cron-web.org

[A1CR]

In this article from 200-11-02, MR looks into Melatonin supplementing:

The subject of HRT (hormone replacement theory) has been on the list of late, and I got into an off-list discussion about melatonin. This prompted me to do a little more digging on this than I've done in the past, and thought I would post the fruits of my labor.

My objection to supplementing or agonizing sex hormones & GH (growth hormone) is that (a)
doing so directly counteracts a known effect of CR, which seems on the
face of it unwise (see upcoming post on GH; my position here has
significantly softened, but I still oppose GH agonism), and (b) there is
specific reason to believe that the reduction in exposure to these hormones is responsible for aspects of the health benefits (esp on immunity and cancer) of CR. Neither of these
CLEARLY applies to melatonin.

(a) Melatonin (M) appears to be increased in BOTH the short (11, 12) and the long
(8 ) term by CR, and the effects of M on sex hormones are parallel to
those seen on CR, and enhanced by same (7,10; but see (30)), while
pinealectomy prevents them (9). M also lowers insulin and leptin, per CR
(22). Likewise, M lowers body temperature, as does CR; in poikilotherms,
this slows aging. ITs effects on GH are quite ambiguous (26-30);
likewise, while it increases conversion of T4 to T3 (eg. 24), which may
be bad, it seems to lower actual in vivo levels of all thyroid
hormones (23-25), which is probably good.

(b) The INCREASE in CR in melatonin may reasonably be advanced as being
responsible for some of its health bennies. M itself (13, 14) or
young-to-old pineal grafts (13) increases mean, and colony max, LS (NOT
species-max LS (life span), i.e. not a true anti-aging effect) in some rodents.

On the other hand, one of the pineal transplant groups (13) was the
quite reasonably longevous C57BL/6 mice, which are a preferred species
for aging studies, and the "extended LS" seen in the transplantees still
was no longer than the CONTROLS in other studies (e.g. (31-34)! So what's
up with that? The "controls" in (13) thus actually had unusually
SHORTENED ls. And another group found that M has no effect AT ALL on LS
in this same strain (15). (BTW, a review discussing this result (16)
also mentions a surprising whack of other antioxidant studies using
single AO's or combinations showing no effect at all, and even the
occasional bad result. Lesson: don't reach for that donut).

In CBA mice, females (but not males) of which are reasonably longevous,
M increased life span (mean or max unspecified), but "Increase in life
span led to higher spontaneous tumor incidence." (17)
This is ambiguous: did their RATE of incidence increase (bad), or did
their rate remain the same over a longer time period (as seems the
more likely reading, and would be neutral)? Also: In a cancer-prone CBA
substrain, pinealectomy DECREASES tumors in (18 ).

Overall, looks safe for reasonably healthy types with no obvious bad
genes, but the idea of it being actively beneficial seems on rather
shaky ground.

One problem with M supplements per se is negative feedback: exogenous M
reduces endogenous release (19), as one might expect. This might be
predicted to lead to pineal atrophy, and also to suppression of the OTHER pineal peptide
"neuroendocrine principle," epithalamin. Since epithalamin increases
longevity in short-lived rodent strains (20), increases feedback
sensitivity of the hypothalamus (21), lowers insulin in rabbits (21),
and retards radiation and chemical carcinogenesis (22), my guess is that
this is a bad idea.

A more physiologic approach is, of course, tryptophan. This is available
in Canada with prescription. In the USA, I don't know the exact
situation, aside from its absurdly banned OTC status; a recent couple of
posts on the LEF forum claim it's now available from some sources, tho'
I know nothing about the operations in question or their quality:

http://forum.lef.org/DCForumID21/137.html#

I strongly urge life extensionists NOT to take 5-HTP: Steve Harris,
formerly of UCLA and now with LEF-funded 21st Century Medicine,
convinced LEF not to market the stuff with what are to my judgment very
sound arguments that long-term 5-HTP will create the same right mitral
valve disorder seen in matoke eaters, phen/fen users, and a serotonergic
lung cancer. This argument is in the presently-offline pre-1999 Dejanews archives.

Adequate Ca, Mg, and B6 (pref. pyridoxamine!! (I mean because of its
anti-glycation effects, not because it's better for M)) are needed for M
synthesis; B3 is good to help preserve serotonin as a precursor.

You can also up melatonin by eating carbohydrates before bed, though this is IMHO a
very bad idea. Eating carbohydrates before bed creates an insulin spike which
sweeps other aminos from the bloodstream; the refractory tryptophan is thus left to
cross the BBB without competition, leading efficiently to serotonin &
hence melatonin synthesis. This is why such a snack is often effective
for sleep, and milk & cookies more so; it's also why the package
instructions on prescription tryp say to take it with a CHO snack.
However, as I've argued before, this is also a great way to bugger up
your nocturnal neuroendocrine rhythm. I strongly recommend against this practice.

-MR

1: Niles LP, Wang J, Shen L, Lobb DK, Younglai EV.
Melatonin receptor mRNA expression in human granulosa cells.
Mol Cell Endocrinol. 1999 Oct 25;156(1-2):107-10.
PMID: 10612428; UI: 20077675

2: Ebisawa T, Kajimura N, Uchiyama M, Katoh M, Sekimoto M, Watanabe T,
Ozeki Y, Ikeda M, Jodoi T, Sugishita M, Iwase T, Kamei Y, Kim K, Shibui K, Kudo
Y, Yamada N, Toyoshima R, Okawa M, Takahashi K, Yamauchi T.
Alleic variants of human melatonin 1a receptor: function and prevalence
In subjects with circadian rhythm sleep disorders.
Biochem Biophys Res Commun. 1999 Sep 7;262(3):832-7.
PMID: 10471411; UI: 99400459

3: Ozeki Y, Yamada N, Aoki H, Yokoyama T, Shirono H, Koga J, Kato N.
A newly developed assay for melatonin using cells expressing human
mel-1a receptor.
Psychiatry Clin Neurosci. 1999 Apr;53(2):247-8.
PMID: 10459701; UI: 99387457

4: Gilad E, Laufer M, Matzkin H, Zisapel N.
Melatonin receptors in PC3 human prostate tumor cells.
J Pineal Res. 1999 May;26(4):211-20.
PMID: 10340723; UI: 99270548

5: Nonno R, Lucini V, Pannacci M, Mazzucchelli C, Angeloni D, Fraschini
F, Stankov BM.
Pharmacological characterization of the human melatonin Mel1a receptor
Following stable transfection into NIH3T3 cells.
Br J Pharmacol. 1998 Jun;124(3):485-92.
PMID: 9647472; UI: 98309687

6: Gilad E, Pick E, Matzkin H, Zisapel N.
Melatonin receptors in benign prostate epithelial cells: evidence for
The involvement of cholera and pertussis toxins-sensitive G proteins in
their signal transduction pathways.
Prostate. 1998 Apr 1;35(1):27-34.
PMID: 9537596; UI: 98196946

7: Wilamowska A, Pawlikowski M, Kunert-Radek J, Klencki M.
[Effect of melatonin on the function of the pituitary-gonadal axis in
food restriction states].
Ginekol Pol. 1993 May;64(5):221-5. Polish.
PMID: 8365677; UI: 93374316

8: Stokkan KA, Reiter RJ, Nonaka KO, Lerchl A, Yu BP, Vaughan MK.
Food restriction retards aging of the pineal gland.
Brain Res. 1991 Apr 5;545(1-2):66-72.
PMID: 1713529; UI: 91316606

9: Chik CL, Ho AK, Brown GM.
Effect of pinealectomy on the undernutrition-induced suppression of the
reproductive axis in rats.
Acta Endocrinol (Copenh). 1989 May;120(5):569-73.
PMID: 2728802; UI: 89269420

10: Nordio M, Vaughan MK, Sabry I, Reiter RJ.
Undernutrition potentiates melatonin effects in maturing female rats.
J Endocrinol Invest. 1989 Feb;12(2):103-10.
PMID: 2502571; UI: 89327818

11: Chik CL, Ho AK, Brown GM.
Effect of food restriction on 24-h serum and pineal melatonin content in
Male rats.
Acta Endocrinol (Copenh). 1987 Aug;115(4):507-13.
PMID: 3630542; UI: 87322130

12: Chik CL, Ho AK, Joshi MG, Brown GM.
Pineal N-acetyltransferase, pineal and serum melatonin response to
Isoproterenol stimulation in underfed male rats.
Life Sci. 1987 Apr 13;40(15):1451-7.
PMID: 3561159; UI: 87172052

13: Pierpaoli W, Regelson W.
Pineal control of aging: effect of melatonin and pineal grafting on
aging mice.
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):787-91.
PMID: 8290600; UI: 94119971

14. Oaknin-Bendahan S, Anis Y, Nir I, Zisapel N.
Effects of long-term administration of melatonin and a putative
antagonist on the ageing rat.
Neuroreport. 1995 Mar 27;6(5):785-8.
PMID: 7605949; UI: 95329660

15: Lipman RD, Bronson RT, Wu D, Smith DE, Prior R, Cao G, Han SN,
Martin KR, Meydani SN, Meydani M.
Disease incidence and longevity are unaltered by dietary antioxidant
supplementation initiated during middle age in C57BL/6 mice.
Mech Ageing Dev. 1998 Jul 15;103(3):269-84.
PMID: 9723903; UI: 98389296

16. Meydani M, Lipman RD, Han SN, Wu D, Beharka A, Martin KR, Bronson R,
Cao G, Smith D, Meydani SN.
The effect of long-term dietary supplementation with antioxidants.
Ann N Y Acad Sci. 1998 Nov 20;854:352-60. Review.
PMID: 9928443; UI: 99127404

17. Anisimov VN, Zavarzina NIu, Zabezhinskii MA, Popovich IG, Anikin IV,
Zimina OA, Solov'ev MV, Shtylik AV, Arutiunian AV, Oparina TI, Prokopenko VM,
Khavinson VKh.
[The effect of melatonin on the indices of biological age, on longevity
and on the development of spontaneous tumors in mice].
Vopr Onkol. 2000;46(3):311-9. Russian.
PMID: 10976278; UI: 20432797

18. Bulian D, Pierpaoli W.
The pineal gland and cancer. I. Pinealectomy corrects congenital
hormonal dysfunctions and prolongs life of cancer-prone C3H/He mice.
J Neuroimmunol. 2000 Aug 1;108(1-2):131-5.
PMID: 10900346; UI: 20361886

19. Drijfhout WJ, Homan EJ, Brons HF, Oakley NR, Skingle M, Grol CJ,
Westerink BH.
Exogenous melatonin entrains rhythm and reduces amplitude of endogenous
melatonin: an in vivo microdialysis study.
J Pineal Res. 1996 Jan;20(1):24-32.
PMID: 8648559; UI: 96253732

(20) Anisimov VN, Mylnikov SV, Khavinson VK.
Pineal peptide preparation epithalamin increases the lifespan of fruit
flies, mice and rats.
Mech Ageing Dev. 1998 Jun 15;103(2):123-32.
PMID: 9701766; UI: 98367088

21. Anisimov VN, Khavinson VKh, Morozov VG.
Twenty years of study on effects of pineal peptide preparation:
epithalamin in experimental gerontology and oncology.
Ann N Y Acad Sci. 1994 May 31;719:483-93. Review. No abstract available.
PMID: 8010617; UI: 94280003

22. Rasmussen DD, Boldt BM, Wilkinson CW, Yellon SM, Matsumoto AM.
Daily melatonin administration at middle age suppresses male rat
visceral fat, plasma leptin, and plasma insulin to youthful levels.
Endocrinology. 1999 Feb;140(2):1009-12.
PMID: 9927336; UI: 99124526

23. Ozturk G, Coskun S, Erbas D, Hasanoglu E.
The effect of melatonin on liver superoxide dismutase activity, serum
nitrate and thyroid hormone levels.
Jpn J Physiol. 2000 Feb;50(1):149-53.
PMID: 10866707; UI: 20325727

24. Prakash P, Laloraya M, Kumar P.
Influence of a melatonin implant on the free radical load in avian
thyroid and its relation with thyroid hormonogenesis.
Biochem Mol Biol Int. 1998 Dec;46(6):1249-58.
PMID: 9891859; UI: 99109008

25. Esquifino A, Agrasal C, Velazquez E, Villanua MA, Cardinali DP.
Effect of melatonin on serum cholesterol and phospholipid levels, and on
prolactin, thyroid-stimulating hormone and thyroid hormone levels, in
hyperprolactinemic rats.
Life Sci. 1997;61(11):1051-8.
PMID: 9307050; UI: 97450609

26. Forsling ML, Wheeler MJ, Williams AJ.
The effect of melatonin administration on pituitary hormone secretion in
man.
Clin Endocrinol (Oxf). 1999 Nov;51(5):637-42.
PMID: 10594526; UI: 20062672

27. Kostoglou-Athanassiou I, Treacher DF, Wheeler MJ, Forsling ML.
Melatonin administration and pituitary hormone secretion.
Clin Endocrinol (Oxf). 1998 Jan;48(1):31-7.
PMID: 9509065; UI: 98169800

28. Coiro V, Volpi R, Caffarri G, Capretti L, Marchesi C, Giacalone G,
Chiodera P.
Effect of melatonin on hypoglycemia and metoclopramide-stimulated
arginine vasopressin secretion in normal men.
Neuropeptides. 1997 Aug;31(4):323-6.
PMID: 9308018; UI: 97453295

29. Valcavi R, Zini M, Maestroni GJ, Conti A, Portioli I.
Melatonin stimulates growth hormone secretion through pathways other
than the growth hormone-releasing hormone.
Clin Endocrinol (Oxf). 1993 Aug;39(2):193-9.
PMID: 8370132; UI: 93380132

30. Waldhauser F, Lieberman HR, Lynch HJ, Waldhauser M, Herkner K,
Frisch H, Vierhapper H, Waldhausl W, Schemper M, Wurtman RJ, et al.
A pharmacological dose of melatonin increases PRL levels in males
without altering those of GH, LH, FSH, TSH, testosterone or cortisol.
Neuroendocrinology. 1987 Aug;46(2):125-30.
PMID: 3114663; UI: 87315685

31: Pugh TD, Oberley TD, Weindruch R.
Dietary intervention at middle age: caloric restriction but not
dehydroepiandrosterone sulfate increases lifespan and lifetime cancer incidence
in mice.
Cancer Res. 1999 Apr 1;59(7):1642-8.
PMID: 10197641; UI: 99211498

32: Harrison DE, Archer JR, Astle CM.
Effects of food restriction on aging: separation of food intake and adiposity.
Proc Natl Acad Sci U S A. 1984 Mar;81(6):1835-8.
PMID: 6608731; UI: 84170397

33. Harrison DE, Archer JR.
Genetic differences in effects of food restriction on aging in mice.
J Nutr. 1987 Feb;117(2):376-82.
PMID: 3559752; UI: 87168769

34. Weindruch R, Walford RL.
Dietary restriction in mice beginning at 1 year of age: effect on
life-span and spontaneous cancer incidence.
Science. 1982 Mar 12;215(4538):1415-8.
PMID: 7063854; UI: 82152762