Epistemic Status: Casual. I’m in a period of blogging more frequently so my posts represent only a few hours of thought.
I love ground-up organs.
Seriously — they’re where a lot of medical progress comes from. Long before we knew what “cortisol” did, we were treating autoimmune diseases with ground-up adrenal cortex extract. Long before we knew what thyroxine did, we were treating hypothyroid patients with ground-up thyroid extract. And a lot of regenerative medicine is still at the stage of “put some mashed-up lymph node tissue or bone marrow on it and see if it grows.”
It’s primitive, but it’s a kind of prudent primitiveness. It is very hard to map out biochemical pathways and extract the precise chemical that binds to the precise receptor that does what you want. Given the messiness of evolution, it is not at all surprising when it turns out that there are many potentially relevant receptors and chemicals related to the disease you want to target. If you just know the organ, you route around all that complexity. You don’t have to know all the growth factors to know that bone marrow contains some kind of growth-y stuff.
So I was very interested, after having been linked to this database of putative life-extension drugs, that the top scorer was epithalamin, an extract of the pineal gland; it’s said to extend life by 31% in mice. The second item on the list was polypeptide pineal preparation, which is another name for epithalamin; and melatonin, the primary hormone produced by the pineal gland, is no slouch either, allegedly giving mice 18% longer lives.
So, I had to ask, is this for real?
First, let’s talk about melatonin.
Melatonin is the “sleep hormone” — it is produced at night much more than in the day, and its primary effect is to make humans and animals sleepy. The cyclical pattern of melatonin secretion provides the circadian rhythm.
The study linked in the database, by Walter Pierpaoli, finds that male mice (but not female mice) given melatonin at night (but not during the day) live 18% longer than control mice, and engrafting young pineal glands onto the thymuses of older mice increases lifespan by 27%.
Unfortunately, this experiment is on strains of mice that happen to be deficient in melatonin already, so it doesn’t tell us much about whether melatonin or pineal-gland transplants will extend the lifespans of normal-melatonin individuals.
A critical paper in 1995, called “Melatonin Madness,” pointed out this mistake, and pointed out that in another study on a strain of mouse that does produce melatonin (C3H/He), the treated mice actually had shorter lifespans because they developed more tumors.
Pierpaoli is…rather problematic. He’s the author of “The Melatonin Miracle: Nature’s Age-Reversing, Disease-Fighting, Sex-Enhancing Hormone” and sells melatonin in his online store. So, a little skepticism is warranted here.
On the other hand, there’s been additional evidence that melatonin can extend life, even in melatonin-producing animals.
In C3H mice (which produce melatonin), melatonin in drinking water prolongs the life of male mice by about 20% (p < 0.01) but not female mice.
In CBA mice, which also produce melatonin, those given melatonin in their night-time drinking water were significantly more likely than controls to get lung cancer and lymphoma, but their lifespan still was extended by 5% relative to controls.
Moreover, a 1979 study by the Russian longevity researcher Vladimir N. Anisimov found that female rats given daily doses of epithalamin at 0.1 or 0.5 mg increased lifespan by 10% and 25% respectively, and aging-related disturbances in the estrus cycle were significantly (p < 0.05) reduced.
Anisimov also found that female C3H mice (a melatonin-producing strain) given daily epithalamin at 0.5 mg lived on average 40% longer than controls.
However, he found that epithalamin given to old rats did not significantly increase lifespan.
In another Russian experiment, by Vladimir Khavinson, a frequent collaborator of Anisimov’s, 94 women aged 66-94 from the War Veterans Home in St. Petersburg were randomized to control, thymus extract (thymalin), pineal extract (epithalamin), or both. At baseline, these elderly women had high B lymphocytes, low NK counts, high IgG levels, high cortisol, insulin, and TSH, and low estrogen and LH, compared to the “normal” levels.
Thymalin normalized the NK levels. Epithalamin normalized NK levels as well as ACTH, TSH, cortisol, and insulin. Thymalin significantly reduced the rate of acute respiratory diseases (from 58% to 25%) and epithalamin significantly reduced the rate of ischemic heart disease. In 6 years, 81.8% of the control patients died, compared to 41.7% of the thymalin patients, 45.8% of the epithalamin patients (both applied for 2 years) and 20.0% of the patients given epithalamin and thymalin for 6 years. The effect on mortality was significant at p<0.001.
This is a pretty small study for a measurement of all-cause mortality, but something might be going on here.
It’s also possible that pineal extract reverses aging-related insulin resistance (which is associated with many aging-related diseases, like heart disease, cancer, and diabetes.)
Old rhesus monkeys have lower melatonin levels than young monkeys. Pineal gland extract, but not placebo, raises old rhesus monkeys’ melatonin levels to that of young monkeys. Old monkeys also have higher blood glucose levels (at baseline and in response to glucose challenge) than young monkeys; pineal gland extract significantly reduces glucose in old monkeys (but not young monkeys.) Old monkeys have a delayed and flatter curve of insulin response to glucose challenge than young monkeys; pineal gland extract reverses this. This suggests that pineal gland extract improves insulin sensitivity in monkeys.
There is a lot of uncontroversial evidence that melatonin has something to do with aging. Mammals and humans secrete less melatonin as they age.
The pineal gland’s melatonin secretion rhythm becomes less regular with age (smaller amplitude) in both rats and hamsters. In hamsters and humans, the pineal gland develops “concretions” of calcium with age. Older animals lose beta-adrenergic receptors on the pineal gland with age. Food-restricted rats, on the other hand, continue to produce more melatonin in old age — and that’s suggestive, because food-restricted animals also live longer.
Old rats had neurons in their pineal glands fire at lower frequencies than young rats, and produced less melatonin.
Food-restricted rats at 28 months (old age) had twice the melatonin levels of ad-lib fed rats. Food-restricted rats were smaller, and had no tumors or cataracts, unlike ad-lib fed rats.
The pineal gland also seems to be associated with insulin sensitivity and other markers associated with aging.
Pinealectomy (the removal of the pineal gland) increases blood pressure in rats, suspected to be caused by an increase in adrenal steroid levels. Melatonin in the drinking water reduces blood pressure to normal levels.
Pinealectomy causes glucose intolerance and insulin insensitivity in rats. At 8 AM, glucose and insulin are normal in response to glucose challenge; but at 4 PM, pinealectomized rats have way higher of a glucose spike and way less insulin production. The pancreas responds less to pinealectomized rats, both morning and afternoon. Pinealectomized rats have significantly less GLUT-4 (glucose transporter) in their adipose tissues.
Pinealectomized rats have higher glucose levels, lower insulin levels, and higher glucagon levels than control rats; treatment of pinealectomized rats with melatonin increases insulin and reduces glucagon. Pinealectomized rats have glucose intolerance. Melatonin supplementation partially recovers glucose tolerance.
Corticosterone (the primary corticosteroid in rodents, serving similar functions to cortisol in humans) rises in rats as they age; two-month-old pinealectomized rats had the same corticosterone levels as 24-month-old aged rats.
So, if you remove the pineal gland, you get higher levels of corticosteroids, higher blood pressure, and more metabolic-syndrome-like changes, just like people and animals do as they age. Pinealectomy also causes “pro-gonadal” effects — higher sex hormones and larger sex organs.
Pinealectomizing rats causes ovarian, pituitary, and adrenal hypertrophy (p < 0.001). Adding bovine pineal extract to the rats reverses this.
Melatonin reduces prostate weight in rats as a fraction of total body weight (p < 0.02) and prostate fructose (p < 0.05); being kept in darkness drops testosterone levels to 1/8th their usual levels; pinealectomy increases prostate weight (p < 0.05) and triples testosterone levels (p < 0.01).
The testes of rats produce more testosterone after pinealectomy, and administering melatonin reverses the effect.
Blinding female rats retards the development of their ovaries and uterus. Pinealectomy recovers the normal size of the ovaries and uterus. (Note that blinding animals or keeping them in darkness is kind of like making it perpetually night for them — the conditions under which melatonin is usually secreted. So that’s also consistent with the “melatonin = less sex hormones” pattern.)
Nighttime, but not continuous, administration of melatonin causes delayed puberty and delayed reproductive senescence in mice. That is, mice given melatonin are slower to reach puberty and slower to become infertile with age.
So this pattern is starting to make sense. Remember how most mutations that increase lifespan have something to do with the GH/IGF pathway that promotes growth and insulin release and sex hormones? And how caloric restriction increases lifespan, improves insulin sensitivity, but impairs fertility? And how higher levels of IGF, sex hormones, and obesity are risk factors for cancer, especially reproductive-organ cancers like breast and prostate? Almost as though there’s an evolutionary toggle between “growth and reproduction” and “surviving through famine”? Well, melatonin and the pineal gland seem to tie into this story; if you take away the pineal gland you get high sex hormone levels and metabolic syndrome, while if you add melatonin or pineal extract you can reverse those phenomena.
But does it really connect to longevity? It’s not clear. The only study I found that measured the lifespan of pinealectomized rats was by Walter Pierpaoli, and found that rats pinealectomized at 3 to 5 months have 20% shorter lifespan (p = 0.014) but that pinealectomy does not alter lifespan in 7 to 9 month rats. Pinealectomy at 14 months actually increases lifespan (by 12.5%) but at 18 months it has no effect. Pierpaoli speculates that there’s a precise age at which the pineal gland promotes aging, but I think this study is nowhere near enough evidence to conclude that.
At any rate, there’s a simple evolutionary story for why we’d have a toggle between “eat, grow, reproduce” and “survive”, and why that would be connected to the circadian rhythm: SEASONS.
Summer has longer days and more food. Winter has shorter days (more melatonin at night!) and less food. You want to grow fat in the summertime and have babies; you want to survive the winter. A lot of species (though not humans) have a seasonal mating pattern.
And, accordingly, you see the effects of the pineal gland on seasonal mating.
Short-day Siberian hamsters (kept under conditions that are dark longer than they are bright), compared to long-day hamsters, have later puberty, more ovarian follicles, and longer fertility. Pinealectomize the hamsters and even the short-day ones lose fertility quickly. (Siberian hamsters in the wild reproduce in spring and summer.) Long-days have higher body mass than short-days, and pinealectomized short-days are the largest of all. This is because short-day hamsters eat 16% fewer calories. The basic bottom line is consistent: darkness = melatonin = less gonadal/growth processes going on = slower reproductive aging.
Siberian hamsters are very cute:
but they have an extremely seasonal pattern of gonadal growth; Google Image Search “siberian hamster testicles” if you dare. Those are summertime testicles. In winter the male Siberian hamster loses thirty percent of his body mass.
Testosterone also rises upon pinealectomy in white-tailed deer at baseline, but it prevents them from having the annual “autumn rut” spike in testosterone that usually peaks in November. Testicular size also rises in the fall in normal white-tailed deer, but in pinealectomized deer it rises steadily throughout the year. In other words, pinealectomy flattens out the seasonal breeding rhythm.
So, the pineal gland maintains a regular seasonal and daily cycle of “growth/sex” vs “rest/survival”, with nighttime and winter being the more “rest/survival” oriented periods. If you destroy the pineal gland, you can keep animals shifted towards “growth/sex” all the time (which doesn’t actually make them more fertile overall, it makes them use up their fertility faster). It’s annoyingly unclear whether pinealectomy makes animal lifespans shorter, and somebody should check that.
It’s also not that clear whether you can get normal animals into more of a “rest/survival” oriented mode by administering extra melatonin or pineal extract. You definitely can’t get them to be in permanent “rest/survival” by administering melatonin 24/7 — continuous melatonin (as opposed to nighttime melatonin) has no effect on longevity or delaying puberty or aging. But there are some apparently okay mice and rat studies that show that melatonin or pineal extract has a longevity-promoting effect. If it pans out, it would be the biggest-effect-size longevity intervention I’ve seen that isn’t a highly restrictive diet (caloric restriction or low-methionine) or obviously very dangerous (high-dose rapamycin).
I might also speculate from all this that getting a good night’s rest is good for you (I know, shocking), and that having artificial light that doesn’t get any shorter in the winter than the summer may be messing with modern people’s metabolisms in some way.
Pierpaoli, Walter, and William Regelson. “Pineal control of aging: effect of melatonin and pineal grafting on aging mice.” Proceedings of the National Academy of Sciences 91.2 (1994): 787-791.
Kasahara, Takaoki, et al. “Genetic variation of melatonin productivity in laboratory mice under domestication.” Proceedings of the National Academy of Sciences 107.14 (2010): 6412-6417.
Reppert, Steven M., and David R. Weaver. “Melatonin madness.” Cell 83.7 (1995): 1059-1062.
Oxenkrug, G., P. Requintina, and S. Bachurin. “Antioxidant and Antiaging Activity of N‐Acetylserotonin and Melatonin in the in Vivo Models.” Annals of the New York Academy of Sciences 939.1 (2001): 190-199.
Anisimov, Vladimir N., et al. “Melatonin increases both life span and tumor incidence in female CBA mice.” The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 56.7 (2001): B311-B323.
Dilman, V. M., et al. “Increase in lifespan of rats following polypeptide pineal extract treatment.” Experimentelle Pathologie 17.9 (1979): 539-545.
Anisimov, V. N., V. Khavinson, and V. G. Morozov. “Twenty years of study on effects of pineal peptide preparation: Epithalamin in experimental gerontology and oncology.” Annals of the New York Academy of Sciences 719.1 (1994): 483-493.
Anisimov, V. N., L. A. Bondarenko, and V. Kh Khavinson. “Effect of pineal peptide preparation (epithalamin) on life span and pineal and serum melatonin level in old rats.” Annals of the New York Academy of Sciences 673.1 (1992): 53-57.
Khavinson, Vladimir Kh, and Vyacheslav G. Morozov. “Peptides of pineal gland and thymus prolong human life.” Neuroendocrinology Letters 24.3-4 (2003): 233-240.
Goncharova, N. D., et al. “Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas.” Experimental gerontology 40.1 (2005): 51-57.
Reiter, Russel J. “The ageing pineal gland and its physiological consequences.” Bioessays 14.3 (1992): 169-175.
Stokkan, Karl-Arne, et al. “Food restriction retards aging of the pineal gland.” Brain research 545.1 (1991): 66-72.
Stokkan, Karl-Arne, et al. “Food restriction retards aging of the pineal gland.” Brain research 545.1 (1991): 66-72.
Holmes, S. W., and D. Sugden. “Proceedings: The effect of melatonin on pinealectomy-induced hypertension in the rat.” British journal of pharmacology 56.3 (1976): 360P.
Lima, Fabio B., et al. “Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats.” American Journal of Physiology-Endocrinology and Metabolism 275.6 (1998): E934-E941.
Diaz, Beatriz, and E. Blazquez. “Effect of pinealectomy on plasma glucose, insulin and glucagon levels in the rat.” Hormone and metabolic research 18.04 (1986): 225-229.
Oxenkrug, Gregory F., Iain M. McIntyre, and Samuel Gershon. “Effects of pinealectomy and aging on the serum corticosterone circadian rhythm in rats.” Journal of pineal research 1.2 (1984): 181-185.
Wurtman, Richard Jay, Mark D. Altschule, and Uno Holmgren. “Effects of pinealectomy and of a bovine pineal extract in rats.” American Journal of Physiology–Legacy Content 197.1 (1959): 108-110.
Kinson, G. A., and Frances Peat. “The influences of illumination, melatonin and pinealectomy on testicular function in the rat.” Life Sciences 10.5 (1971): 259-269.
 “Effects of melatonin on Leydig cells in pinealectomized rat: an immunohistochemical study.” Acta histochemica 104.1 (2002): 93-97.
Reiter, Russel J., Peter H. Rubin, and John R. Richert. “Pineal-induced ovarian atrophy in rats treated neonatally with testosterone.” Life sciences 7.5 (1968): 299-305.
Meredith, S., et al. “Long-term supplementation with melatonin delays reproductive senescence in rats, without an effect on number of primordial follicles☆.” Experimental gerontology 35.3 (2000): 343-352.
PIERPAOLI, WALTER, and DANIELE BULIAN. “The Pineal Aging and Death Program: Life Prolongation in Pre‐aging Pinealectomized Mice.” Annals of the New York academy of sciences 1057.1 (2005): 133-144.
Place, Ned J., et al. “Short Day Lengths Delay Reproductive Aging 1.” Biology of reproduction 71.3 (2004): 987-992.
Plotka, E. D., et al. “Early effects of pinealectomy on LH and testosterone secretion in white-tailed deer.” Journal of endocrinology 103.1 (1984): 1-7.