice
- 3 Downloads
Melatonin is subcutaneously administered in a single dose of 1.2 μg to 129/Sv mice at days 3, 5, and 7 after birth, and the mice are observed until natural death. In adult males, a decrease in the body weight and a reduction of the contribution of lung lesions detected during postmortal autopsy to mortality are detected. In adult females, an increase in the proportion of mice with impaired estrous cycle at the later stages of life and an acceleration of the mortality associated with uterine hemangioma are observed with the absence of any effect of melatonin on the body weight. Changes in the frequency of detection of other tumors are multidirectional: there is a decrease in the frequency in males and an increase in females. The age of death of the last 25% and 10% of males increases, while in females it decreases. An analysis of the complete survivorship curves using the Gompertz model does not reveal changes in the rate of aging and initial mortality sufficient to go beyond the limits determined by the artifact component of the Strehler–Mildvan correlation between these parameters. In general, the tendencies noted in males and females are multidirectional: favorable and unfavorable, respectively. Melatonin is contraindicated for pregnant and nursing women and children under 18 years old. The gender specificity of the effects of melatonin, apparently, should be considered when assessing the feasibility of its prescription to these categories.
Keywords:melatonin neonatal administration lifespan aging Gompertz law Strehler–Mildvan model estrous cycles tumors gender-specific effects
This work was partly supported by the Russian Presidential Scholarship (project no. SP-1252.2016.4) and the Russian Science Foundation (project no. 17-304-50013\17).
COMPLIANCE WITH ETHICAL STANDARDS
Conflict of interests. The authors declare that they have no conflict of interest.
Statement on the welfare of animals. The European Convention for the Protection of Vertebrate Animals Used for Experimental and other Scientific Purposes (CETS no. 123) was followed.
- 1.Vinogradova, I.A., Bukalev, A.V., Zabezhinskii, M.A., Semenchenko, A.V., and Anisimov, V.N., Effect of illumination regime and melatonin on homeostasis, life expectancy, and the development of spontaneous tumors in female rats, Usp. Gerontol., 2007, vol. 20, no. 4, pp. 40–47.Google Scholar
- 2.Vinogradova, I.A., Bukalev, A.V., Zabezhinskii, M.A., et al., Effect of illumination regime and melatonin on homeostasis, life expectancy, and the development of spontaneous tumors in female rats, Vopr. Onkol., 2008, vol. 54, no. 1, pp. 70–77.Google Scholar
- 3.Anisimov, V.N., Effects of melatonin on longevity, in Modulating Aging Longevity, Rattan, S., Ed., Dordrecht: Kluwer, 2003, vol. 5, pp. 239–260.Google Scholar
- 13.Anisimov, V.N., Zavarzina, N.Y., Zabezhinski, M.A., et al., Melatonin increases both life span and tumor incidence in female CBA mice, J. Gerontol., Ser. A, 2001, vol. 56, pp. B311–B323.Google Scholar
- 14.Anversa, P., Aging and longevity: the IGF-1 enigma, Circ. Res., 2005, vol. 97, pp. 411–414. https://doi.org/10.1161/01.res.0000182212.09147.56 CrossRefGoogle Scholar
- 22.Ding, A.-J., Zheng, S.-Q., Huang, X.-B., et al., Current perspective in the discovery of anti-aging agents from natural products, Nat. Prod. Bioprospect., 2017. https://doi.org/10.1007/s13659-017-0135-9
- 24.Forman, H.J., Redox signaling: an evolution from free radicals to aging, Free Radical Biol. Med., 2016, vol. 97, pp. 398–407. https://doi.org/10.1016/j.freeradbiomed.2016.07.003 CrossRefGoogle Scholar
- 25.Gavrilov, L.A. and Gavrilova, N.S., The Biology of Life Span: A Quantitative Approach, New York: Harwood Academic, 1991.Google Scholar
- 26.Golubev, A., Hanson, A.D., and Gladyshev, V.N., A tale of two concepts: Harmonizing the free radical and antagonistic pleiotropy theories of aging, Antioxid. Redox Signaling, 2017. https://doi.org/10.1089/ars.2017.7105
- 31.Jenwitheesuk, A., Park, S., Wongchitrat, P., et al., Comparing the effects of melatonin with caloric restriction in the hippocampus of aging mice: involvement of sirtuin1 and the FOXOs pathway, Neurochem. Res., 2018, vol. 43, pp. 144–152. https://doi.org/10.1007/s11064-017-2369-7 CrossRefGoogle Scholar
- 34.Martin-Montalvo, A., Mercken, E.M., Mitchell, S.J., et al., Metformin improves health span and lifespan in mice, Nat. Commun., 2013, vol. 4. https://doi.org/10.1038/ncomms3192
- 35.Mayo, J.C., Sainz, R.M., Menéndez, P.G., et al., Melatonin and sirtuins: a “not-so unexpected” relationship, J. Pineal Res., 2017, vol. 62. https://doi.org/10.1111/jpi.12391
- 43.Posadzki, P.P., Bajpai, R., Kyaw, B.M., et al., Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action, BMC Med., 2018, vol. 16. https://doi.org/10.1186/s12916-017-1000-8
- 45.Ramis, M.R., Esteban, S., Miralles, A., et al., Caloric restriction, resveratrol and melatonin: role of SIRT1 and implications for aging and related-diseases, Mech. Ageing Dev., 2015, vols. 146–148, pp. 28–41. https://doi.org/10.1016/j.mad.2015.03.008
- 51.Sohal, R.S. and Forster, M.J., Caloric restriction and the aging process: a critique, Free Radical Biol. Med., 2014, vol. 73, pp. 366–382. https://doi.org/10.1016/j.freeradbiomed.2014.05.015 CrossRefGoogle Scholar
- 54.Sun, L.Y., Fang, Y., Patki, A., et al., Longevity is impacted by growth hormone action during early postnatal period, eLife, 2017, vol. 6. https://doi.org/10.7554/eLife.24059
- 55.Tain, Y.-L., Huang, L.-T., and Hsu, C.-N., Developmental programming of adult disease: reprogramming by melatonin?, Int. J. Mol. Sci., 2017, vol. 18. https://doi.org/10.3390/ijms18020426
- 57.Terrón, M.P., Delgado-Adámez, J., Pariente, J.A., et al., Melatonin reduces body weight gain and increases nocturnal activity in male Wistar rats, Physiol. Behav., 2013, vol. 118, pp. 8–13. https://doi.org/10.1016/j.physbeh.2013.04.006
- 58.Vaiserman, A. and Lushchak, O., Implementation of longevity promoting supplements and medications in public health practice: achievements, challenges and future perspectives, J. Translat. Med., 2017, vol. 15. https://doi.org/10.1186/s12967-017-1259-8
- 59.Wilkinson, D., Shepherd, E., and Wallace, E.M., Melatonin for women in pregnancy for neuroprotection of the fetus, Cochrane Database Syst. Rev., 2016, vol. 3. https://doi.org/10.1002/14651858.CD010527.pub2
- 61.Wu, Y.H., Zhou, J.N., Balesar, R., et al., Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: co-localization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone, J. Comp. Neurol., 2006, vol. 499, pp. 897–910. https://doi.org/10.1002/cne.21152 CrossRefGoogle Scholar