About-Daily (Circadian) and About-Weekly (Circaseptan) Patterns of Human Salivary Melatonin

Summary: Chronobiology weekly.

Interestingness: 1

Paper by Manfred Herold, Germaine Cornélissen, Mary Jo Rawson, George S. Katinas, Cheryl Alinder, Chris Bratteli, Denis Gubin, Franz Halberg in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, Spring 2000.


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They analysed the melatonin and cortisol content of the saliva of five people 29-73 years of age for a week. They think there's a weekly cycle in melatonin, peaking on Tuesday. I'm close-minded.
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Abstract follows:

Circadian rhythms in circulating, urinary, salivary, pineal, pituitary and hypothalamic melatonin have been mapped. About weekly (circaseptan) rhythms, mapped previously in several other species, are demonstrated herein for human saliva, in individuals of widely differing ages. Whether or not the now demonstrated decrease with age in the circadian amplitude of human adults is accompanied by an increase in the circaseptan amplitude, as it is the case for blood pressure, remains to be determined.

Thyrotropin-Releasing Hormone Accelerates and Enhances the Age-Postponing Effects of Melatonin

Summary: Thyrotropin-releasing hormone (TRH) plus melatonin increase lifespan of old mice by three months

Interestingness: 4

Paper by Walter Pierpaoli, Daniele Bulian, Gordana Bulian and Gonzague Kistler in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

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The sample size is small, 15 mice per group, but the effect size is interesting. The main table of results shows the following: for four groups of 15+-1 BALB/cJ female mice, 20 months old at the start of the experiment, a control group, one given melatonin, one TRH, one both, mean survival was 765+-54 days, 810+-50 days, 804+-80 days, and 861+-70 days respectively. There's also other results, with the TRH plus melatonin combination raising numbers of leukocytes and blood lymphocytes, and lowering cholesterol and triglycerides in old mice.

TRH induces release of thyrotropin, aka thyroid-stimulating hormone (TSH) which then induces the thyroid to release T3 and T4. Wikipedia has TRH being produced in the hypothalamus but the paper says it's produced by the hypothalamus and the pineal gland.

The mechanism behind this isn't precisely hypothesised but they do mention immune system upregulation. The authors hype TRH as the real reason for the supposed effects of melatonin on aging, saying that melatonin dosing stops the pineal gland making its own, so it can stay young and keep on making TRH later. TRH is also given as the explanation of why pineal gland transplantation from young to old mice, mentioned in http://readingrejuvenationresearch.blogspot.com/2010/03/perspective-on-proposed-association-of.html, increases the longevity of those mice.

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Abstract follows:

Studies over a period of several years have suggested an age-postponing effect of circadian nocturnal administration of melatonin and of young-to-old pineal grafting in rodents. Of the two procedures, the effect of pineal grafting was significantly more pronounced. Also, old-to-young and young-to-old pineal transplantation in normal or pinealectomized recipients suggested that the pineal itself contains the capacity to prevent or to accelerate the course of aging depending on the age of the donor and/or of a recipient when the pineal is transplanted. This observation prompted the idea that the "program of aging" might be governed by the capacity of the pineal to maintain the control of central neuroendocrine functions and to constantly synchronize the synthesis and release of hormones according to a strict circadian periodicity and seasonal rhythmicity. This report deals with the experimental evidence that, while melatonin alone exerts a low-level age-postponing activity, its age-delaying effects are greatly enhanced and accelerated when given in combination with a pineal peptide, thyrotropin-releasing hormone (TRH). This peptide may be a key element in the mechanism by which both melatonin and pineal grafting might postpone aging. In fact, as suggested by our data here, TRH could be one of the basic mediators in the brain (pineal-hypothalamic-hypophyseal axis) and in peripheral endocrine glands (e.g., the beta, insulin-producing cells in the pancreas). TRH may directly translate the light and temperature-mediated environmental stimuli into rapid energy-adapting biochemical processes which constantly monitor cell functions relating to energy production, in particular those required for thermoregulation. We show here that this energy-monitoring action of TRH is not thyroid mediated. We also show that TRH is not itself a toxic agent even when administered daily for long periods at a very high pharmacological dosage.

A Perspective on the Proposed Association of Melatonin and Aging

Summary: Melatonin is another substance that we need more data on but doesn't look all that promising.

Interestingness: 1

Paper by Russel J Reiter, Dun-Xian Tan, Seok Joong Kim, Javier Cabrera and Daniele D'Arpa in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.

(((Melatonin is a molecule produced by the pineal gland that regulates the circadian rhythm. It puts you to sleep. It gets produced in the darkness, and bright light interrupts its production)))

Melatonin is another hormone which the body produces less of as it gets older. A graph with a linear best fit seems to indicate that peak melatonin concentration drops by about half between the ages of 20 and 70, although the text mentions a pronounced drop between the ages of 40 and 60. It also mentions factor of two differences between young people of the same age (((which makes it a bit less important in my eyes))). Production of melatonin in calorie-restricted rats drops slower than in normal rats (((probably more of an endorsement of calorie restriction as a method to slow aging than support for melatonin being important in the process)))

(((The paper now switches to melatonin as an anti-oxidant, which doesn't interest me much))) Melatonin mops up hydroxy radicals, peroxyl radicals, and neutralises single oxygen atoms and peroxynitrite anions (ONOO-). It also stimulates activity glutathione peroxidase and glutathione reductase (((dunno how))) which neutralise hydrogen peroxide. The paper stresses the effectiveness in protecting against lipid peroxidation.

Switching to direct aging studies, it mentions a study where the pineal glands of young rats were transplanted into old rats and these older rats were judged to have become younger, a result which the authors of this paper say is hard to accept since the pineal gland stops producing melatonin after the nerves are destroyed (((edit: the author of that paper seemed unhappy with these comments on this paper, and wrote to the editor in the next issue. They do not think the effect is mediated by restoring melatonin levels. Maybe I'll read their paper))) (((edit 2: paper seems reasonable. Part of it is the drugging of the water with interesting results. The pineal transplantations are into the other mice's (not rats) thymus, because they are supposedly similar tissue. Tiny samples, 15 mice transplanted with pineal glands total, but quite a strong effect (810 days vs 747 days mean survival on mice operated on in the 20th month). Probably completely unrelated to melatonin though.))) (((For reference, other paper is "Pineal Control of Aging: Effect of melatonin and pineal grafting on aging mice" by Walter Pierpaoli and William Regelson)))

Studies of long term melatonin administration in rats have had inconclusive results. Drugging the drinking water extended lifespan when it was given during the night but not during the day. Injecting melatonin directly extended lifespan when done in the morning, but not in the afternoon. (((These studies were done on groups of 10 and 15 mice respectively. The second one focuses on the effect of injections of lithium chloride, and melatonin has no effect on top of lithium chloride. The effects look sort of interesting to me, but this paper doesn't think much of them)))



Abstract follows:

Melatonin, the chief secretory product of the pineal gland, has been proposed to have some functional association with aging. Certainly, melatonin production in vertebrates, including humans, wanes with increasing age. This age-related drop in melatonin has been inferred to be consequential in terms of accelerating some aspects of aging, although the experimental evidence for this is not compelling at this point. There are several functional aspects of melatonin that make it of interest to gerontologists. Thus, the cyclic production of melatonin is reflective of the biological clock, and circadian disturbances in general are a feature of aging. These alterations may impact the rate of aging. Also, melatonin is an antioxidant and, as such, it reduces free radical damage. A primary theory of aging is accumulated oxidative damage, and any molecule, such as melatonin, that retards the accumulation of that molecular damage may forestall some aging processes. The experimental data are incomplete, however, and the specific association of the diminished melatonin cycle with aging or age-related diseases remains suggestive but unproven.