Melatonin regulates the activities of ovary and delays the fertility decline in female animals via MT1/AMPK pathway

The free radical theory of aging, conceived in 1956, has turned 40 and is rapidly attracting the interest of the mainstream of biological research. From its origins in radiation biology, through a decade or so of dormancy and two decades of steady phenomenological research, it has attracted an increasing number of scientists from an expanding circle of fields. During the past decade, several lines of evidence have convinced a number of scientists that oxidants play an important role in aging. (For the sake of simplicity, we use the term oxidant to refer to all "reactive oxygen species," including O2-., H2O2, and .OH, even though the former often acts as a reductant and produces oxidants indirectly.) The pace and scope of research in the last few years have been particularly impressive and diverse. The only disadvantage of the current intellectual ferment is the difficulty in digesting the literature. Therefore, we have systematically reviewed the status of the free radical theory, by categorizing the literature in terms of the various types of experiments that have been performed. These include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, the manipulation of metabolic activity and oxygen tension, treatment with dietary and pharmacological antioxidants, in vitro senescence, classical and population genetics, molecular genetics, transgenic organisms, the study of human diseases of aging, epidemiological studies, and the ongoing elucidation of the role of active oxygen in biology.

Menopause is the final step in the process referred to as ovarian ageing. The age related decrease in follicle numbers dictates the onset of cycle irregularity and the final cessation of menses. The parallel decay in oocyte quality contributes to the gradual decline in fertility and the final occurrence of natural sterility. Endocrine changes mainly relate to the decline in the negative feedback from ovarian factors at the hypothalamo-pituitary unit. The declining cohort of antral follicles with age first results in gradually elevated FSH levels, followed by subsequent stages of overt cycle irregularity. The gradual decline in the size of the antral follicle cohort is best represented by decreasing levels of anti-Mullerian hormone. The variability of ovarian ageing among women is evident from the large variation in age at menopause. The identification of women who have severely decreased ovarian reserve for their age is clinically relevant. Ovarian reserve tests have appeared to be fairly accurate in predicting response to ovarian stimulation in the assisted reproductive technology (ART) setting. The capacity to predict the chances for spontaneous pregnancy or pregnancy after ART appears very limited. As menopause and the preceding decline in oocyte quality seem to have a fixed time interval, tests that predict the age at menopause may be useful to assess individual reproductive lifespan. Especially genetic studies, both addressing candidate gene and genome wide association, have identified several interesting loci of small genetic variation that may determine fetal follicle pool development and subsequent wastage of his pool over time. Improved knowledge of the ovarian ageing mechanisms may ultimately provide tools for prediction of menopause and manipulation of the early steps of folliculogenesis for the purpose of contraception and fertility lifespan extension.

Oxidative stress has been proven to be related to the onset of a large number of health disorders. This chemical stress is triggered by an excess of free radicals, which are generated in cells because of a wide variety of exogenous and endogenous processes. Therefore, finding strategies for efficiently detoxifying free radicals has become a subject of a great interest, from both an academic and practical points of view. Melatonin is a ubiquitous and versatile molecule that exhibits most of the desirable characteristics of a good antioxidant. The amount of data gathered so far regarding the protective action of melatonin against oxidative stress is overwhelming. However, rather little is known concerning the chemical mechanisms involved in this activity. This review summarizes the current progress in understanding the physicochemical insights related to the free radical-scavenging activity of melatonin. Thus far, there is a general agreement that electron transfer and hydrogen transfer are the main mechanisms involved in the reactions of melatonin with free radicals. However, the relative importance of other mechanisms is also analyzed. The chemical nature of the reacting free radical also has an influence on the relative importance of the different mechanisms of these reactions. Therefore, this point has also been discussed in detail in the current review. Based on the available data, it is concluded that melatonin efficiently protects against oxidative stress by a variety of mechanisms. Moreover, it is proposed that even though it has been referred to as the chemical expression of darkness, perhaps it could also be referred to as the chemical light of health. © 2011 John Wiley & Sons A/S.