Melatonin


Melatonin, once touted as a panacea and lynchpin of the anti-aging pharmacopoeia, went silent for a few years after the mid-1990s hype surrounding it was largely discredited. It still occasionally rears its head in an biogerontological context, however, with recent studies demonstrating beneficial effects of the compound on age-related decline in the brain and skin.

Now, more good news: Melatonin restores impaired contractility in aged guinea pig urinary bladder. It’s especially good news if you happen to be an incontinent guinea pig.

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The hormone melatonin, released by the pineal gland, plays a major role in determining the sleep cycle in humans. The molecule is also an activator of the immune system, exerts a potent anti-oxidant effect in cells, and — of great interest to biogerontologists — has long (though somewhat controversially) been implicated in the determination of lifespan. Recently, melatonin supplementation in rats was shown to slow age-related decline in the morphology and function of the skin (see our earlier posting, Melatonin, mitochondria, and dermal aging).

Melatonin has also been proposed as a potential therapeutic agent against age-related diseases of the brain, and even against brain aging per se. A detailed discussion of the relevant aspects of brain aging, along with a summary of studies demonstrating a beneficial effect of the compound on animal models neurological diseases such as Parkinson’s and Alzheimer’s, can be found in a recent review by Bondy and Sharman at UC-Irvine:

The events associated with brain aging are enumerated with emphasis on increased oxidative and inflammatory processes and on mitochondrial dysfunction. Several of these factors are further increased in a wide range of overt age-related neurological diseases. This generality has given impetus to concepts concerning similar therapeutic approaches common to a series of neurodegenerative disorders. Animal and cell culture models of several such disorders have benefited from the application of melatonin. The mechanisms underlying the neuroprotective properties of melatonin are likely to involve activation of specific melatonin receptors. This can lead to modulation of transcription factors and consequent altered gene expression, resulting in enhancement of antioxidant enzymes and downregulation of basal levels of inflammation. Melatonin has potential utility both in slowing normal brain aging and in treatment of neurodegenerative conditions. This is reinforced by the low cost of melatonin and its very low toxic hazard.

The manuscript reviews the evidence for oxidative damage as a prominent feature of aging in the brain, address the evidence that inflammation plays a contributory role in age-related decline of the CNS, and describe the age-associated onset of mitochondrial dysfunction — which is itself caused by, and a further cause of, oxidative damage.

Despite the significance of oxidation in brain aging and neurodegeneration, the authors warn against the use of antioxidants as therapeutics, for two reasons: First, many anti-oxidants (such as vitamin E) are simply poorly bioavailable to the CNS, taking months of heavy supplementation before equilibrium is reached. Second, many processes in the brain rely on oxidative molecules for signaling; hence broad-spectrum antibiotics might interfere with specific pathways and therefore have deleterious side effects.

Melatonin appears to escape both criticisms. The molecule is highly bioavailable to the CNS following oral administration. Furthermore, while it is (chemically speaking) a potent antioxidant, it is present at concentrations far lower than many dietary antioxidants — picomolar opposed to high micromolar or millimolar. For that matter, its levels are far lower than those of the oxidative species against which we might hope for protection. It is thought to exert its antioxidant effects indirectly, via induction of anti-oxidant proteins that catalytically convert free radicals and reactive oxygen species (ROS) into harmless water (and, as a bonus, have probably been evolutionarily selected not to interfere in cellular signaling pathways). Thus, by activating cellular defenses, melatonin can ameliorate oxidative damage far beyond its capacity as a molecular radical scavenger.

Whether via its effects on oxidation, mitochondrial function or inflammation, melatonin has been shown to improve outcomes in animal models of neurological disease. (If you’re able to access the paper, the table summarizing the results is here).

Melatonin’s effect on gene transcription is mediated by specific receptors, of which the human genome contains two (MT1/MTNR1A and MT2/MTNR1B). Interestingly, the FDA recently approved a melatonin receptor agonist for use as a sleep aid. The drug, ramelteon, is marketed as Rozerem (via an incomprehensible campaign involving Abraham Lincoln and a beaver).

Intriguing possibility: If melatonin exerts its effects against brain aging via these receptors, it means that a pharmaceutical with potential as an anti-aging therapeutic has already been subjected to trials and approved for daily use. (Can you say “off-label prescription“?)

I’m sleeping easier already.

Melatonin is a hormone involved in regulation of sleep and the circadian rhythm, as well as the immune system. The molecule has also been demonstrated to have a positive effect on lifespan in some rodent model systems, though it is unclear whether this is due to receptor-mediated functions or can instead be ascribed to its potent antioxidant activity.

A recent study by Eşrefoğlu et al. demonstrates that supplemental melatonin slows age-related deterioration, including severe mitochondrial dystrophy, in the skin of pinealectomized rats (the pineal gland is the site of melatonin production):

… The present study was aimed to determine the fine structure of the abdominal and thoracic skin in pinealectomized rats and the effect of melatonin on skin ultrastructure. Rats were pinealectomized or sham operated (control) for 6 months. Half of the pinealectomized rats were treated with 4 mg/kg melatonin during the last month of the experiment. Pinealectomy resulted in prominent ultrastructural changes in the skin. Epidermal atrophy, disorganization and cytological atypia were obvious. Tonofilament distribution was not uniform, and intercellular space was narrow. Nuclear irregularity and heterochromatin condensation were detected. Many mitochondria were irregular and edematous with increased translucence of the matrix, either partial or total destruction of crests and frequently the presence of vacuoles, myelin figures and dense bodies. … The epidermis in melatonin administered pinealectomized rats was obviously thicker than that of pinealectomized rats. The cells of each layers had characteristic morphological and ultrastructural features. Nuclear irregularity and heterochromatin condensation were not seen. Mitochondria were generally normal in ultrastructural appearance but rarely vacuoles and myelin figures were observed. … This paper provides an additional ultrastructural evidence that the damage to mitochondria is the major contributory factor to skin aging and that melatonin has potent therapeutic effects in reducing age-related changes via protecting fine structure of the skin.

While the system may seem a little bit artificial (an major hormone-producing gland has been removed), I think the logic is sound: Pinealectomized rats undergo premature skin aging, implying that some product of the pineal is working to prevent skin aging in an unmolested rat. Adding back melatonin alone (of all the many hormones now absent) prevents this premature aging completely, implying that melatonin is the relevant pineal product.

One alternative interpretation is that the pineal produces some other product that prevents skin aging, but that the mechanism of skin aging is primarily oxidative, so that the truly gigantic doses of melatonin used here (4 mg/kg, or ~300 mg for a human adult; by comparison, the over-the-counter pills one can buy to help with jetlag or sleep disorders are 1 to 3 mg each) are acting via the compound’s antioxidant properties rather than its receptor-mediated functions.

An open question is whether supplemental melatonin will slow or prevent dermal aging in animals with intact pineal glands. The levels of melatonin produced at night do decrease with age, so it’s possible that at some point in the lifespan the hormone is present at insufficient levels to prevent the cellular damage described here. If that happens before other forces have wreaked havoc, and can therefore be considered a primary cause of early age-related decline in skin cells, then supplementation should be a good strategy for extending the healthy functionality of the body’s largest organ.

Something to think about. I’ll sleep on it.

Continuing the tradition I began last week, I give you some of the articles I would have treated at greater length last week if there were more of me (that is to say, more of us).

In no particular order:

Mitochondrial mutation: Mitochondrial DNA-Deletion Mutations Accumulate Intracellularly to Detrimental Levels in Aged Human Skeletal Muscle Fibers, Bua et al.,:

Deletion mutations were clonal within a fiber and concomitant to the COX-/SDH++ region. Quantitative PCR analysis of wild-type and deletion-containing mtDNA genomes within ETS-abnormal regions of single fibers demonstrated that these deletion mutations accumulate to detrimental levels (>90% of the total mtDNA).

Systems biology: Systems approaches to the networks of aging, Kriete et al.:

To increase our understanding of how aging works, we have to analyze and integrate quantitative evidence from multiple levels of biological organization. Here, we define a broader conceptual framework for a quantitative, computational systems biology approach to aging.

Melatonin: Melatonin treatment reverts aged-related changes in guinea pig gallbladder neuromuscular transmission and contractility, Gomez-Pinilla et al.:

Melatonin treatment for four weeks restored neurogenic responses to normal values, with an associated recovery of nitrergic function and the disappearance of the capsaicin-sensitive component. Aging also reduced the contractile responses to cholecystokinin (CCK) and Ca2+ influx.

Our favorite roundworm: Identifying factors that promote functional aging in Caenorhabditis elegans, Catherine Wolkow:

In C. elegans, aging leads to significant functional declines that correlate with muscle deterioration, similar to those documented for longer-lived vertebrates. This article will examine the current research into aging-related functional declines in this species, focusing on recent studies of locomotory and feeding decline during aging in the nematode, C. elegans.

Protein oxidation in Parkinson’s: Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging Meulener et al.:

Inherited mutations in PARK7, the gene encoding DJ-1, are associated with loss of protein function and early-onset parkinsonism. … Overoxidation of DJ-1 with age and exposure to oxidative toxins may lead to inactivation of DJ-1 function, suggesting a role in susceptibility to sporadic Parkinson’s disease.

Calorie restriction and mitochondria: Calorie Restriction in Mice: Effects on Body Composition, Daily Activity, Metabolic Rate, Mitochondrial Reactive Oxygen Species Production, and Membrane Fatty Acid Composition, Faulks et al.:

There was no CR-effect on in vitro reactive oxygen species production by liver or muscle mitochondria at 3 months, but after 6 months the effect was significantly reduced in liver mitochondria from 40 kcal/wk mice compared to 125 kcal/wk mice.