Melatoninand

Lifestyle Diseases Dr. Fathi Neana, MD

Chief of OrthopaedicsDr. Fakhry & Alrajhy Hospital

Saudi ArabiaDecember, 11 – 2016

11 Lifestyle diseases you should take seriouslyRenita Tisha Pinto, Health Me Up | Oct 2, 2015

Globally 14.2 million people - 30-69 years olddie / year from these diseases.

These diseases emerged as bigger killers than infectious or hereditary ones.

Lifestyle diseases

Type II diabetes Arteriosclerosis Heart disease High blood pressure Swimmer's earCancer Stroke Chronic obstructive pulmonary disease CirrhosisNephritis Obesity & Metabolic syndrome

Lifestyle diseasesOrthopaedic complaints accounts for the epidemic proportions (cases of low back ache, joint disorders,

degenerative diseases that we find in our clinics and also around us)

Orthopedic disorders Metabolic syndromeNeck & LBPDeg Disc disorders - SpondylosisDeg Joint diseases - OAOsteoporosisOsteomalacia/RicketsInflammatory joint diseasesAuto immunityFracturesHost A B CSurgical difficultiesComplications

The common risk factors attributing to the orthopedic complaints are:

Lack of proper exercisesImproper posturesSedentary lifestyleChange in work methodsObesityLack of Nutritious diet (especially vitamins and minerals)Stress, Stress, Stress!!!

Healthy lifestyle vs medicines include:Regular exerciseHealthy eatingProper postureNo smokingManaging stress

سباتا ) نومكم لباسا( )9وجعلنا يل الل معاشا( 10وجعلنا هار الن وجعلنا(11)

النبإ سورة9. “And We made your sleep for repose,” 10. “And We made the

night as a covering” 11. “And We made the day for (seeking) livelihood,”

سباتا )و نومكم لباسا( )9جعلنا يل الل معاشا( 10وجعلنا هار الن وجعلنا(11)

النبإ سورة9. “And We made your sleep for repose,” 10. “And We made the

night as a covering” 11. “And We made the day for (seeking) livelihood,”

Blue light like from monitor screens suppress almost completely melatonin secretion

NB: Blue light from television, PC and laptop screens, smart phones are of the sources of the worst blue lights one can be exposed to and by leaving a television set or laptop

screen on during the night will suppress melatonin production significantly.

Melatonin, hormone secreted by the pineal gland

Melatonin was first isolated in 1958 by American physician Aaron B. Lerner and his colleagues at Yale

University School of Medicine

They gave the substance its name on the basis of its ability to lighten skin colour in frogs by reversing the skin-

darkening effects of melanocyte-stimulating hormone .

Melatonin, a derivative of the amino acid tryptophan ,In humans, melatonin plays an important role in the

regulation of sleep cycles (i.e., circadian rhythm).

Serotonin N transferase: the rate-limiting enzyme

Melatonin synthesis

The pineal glandThe retina

LymphocytesThe GI tract

Bone marrow cellsPlatelets

Skin

Melatonin's immediate precursor is the neurotransmitter Serotonin

A major player in regulating of the mood

Like serotonin, melatonin plays important roles in physical and

mental health

Physical and Mental health

Central and peripheral clocks in mammalsOrganized in a hierarchical manner

Central oscillator: controls the behavioral rhythm reset by external light signal

Peripheral oscillators : slave oscillators

regulate local rhythms reset by feeding

Circadian rhytms are endogenously generated; modulated by external signals (day/night rhytm)

Circadian rhytms – brain wave activity, hormone production, cell regeneration and other biological activities linked to this daily cycle

Regulation of a circadian rhytm1- The retinohypothalamic tract , the information about illumination from the retina (retinal

ganglion cells with melanopsin); 2. The circadian "clock" in the suprachiasmatic nucleus (SCN)3. The SCN interprets the information on day lenght and passes it on to the pineal gland which

then secretes the hormone melatonin (secretion of melatonin peaks at night)

Melatonin participates in various physiological functions according to 24-hour cycle

A circadian rhytm is 24-hour cyclein the physiological processes of living beings

Melatonin:

Ubiquitously in nature (everywhere, same time)One of the most phylogenetically ancient of all biological signaling mechanisms

A potent antioxidant (its primary function)

AntioxidantBesides its function as synchronizer of the biological clock, melatonin is a powerful free-radical scavenger and wide-spectrum antioxidant as discovered in 1993.[52] In many less-

complex life forms, this is its only known function.[27] Melatonin is an antioxidant that can easily cross cell membranes and the blood-brain barrier.[6][53] This antioxidant is a direct

scavenger of radical oxygen and nitrogen species including OH•, O•2

−, and NO•.[54][55]

Melatonin works with other antioxidants to improve the overall effectiveness of each antioxidant.[55] Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant.[56] An important characteristic of melatonin that distinguishes it from other classic radical scavengers is that its metabolites are also

scavengers in what is referred to as the cascade reaction.[27] Also different from other classic antioxidants, such as vitamin C and vitamin E, melatonin has amphiphilic

properties. When compared to synthetic, mitochondrial-targeted antioxidants (MitoQ and MitoE), melatonin proved to be a comparable protector against mitochondrial oxidative

stress.[57]

Melatonin is involved in various physiological functions:

Circadian rhytm regulation, sleep propensity, control of sleep/wake rhytm,

blood pressure regulation, immune function, retinal functions,

detoxification of free radicals, control of tumor growth,

bone protection, the regulation of bicarbonate secretion in the GI tract

Melatonin in plants

in high concentrations (protection from oxidative damage) many plants represent an excellent dietary source of melatonin as an antioxidant

nutrient

The majority of herbs used in traditional Chinese medicine for retarding age-related changes and for treating diseases associated with the generation of free radicals

contain the highest levels of melatonin

Melatonin is primarily secreted by the pineal gland; synthesis also occurs in other cells and organs

secretion is synchronized to the light/dark cycle, with a nocturnal maximum

Exogenous administrationCircadian rhytm sleep disorders (CRSD), insomnia, cancer, neurodegenerative diseases,

disorders of the immune function, oxidative damage

Melatonin exerts actions in almost every cell in the body

1. Melatonin receptors-receptor mediated effects

2. Melatonin diffuses through membranes easily- receptor independent effects

Melatonin produces effects in:

Receptor-independent:

1. Free radical scavenging properties2. Inhibition of calmodulin

-an attenuation of cAMP-dependent signaling cascades-decrease ER binding and activation of ERE-containing genes3. Regulation of the quinone reductase 2 activity

Receptor-dependent:

1. G-protein coupled receptors (MT1 or MT2)- an attenuation of cAMP-dependent signaling cascades

- inhibition of ER 2. The mitogen activated protein kinase cascade (MEK/ERK)

Melatonin

Circadian pacemaker: suprachiasmatic nucleus

Seasonal breeding (hypothalamus and other

organs relevant to reproduction)

Vasomotor control: constriction via MT1 dilation via MT2

Immune system (B cells, T cells, NK cells, thymocytes,

bone marrow)

Scavenging of reactive oxygen species (ROS), reactive nitrogen species (RNS)

and organic radicals

Elimination of toxic quinones

CNS: antiexcitatory effects, avoidance of Ca2+ overload

Cytoskeletal effects: binding to calmodulin, activation of protein

kinase C

Upregulation of antioxidant and downregulation of prooxidant

enzymes

Attenuation of mitochondrial electron leakage

Decrease of free radicals and other oxidants

Prevention of apoptosis

Direct inhibition of mitochondrial permeability transition pore

opening

MT1, MT2

Quinone reductase 2 (MT3)

More efficient than other antioxidants; devoid of pro-oxidant side-effects

1. Scavenging of free radicals2. Up-regulation of antioxidant enzymes

3. Direct inhibition of free radical formation

Neurodegenerative diseases (Alzheimer‘s, Parkinson‘s and Huntington‘s disease) - potential role of

melatonin

Melatonin as an antioxidantMelatonin Combats Inflammation able to cross the blood-brain barrier

Melatonin Combats Inflammation, Offers Mood and Anti-Aging Brain SupportMelatonin is a powerful antioxidant and free radical scavenger that helps 'cool

down' excess inflammation.

Melatonin is so integral to the health of immune system . A lack of it causes thymus gland, a key component of immune system, to shrink in size

Because melatonin is a strong antioxidant and is able to cross the blood-brain barrier, it is thought to help protect against Alzheimer's disease as well as

brain aging.

Melatonin as an antioxidantMelatonin Combats Inflammation able to cross the blood-brain barrier

1. Antioxidant activity2. Modulation of the estrogen signalling pathway

Melatonin has demonstrated oncostatic effects against a variety of tumor cells: estrogen-positive breast cancer cell lines, ovarian carcinoma cell lines, endometrial carcinoma,

human uveal melanoma cells, prostate tumor cells, intestinal tumors

Melatonin ameliorates side effects of antitumoral therapeutic regimens (myelotoxicity, lymphocytopenia)

Melatonin as an oncostatic substanceMelatonin inhibits the carcinogenesis

1- melatonin has a calming effect on several reproductive hormones, which may explain why it seems to protect

against sex hormone-driven cancers

2- Causing cancer cells to self-destruct, melatonin boosts production of immune-optimizing substances such as

interleukin-2, which helps identify and attack the mutated cells that lead to malignant cancer

Melatonin's Role in Fighting Cancer

Some of the more impressive studies include the following:•The journal Epidemiology5 reported increased breast cancer risk among women who

work predominantly night shifts•Women who live in neighborhoods with large amounts of night time illumination are more likely to get breast cancer than those who live in areas where nocturnal darkness

prevails, according to an Israeli study6•From participants in the Nurses' Health Study, it was found that nurses who work

nights had 36 percent higher rates of breast cancer7•Blind women, whose eyes cannot detect light and so have robust production of

melatonin, have lower-than-average breast cancer rates8•When the body of epidemiological studies are considered in their totality, women who

work night shift are found to have breast cancer rates 60 percent above normal, even when other factors such as differences in diet are accounted for9

Melatonin's Role in Fighting CancerThe greatest area of melatonin research to date has to do with breast

cancer.

1. Enhances the production of cytokines2. Antiapoptotic and antioxidant actions

3. Direct effect on the regulation of the immune system (via receptors)

Inhibition of melatonin synthesis results in the attenuation of cellular and humoral responses: exogenous melatonin

counteracts immunodeficiences The role of melatonin in the pathogenesis of autoimmune

diseases: the increased prevalence of auto-immune diseases at winter (long nights, increased levels of melatonin)

Melatonin‘s immunomodulatory functionMelatonin has an immunomodulatory role

MT1 receptors in SCN

The treatment of insomnia (particularly in individuals with melatonin deficiency)

Melatonin as a hypnoticMelatonin promotes sleep in healthy humans

MT2 receptors in SCN

Implication in circadian rhythm sleep disorders1. Shift-work disorder

2. Jet lag syndrom3. Delayed sleep phase syndrome

4. Circadian rhythm disruption with ageing

Melatonin as a chronobiotic moleculeMelatonin acts as an endogenouos synchronizer of

bodily rhythms

Melatonin is synthesized in the enterochromaffin cells of the GI tract and can be released to the circulation

Functions in the GIT:1. Increase duodenal mucosal secretion of bicarbonate -

duodenal protection against gastric acid2. High concentration in the bile-prevents oxidative

damage to the intestinal epithelium caused by bile acids3. Gastroprotective efficacy: as an antioxidant

GIT melatonin

Melatonin reduces blood pressure in hypertensive patients

1. Peripheral mechanism: vasodilatation via MT2

vasoconstriction via MT1 (cerebral vessels)2. Central mechanism

Melatonin in cardiovascular diseases

Melatonin stimulates the appearance of 'beige' fat, which, similar to brown fat

The study… showed that chronic administration of melatonin sensitizes the thermogenic effect of exposure to cold, heightens

the thermogenic effect of exercise and, therefore, constitutes excellent therapy against obesity.

'beige fat' cell mitochondria express levels of UCP1 protein, responsible for burning calories and generating heat."

Melatonin Help You Fight Fat?

Beneficial effects for heart disease, including reducing the severity of high blood pressure, limiting the frequency of heart

failure and protecting against drug-related damage to the heart.Useful for restoring imbalances in bone remodeling to prevent

bone losslower levels of melatonin have double the risk of developing type

2 diabetes Reduced the frequency of migraine headaches by half (or more)

after three months

Help for Heart Disease, Headaches, Diabetes and Osteoporosis?

Melatonin causes inhibition of bone resorption (protects bone during treatment with gluococorticoids that affect

bone remodeling and cause osteoporosis)

1. Down-regulation of osteoclast activation2. Direct inhibition of osteoclast function (antioxidant)

Melatonin effects on bone

1. Via MT receptors2. Via nuclear receptors

Melatonin inhibits the hypothalamic-pituitary-gonadal axis (important for sexual maturation)

The decline in melatonin concentration is very important for the initiation of puberty

Melatonin down-regulates GnRH gene in a cyclicyl pattern over a 24-h period; the pulsatile secretion of GnRH controls

LH a FSH

Melatonin in sexual maturation and in reproduction

Melatonin Regulates Our Cycles, Mood, Reproduction, Weight and May Help Combat Cancer

October 10, 2013 | 279,344 views

01 AUG 2016Melatonin – health and repair mechanisms

By Robert Gorter, MD, PhD,

Melatonin help us to sleep. This benefit is only one of many.

Melatonin protect against heart disease, diabetes, Alzheimer's & migraine headaches? It help with weight control , strengthening the immune system?

It play a role in cancer prevention.

Artificial lighting, laptop & TV monitors , smart phones disrupts melatonin production . Many Americans may be lacking this 'wonder hormone.

Disorders of melatonin

• Hypomelatonism

• Hypermelatonism

• Dysmelatonism

Hypomelatonism

• Old age• Pineal tumors• Psychiatric

disorders: depression, schizophrenia

• Mentally retarded and autistic

• Alcohlism

• Autonomopathy• Klinefelder's and Turner's

syndrome• Neoplasm: liver, kidney,

upper respiratory tract, breast, skin and prostate

• Some cases of coronary heart disease.

Drug induced hypomelatonism

• Beta blockers: Metaprolol->propranolol->Atenolol

• Alpha 2 blocker: Clonidine• Naloxone• NSAID ibuprofen • Alcohol, tobacco, caffeine• Benzodiazepine

Effects of hypomelatonismDecreased immune function

Blood pressure instabilityIncreased plaques in the brain, like those seen with

Alzheimer's diseaseDiabetic microangiopathy (capillary damage)

Accelerated cancer cell proliferation and tumor growth (including leukemia)

Decreased free radical scavenging Increased risk of osteoporosis

Depression and/or seasonal affective disorder (SAD)

insomniadifficulty getting to sleepdifficulty falling back to sleep when awaken during the nightlight sleeper/easy waking during the nightearly morning awakeningun-refreshing sleeplack of dreamingfamily history of insomniapersonal or family history of breast cancerpersonal or family history of prostate cancerprostate enlargementfatigue

depressionirregular menstrual cycleunusual menstrual flow (light or heavy)PMSscoliosispoor sleeping prior to mensesanxietysensitivity to stresscataractsneurodegerative disorder (MS, Parkinson's, Alzheimer's, ALS, etc)elevated cholesterolhigh blood pressureblood clotsheart attackheart arrhythmias

Common symptoms and signs of melatonin deficiencyto many to remember

Hypermelatonism

Seasonal affective disorder (SAD)

• Extreme fatigue and lack of energy• Increased need for sleep• Carbohydrate cravings• Weight gain• Reduced work productivity• Withdrawal from social contacts• Exposure to light improve

Dysmelatonism

Circadian rhythm Syndrome• Blind• Jet lag• Night shift workers ( Industrial

jet lag)• Delayed sleep phase syndrome

• Disruption of sleep• Decreased attention

span– Decreased work

efficiency – Work- and non-work

related accidents• Irritability• Headaches

• Fatigue

• Substance abuse• Depression• Reduced Immunity

• Cardiovascular and • Gastrointestinal

disorders

DysmelatonismClinical features of Circadian rhythm Syndrome (CRS)

Natural way to increase melatonin

• Early to bed and early to rise• Food: Oats, sweet corn, rice, barley,

tomatoes and bananas• Vitamin B3, B6 (dried apricots, barley,

whole wheat, tuna and turkey, rice, bananas, lentils, shrimp and carrots)

Foods containing melatonin or induce the natural production of melatoninImprove your nights sleep with these

9 foods Turkey Oats Almonds Marmite

بخميرة/ أسود عسل مارمايت Warm milk Bananas Tart CherriesGrapes Whole Grain Cereals

سباتا ) نومكم لباسا( )9وجعلنا يل الل معاشا( )10وجعلنا هار الن النبإ( 11وجعلنا سورة9. “And We made your sleep for repose,” 10. “And We made the night as a covering” 11. “And We

made the day for (seeking) livelihood,”

Deep sleep in the dark is the cheapest source of Melatonin

Conclusions

Melatonin is distributed widely in nature; it acts as a photoperiod messenger molecule, transducing photoperiod changes to various

cyclic function in organism (reproduction, sleep-wake rhythms)

Melatonin is very important antioxidant (primary function in evolution)

Melatonin influences various cell mechanisms via receptors (plasmatic, nuclear)

Melatonin play a role in many pathological states: neurodegenerative disorders, circadian rhythm sleep disorders, depression, cardiovascular

diseases, tumor growth, immune pathologies, bone resorption (potential therapeutic agent)

Summary

The New Lifestyle diseases is a Buzzlesearching for an answer

How to avoid Lifestyle diseases

My long life experience precious advice is

1- Trusted sources then Calibrate with the absolute truth2- Live a Biological, Anti inflammatory and Natural Life style

Attach to the absolute truths in the sayings of almightly ALLAH and his Messenger (peace and

blessings be upon him)

Avoid Mankind processed deviations & inherited Myths

How to Improve and Protect Your Melatonin ProductionImprove your sleep hygiene, article "33 Secrets to a Good Night's Sleep.”

Avoid watching TV or using computer in the evening, at least an hour before going to bed.

Make sure you get BRIGHT sun exposure regularly. Sleep in complete darkness, or as close to it as possible.

Install a low-wattage yellow, orange or red light bulb if you need a source of light for navigation at night.

Keep the temperature in your bedroom no higher than 70 degrees F. optimal room temperature for sleep is 60 to 68 degrees F.

Take a hot bath 90 to 120 minutes before bedtime. Avoid using loud alarm clocks. Regular enough sleep, not even need an alarm.

Get some sun in the morning, Circadian system needs bright light to reset itself. Be mindful of electromagnetic fields in your bedroom. EMFs can disrupt your

pineal gland and its melatonin production, and may have other negative biological effects as well.