MELATONIN

These notes provide detailed information about melatonin and aging.

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Properties of melatonin:  
  1.    melatonin was discovered in 1958  
  2.    it is an indole  
  3.    half-life in blood is approximately 40 minutes  
  4.    it is soluble in lipids and in aqueous environments. Therefore able to enter all cellular and body compartments and move from one to the other.
  5.    administered melatonin accumulates in all body cells and reaches concentrations higher than that found in the blood. This may be due to melatonin’s high lipid and water solubility and the presence of melatonin receptors on cell membranes and in nuclei.  

Sources of melatonin:  
   1.    found in pineal and retina of all vertebrates

      - melatonin in blood is produced by pineal gland

 2.    produced by retina and G.I. tract

      - melatonin in retina and in G.I. tract may act locally rather than contributing to blood levels of melatonin

 3.    found in invertebrates, phytoplankton, edible plants

      - relatively high concentrations in plants in the rice family

      - eating plants that contain melatonin increases blood levels and brain levels of melatonin

 4.   easily absorbed from foods

 5.    easy and inexpensive to obtain or produce (e.g., from plants)

      -  easily administered by injection

 6.    blood levels can be increased by implanting pineal gland

 7.    nontoxic

Timing of secretion and blood levels of melatonin:

 1.    normal diurnal rhythm based on amount of light entering eyes

      -  secretion and blood levels increase with little or no light entering eyes (e.g., during night)

      -  secretion and blood levels decrease with little or no light entering eyes (e.g., during day)

      -  secretion and blood levels also influenced by duration of light exposure, intensity of light, and wavelength of light entering eyes (e.g., incandescent light vs. fluorescent light)

      -  shows diurnal rhythm with nighttime peaks in certain unicellular algae

 2.    nighttime peaks in youth may reach 30-40 times the daytime basal levels

 3.    great variation in melatonin peaks during youth and during aging among individuals, largely based on genetics

      - ? could the intrinsic variations in melatonin among individuals be a main reason for the variability in rates of aging among individuals?

      - ? could extrinsically altered levels of melatonin modify the intrinsic rates of aging influenced by melatonin?

 4.    melatonin secretion follows a seasonal rhythm as well as a diurnal rhythm. In elders, melatonin levels were lowest in November, rose through February, and peaked in April

Physiological actions of melatonin:

 1.    seems to inhibit sexual maturation when at high levels (e.g., childhood)

 2.    regulates diurnal rhythms = circadian rhythms

      -  affects daily rhythms (e.g., sleep/wakefulness, body temperature, mood and depression)

      -  may affect diurnal rhythms of other hormones (e.g., GH, testosterone)

 3.    melatonin affects many cells as a hormone by first binding to melatonin receptors on the cell surface or within the nucleus

 4.    antioxidant properties of melatonin were first discovered in 1993 in studies of cardiac muscle calcium transport

Free radicals from O₂ metabolism:  
 1.    important because of free radical theory of aging, which was first proposed by D. Harman in 1956

      - free radicals = atoms or molecules with one or more unpaired electrons

      -  free radicals are oxidizing agents because they tend to take electrons from other atoms and molecules to achieve paired electrons

      - free radicals damage DNA, proteins, and lipids in various ways, leading to damage in genes, structural proteins, enzymes, and cellular membranes -> age changes including altered structure (e.g., collagen cross-links) and reduced functioning -> disease/death

 2.    in natural systems with aerobic metabolism in mitochondria, free radicals containing oxygen are produced

      -  although more than 95 of the O2 used by cells results in no oxygen free radical formation, somewhat less than 5 of the O2 used by cells is converted to oxygen free radicals, starting with O2- superoxide free radical when O2 is used in mitochondria when they release electrons from nutrients. Though most of the released electrons enter the electron transport system, some of the electrons enter ordinary O2 molecules, which become O2- superoxide free radicals with 17 electrons

 3.    O2- superoxide free radical (with 17 e-) + e- + 2H+ (from mitochondrial reactions) -> H2O2 (hydrogen peroxide with 18 e-) + e- (from additional mitochondrial reactions) -> OH- hydroxyl ion (with 10 e-) + .OH hydroxyl free radical (with 9 e-)

      -  O2- superoxide free radical is converted to H2O2 (hydrogen peroxide) by obtaining one e- plus two H+ from mitochondrial reactions or from other molecules elsewhere

            - enzyme used is superoxide dismutase

            - the e- can come from another O2- superoxide free radical or from an organic molecule that is oxidized, along with an H+ from that same molecule (e.g., fatty acid)

 4.    H2O2 (hydrogen peroxide) is not a free radical, but it is converted to an .OH hydroxyl free radical, which is a highly toxic free radical

      -  H2O2 (hydrogen peroxide) crosses cell membranes easily, so it spreads out and leads to .OH formation in other areas

      -  the free substance H2O2 moves freely through cell compartments and between cells, spreading the damage from O2- superoxide free radicals produced in mitochondria

      -  H2O2 (hydrogen peroxide) is inactivated by glutathione peroxidase and by catalase to form H2O

      - H2O2 (hydrogen peroxide) can be converted to H2O by getting e- and H+ from reduced glutathione using enzyme glutathione peroxidase to produce oxidized glutathione

      -  glutathione peroxidase needs selenium to work to convert H2O2 (hydrogen peroxide) to H2O

      -  the reaction by glutathioine peroxidase uses reduced glutathione as an electron source

 5.    .OH can be derived from H2O2 (hydrogen peroxide) or when ionizing radiation strikes H2O

      -  H2O2 (hydrogen peroxide) is converted to .OH hydroxyl free radical by being converted to a plain OH- hydroxyl ion and a .OH hydroxyl free radical

      -  the conversion of H2O2 to .OH hydroxyl free radical is promoted by Fe+2 ions and Cu+ ions, which become Fe+3 or Cu+2 respectively while producing an H2O and an .OH hydroxyl free radical

            - an electron is donated by metal ion (e.g., Fe+2 or Cu+)

 6.    different free radicals have different potentials to take electrons from other substances. The differences are in terms of orders of magnitude. (e.g., O2 has a very low potential, the O2- superoxide free radical has high potential, the .OH hydroxyl free radical has the highest potential

      - ordinary O2 is a very low activity free radical with two unpaired electrons because the unpaired electrons have opposite spins

      -  O2- superoxide free radical is a potent oxidizer

      -  .OH hydroxyl free radical is the most potent oxidizing free radical

      -  O2- superoxide free radical and .OH do not move far in cells or between cells because they are so reactive that they oxidize molecules before they can get very far

 7.    increasing exercise decreases formation of some free radicals

 8.    extreme exercise increases the formation of free radicals

 9.    organisms limit free radical damage by (a) limiting intake of substances that contain or promote production of free radicals (e.g., types or quantities of food) (b) taking in substances that limit free radical production or increase free radical destruction (e.g., vitamin E, vitamin C, melatonin, selenium) (c) limiting free radical production using alternate metabolic pathways (e.g., hexose pathway rather than pentose pathway for glucose metabolism) (d) producing substances that destroy or inactivate free radicals (e.g., enzymes, melatonin)

            - anti-free radical mechanisms are not perfect, so free radicals are inevitable and some free radical damage is inevitable and is often cumulative or increases in rate as age increases

10.   atherogenesis and the development of atherosclerosis seem to involve free radical damage to arterial walls

            - melatonin may be able to decrease atherogenesis by reducing free radical damage to arterial walls

11.   melatonin may protect the retina from free radical damage to photoreceptor membranes, which is initiated by light causing free-radical-yielding reactions in the photoreceptors

12.   melatonin does not promote free radical formation except in certain monocytes, where the free radicals assist in destroying microbes

Free radicals and melatonin in the brain:  
  1.    the brain uses a great deal of O2 and oxidative metabolism (e.g., 20 of O2 used by body, though it weighs about 2 of body weight

      -  brain produces many O2 free radicals from its rapid O2 metabolic pathways

      -  brain produces more free radicals per gram than any other tissue

      -  brain and its neurons are adversely affected by oxidation by free radicals, perhaps more than any other structures in the body

 2.    free radical damage to lipids is high in the brain because the brain has a high lipid content in neuron membranes

 3.    free radical damage in the brain is increased because the brain uses glutamate, norepinephrine and epinephrine as neurotransmitters, and they promote free radical production

 4.    in the brain, several metabolic reactions outside of the mitochondria generate free radicals (e.g., monoamine oxidase metabolism)

 5.    since brain neurons do not regenerate, free radical damage in allowed to accumulate within each cell over time

 6.    free radical formation from H2O2 (hydrogen peroxide) is high in the brain because brain tissue contains much non-heme iron (Fe+2), which converts H2O2 (hydrogen peroxide) to .OH

      -  the formation of .OH from H2O2 (hydrogen peroxide) in the brain by using iron is enhanced because vitamin C assists the reaction of H2O2 (hydrogen peroxide) with iron

 7.    brain has antioxidant defense mechanisms

      - vitamin E, a lipid soluble vitamin, protects cellular membranes by scavenging free radicals

      - vitamin C, a water soluble vitamin, protects cytosol and nucleoplasm by scavenging free radicals

      - glutathione peroxidase, an intracellular enzyme, protects by converting H2O2 (hydrogen peroxide) to H2O by oxidizing reduced glutathione. This reduces .OH hydroxyl free radical production

      - catalase and glutathione peroxidase protect by converting H2O2 to H2O by transferring an H+ and an e- to H2O2

      - glutathione reductase helps by reducing the oxidized form of glutathione back to the reduced form after it has been used to convert H2O2 to H2O. Thus, the glutathioine is recycled.

      -  melatonin reduces free radical damage to brain neurons

      -  melatonin is much more effective than vitamin E at inactivating fatty acid free radicals

      - melatonin neutralizes O2- superoxide, H2O2, and .OH hydroxyl free radicals

      - melatonin stimulates production of glutathione peroxidase

      - melatonin may be able to slow development and progress of certain neurological diseases by slowing brain cell damage by free radicals

 8.    melatonin administration increases longevity and prolongs good health in mice

 9.    melatonin administration preserves and/or increases immune system functioning in mice

10.   melatonin reduces free radical damage to lipids such as in the brain and lungs

11.   melatonin decreases DNA damage by free radicals in vivo at physiological levels as well as at pharmacological levels

12.   melatonin reduces free radical oxidation damage due to exogenous toxins and carcinogens and ionizing radiation

13.   melatonin reduces free radical damage to protein such as that seen in experimentally induced cataract formation in young mice

14.   melatonin is a very effective antioxidant and anti-free radical agent for several reasons

      -  melatonin neutralizes O2- superoxide free radicals and .OH hydroxyl free radicals

            - melatonin seems to inactivate .OH hydroxyl free radical by contributing an e-. The oxidized form of melatonin that results is nontoxic and has low potential to oxidize materials.

            - the oxidized form of melatonin produced when it inactivates .OH hydroxyl free radicals seems to be used to inactivate O2- superoxide free radicals. The final melatonin product is eliminated in the urine. This means that one melatonin molecule can inactivate one .OH hydroxyl free radical and one O2- superoxide free radical and produce a completely harmless substance that is easily excreted in the urine. By eliminating O2- superoxide free radicals, the melatonin also reduces the production of .OH hydroxyl free radicals because .OH hydroxyl free radicals can be derived from O2- superoxide free radicals through H2O2 (hydrogen peroxide). Some of this melatonin product may actually be converted back to melatonin to be used again (i.e., melatonin molecules may be recycled as they eliminate O2- superoxide free radicals and .OH hydroxyl free radicals).

      - melatonin may be recycled after neutralizing fatty acid free radicals

      - melatonin increases the activity of glutathione peroxidase and thereby increases the elimination of H2O2 (hydrogen peroxide) by converting it to H2O

      - melatonin induces the synthesis of glutathione peroxidase, further increasing the conversion of H2O2 to H2O

      - melatonin acts synergistically with vitamin E, vitamin C, and reduced glutathione to destroy free radicals

      -  vitamin E inactivates fatty acid free radicals (lipid peroxides) by adding e-. The resulting oxidized vitamin E is recycled back to reduced vitamin E by vitamin C

      -  melatonin is approximately 5 times more powerful at destroying .OH hydroxyl free radicals than is reduced glutathione

      - melatonin neutralizes fatty acid free radicals

      -  when O2- superoxide free radical or .OH hydroxyl free radical oxidizes fatty acids in lipids, the resulting oxidized fatty acid (a lipid peroxide) is itself a free radical, which can then oxidize yet another fatty acid in a lipid. This creates a chain reaction whereby many fatty acids can be oxidized in sequence. Each oxidized fatty acid is damaged because it reacts with O2 to form a distorted fatty acid (a lipid peroxide) and then oxidizes another fatty acid. Hence, the chain reaction produces an ever growing number of damaged fatty acids. The damaged fatty acids in membrane lipids make the membranes less flexible and less permeable and thereby less able to function normally in cells.

            - melatonin can inactivate lipid free radicals produced when O2- superoxide free radical or .OH hydroxyl free radical oxidizes lipids. This is important because this breaks the chain reaction whereby lipid free radicals oxidize other fatty acids, which become free radicals and in turn, oxidize still other fatty acids.

      - melatonin inhibits nitric oxide synthetase, thereby reducing nitric oxide production

      - nitric oxide is used by brain neurons and it can increase the production of free radicals such as .OH hydroxyl free radical

      - melatonin seems to inactivate 1O2, which is a single oxygen atom and a free radical formed during re-perfusion of ischemic tissue. The 1O2 is believed to be a major cause of re-perfusion injury due to free radical oxidation

      - since any hemorrhage results in the release of iron into tissue spaces and since iron can form the highly toxic and damaging .OH from H2O2 (hydrogen peroxide). Melatonin may reduce this damage especially in the brain after hemorrhagic events such as small hemorrhagic strokes

            - iron and copper ions can reactivate fatty acids damaged by free radicals, converting the damaged fatty acids to lipid free radicals

            - since protein molecules often have iron associated with them, the iron promotes .OH formation from H2O2 (hydrogen peroxide) and from damaged fatty acids, the iron held in proteins can continue to promote ongoing local free radical damage in protein molecules  

Changes in melatonin with aging:  
    1.    age-related reduced nighttime peaks of melatonin have been shown in X.S. studies, but not yet in L.S. studies

 2.    though the maximum melatonin peak decreases with aging, the basal level remains stable

 3.    decrease in maximum rates of synthesis and blood levels, but apparently no change in the rate of elimination of melatonin

 4.    decline in total amount produced each 24-hour day

 5.    nighttime peaks decrease with aging until there is virtually no diurnal rhythm of melatonin synthesis and blood levels. Steady daylight basal levels are maintained throughout the 24 hour day

 6.    in women, melatonin production drops markedly before the increase in FSH associated with the onset on menopause

 7.    decrease production may be due to decreased receptors on pineal cells

 8.    decreased production may be due to deterioration of cells in suprachiasmatic nucleus (SCN) of the hypothalamus, which signals melatonin production by the pineal

            - SCN cells may be damaged by free radicals produced from glutamate, the neurotransmitter released at the SCN when there is little light on the retina

 9.    age-related decreases in melatonin may be due to increased oxidative damage to one of its metabolic precursors derived from serotonin

10.   the dampening of melatonin rhythms with aging may contribute to aging by reducing the main signal controlling many other diurnal rhythms (e.g., hormones, sleep/wakefulness), and this loss of normal youthful rhythmicity is detrimental to many cells, tissues, and organ/systems

11.   the decline in melatonin and the dampening of melatonin rhythms with aging may contribute to aging because melatonin affects genetic actions, and declining melatonin levels may adversely affect gene activity

12.   there is little age-related change in antioxidants except for the decline in melatonin

13.   food restriction preserves melatonin peaks as age increases

14.   food restriction seems to preserve the melatonin peaks with aging by helping maintain the receptors on pineal cells

15.   food restriction also seems to decrease free radical formation and damage, perhaps by helping to maintain melatonin peaks and total 24-hour production since melatonin reduces free radical damage by several mechanisms

16.   short term (several weeks) dietary restriction can reverse the amount of oxidative damage accumulated in the brain of well-fed animals

17.   long term dietary restriction results in less oxidative damage in brains

18.   attenuation of the melatonin peak in aging men may be a main reason for less drop in body temp. during the night as age increases

19.   in older women, there is a decrease in sensitivity to melatonin such that in older women (54-62 years old), melatonin does not cause as great a decrease in body temperature during the night as melatonin does in younger women. One mechanism of this effect is the reduced ability of melatonin in older women to increase heat loss through the skin.

      -  melatonin causes 40 -50 of the decrease in body core temperature during the night in young humans

20.   possible mechanisms by which melatonin administration, such as by pineal transplant, increases longevity and health include (a) increased immune system functioning, (b) increased thyroid functioning, and (c) decrease free radical oxidation damage

      -  melatonin supplementation sustains the thymus gland by reducing normal thymus cell death. This may occur by melatonin’s antioxidant effect on thymus cells

21.   attempts to alter melatonin levels to slow aging or reduce certain diseases must be done carefully since in addition to its roles as an antioxidant, melatonin also affects the levels and temporal patters of other hormones, sleep, and psychological characteristics (e.g., mood, depression)

22.   reduction in melatonin production can be cause be B-adrenergic blockers, such as used in a number of medications taken by elderly

Miscellaneous information:  
        -  melatonin inhibits growth of certain types of cancer

      -  melatonin seems to alleviate tremors associated with Parkinson’s disease. This action by melatonin may be due to its antioxidant activity in the brain  

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Main references for information and illustrations:

1.     Reiter, R.J., et al. (1996) Melatonin in the Context of the Free Radical Theory of Aging , Ann. N. Y. Acad. Sci., 786:362-378.

 

2.     Reiter, R.J. (1995) Oxygen Detoxification Processes During Aging: The Functional Importance of Melatonin , Aging Clin. Exp. Res., 7:340-351.

 

3.     Reiter, R.J. (1995) Oxidative Processes and Antioxidative Defense Mechanisms , The FASEB Journal, 9:526-533.

 

4.     Reiter, R.J. (1996) Functional Aspects of the Pineal Hormone Melatonin in Combating Cell and Tissue Damage Induced by free Radicals , European Journal of Endocrinology, 143:421-420.

 

5.     Reiter, R.J. (1996) Functional Diversity of the Pineal Hormone Melatonin: Its Role as an Antioxidant , Experimental and Clinical Endocrinology & Diabetes, 104:10-16.

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