Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians Introduction Blood melatonin concentrations, primarily derived from the pineal gland, exhibit evident circadian fluctuations with the highest levels during nighttime and the lowest values during daytime [1]. Melatonin circadian rhythm is modu- lated by the hypothalamic suprachiasmatic nucleus (SCN), i.e. the biological clock [2, 3]. The SCN receives light impulses throughout the retinohypothalamic pathway and it is related to the pineal gland via the peripheral sympa- thetic nervous system. Although light inhibits melatonin secretion, it is important to note that the melatonin circadian rhythm has an endogenous origin. Furthermore, melatonin can directly influence the SCN throughout complex feed forward and feed back mechanisms [4, 5]. Noradrenalin (NA) after its binding to a1 and b1 adrenergic receptors, is the main neurotransmitter involved in melatonin secretion. During light exposure the NA release is inhibited after the hyperpolarization of the retinal photoreceptor cells [6]; on the contrary, the darkness leads to the activation of the system and the melatonin secretion increases [7]. Melatonin is then rapidly metabolized, espe- cially by the liver, and excreted in the urine. The urinary levels of 6-sulfatoxymelatonin (aMT6s), the main melatonin urinary metabolite, closely parallel plasma melatonin concentrations [8]. The melatonin circadian rhythm becomes apparent after the second or third month of life, reaching the highest nocturnal levels in children aged 1–3 yr. Thereafter, the melatonin circadian fluctuations, although persisting, show two significant declines: the first during puberty and the second during the progression from adulthood to senes- cence [9–12]. The actual nocturnal melatonin decline is 40–50% in elderly subjects [13]. Thus while aging may be considered a condition of relative melatonin deficiency, it seems unlikely that aging is merely a consequence of the loss of melatonin as provided by Rozenzweig et al. [14]. Melatonin has several properties that could be consid- ered as anti-aging. The first and well-studied effect of melatonin concerns its positive action on the duration and quality of sleep and on the speed of falling asleep [15]. This is particularly interesting because sleep disturbances or changes in the sleep–wake pattern are often observed in geriatric population. This hypnotic effect of melatonin seems to be mediated by reducing body temperature [16]. Many groups have studied the role of melatonin as free radical scavenger [17], showing that melatonin protects against the oxidative damage [18] both directly and Abstract: Melatonin secretion is an endogenous synchronizer, and it may possess some anti-aging properties. Thus we examined melatonin levels in physiological aging, in extreme senescence and in senile dementia. In healthy old (age 66–94 yr) and young subjects (age 23–39 yr) and in demented patients (age 68–91 yr) plasma melatonin was measured by radioimmunoassay in eight serial blood samples. In centenarians (age 100–107 yr) melatonin levels were estimated by assaying urinary 6-hydroxymelatonin sulfate (aMT6s) in two different urine samples collected from 08:00 to 20:00 hours and from 20:00 to 08:00 hours. These data were compared with the aMT6s excretion of old and young controls. Elderly subjects, demented or not, exhibited a flattened circadian profile of plasma melatonin, because of the suppression of the nocturnal peak. An age-related decline of the circadian amplitude of the melatonin rhythm occurred in old subjects, especially in demented individuals. Furthermore, the melatonin nocturnal peak was significantly correlated with the severity of the cognitive impairment. aMT6s urinary excretion also declined with age. However, as in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In conclusion, pineal melatonin secretion is affected by age and by the degree of cognitive impairment. In centenarians the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status. Flavia Magri, Serena Sarra, Wilma Cinchetti, Valeria Guazzoni, Marisa Fioravanti, Luca Cravello and Ettore Ferrari Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy Key words: centenarians, circadian rhythm, physiological aging, pineal, senile dementia Address reprint request to Flavia Magri, Department of Internal Medicine and Medical Therapy, University of Pavia, Italy P.zza Borromeo 2 – 27100, Pavia, Italy. E-mail: flaviamagri@libero.it Received October 22, 2003; accepted January 9, 2004. J. Pineal Res. 2004 Doi:10.1111/j.1600-079X.2004.00125.x Copyright Ó Blackwell Munksgaard, 2004 Journal of Pineal Research 256