This article originally appeared in the August 1990 issue (#27) of the Journal of the MegaHealth Society, right before it was renamed ForeFront--Health Investigations. Illustrations mentioned in the text have not yet been installed.

A Biomarker of Aging?

Brain Melatonin

by Steven Wm. Fowkes

The brain has long been a focus for researchers investigating aging mechanisms. The pituitary and hypothalamus glands have major roles in regulation of homeostatic control and the aging rate. Hypothalamic hormones stimulate the pituitary to release hormones which then stimulate the adrenal glands. Adrenal steroids in turn stimulate the liver, pancreas, kidney, gonads and cardiovascular system. And finally, adrenal and gonadal steroids, along with pituitary hormones, provide feedback control to the hypothalamus.

The interrelationship between these glands provides a mechanism for long-term homeostatic control of metabolic functions. Part of this control is provided by a circadian (daily, 24-hour) mechanism whereby hormones are released at a particular time of the day or night. Growth hormone releasing factor and growth hormone fall into this category -- being released in a pulse lasting for minutes in the middle of the night. This pulsatile hormone stimulation is like the push given to children on a swing; the brief push at the beginning of the downward swing serves to keep the child moving. Circadian hormones serve to establish and resynchronize a 24-hour oscillation in metabolic activity which optimizes us for performance and survival.

The Pineal Gland

Another important part of the circadian mechanism is provided by the pineal gland and the pineal hormone melatonin. The pineal gland is a tiny gland buried deep in the brain behind the eyes. It takes serotonin, the brain neurotransmitter produced from tryptophan by serotonergic neurons, and produces melatonin, a serotonin-like neurochemical which induces sleep (see illustration below-right). New research now shows that serum melatonin exhibits significant age-related changes which affect the timing of its release, peak levels and total 24-hour secretion [Nair 1986]. All three parameters showed a significant correlation with age.

Between ages 20 and 70, total 24-hour secretion decreased 37%, peak secretion decreased 47%, and the peak timing was delayed 1 hour. In this study, none of the three factors showed any correlation with height, weight or obesity, although previous researchers have shown such correlations in specific populations. Schizophrenic patients have shown a positive correlation between plasma melatonin and weight [Ferrier 1982], and depressed patients have shown a negative correlation between peak melatonin and height [Beck-Friis 1984]. The close agreement between the estimated maximum lifespan (110-120 years) and the extrapolation of the decline in melatonin levels to zero (120-130 years) suggests a possible intimate relationship between melatonin and aging.

Seasonal Depressions

Melatonin has been a focus of investigations into the causes of depression because of its positive relationship to the length of the photoperiod (daylight hours) and the prevalence of depressions during the winter season. Seasonal Affective Disorder (SAD) effects millions of people each year. One of the most popular non-drug treatments for SAD is phototherapy which artificially increases the amount of light entering the eyes and/or the length of daylight. Light entering the eyes is believed to stimulate the pineal gland to produce more melatonin.

Preliminary anecdotal reports suggest that melatonin may be many times more effective than tryptophan at resetting the circadian clock and overcoming jet lag.

Menopause and Aging

Although the sample size in this study is too limited for a firm conclusion, the grouping of women's melatonin values suggests an accelerated aging rate at menopause. The curve that best fits the data points has an inflection point at the age of menopause. In previous aging studies, gerontologists have suggested that menopause is a time of accelerated aging for women. Further research will be required to confirm this observation.

Melatonin, Immunity, Stress

According to Dr. Maestroni and colleagues, "Melatonin reverses the depression of antibody response induced by corticosterone" an adrenal stress hormone. This effect is blocked by naltrexone, an opiate antagonist, suggesting that melatonin works via the endogenous opioid system (e.g., endorphins and enkephalins). Melatonin may have important applications to immunization/inoculation procedures. The immuno-protective effect of melatonin is specific to T-cells and the thymus gland. The shrinking of the thymic cortex (the outer layer of the thymus gland) which normally occurs with aging -- and is experimentally accelerated by adrenal stress hormones -- is not prevented by concomitant melatonin administration. Rather, the thymic medulla (center portion of the thymus) undergoes "striking" enlargement with melatonin administration. This antistress action may be adaptive for handling and coping with the stress of daily life through relaxation and sleep.

Maestroni's research team concludes that the pineal gland is a "fundamental modulator" and "metabolic up-regulator" of the entire neuroendocrine system. Its effect is distinctly circadian in nature. "When administered to mice in the evening, melatonin increased the primary antibody response (IgM + IgG) to T-dependent antigens" at doses from 10 mcg to 10 mg per kg of body weight. In the morning, no such effect was seen.

Homeostasis

The pineal gland may be thought of as a homeostatic computer, receiving environmental information from diverse sources (light-darkness cycle, temperature, stress, antigens, etc.), processing it, and then outputting appropriate hormone-messages to other endocrine glands. With this view, the aging process can be seen to be a progressive inability of this organ to cope with environmental changes.

Pineal Aging

Tissue calcification is strongly connected with the aging process. Calcification of the pineal gland begins before puberty, is well established in early adulthood, and is so advanced in middle age that it is used as a reference location in x-rays and CAT scans. In terms of calcification, the pineal gland leads the rest of the body in the aging process. It is possible that some of the therapeutic benefits of chelation therapy [see JMS #20] may be due to its removal of calcium from the pineal gland.

Life Extension

The role of the pineal gland in aging is more than theoretical. In one experiment, Maestroni's research team administered 10 mcg/ml melatonin in the drinking water of 19-month-old healthy mice (late middle age). The mice on melatonin progressively improved in appearance. At five months into the experiment, the control mice started to lose weight quickly. Their fur, vigor, activity and posture began to decline. No such changes were seen in the melatonin group. The melatonin group lived 931 +/- 90 days mean compared to 752 +/- 81 days for the control group -- an approximate 20% lifespan increase, begun late in life.

Further Research

Although the therapeutic use of melatonin in humans has begun, the specific mechanisms by which melatonin and other pineal hormones influence the aging process still need further elucidation. If early research is confirmed, an evening dose of supplemental melatonin may prove to have the same effect on neuroendocrine function that a pacemaker has on the heart.

References:

H Aguchi, K I Kato, and H Ibayashi, "Age-dependent reductions in serum melatonin concentrations in healthy human subjects." J Clin Endocrinol Metabolism 55: 27-29, 1982.

J Beck-Friis, D Von Rosen, B F Kjellman, J G Ljunggren and L Wetterberg, "Melatonin in relation to body measures, sex, age, season and the use of drugs in patients with major affective disorders and healthy subjects." Psychoneuroendocrinology 9: 261-278, 1984.

I N Ferrier, J Arendt, E C Johnstone and T J Crow, "Reduced nocturnal melatonin secretion in chronic schizophrenia: relationship to body weight." Clinical Endocrinology 17: 181-87, 1982.

G J M Maestroni, A Conti, and W Pierpaoli, "Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effects of corticosterone. J Neuroimmunology 13: 19-30, 1986.

G J M Maestroni, A Conti, and W Pierpaoli, "Role of the pineal gland in immunity. II. Melatonin enhances the antibody response via an opiatergic mechanism. Clin Exp Immunology 68: 384-391, 1987.

Georges J M Maestroni, Ario Conti, and Walter Pierpaoli, "Pineal melatonin, its fundamental immunoregulatory role in aging and cancer." Neuroimmunomodulation: Interventions in Aging and Cancer First Stromboli Conference on Aging and Cancer, Annals of the New York Academy of Sciences 521: 140-148, 29 March 1988.

G J M Maestroni, A Conti, and W Pierpaoli, "The pineal gland and the circadian, opiatergic, immunoregulatory role of melatonin. Ann N Y Acad Sci In press.

N P V Nair, N Hariharasubramanian, C Pilapil, I Issac and J X Thavundayil, "Plasma Melatonin -- An Index of Brain Aging in Humans?" Biological Psychiatry 21: 141-50, 1986.