Three-Step Strategy to Reverse Mitochondrial Aging

Reposted from Life Extension
http://www.lef.org/magazine/mag2013/aug2013_Three-Step-Strategy-to-Reverse-Mitochondrial-Aging_01.htm

By Michael Downey

Have you ever wondered how long you’re going to live? The potential answer can be found in the energy-producing cellular powerhouses called mitochondria.
According to a growing number of cell biologists, the number and functionality of the mitochondria specifically determine an individual’s life span.^1-3
When we’re young, we are relatively protected against mitochondrial deterioration. As we age, however, changes within our cells lead to the destruction of mitochondria—paving the way for aging and disease.^4-8
In 2007 scientists made a remarkable age-reversal discovery:

Damage to mitochondrial DNA becomes permanent a decade after mitochondrial dysfunction begins—and in the early stages, this damage remains reversible.⁹

In this article, you’ll learn about a 3-step program aimed at restoring your body’s vital mitochondrial health:

Step 1: Boost your body’s natural mitochondrial DNA defenses with CoQ10.
Step 2: Stimulate the creation of new mitochondria with PQQ.
Step 3: Support your body’s mitochondrial defense system with shilajit.

This strategy to reduce damage to existing mitochondrial DNA and create new mitochondria—is essential to inhibit a destructive cycle believed to be a root cause of aging.

Why We Need Mitochondria

 

Found inside the body’s cells, mitochondria are responsible for producing our primary source of energy, adenosine triphosphate (ATP). ATP provides at least 95% of the cellular energy that powers all living functions.
Unfortunately, a byproduct of this energy generation is the formation of a huge stream of free radicals.^4-7 Free radicals are molecules that possess a free electron—a property that makes them react with other molecules in volatile and highly destructive ways.^10-12
Free radicals attack the structure of our cell membranes, creating metabolic waste products that disturb DNA and RNA production, interfere with the synthesis of protein, and destroy important cellular enzymes. Vital tissues and molecules decay under the assaults of free radicals.^10-14 In addition, free-radical disruption of cell mechanics creates mutant cells, which are linked to cancer and cellular aging.^15,16
Mitochondria are the easiest targets of free-radical injury for two reasons:

1. They are located exactly where these free radicals are produced, and
2. They lack most of the antioxidant defenses found in other parts of the cell.^17,18

Evidence strongly indicates that over time, accumulated damage to the DNA of the mitochondria in particular leads directly to metabolic disorders (such as diabetes) and degenerative disorders (such as Alzheimer’s).^4-8,19-23
Mitochondrial dysfunction is primarily seen in organs and tissues that have a high demand for energy—explaining why cardiovascular tissue and brain neurons are among the most susceptible.²⁴
When we’re young, we are largely protected against mitochondrial deterioration because our bodies produce substances to defend mitochondria from the onslaught of free radicals. However, as we age, that protection wanes, setting us up for a destructive cycle that accelerates aging and disease. As a result of this rapidly accelerating process, mitochondria in the cells of elderly people are mostly dysfunctional, whereas young individuals have virtually no mitochondrial damage.^8,25-27

The Mitochondrial Theory of Aging

 

Over time, there are three devastating changes within our cells that lead to the destruction of mitochondria—paving the way for aging and disease:^4-7

• The rate of cellular production of two free radicals—superoxide anions and hydrogen peroxide —significantly increases, attacking mitochondria the most.
• At the same time, intracellular levels of endogenous antioxidants that help prevent the harmful effects of free radicals decrease. There’s also a reduction in activities of free radical-scavengers that neutralize free radicals before they can attach themselves to other molecules. These decreases diminish the mitochondria’s normal defenses.
• The accumulated oxidative damage to the mitochondrial DNA and other mitochondrial components (as well as the cell as a whole) leads to decay of the mitochondria—and from that decay, the release of even more free radicals!

According to the mitochondrial theory of aging, this ever-increasing spiral is—in itself—an aging process.^{4-8, 25,26} In fact, a growing number of cell biologists have suggested that the number and functionality of the mitochondria can specifically determine an individual’s longevity.^1-3
Based on this body of scientific evidence, scientists determined that a key to slowing—and even reversing—a “natural” aging process would be a substance aimed at revitalizing youthful mitochondrial protection from free radicals.²⁷
They discovered this mitochondrial solution in a substance that may already be in your nutrient regimen…coenzyme Q10.

What You Need to Know

Block Mitochondrial Aging

• Daily damage to mitochondrial DNA appears to be a root mechanism of aging.
• If caught before it becomes permanent, early stage mitochondrial dysfunction can be reversed!
• Levels of CoQ10—the body’s natural mitochondrial defense—decline rapidly with age. But breakthrough research has found that supplemental CoQ10 blocks mitochondrial aging.
• Shilajit works synergistically with CoQ10 by replenishing its electron supply and increasing CoQ10 levels.
• PQQ powerfully supports the protection afforded by CoQ10 and shilajit by triggering the creation of new mitochondria.
• Taken together, CoQ10, PQQ, and shilajit offer a potent program to inhibit the intensely destructive cycle believed to be one of the root sources of aging!

Coenzyme Q10 Protects Mitochondria

Scientists have established that coenzyme Q10 (CoQ10) is an essential nutrient for normal mitochondrial function (namely, the production and transfer of energy).^28-30 When CoQ10 levels fall, mitochondrial dysfunction skyrockets.²⁸ Studies have found that boosting CoQ10 levels via supplementation increases mitochondrial electron transport—whether the cells are deficient in CoQ10 or not.^29,30
CoQ10’s ability to protect the vital mitochondria helps put an end to the vicious cycle that underscores a critical aspect of pathological aging. In fact, research with laboratory models has suggested that CoQ10 may be one of our most potent anti-aging nutrients. Studies have found that when cells or organisms are deficient in CoQ10, mitochondrial oxidative stress increases and aging is accelerated.^28,31 However, supplementation triggers a significant slowing down of the aging process and an extended life span.^32,33
One study showed that rats supplemented with CoQ10 experience a 24% increase in maximum life span and an 11.7% increase in average life span.³⁴ In human terms, based on today’s life expectancy of 78.5 years, this mean increase translates to a more than 9-year increase in life span!³⁵
CoQ10 also seems to work via a multi-targeted set of epigenetic mechanisms that not only slow aging—but that also protect against a variety of mitochondria-related diseases.^36-38 Epigenetic mechanisms involve changes in gene function that do not relate to changes in gene structure.³⁹ Studies have shown that CoQ10 protects against neurodegenerative diseases^40-42 and mental health disorders,⁴³ enhances lung function,^44,45 guards against the effects of elevated glucose in diabetes and metabolic syndrome,^46-48 and offers impressive defense against cardiovascular disease, one of the primary diseases of aging.^49-51
Animal studies demonstrate that supplementation with CoQ10 reduces oxidative stress and reduces the buildup of amyloid-beta plaque (associated with Alzheimer’s disease)^40-42,52,53 —resulting in a significant improvement in cognitive performance and memory.⁵³
In human studies, 4 weeks to 6 months of CoQ10 supplementation at 60-300 milligrams a day was shown to improve cardiac systolic function and ejection fraction.^49,50 One study showed that 8 weeks of CoQ10 supplementation at 300 milligrams a day improved heart-muscle systolic function by enhancing both mitochondrial performance and endothelial function.⁵⁰ And in a 5-year, randomized, double-blind, placebo-controlled trial among elderly individuals, CoQ10 combined with selenium slashed the death rate from cardiovascular disease by more than half!⁵⁴ In fact, the authors of one study recognized CoQ10 as a “scientific breakthrough in the management of chronic heart failure.”⁵⁵
CoQ10 offers a powerful way to help slow—or even reverse—a natural aging process by restoring youthful mitochondrial protection from free radicals.^27,56
 

CoQ10: Potential Therapy for Inherited Mitochondrial Disorder

Newly released research underscores the vital importance of coenzyme Q10 (CoQ10) to mitochondrial health.
A study released ahead of print in April 2013 by the journal Mitochondrion has found that patients with mitochondrial DNA depletion syndrome (MDS) have significantly deficient levels of CoQ10.⁸⁵ MDS is a hereditary condition characterized by grossly reduced cellular levels of mitochrondrial DNA in infancy. MDS involves various progressive disorders that are often fatal in childhood.⁸⁶
Currently, there are no effective therapies available for MDS⁸⁶—but this recent finding indicates that CoQ10 could represent a candidate therapy for this condition.
The suggestion that CoQ10 may constitute a therapeutic hope for treating this serious mitochondrial-deficiency disorder demonstrates just how powerfully CoQ10 protects mitochondria.
This also underscores CoQ10’s vital importance in slowing or reversing the “natural” aging process in healthy individuals.

PQQ Creates New Mitochondria

While coenzyme Q10 optimizes mitochondrial function and protects them from free radical damage, scientists have found another coenzyme that triggers the creation of new mitochondria altogether.
A huge research advance in 2012 showed that the coenzyme pyrroloquinoline quinone (or PQQ) activates genes that induce mitochondrial biogenesis—the spontaneous formation of new mitochondria in aging cells!⁵⁷
This represents a major breakthrough in battling the mitochondrial destruction that underlies aging.
PQQ deficiency has a profound effect on your genes—especially those involved in cellular stress, cell signaling, transport of metabolites, and of course, the creation of new mitochondria.⁵⁷ Specifically, PQQ deficiency negatively affects the expression pattern of 438 genes—but research has found that this effect is reversed after supplementation with PQQ.⁵⁷
Prior to this breakthrough, some of the only scientifically validated ways to reliably stimulate the creation of new mitochondria were sustained calorie restriction or strenuous physical activity—both of which are too rigorous and impractical for most aging people.^58,59 PQQ now provides the most practical means of reversing the deadly decline in functional mitochondria that is the underlying cause of premature aging and degenerative disease.
Earlier findings repeatedly indicated PQQ’s central role as a potent growth factor.^60,61 In preclinical trials, when animals were deprived of dietary PQQ, they exhibited stunted growth, impaired conception rates, and most importantly, fewer mitochondria.^62-64 However, re-introducing PQQ into the diet reversed these effects—while simultaneously increasing mitochondrial number and energetic efficiency.^62,63
Like CoQ10, PQQ also actively supports the energy transfer within the mitochondria that supplies the body with most of its bioenergy. Its exceptional stability allows it to carry out thousands of these transfers without undergoing molecular breakdown. PQQ has been proven especially effective in neutralizing two of the most potent free radicals, the superoxide and hydroxyl radicals.⁶⁵

5,000 Times More Effective than Vitamin C!

Research demonstrates that PQQ is 30 to 5,000 times more efficient at reducing oxidation than other common antioxidants such as vitamin C.⁶⁰
In a revealing 2010 study, scientists reported that similar protection of mitochondrial function that is seen with some other compounds (such as quercetin, hydroxytyrosol, and resveratrol) at high dietary concentrations measured in millimoles occurs with PQQ at dietary concentrations measured in nanomoles.⁶⁶ In other words, it takes a million times more of these other compounds to have a mitochondria-protective effect equivalent to PQQ!
The revelation of its ability to favorably affect system-wide cell development, metabolism, and mitochondrial biogenesis helps explain the wealth of data on PQQ’s neuroprotective and cardioprotective benefits.
PQQ has now been shown to block the development of abnormal proteins linked with neurodegenerative diseases. For example, it prevents cellular damage and demise due to accumulation of amyloid beta protein associated with Alzheimer’s disease,^67,68 and of the alpha-synuclein protein that is associated with Parkinson’s disease.^57,69
In humans, supplementation with 20 milligrams a day of PQQ significantly improved cognitive function in middle-aged and elderly people. These results were amplified when the subjects also took 300 milligrams per day of CoQ10.⁷⁰
In animal studies, researchers investigating its impact on cardiovascular disease have demonstrated that PQQ reduces the size of the heart area damaged by acute heart attack and favorably decreases lipid peroxidation.⁷¹ PQQ also helps heart muscle cells resist acute oxidative stress—specifically by preserving and enhancing mitochondrial function.⁷²
Neither humans nor the bacteria that colonize the human digestive tract have demonstrated the ability to synthesize PQQ,⁷³ which has led researchers to classify it as an essential micronutrient. This means that the body can’t make enough of it for good health—and that supplementation is essential.⁷⁴

Shilajit Revitalizes CoQ10

Shilajit

We’ve already learned that CoQ10 protects mitochondria from free radical damage. It does this by “depleting” itself—by donating its own electrons to (and thus neutralizing) the flood of free radicals generated during cellular energy production. Of course, this results in depleted stores of active CoQ10.
Studies have detailed how shilajit, a phyto-mineral pitch substance found in the Himalayas,^75-77 stabilizes, revitalizes, and preserves CoQ10 in its active (ubiquinol) form, boosting the levels of CoQ10 available to protect against mitochondrial aging. ^78-81
Cutting-edge scientific evidence has demonstrated that components of shilajit serve as electron reservoirs, replenishing electrons lost by CoQ10 and allowing this vital coenzyme to remain active longer.^78-80
Shilajit’s potent support of CoQ10’s mitochondrial protection against aging was validated when laboratory mice were subjected to strenuous and stressful physical exercise. The combination of shilajit and CoQ10 resulted in 27% greater ATP energy production in muscle cells—and in 40% greater energy production in brain cells—than the energy increase measured in these tissues with CoQ10 alone.⁸⁰
In other research, mice were initially supplemented with oral CoQ10 alone. As expected, CoQ10 levels rose in heart, liver, and kidney tissue. Remarkably, when components from shilajit were added to the supplement, CoQ10 levels rose even further—as much as 29% in liver tissue.⁸¹
Another element of shilajit—fulvic acid—has been shown to further support this process by channeling other electron-rich shilajit components into the mitochondria to support CoQ10 and electron transfer.⁸² Fulvic acid also works independently to stimulate mitochondrial energy metabolism and protect mitochondrial membranes from oxidative damage.^82,83
In an unpublished study, people who took 200 milligrams of shilajit once daily for 15 days registered an increase in ATP levels in the blood after exercise. ⁸⁴
Ultimately, the synergistic effects of shilajit plus CoQ10—combined with the capacity of PQQ to create new mitochondria—offer an unparalleled option to protect mitochondrial DNA and combat aging!

Ubiquinol Provides Superior Bioavailability

Called a “coenzyme” because of its unique ability to participate in chemical reactions but remain at steady-state levels in the cell, coenzyme Q10 plays a central role in energy metabolism.^28-30
CoQ10’s ability to cycle back and forth between ubiquinone and ubiquinol accounts for many of its unique properties. Ubiquinol, with its ability to scavenge free radicals, is an electron donor, while ubiquinone is an electron acceptor. This remarkable ability to cyclically accept and donate electrons, as well as to effect complementary chemical reactions in the mitochondria, accounts for CoQ10’s unparalleled value to almost all life forms.
The chemical difference between ubiquinone and ubiquinol is that the ubiquinol compound contains two hydroxyl groups. These two hydroxyl groups enable ubiquinol to be more easily dissolved into water than ubiquinone, thus making it easier to assimilate, which helps explain why it is so much more bioavailable than ubiquinone.
In a side-by-side single-dose human study, ubiquinol absorption was compared directly to conventional CoQ10 (ubiquinone) using the same delivery system. Subjects were given either 100 mg of ubiquinol or 100 mg of ubiquinone. The findings showed that in aged test subjects, ubiquinol absorption was 60% greater in this single-dose side-by-side comparison.⁸⁷
A review of published studies on human subjects reveals that it requires very high doses of ubiquinone CoQ10 to achieve the same levels attainable with modest amounts of ubiquinol CoQ10.^88-92 Clinical studies using 1,200 and 2,400 mg per day of ubiquinone achieved CoQ10 blood levels similar to 150 and 300 mg per day respectively of ubiquinol.^88-91

Summary

According to the mitochondrial theory of aging, damage to mitochondrial DNA from the massive free-radical assault of cellular energy production is a root mechanism of aging. The body produces CoQ10 to protect mitochondrial DNA, but levels decline rapidly with age.
Scientists have discovered that it can take almost a decade for this aging damage to become permanent. The good news is that early stage mitochondrial dysfunction can be reversed!
Breakthrough research found that two coenzymes (CoQ10 and PQQ) can work together to protect mitochondria against free radical assaults—and to create new mitochondria in the process.
Supplemental coenzyme Q10 blocks mitochondrial aging, while PQQ triggers the creation of new mitochondria. In addition, shilajit works synergistically with CoQ10, replenishing its electrons and prolonging its antioxidative effectiveness.
Taken together, CoQ10 and PQQ and shilajit offer a potent program to inhibit—and reverse—the intensely destructive cycle that is believed to be a root source of aging!
If you have any questions on the scientific content of this article, please call a Life Extension^® Health Advisor at 1-866-864-3027.
 

References

1. Lanza IR, Nair KS. Mitochondrial function as a determinant of life span. Pflugers Arch. 2010 Jan;459(2):277-89.
2. Robb EL, Page MM, Stuart JA. Mitochondria, cellular stress resistance, somatic cell depletion and lifespan. Curr Aging Sci. 2009 Mar;2(1):12-27.
3. Alexeyev MF, LeDoux SP, Wilson GL. Mitochondrial DNA and aging. Clin Sci (Lond). 2004 Oct;107(4):355-64.
4. Wei YH, Lu CY, Lee HC, Pang CY, Ma YS. Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function. Ann NY Acad Sci. 1998 Nov 20;854:155-70.
5. Mandavilli BS, Santos JH, Van Houten B. Mitochondrial DNA repair and aging. Mutat Res. 2002 Nov 30;509(1-2):127-51.
6. Cadenas E, Davies KJ. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic Biol Med. 2000 Aug;29(3-4):222-30.
7. Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood). 2002 Oct;227(9):671-82.
8. Hamilton ML, Van Remmen H, Drake JA, et al. Does oxidative damage to DNA increase with age? PNAS. 2001;98(18):10469-74.
9. Conley KE, Marcinek DJ, Villarin J. Mitochondrial dysfunction and age. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):688-92.
10. Barja G. Free radicals and aging. Trends Neurosci. 2004 Oct;27(10):595-600.
11. Hekimi S, Lapointe J, Wen Y. Taking a “good” look at free radicals in the aging process. Trends Cell Biol. 2011 Oct;21(10):569-76.
12. Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med. 2013 Jul;60:1-4.
13. Sinha K, Das J, Pal PB, Sil PC. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 2013 Mar 30. [Epub ahead of print]
14. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J. 2012 Jan;5(1):9-19.
15. Kumar A, Pant MC, Singh HS, Khandelwal S. Determinants of oxidative stress and DNA damage (8-OhdG) in squamous cell carcinoma of head and neck. Indian J Cancer. 2012 Jul-Sep;49(3):309-15.
16. Berquist BR, Wilson DM 3rd. Pathways for repairing and tolerating the spectrum of oxidative DNA lesions. Cancer Lett. 2012 Dec 31;327(1-2):61-72.
17. Barja G. Updating the Mitochondrial Free Radical Theory of Aging: An integrated view, key aspects, and confounding concepts. Antioxid Redox Signal. 2013 May 5. [Epub ahead of print]
18. Neustadt J, Pieczenik SR. Medication-induced mitochondrial damage and disease. Mol Nutr Food Res. 2008 Jul;52(7):780-8.
19. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989;1(8639):642-5.
20. Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78.
21. Picard M, Turnbull DM. Linking the metabolic state and mitochondrial DNA in chronic disease, health, and aging. Diabetes. 2013 Mar;62(3):672-8.
22. Scheffler K, Krohn M, Dunkelmann T, et al. Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis. Acta Neuropathol. 2012 Aug;124(2):199-208.
23. Maruszak A, Zekanowski C. Mitochondrial dysfunction and Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Mar 30;35(2):320-30.
24. De Pauw A, Tejerina S, Raes M, Keijer J, Arnould T. Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am J Pathol. 2009 Sep;175(3):927-39.
25. Short KR, Bigelow ML, Kahl J, et al. Decline in skeletal muscle mitochondrial function with aging in humans. Proc Natl Acad Sci USA. 2005 Apr 12;102(15):5618-23.
26. Linnane AW, Kovalenko S, Gingold EB. The universality of bioenergetic disease: age-associated cellular bioenergetic degradation and amelioration therapy. Ann N Y Acad Sci. 1998 Nov 20;854:202-13.
27. Karbowski M, Neutzner A. Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathol. 2012 Feb;123(2):157-71.
28. Duberley KE, Abramov AY, Chalasani A, Heales SJ, Rahman S, Hargreaves IP. Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment. J Inherit Metab Dis. 2013 Jan;36(1):63-73.
29. Fernández-Ayala DJ, López-Lluch G, García-Valdés M, Arroyo A, Navas P. Specificity of coenzyme Q10 for a balanced function of respiratory chain and endogenous ubiquinone biosynthesis in human cells. Biochim Biophys Acta. 2005;1706:174-83.
30. López-Martín JM, Salviati L, Trevisson E, et al. Missense mutation of the COQ2 gene causes defects of bioenergetics and de novo pyrimidine synthesis. Hum Mol Genet. 2007;16:1091-7.
31. Cordero MD, Cotán D, del-Pozo-Martín Y, et al. Oral coenzyme Q10 supplementation improves clinical symptoms and recovers pathologic alterations in blood mononuclear cells in a fibromyalgia patient. Nutrition. 2012 Nov-Dec;28(11-12):1200-3.
32. Takahashi M, Ogawara M, Shimizu T, Shirasawa T. Restoration of the behavioral rates and lifespan in clk-1 mutant nematodes in response to exogenous coenzyme Q(10). Exp Gerontol. 2012 Mar;47(3):276-9.
33. Ishii N, Senoo-Matsuda N, Miyake K, et al. Coenzyme Q10 can prolong C. elegans lifespan by lowering oxidative stress. Mech Ageing Dev. 2004 Jan;125(1):41-6.
34. Quiles JL, Ochoa JJ, Huertas JR, Mataix J. Coenzyme Q supplementation protects from age-related DNA double-strand breaks and increases lifespan in rats fed on a PUFA-rich diet. Exp Gerontol. 2004 Feb;39(2):189-94.
35. Available at: http://www.cdc.gov/nchs/fastats/lifexpec.htm. Accessed May 14, 2013.
36. Schmelzer C, Kohl C, Rimbach G, Doring F. The reduced form of coenzyme Q10 decreases the expression of lipopolysaccharide-sensitive genes in human THP-1 cells. J Med Food. 2011 Apr;14(4):391-7.
37. Santos-Gonzalez M, Gomez Diaz C, Navas P, Villalba JM. Modifications of plasma proteome in long-lived rats fed on a coenzyme Q10-supplemented diet. Exp Gerontol. 2007 Aug;42(8):798-806.
38. Lee BJ, Huang YC, Chen SJ, Lin PT. Effects of coenzyme Q10 supplementation on inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, and homocysteine) in patients with coronary artery disease. Nutrition. 2012 Jul;28(7-8):767-72.
39. McGowan PO, Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24.
40. Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer’s disease. J Alzheimers Dis. 2008 Jun;14(2):225-34.
41. Moreira PI, Santos MS, Sena C, Nunes E, Seica R, Oliveira CR. CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol. 2005 Nov;196(1):112-9.
42. Yang X, Yang Y, Li G, Wang J, Yang ES. Coenzyme Q10 attenuates beta-amyloid pathology in the aged transgenic mice with Alzheimer presenilin 1 mutation. J Mol Neurosci. 2008 Feb;34(2):165-71.
43. Forester BP, Zuo CS, Ravichandran C, et al. Coenzyme Q10 effects on creatine kinase activity and mood in geriatric bipolar depression. J Geriatr Psychiatry Neurol. 2012 Mar;25(1):43-50.
44. Gvozdjáková A, Kucharská J, Bartkovjaková M, Gazdíková K, Gazdík FE. Coenzyme Q10 supplementation reduces corticosteroids dosage in patients with bronchial asthma. Biofactors. 2005;25(1-4):235-40.
45. Fujimoto S, Kurihara N, Hirata K, Takeda T. Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases. Clin Investig. 1993;71(8 Suppl):S162-6.
46. Mezawa M, Takemoto M, Onishi S, et al. The reduced form of coenzyme Q10 improves glycemic control in patients with type 2 diabetes: an open label pilot study. Biofactors. 2012 Nov-Dec;38(6):416-21.
47. El-ghoroury EA, Raslan HM, Badawy EA, et al. Malondialdehyde and coenzyme Q10 in platelets and serum in type 2 diabetes mellitus: correlation with glycemic control. Blood Coagul Fibrinolysis. 2009 Jun;20(4):248-51.
48. Hodgson JM, Watts GF, Playford DA, Burke V, Croft KD. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr. 2002 Nov;56(11):1137-42.
49. Sander S, Coleman CI, Patel AA, Kluger J, White CM. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail. 2006 Aug;12(6):464-72.
50. Dai YL, Luk TH, Yiu KH, et al. Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial. Atherosclerosis. 2011 Jun;216(2):395-401.
51. Mikhin VP, Kharchenko AV, Rosliakova EA, Cherniatina MA. Application of coenzyme Q(10) in combination therapy of arterial hypertension. Kardiologiia. 2011;51(6):26-31.
52. Yang X, Dai G, Li G, Yang ES. Coenzyme Q10 reduces beta-amyloid plaque in an APP/PS1 transgenic mouse model of Alzheimer’s disease. J Mol Neurosci . 2010 May;41(1):110-3.
53. Dumont M, Kipiani K, Yu F, et al. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis. 2011;27(1):211-23.
54. Alehagen U, Johansson P, Bjornstedt M, Rosen A, Dahlstrom U. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: A 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. Int J Cardiol. 2012 May 22.
55. Mortensen SA, et al. Coenzyme Q10: clinical benefits with biochemical correlates suggesting a scientific breakthrough in the management of chronic heart failure. Int J Tissue React. 1990;12(3):155-62.
56. Lenaz G, Bovina C, D’Aurelio M, et al. Role of mitochondria in oxidative stress and aging. Ann N Y Acad Sci. 2002 Apr;959:199-213.
57. Misra HS, Rajpurohit YS, Khairnar NP. Pyrroloquinoline-quinone and its versatile roles in biological processes. J Biosci. 2012 Jun;37(2):313-25.
58. Steiner JL, Murphy EA, McClellan JL, Carmichael MD, Davis JM. Exercise training increases mitochondrial biogenesis in the brain. J Appl Physiol. 2011 Oct;111(4):1066-71.
59. Guarente L. Mitochondria--a nexus for aging, calorie restriction, and sirtuins? Cell. 2008 Jan 25;132(2):171-6.
60. Rucker R, Chowanadisai W, Nakano M. Potential physiological importance of pyrroloquinoline quinone. Altern Med Rev. 2009 Sep;14(3):268-77.
61. Choi O, Kim J, Kim JG, et al. Pyrroloquinoline quinone is a plant growth promotion factor produced by Pseudomonas fluorescens B16. Plant Physiol. 2008 Feb;146(2):657-68.
62. Stites T, Storms D, Bauerly K, et al. Tchaparian. Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. J Nutr. 2006 Feb;136(2):390-6.
63. Steinberg F, Stites TE, Anderson P, et al. Pyrroloquinoline quinone improves growth and reproductive performance in mice fed chemically defined diets. Exp Biol Med (Maywood). 2003 Feb;228(2):160-6.
64. Bauerly KA, Storms DH, Harris CB, et al. Pyrroloquinoline quinone nutritional status alters lysine metabolism and modulates mitochondrial DNA content in the mouse and rat. Biochim Biophys Acta. 2006 Nov;1760(11):1741-8.
65. Urakami T, Yoshida C, Akaike T, Maeda H, Nishigori H, Niki E. Synthesis of monoesters of pyrroloquinoline quinone and imidazopyrroloquinoline, and radical scavenging activities using electron spin resonance in vitro and pharmacological activity in vivo. J Nutr Sci Vitaminol (Tokyo). 1997 Feb;43(1):19-33.
66. Tchaparian E, Marshal L, Cutler G, et al. Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways. Biochem J. 2010 Aug 1;429(3):515-26.
67. Zhang JJ, Zhang RF, Meng XK. Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Neurosci Lett. 2009 Oct 30;464(3):165-9.
68. Kim J, Kobayashi M, Fukuda M, et al. Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins. Prion. 2010 Jan;4(1):26-31.
69. Kobayashi M, Kim J, Kobayashi N, et al. Pyrroloquinoline quinone (PQQ) prevents fibril formation of alpha-synuclein. Biochem Biophys Res Commun. 2006 Oct 27;349(3):1139-44.
70. Nakano M, Ubukata K, Yamamoto T, Yamaguchi H. Effect of pyrroloquinoline quinone (PQQ) on mental status of middle-aged and elderly persons. FOOD Style 21. 2009;13(7):50-3.
71. Zhu BQ, Simonis U, Cecchini G, et al. Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther. 2006 Jun;11(2):119-28.
72. Tao R, Karliner JS, Simonis U, et al. Pyrroloquinoline quinone preserves mitochondrial function and prevents oxidative injury in adult rat cardiac myocytes. Biochem Biophys Res Commun. 2007 Nov 16;363(2):257-62.
73. Smidt CR, Bean-Knudsen D, Kirsch DG, Rucker RB. Does the intestinal microflora synthesize pyrroloquinoline quinone? Biofactors.1991 Jan;3(1):53-9.
74. Zhang Y, Rosenberg PA. The essential nutrient pyrroloquinoline quinone may act as a neuroprotectant by suppressing peroxynitrite formation. Eur J Neurosci. 2002 Sep;16(6):1015-24.
75. Schepetkin IA, Xie G, Jutila MA, Quinn MT. Complement-fixing activity of fulvic acid from Shilajit and other natural sources. Phytother Res. 2009 Mar;23(3):373-84.
76. Goel RK, Banerjee RS, Acharya SB. Antiulcerogenic and antiinflammatory studies with shilajit. J Ethnopharmacol. 1990 Apr;29(1):95-103.
77. Agarwal SP, Khanna R, Karmarkar R, Anwer MK, Khar RK. Shilajit: a review. Phytother Res. 2007 May;21(5):401-5.
78. Ghosal S. Shilajit in Perspective. Oxford, U.K.: Narosa Publishing House; 2006.
79. Islam A, Ghosh R, Banerjee D, Nath P, Mazumder U, Ghosal S. Biotransformation of 3-hydroxydibenzo-pyrone into 3,8 dihydroxydibenzo-pyrone and aminoacyl conjugates by Aspergillus niger isolated from native “shilajit.” Electro J Biotechno. 2008 Jul 15;11(3):2-10.
80. Bhattacharyya S, Pal D, Gupta AK, Ganguly P, Majumder UK, Ghosal S. Beneficial effect of processed shilajit on swimming exercise induced impaired energy status of mice. Pharmacologyonline. 2009;1:817-25.
81. Bhattacharyya S, Pal D, Banerjee D, et al. Shilajit dibenzo—pyrones: Mitochondria targeted antioxidants. Pharmacologyonline. 2009; 2:690-8.
82. Kang SH, Choi W. Oxidative degradation of organic compounds using zero-valent iron in the presence of natural organic matter serving as an electron shuttle. Environ Sci Technol. 2009 Feb 1;43(3):878-83.
83. Visser SA. Effect of humic substances on mitochondrial respiration and oxidative phosphorylation. Sci Total Environ. 1987 Apr;62:347-54.
84. Pal D, Bhattacharya S. Pilot Study on the Improvement of Human Performance with ReVitalETTM as Energy Booster: Part-IV. 2006. Data on file. Natreon, Inc.
85. Montero R, Grazina M, López-Gallardo E, et al. Coenzyme Q10 deficiency in mitochondrial DNA depletion syndromes. Mitochondrion. 2013 Apr 11.
86. Available at: http://rarediseasesnetwork.epi.usf.edu/NAMDC/learnmore/diseases.htm. Accessed May 15, 2013.
87. Age difference of bioavailability. Unpublished data, Kaneka Corp.
88. Hosoe K, Kitano M, Kishida H, et al. Study on safety and bioavailability of ubiquinol (Kaneka QH(trade mark)) after single and 4-week multiple oral administration to healthy volunteers. Regul Toxicol Pharmacol. 2006 Aug 17.
89. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50.
90. Shults CW, Flint BM, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol. 2004 Aug;188(2):491-4.
91. Kurowska EM, Dresser G, Deutsch L, Bassoo E, Freeman DJ. Relative bioavailability and antioxidant potential of two coenzyme q10 preparations. Ann Nutr Metab. 2003;47(1):16-21.
92. Shults CW, Haas RH, Beal MF. A possible role of coenzyme Q10 in the etiology and treatment of Parkinson’s disease. Biofactors. 1999;9(2-4):267-72.

Statin Use Tied To Cataract Development

Reposted from FoxNews
http://www.foxnews.com/health/2013/09/20/statin-use-tied-to-cataract-development/?intcmp=obnetwork

The risk of developing cloudy lenses in the eyes may be linked to the use of cholesterol-lowering drugs known as statins, according to a new study.
While the researchers can't prove the drugs caused the eye condition, they found that people who took statins - such as Zocor and Lipitor - were about 27 percent more likely to develop cataracts, compared to people who didn't take the medication.
"The results were consistent that there was a higher risk of being diagnosed with cataracts among statin users," Dr. Ishak Mansi, the study's senior author from UT Southwestern Medical Center and the Dallas VA Medical Center in Texas, said.
Statins are popular drugs that block a substance the body needs to make cholesterol, which can get trapped in arteries and ultimately lead to heart attacks and strokes.
About one-quarter of U.S. adults aged 45 and older take statins. The drugs are especially recommended for people with diabetes or a history of cardiovascular problems.
Researchers have looked at the link between statins and cataracts before with mixed results. While some studies found that taking statins lowered the risk of developing cataracts, other studies found the drugs increased the risk.
For the new research, Mansi and his colleagues used data collected from the medical records of people between the ages of 30 and 85 years old who were enrolled in one healthcare system in San Antonio, Texas, and received care between 2003 and 2005.
In one analysis, they compared about 7,000 people who were on statins for at least 90 days to about 7,000 people who were not on statins but were similar in about 40 other characteristics, including other health conditions, medications and healthcare use.
About 36 percent of statin users were diagnosed with cataracts, compared to about 34 percent of people not taking statins.
In a second analysis, the researchers looked at people with no other known health conditions. It included 6,113 statin users and 27,400 people who did not take statins.
After adjusting the results for the participants' age, sex, weight, medications, healthcare use, other vision conditions and cigarette, alcohol and drug use, the researchers found about 34 percent of statin users were diagnosed with cataracts, compared to about 10 percent of people not taking statins.
What's more, the researchers found that the risk of developing cataracts increased with the length of time a person took the medication.
While Mansi and his colleagues can't say how statins may affect the formation of cataracts, they write in JAMA Ophthalmology that there are a few possible explanations.
One is that the body needs high levels of cholesterol to maintain a clear lens and statins may interfere with the cells that control that process.
Dr. Jack Cioffi, head of ophthalmology at Columbia University Medical Center in New York, said the study is very well done, but has some limitations, including that the researchers used billing data rather than medical records, so they can't say how severe the cataracts were.
"I don't think we should overstate the significance of this. It goes back to if there is a good reason for you to be on that statin, it outweighs the risk of a mild increase in risk of cataract," Cioffi, who was not involved in the new study, said.
He added that the treatments for cataracts have evolved over time. The National Institutes of Health says the procedures to remove cataracts are some of the most common and safest surgeries performed in the U.S.
"For patients themselves, my advice is to discuss what your benefit and risk ratio is for you with your doctor," said Mansi, who added that he hopes the results will also encourage people to improve their cholesterol levels through lifestyle changes.
"This should motivate patients to do their part. Quit smoking, eat healthy and be active so doctors don't have to give you a tablet that may have some side effects," he said.


Read more: http://www.foxnews.com/health/2013/09/20/statin-use-tied-to-cataract-development/?intcmp=obnetwork#ixzz2fckKAXEm

Statin Drugs Cause Even More Nerve Damage Than We Thought

Reposted from Live In The Now

 http://www.liveinthenow.com/article/statin-drugs-cause-even-more-nerve-damage-than-we-thought

Have the nerve-damaging properties of statin drugs now been confirmed? There are over 300 adverse health effects associated with the use of this chemical class of cholesterol-lowering medications known as statins, with myotoxicity (muscle-damaging) and neurotoxicity (nerve-damaging) top on the list. When will the FDA step in and warn the public, as proof of the problem in the biomedical literature reaches an alarming level of clarity?
The neurotoxicity of statin drugs are back in the news. Following on the heels of the FDA decision earlier this year to require statin drugs manufacturers to add “memory loss” as a side effect of this chemical class, a new study in published in the Journal of Diabetes reveals a clear association between statin use and peripheral neuropathy in a US population 40 years of age and older.
The study found “The prevalence of peripheral neuropathy was significantly higher among those who used statins compared to those who did not (23.5% vs. 13.5%; p < 0.01),” which is a 75% increase in relative risk.

Also Read

A Simple Cholesterol Solution Your Doctor Won’t Tell You About

Case reports of statin-induced peripheral neuropathy have existed in the medical literature for over 15 years. Now, larger human studies are confirming that statin drugs do damage to the peripheral nerves. Moreover, much of the damage is occurring below the threshold of clinical surveillance, silently causing harm in unsuspecting patients.
For example, in 2011, the results of a 36-month prospective clinical and neurophysiological follow-up of patients treated with statins over 3 years was published in the journal Neuro Endocrinology Letters, revealed in forty-two patients that despite the fact that they did not report subjective symptoms typical for peripheral neuropathy, damage was occurring.  They concluded: “The study confirmed that long-term treatment with statins caused a clinically silent but still definite damage to peripheral nerves when the treatment lasts longer than 2 years.” Click the hyperlink to view all 9 studies on statin-induced peripheral neuropathy on Greenmedinfo.com. Or, view an even more sizeable dataset (54 studies) on statin-associated neurotoxicity.

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While this research is adding to a growing awareness of the nerve-damaging properties of statins, this side effect is just the tip of a massive iceberg of under reported deleterious effects. For example, our project has identified 314 possible adverse effects of statins thus far.  Conversely, we have identified a wide range of health benefits of cholesterol, running diametrically opposed to the over-simplification inherent in the cholesterol hypothesis (some say “cholesterol myth“) of heart disease causation.
For those who are interested in learning more about natural cholesterol modulating substances, or, better yet, the wider array of research relevant to cardiovascular health, visit this Health Guide: Heart Health.
Sources:
[1] Pavel Otruba, Petr Kanovsky, Petr Hlustik. Treatment with statins and peripheral neuropathy: results of 36-months a prospective clinical and neurophysiological follow-up. Neuro Endocrinol Lett. 2011 Sep 3 ;32(5):688-690. Epub 2011 Sep 3. PMID: 22167150
[2] T Phan, J G McLeod, J D Pollard, O Peiris, A Rohan, J P Halpern. Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatry. 1995 May ;58(5):625-8. PMID: 7745415

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This article is republished with permission from Green Med Info, November 15, 2012. Go straight to the source.

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Sayer Ji is the founder and director of GreenMedInfo.com and co-author of the book The Cancer Killers: The Cause Is The Cure. His writings and research have been published in the Wellbeing Journal, the Journal of Gluten Sensitivity, and have been featured on Mercola.com, NaturalNews.com, Reuters.com, GaryNull.com, and Care2.com. Check out his newest project with co-author Tania Melkonian: EATomology: An Edible Philosophy of Food

DHA linked to Intelligence in Children

Reposted from Dr. Mercola
http://articles.mercola.com/sites/articles/archive/2013/08/19/omega-3-fat-dha.aspx

By Dr. Mercola

If you want your child to reach his or her maximum intellectual potential, the research is clear that plentiful intake of the omega-3 fat DHA (docosahexaenoic acid) is essential.
In the US, most kids get hardly any of this healthful fat, found primarily in seafood, in their diets, and may be missing out on this simple opportunity to boost brain performance.
Most recently, two new studies have confirmed that boosting your child’s intake of DHA as an infant and into the school-age years may be a simple way to generate measurable improvements in their brain function.

Low DHA Levels May Impact Reading, Memory and Behavior  

The first study involved children aged 7-9 who had below-average reading scores. In these kids, low levels of DHA and other omega-3 fats were associated with poor reading, memory and behavioral problems.¹
Previous studies have also found children with attention deficit hyperactivity disorder (ADHD) and related behavior/learning disabilities are more likely to have low omega-3 fat levels that could benefit from supplementation.
The new study was unique in that it looked at healthy children without learning disabilities, but with poor reading skills, and still found a link with low omega-3 levels.

“These findings require confirmation, but suggest that the benefits from dietary supplementation with Omega-3 LC-PUFA [long-chain polyunsaturated fatty acids] found for ADHD, Dyspraxia, Dyslexia, and related conditions might extend to the general school population,” the researchers concluded.

DHA Supplementation Early in Life Increases Intelligence as Older Children

In the second study, a group of infants received either an omega-3 fat supplement or a placebo.² Tests to evaluate their cognition were given every six months starting at age 18 months and continuing until they were 6 years old.
While no changes were noted in the early test done at 18 months, the study found that infants consuming omega-3 fats consistently outscored the placebo group later, between 3 and 5 years old.
Specifically, the omega-3 fat group scored higher on rule learning, vocabulary and intelligence testing, which suggests early omega-3 fat supplementation, during the key period when your child’s brain is still developing, may translate directly into greater intelligence in the pre-school and school-aged years. The researchers noted:

“ … although the effects of LCPUFAs [omega-3 fats] may not always be evident on standardized developmental tasks at 18 mo[nths], significant effects may emerge later on [for] more specific or fine-grained tasks.”

Omega-3s Found to Alter and Boost Brain Function

Sixty percent of your brain is made up of fat. DHA alone makes up about 15 percent to 20 percent of your brain's cerebral cortex. It's found in relatively high levels in your neurons – the cells of your central nervous system, where it provides structural support.
Because your brain is literally built from omega-3 fats, it makes sense that it would play an integral role in brain function (and even may help support healing after a brain injury).
Still more research found, for instance, that DHA supplementation might affect functional cortical brain activity in 8-10-year-old boys.³
The study included 33 healthy boys who were randomly assigned to receive a daily dose of either 400 milligrams (mg) of DHA, 1,200 mg of DHA, or a placebo, for two months. Researchers then measured the boys’ brain activation patterns, using functional magnetic resonance imaging (fMRI), while the boys were playing video games.
In the group receiving the highest daily dose, the DHA levels in the membrane of red blood cells (erythrocytes) increased by a whopping 70 percent. The lower dose group saw an increase of 47 percent, while the placebo group had an 11 percent reduction in DHA levels while performing this type of sustained attention task.
The fMRI data indicates that there were significant increases in the activation of the dorsolateral prefrontal cortex part of the brain in the groups receiving supplemental DHA. This is an area of your brain that is associated with working memory.

They also noticed changes in other parts of the brain, including the occipital cortex (the visual processing center) and the cerebellar cortex (which plays a role in motor control). The researchers noted:

“These findings suggest that this imaging paradigm could be useful for elucidating neurobiological mechanisms underlying deficits in cortical activity in psychiatric disorders associated with DHA deficiencies, including ADHD and major depression.”

Omega-3 Fats Are Essential During Pregnancy (and Later in Life) Too

A high-quality, animal-based omega-3 supplement is something that I recommend for virtually everyone, especially if you're pregnant, as the benefits likely begin in utero. Research has, in fact, linked inadequate intake of omega-3 fats in pregnant women to premature birth and low birth weight, in addition to hyperactivity in children. So not only is this one healthful fat your children should be consuming, but you should likely be consuming as well – and this includes in later life, too.
It is a point well worth emphasizing that omega-3 fats are considered essential because your body cannot produce them, and must get them from your daily diet. DHA-rich foods include wild fish, liver, and brain—all of which are no longer consumed in great amounts by most Americans. When your omega-3 intake is inadequate, your nerve cells become stiff and more prone to inflammation as the missing omega-3 fats are substituted with cholesterol and omega-6 instead. Once your nerve cells become rigid and inflamed, proper neurotransmission from cell to cell and within cells become compromised.
It's thought that the unsaturated fatty acid composition of normal brain tissue is age-specific, which could imply that in addition to their importance during brain development, the older you get, the greater your need for animal-based omega-3 fat to prevent mental decline and brain degeneration becomes.⁴
For example, low DHA levels have been linked to memory loss and Alzheimer's disease, and research suggests degenerative conditions can not only be prevented but also potentially reversed. For example, in one study, 485 elderly volunteers suffering from memory deficits saw significant improvement after taking 900 mg of DHA per day for 24 weeks, compared with controls.⁵ The point is, consuming omega-3 fats is a lifelong habit you should get into, just as important as drinking plenty of pure water and eating vegetables…

What’s the Optimal Source of Omega-3 Fats?

While a helpful form of omega-3 (ALA) can be found in flaxseed, chia, hemp, and a few other foods, the most beneficial form of omega-3 -- containing the two fatty acids, DHA and EPA, which are essential to brain function -- can only be found in fish and krill. While your body can convert ALA into DHA/EPA, it does so at a very low ratio, and only when sufficient enzymes (that many people are deficient in) are present.
Unfortunately, nearly all EPA- and DHA-rich fish are now severely contaminated with toxic mercury, which is why I generally don’t recommend consuming fish on a regular basis. About the only exception to this rule is wild-caught Alaskan salmon or very small fish, like sardines. Alaskan salmon is really the ONLY fish I eat regularly, and the only one I feel comfortable recommending as a good source of healthful fats. AVOID farmed salmon, as it contains only about half of the omega-3 levels of wild salmon. Farmed salmon may also contain a range of harmful contaminants, including environmental toxins, synthetic astaxanthin, and dangerous metabolic byproducts and agrichemical residues of genetically engineered organisms from the corn- and soy-based feed they’re given.
My latest recommendation for a source of high-quality omega-3 fats is krill oil. The omega-3 in krill is attached to phospholipids that increase its absorption, which means you need less of it, and it won't cause belching or burping like many other fish oil products. Additionally, it contains naturally occurring astaxanthin, a potent antioxidant—almost 50 times more than is present in fish oil.
This prevents the highly perishable omega-3 fats from oxidizing before you are able to integrate them into your cellular tissue. In laboratory tests, krill oil remained undamaged after being exposed to a steady flow of oxygen for 190 hours. Compare that to fish oil, which went rancid after just one hour. That makes krill oil nearly 200 times more resistant to oxidative damage (i.e. rancidity) compared to fish oil! When purchasing krill oil, you'll want to read the label and check the amount of astaxanthin it contains. The more the better, but anything above 0.2 mg per gram of krill oil will protect it from rancidity.

Tips for Giving Omega-3 Fats to Kids

As for your kids, I recommend supplementing with krill oil before and during pregnancy, and while breastfeeding. Infants receive vital DHA through your breast milk, so if you can continue breastfeeding through the first year, you will give your child a great head start for success in life.
Then, as soon as your child can safely swallow a capsule, he or she can start taking a high-quality krill oil supplement. The capsules should be kid-sized – about half the size of a regular capsule – and odor-free, making them easy and palatable for kids to swallow.

References provided at original link

Flaxseed: Protection against Heart Disease, Cancer and more.

Reposted from Life Extension
http://www.lef.org/magazine/mag2008/oct2008_Flaxseed_01.htm

By Milly Dawson

Revered for its benefits as far back as 4,000 years ago to the time of Hippocrates,1 flaxseed has been a long-held staple of human diets across Africa, Asia, and Europe. Lately, this versatile grain has begun to receive well-deserved attention in North America for its ability to help fend off the major life threatening diseases including cancer and heart disease. A rich source of minerals, omega-3 fatty acids, phytoestrogens, and soluble and insoluble fiber, abundant evidence supports the value of flaxseed in preventing diverse illnesses such as heart disease and cancer,2,3 as well as helping to address common ailments such as menopausal complaints and digestive irregularity.4,5 As part of a snack or meal, it’s easy to incorporate tasty and nutritious flaxseed as a staple ingredient in your own diet. Protecting Against Heart Disease Dietary omega-3 fatty acids have proven their mettle as preventive therapy against cardiovascular disease.2 Fish oil is the richest source of these heart-healthy fats. Among the plant foods that offer omega-3s, flaxseed stands far above the rest. Analyses have shown that while canola and corn oil contain approximately 10% and 1% omega-3s, respectively, flaxseed oil contains a far greater concentration of 57% omega-3s, in the form of alpha-linolenic acid.6-8 The value of omega-3s has emerged repeatedly from large population studies that normally consume large amounts of these heart-healthy oils.2 Scientific support for flaxseed is also abundant from dietary-modification studies, which have shown the benefits of omega-3-rich seeds in decreasing risk factors for cardiovascular disease.9,10 Typical of these experiments is a recent study in which postmenopausal women with mildly elevated cholesterol levels supplemented with approximately 30 grams of flaxseed (just over four tablespoons) daily for three months. Flaxseed supplementation lowered total cholesterol by 7% and decreased dangerous low-density lipoprotein (LDL) by 10%. These findings led the study authors to conclude that regular flaxseed consumption may offer cardiovascular disease protection by modulating blood lipid levels.9 Another study compared the effect of flaxseed with cholesterol-lowering statin therapy in people with a high total cholesterol level (more than 240 mg/dL). Researchers divided subjects into three groups: a low-fat diet plus either a statin drug or 20 grams (about three tablespoons) of ground flaxseed daily for two months, while a third control group received the low-fat diet only. Supplementation with flaxseed reduced blood lipids: total cholesterol levels fell by 17%, LDL levels dropped by 4%, and triglycerides plummeted by 36%. These improvements in total cholesterol and LDL levels in the flaxseed group were comparable to those seen in the statin group.10 Fighting Cancers Scientists have estimated that a remarkable 30-40% of all cancers could be prevented through dietary and lifestyle strategies alone. Flaxseed may play an important role in a cancer-preventive diet. “Intake of flaxseed, especially its lignan fraction, and abundant portions of fruits and vegetables will lower cancer risk,” notes one research review.3 The phytoestrogens so richly present in flaxseed—known as lignans— have proven, in numerous studies, to have great value in blocking hormone-dependent cancers, including breast and prostate cancer.3,11 Canadian researchers studied the effects of dietary flaxseed on key markers of tumor activity in women newly diagnosed with breast cancer. For approximately one month, patients in one group ate a flax-rich muffin (containing 25 grams flaxseed) daily, while a control group ate an ordinary muffin each day. The flax-eaters showed significantly reduced levels of a marker for tumor-cell growth and increased levels in the orderly process of cancer cell death (called apoptosis).12 The investigators concluded that dietary flaxseed may help reduce tumor growth in breast cancer patients. Growing evidence suggests that flaxseed may also help avert prostate cancer by boosting blood levels of beneficial enterolactones. After flaxseed is consumed, its lignans are converted in the intestine into enterolactones, which then enter the bloodstream. In a large study that examined blood enterolactone levels in men with prostate cancer versus healthy controls, men with the highest enterolactone levels were 82% less likely to have prostate cancer.13 Further studies are needed to determine if flaxseed may offer protection against other cancers. Flaxseed Nutritional Facts15 Flaxseed is a rich source of fiber, omega-3 fatty acids, and minerals. One tablespoon of ground flaxseed (7 g) contains the following:   Daily Value (DV)* Calories 37 Calories from fat 25   Total fat 3 g Saturated fat 0 g Trans fat 0 g Omega-3 fatty acids 1,597 mg Omega-6 fatty acids 414 mg 5%         Cholesterol 0 mg Sodium 2 mg Total carbohydrate 2 g Dietary fiber 2 g Sugars 0 g Protein 1 g   0% 1% 8%     Thiamin 0.1 mg Magnesium 27.4 mg Copper 0.1 mg Manganese 0.2 mg 8% 7% 4% 9% Daily values are based on a 2,000 calorie diet. Your daily values may be higher or lower depending on your calorie needs. Easing Symptoms Tied to Menopause Rich in phytoestrogens, flaxseed may offer welcome relief to women suffering the discomforts of menopause.11 Researchers at the Mayo Clinic demonstrated that flaxseed significantly decreased the occurrence of hot flashes in women who chose not to take estrogen therapy. Women suffering from regular hot flashes consumed 40 grams of flaxseed daily for six weeks. The daily frequency of hot flashes was reduced by a dramatic 50% at the study’s end, from an average of 7.3 hot flashes daily to 3.6 hot flashes per day.14 Nutritional scientists increasingly believe that phytoestrogens may help moderate a variety of other menopausal symptoms ranging from night sweats to moodiness.11 Ongoing research is investigating this promising possibility. Scientists describe phytoestrogens as plant-derived compounds that exert both estrogenic and anti-estrogenic effects in the body. As such, they may offer relief of symptoms associated with low estrogen levels, without the risks associated with estrogen itself. Flaxseed is rich in the phytoestrogens known as lignans, while soy provides an abundant source of the isoflavone phytoestrogens.11 Flaxseed Fiber Supports Healthy Digestion, Blood Sugar Flaxseed is a rich source of both soluble and insoluble fiber.5 Soluble fiber forms a gel-like matrix with water that adds bulk to stools and promotes more regular bowel movements. Nutritional scientists believe that the insoluble fiber found in flaxseed helps slow the release of sugar into the bloodstream following a meal, preventing spikes in blood glucose levels.5 One ounce of flaxseed contains 32% of the fiber recommended by the US Department of Agriculture.15 If you increase your intake of flax, remember to drink plenty of water as well. An Adaptable Ingredient Choose ground flaxseed rather than whole. The whole form simply passes through your digestive tract without surrendering its beneficial components. Alternately, you can grind whole flaxseeds in a coffee grinder before consumption. Sprinkle flaxseed on cereal, yogurt, steamed vegetables, and salads. Bake it into meat loafs and muffins, and use it as a healthful coating on oven-baked chicken or fish. For best results, store ground flaxseed in the refrigerator. If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.

References

1. Available at: www.medicinenet.com/script/main/art.asp?articlekey=52040. Accessed July 9, 2007. 2. Psota TL, Gebauer SK, Kris-Etherton P. Dietary omega-3 fatty acid intake and cardiovascular risk. Am J Cardiol. 2006 Aug 21;98(4A):3i-18i. 3. Donaldson MS. Nutrition and cancer: a review of the evidence for an anti-cancer diet. Nutr J. 2004 Oct 20;3:19. 4. Tham DM, Gardner CD, Haskell WL. Clinical review 97: Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab. 1998 Jul;83(7):2223-35. 5. Dahl WJ, Lockert EA, Cammer AL, Whiting SJ. Effects of flax fiber on laxation and glycemic response in healthy volunteers. J Med Food. 2005;8(4):508-11. 6. Available at: http://www.flaxcouncil.ca/english/index.php?p=g1&mp=nutrition. Accessed May 15, 2008. 7. Available at: http://www.nutritiondata.com/facts-C00001-01c20A1.html. Accessed May 15, 2008. 8. Available at: www.nutritiondata.com/facts-C00001-01c209M.html. Accessed May 15, 2008. 9. Patade A, Devareddy L, Lucas EA, Korlagunta K, Daggy BP, Arjmandi BH. Flaxseed reduces total and LDL cholesterol concentrations in Native American postmenopausal women. J Womens Health (Larchmt). 2008 Apr;17(3):355-66. 10. Mandasescu S, Mocanu V, Dascalita AM, et al. Flaxseed supplementation in hyperlipidemic patients. Rev Med Chir Soc Med Nat Iasi. 2005 Jul;109(3):502-6. 11. Stark A, Madar Z. Phytoestrogens: a review of recent findings. J Pediatr Endocrinol Metab. 2002 May;15(5):561-72. 12. Thompson LU, Chen JM, Li T, Strasser-Weippl K, Goss PE. Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res. 2005 May 15;11(10):3828-35. 13. Hedelin M, Klint A, Chang ET, et al. Dietary phytoestrogen, serum enterolactone and risk of prostate cancer: the cancer prostate Sweden study (Sweden). Cancer Causes Control. 2006 Mar;17(2):169-80. 14. Pruthi S, Thompson SL, Novotny PJ, et al. Pilot evaluation of flaxseed for the management of hot flashes. J Soc Integr Oncol. 2007;5(3):106-12. 15. Available at: www.nutritiondata.com/facts-C00001-01c20p1.html. Accessed February 15, 2007.

Beyond Sleep: 7 Ways Melatonin Attacks Aging Factors

Reposted from Life Extension
http://www.lef.org/magazine/mag2012/sep2012_7-Ways-Melatonin-Attacks-Aging-Factors_01.htm?utm_source=facebook&utm_medium=social&utm_campaign=normal

By Claudia Kelley, PHD, RD, CDE

Melatonin is known for helping some people achieve a better night's sleep, which is how it earned its nickname as "the sleep hormone." While melatonin is involved in regulating our internal body clock, that's just the beginning of its health-promoting benefits. Based on extensive research, scientists have discovered that this hormone has beneficial effects on everything from heart disease and diabetes, to bone health and obesity. And best of all, emerging science now suggests that it may protect our genetic material and guard against age related disease and decline.1 Preclinical studies found that melatonin increased the life span of animals by up to 20%—prolonging their youthful character in the process.2-4 Scientific evidence now suggests that melatonin plays a crucial role in a variety of metabolic functions,5 including antioxidant and neuroprotection,6,7 anti-inflammatory defense,8 and immune system support.9 Because melatonin production reduces with age,10-14 experts believe that its decline contributes to both the aging process and a generalized deterioration of health.5,15-17 Years ago, scientists could only speculate at the underlying mechanisms behind melatonin's anti-aging properties. A growing body of evidence reveals how melatonin is able to play such a major role in the combating aging process.18-20 #1: Antioxidant Defense—Combat Free Radical Damage While You Sleep Since its discovery over 50 years ago, melatonin has demonstrated itself as a functionally diverse molecule, with its antioxidant properties being amongst its most well-studied attributes.26,27 Since then, a vast amount of experimental research has revealed its vital role in the body's defense against numerous cell-damaging free radicals—and for good reason.27-30 Melatonin has been found to possess 200% more antioxidant power than vitamin E.31 Melatonin has been found to be superior to glutathione as well as vitamins C and E in reducing oxidative damage.6 As such a potent antioxidant, melatonin plays a powerful role in fighting free-radical-related diseases—from cardiovascular disease to cancer and practically everything in between. In post-menopausal women, for example, melatonin has been found to inhibit lipid peroxidation (damage to your fat cells caused by free radicals), thus leading to decreased levels of low-density lipoprotein (LDL) cholesterol,31 one of the primary ingredients for the formation of atherosclerosis. A newer study on men confirmed these findings, suggesting that melatonin leads to overall lower levels of oxidative stress in humans.32 In individuals undergoing cardiopulmonary bypass surgery, melatonin exhibited a higher reduction in lipid peroxidation and improvements in red blood cell membrane stiffness.33 Other widely feared free radical diseases, such as age-related macular degeneration (AMD),34 acute respiratory distress syndrome (ARDS),35 glaucoma,36 and sepsis37 have also been responsive to increased melatonin levels. #2: Melatonin Fights Back Against America's Major Killer Since cardiovascular disease is the leading cause of death in the United States, melatonin's ability to protect against heart damage is especially noteworthy.38 In the past decade, melatonin has received considerable attention investigating its potential as a cardioprotective nutrient. Animal studies have provided ample evidence supporting melatonin's antioxidant protection against heart muscle injury,39,40 reducing the damage done by a heart attack,41,42 and improving the strength of the heart's pumping action following a heart attack.43-46 Other investigators reported that it decreases total cholesterol and LDL levels and increases HDL cholesterol levels.33,34 Scientists have discovered that individuals with metabolic syndrome have a lower melatonin production rate compared to healthier counterparts without metabolic syndrome and that individuals with metabolic disturbances in blood pressure, cholesterol, and blood sugar management (all classic features of metabolic syndrome) possess lower melatonin levels than those with normal metabolic function.47 Additional in-vivo studies have confirmed that melatonin can lower blood pressure levels.44-48 #3: Cancer Therapy Adjuvant and Immune Regulator Emerging research suggests that melatonin has anticarcinogenic properties—that is, it has the ability to prevent cancer from occurring, or to induce the cancer cell death if it does occur. This has been attributed to melatonin's antioxidant, anti-inflammatory, anti-proliferative, and hormone-modulating properties.49,50 Melatonin's ability to interfere with cancer cell multiplication and growth ("proliferation"), as well as inducing cancer cell death ("apoptosis"), has been documented in cancer patients.51, 52 It has been successfully used in individuals with advanced stage cancers undergoing conventional anticancer therapy, by either slowing disease progression and/or decreasing treatment side effects.53-60 In a review of 8 randomized, controlled clinical trials evaluating the benefits of melatonin as an adjuvant therapy for cancer patients with solid tumors undergoing chemotherapy or radiation therapy, researchers found that concurrent use of 20 mg of melatonin once daily versus conventional treatment alone, improved the rate of complete or partial remission by nearly 50%, increased the one-year survival rate by 45%, and decreased the devastating side effects of conventional therapy such as low platelet count, neuropathy, and fatigue by 89%, 83%, and 65% respectively.59 What's more, these effects were consistent across different types of cancer and there were no adverse events reported.59 Melatonin's anticarcinogenic properties can also be attributed to its effect on your immune system. Laboratory studies revealed that melatonin can activate T-helper cells, which triggers other immune cells in order to help kill off foreign invaders or pathogens.61,62 Additionally, melatonin stimulates natural killer cell, monocyte, and macrophage synthesis, and has been found to facilitate healthy cell-to-cell communication, which enhances the body's appropriate immune system response to foreign invaders.63,64 Based on available evidence, leading experts suggest that patients with cancers and particularly metastatic solid tumors, might benefit from melatonin use, potentially leading to improved therapeutic outcomes.62-70 Certainly, more research is warranted. #4: Protect Against Diabetic Complications Diabetes—as with cardiovascular disease and cancer—belongs to the family of "free radical diseases."71 Research has found that people with type 2 diabetes and retinopathy experience alterations of their melatonin secretion.72 Considering the large body of evidence identifying melatonin as a major free-radical scavenger, it is not surprising that preclinical research repeatedly and consistently documents its beneficial antioxidative effects in diabetics and those with high blood sugar (hyperglycemia).73,74 Melatonin has also been shown to protect pancreatic beta-cells and several diabetes-affected organs (including kidney, retina, brain, and vasculature) from free radical damage.75 In studies, melatonin treatment has produced reductions in blood glucose, hemoglobin A1c, and cholesterol.75 Scientists see great promise for melatonin's potential to improve quality of life by alleviating many of the complications associated with diabetes, such as retinopathy, nephropathy, and cardiovascular disease.49,74,75 What You Need to Know: More Than Sleep; Melatonin's Multiple Benefits Melatonin (N-acetyl-5-methoxytryptamine) is a derivative of the amino acid tryptophan and widely distributed in food sources, such as milk, almonds, bananas, beets, cucumbers, mustard, and tomatoes.21-23 In humans, melatonin is primarily synthesized by the pineal gland, but it is also produced in the gastrointestinal tract and retina.24,25 Melatonin and its metabolites are potent antioxidants with anti-inflammatory, hypotensive, cell communication enhancing, cancer fighting, brown fat-activating, and blood-lipid-lowering effects, thereby protecting tissues from a variety of insults.5-9 Melatonin has been shown to support circadian rhythm, hormone balance, reproductive health, cognition, mood, blood sugar regulation, and bone metabolism, while improving overall antioxidant status and lowering blood pressure.1,10-17 Melatonin may assist in preventing diabetic complications, and improving treatment outcomes in patients with cardiovascular disease and certain types of cancer.1,2,7,9,10

#5: Help Delay Alzheimer's Disease Another unique and powerful property of melatonin is its ability to cross the blood-brain barrier. Oral intake of melatonin has been shown to increase levels of melatonin in the brain.76 Melatonin also protects the blood brain barrier particularly in cases of hypoxic injury that may cause increased permeability of the blood brain barrier and lead to more damage to the delicate brain tissue as compounds that normally would be kept out by a functioning blood brain barrier gain entrance to the brain.77 Intensive research over the past decade has indicated melatonin's beneficial effects in experimental models of neurodegenerative disorders, specifically those linked to oxidative damage.78 In fact, melatonin's broad spectrum antioxidant activity in many central nervous system neurodegenerative diseases has been well-documented and reviewed.78,79 Specifically, melatonin can help delay the onset of Alzheimer's disease (AD) and help protect vital cellular structures, such as mitochondria, from oxidative damage and decay.80 Declines in mitochondrial function are a hallmark feature of many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and Huntington's disease.81 Melatonin may also promote improved sleep patterns and prevent cognitive impairment and improve the confusion and restlessness that often occurs in the evening (called sundowning) in AD patients.80,82,83 Preclinical studies revealed that melatonin exerts pronounced neuroprotective effects against beta amyloid plaque, one of the specific underlying causes of Alzheimer's disease.84-86 More recent investigations show that melatonin may prevent brain cell death while maintaining energy and oxygen metabolism in highly stressed neuronal mitochondria.87,88 Interestingly, decreased night time melatonin levels have been associated with the severity of mental impairment in dementia patients, and disturbed circadian rhythms seem to be correlated with cognitive performance in elderly and Alzheimer's patients.81,89,90 It is important to note that while melatonin may prove beneficial in earlier stages of Alzheimer's disease, it is much less effective in late stage Alzheimer's and may fail to improve sleep or agitation.92,93 #6: Combat Obesity with Melatonin In recent years, dietitians and medical experts have recognized that obesity is often associated with stress, emotional eating, sleep-deprivation, and hormonal changes later in life. A recent study in women with night eating syndrome (an eating disorder characterized by late-night binge eating) added further confirmation to this. It found that women suffering from this disorder had pronounced circadian melatonin rhythm disturbances, which also affected levels of cortisol (a stress hormone that can be a factor in weight problems) and ghrelin (a hormone that stimulates hunger). It also affected a variety of other behavioral and physiological circadian markers involved in appetite and neuroendocrine regulation.94 While no human weight-management trials using melatonin have been published thus far,95 preclinical trials are encouraging. In middle-aged rodents, daily melatonin administration was found to suppress abdominal fat, plasma leptin levels, and insulin levels, while also reducing body weight and food intake.96,97 Other researchers reported that melatonin was associated with decreased intra-abdominal fat, decreased plasma insulin and leptin levels, and the absence of age-related weight gain.95,98 Furthermore, laboratory investigations discovered melatonin's ability to activate brown adipose tissue, which encourages your body to burn fat instead of storing it.99-101In recent years, brown fat has increasingly become a target for halting the global obesity epidemic.102 In a rat model of pre-diabetic, diet-induced obesity, supplementing obese rats with 4mg/kg/day of melatonin resulted in reductions in body weight, belly fat, serum insulin levels, and triglycerides.103 In humans, the equivalent dose is 48 mg for a 165 lb adult, which is a very high dose that could produce next day drowsiness. Typical human doses for melatonin range from 300 micrograms to 10 milligrams at bedtime. #7: Help Prevent Osteoporosis Data derived from animal research suggests that melatonin has beneficial effects on bone repair and remodeling, and bone mineral density,104 which would make it an ideal candidate for the prevention of osteoporosis or as adjuvant after bone fractures. A very small, yet compelling recently published double-blind, placebo-controlled pilot study investigated the effects of melatonin on bone health and quality of life in 18 perimenopausal women (ages 45-54) for 6 months. It found that melatonin improved physical symptom scores (e.g., feeling and sleeping better), increased osteocalcin (a marker for bone formation), and decreased levels of Type-I collagen cross-linked N-telopeptide (a marker for bone resorption), indicating that melatonin may restore imbalances in bone remodeling and prevent bone loss.105 However, while the results from this small study appear clinically relevant, further investigation is warranted. Summary Aging is a multi-factorial process, involving a heavy load of free radicals, metabolic, hormonal, and changes in immunity. Although there is currently no direct clinical evidence demonstrating that melatonin may prolong the human life span, there are several reasons to postulate its role in the aging cascade: Melatonin participates in many vital life processes, and its secretion falls gradually over time. Diminished melatonin levels appear to correlate with the deterioration of many metabolic functions and decreasing hormone levels, thus possibly contributing to the acceleration of aging processes. Melatonin exhibits immunomodulatory properties; suppressed immunity has been implicated in the acceleration of aging processes. Melatonin has remarkable low toxicity and is without significant side effects if used at <10 mg/day (provided as 'regular' or 'fast-release');106 If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027. References 1. Zawilska JB, Skene DJ, Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep. 2009 May-Jun;61(3):383-410. 2. Maestroni GJ, Conti A, Pierpaoli W. Pineal melatonin, its fundamental immunoregulatory role in aging and cancer. Ann N Y Acad Sci. 1988;521:140-8. 3. Lesnikov VA, Pierpaoli W. Pineal cross-transplantation (old-to-young and vice versa) as evidence for an endogenous "aging clock." Ann N Y Acad Sci. 1994 May 31;719:456-60. 4. 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. 5. Korkmaz A, Topal T, Tan DX, Reiter RJ. Role of melatonin in metabolic regulation. Reviews in Endocrine & Metabolic Disorders 2009 Dec; 10(4): 261-70. 6. Reiter RJ, Paredes SD, Korkmaz A, Jou MJ, Tan DX. Melatonin combats molecular terrorism at the mitochondrial level. Interdiscip Toxicol. 2008 Sep;1(2):137-49. 7. Daglioglu E, Serdar Dike M, Kilinc K, et al. Neuroprotective effect of melatonin on experimental peripheral nerve injury: an electron microscopic and biochemical study. Cent Europ Neurosurg. 2009 Aug; 70(3): 109-14. 8. Esposito E, Cuzzocrea S. Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol. 2010 Sep;8(3):228-42. 9. Srinivasan V, Pandi-Perumal SR, Brzezinski A, Bhatnagar KP, Cardinali DP. Melatonin, immune function and cancer. Recent Pat Endocr Metab Immune Drug Discov. 2011 May;5(2):109-23. 10. Iguchi H, Kato K-I, Ibayashi H. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J Clin Endocrinolo Metab. 1982;55:27-29. 11. Magri F, Sarra S, Cinchetti W, Guazzoni V, Fioravanti M, Cravello L, Ferrari E. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. J Pineal Res. 2004 May;36(4):256-61. 12. Zhao ZY, Xie Y, Fu YR, Bogdan A, Touitou Y. Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age. Chronobiol Int. 2002 Nov;19(6):1171-82. 13. Thomas DR, Miles A. Melatonin secretion and age. Biol Psychiatry. 1989;25:365-7. 14. Touitou F, Fevre M, Bogdan A, et al. Patterns of plasma melatonin with ageing and mental condition: stability of nyctohemeral rhythms and differences in seasonal variations. Acta Endocrinol. 1984; 106:145-51. 15. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Lopez-Burillo S . Melatonin, longevity and health in the aged: an assessment. Free Radic Res. 2002 Dec;36(12):1323-9. 16. Paredes SD, Reiter RJ. Melatonin: Helping cells cope with oxidative disaster. Cell Membr Free Radic Res. 2010 Dec; 2(3): 99-111. 17. Rodella LF, Favero G, Rossini C, et al. Aging and vascular dysfunction: beneficial melatonin effects. Age. 2011 Nov 23. Epub ahead of print. 18. Reiter R, Tang L, Garcia JJ, Muñoz-Hoyos A. Pharmacological actions of melatonin in oxygen radical pathophysiology. Life Sci. 1997;60(25):2255-71. 19. Gruber J, Schaffer S, Halliwell B. The mitochondrial free radical theory of ageing—where do we stand? Front Biosci. 2008 May 1;13:6554-79. 20. Hekimi S, Lapointe J, Wen Y. Taking a "good" look at free radicals in the aging process. Trends Cell Biol. 2011 Oct;21(10):569-76. 21. Illnerova H, Buresova M, Presl J. Melatonin rhythm in human milk. J Clin Endocrinol Metab. 1993 Sep;77(3): 838-41. 22. Dubbels R, Reiter RJ, Goebel A, et al. Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res. 1995 Jan;18(1):28-31. 23. Tan DX, Hardeland R, Manchester LC, et al. Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. J Exp Botany. 2012 Jan; 63(2): 577-97. 24. Baba K, Pozdeyev N, Mazzoni F, et al. Melatonin modulates visual function and cell viability in the mouse retina via the MT1 melatonin receptor. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):15043-8. 25. Chen CQ, Fichna J, Bashashati M, Li YY, Storr M. Distribution, function and physiological role of melatonin in the lower gut. World J Gastroenterol. 2011 Sep 14;17(34):3888-98. 26. Reiter RJ, Tan DX, Fuentes-Broto L. Melatonin: a multitasking molecule. Prog Brain Res. 2010;181:127-51. 27. Stetinová V, Smetanová L, Grossmann V, Anzenbacher P. In vitro and in vivo assessment of the antioxidant activity of melatonin and related indole derivatives. Gen Physiol Biophys. 2002 Jun;21(2):153-62. 28. Reiter RJ, Tan D, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress: a review. J Biomed Sci. 2000;7:444-58. 29. Cuzzocrea S, Reiter RJ. Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol. 2001;426:1-10. 30. Cardinali DP, Furio AM, Reyes MP. Clinical perspectives for the use of melatonin as a chronobiotic and cytoprotective agent. Ann N Y Acad Sci. 2005;1057:327-36. 31. Sofic E, Rimpapa Z, Kundurovic Z, et al. Antioxidant capacity of the neurohormone melatonin. J Neural Transm. 2005;112:349-58. 32. Reiter RJ, Tan DX, Mayo JC, et al. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol. 2003;50:1129-46. 33. Wakatsuki A, Okatani Y, Ikenoue N, et al. Melatonin inhibits oxidative modification of low-density lipoprotein particles in normolipidemic post-menopausal women. J Pineal Res. 2000;28:136-42. 34. Chakravarty S, Rizvi SI. Day and night GSH and MDA levels in healthy adults and effects of different doses of melatonin on these parameters. Int J Cell Biol. 2011;2011:404591. Epub 2011 Apr 28. 35. Ochoa JJ, Vilchez MJ, Palacios MA, et al. Melatonin protects against lipid peroxidation and membrane rigidity in erythrocytes from patients undergoing cardiopulmonary bypass surgery. J Pineal Res. 2003; 35:104-8. 36. Yi C, Pan X, Yan H, Guo M, Pierpaoli W. Effects of melatonin in age-related macular degeneration. Ann N Y Acad Sci. 2005 Dec;1057:384-92. 37. Gitto E, Reiter RJ, Amodio A, et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res. 2004 May;36(4):250-5. 38. Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg. 2009 Apr;108(4):1146-51. 39. Srinivasan V, Mohamed M, Kato H. Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent Pat Endocr Metab Immune Drug Discov. 2012 Jan;6(1):30-9. 40. Reiter RJ, Tan DX, Paredes SD, Fuentes-Broto L. Beneficial effects of melatonin in cardiovascular disease. Ann Med. 2010 May 6;42(4):276-85. 41. Baykan A, Narin N, Narin F, Akgün H, Yavaşcan S, Saraymen R. The protective effect of melatonin on nicotine-induced myocardial injury in newborn rats whose mothers received nicotine. Anadolu Kardiyol Derg. 2008 Aug;8(4):243-8. 42. Mukherjee D, Roy SG, Bandyopadhyay A, et al. Melatonin protects against isoproterenol-induced myocardial injury in the rat: antioxidative mechanisms. J Pineal Res. 2010 Apr;48(3):251-62. 43. Chen Z, Chua CC, Gao J, Hamdy RC, Chua BH. Protective effect of melatonin on myocardial infarction. Am J Physiol Heart Circ Physiol. 2003 May;284(5):H1618-24. 44. Sahna E, Parlakpinar H, Turkoz Y, Acet A. Protective effects of melatonin on myocardial ischemia/reperfusion induced infarct size and oxidative changes. Physiol Res. 2005;54(5):491-5. 45. Sallinen P, Manttari S, Leskinen H, et al. Long-term postinfarction melatonin administration alters the expression of DHPR, RyR(2), SERCA2, and MT(2) and elevates the ANP level in the rat left ventricle. J Pineal Res. 2008 Feb 13. 46. Dominguez-Rodriguez A, breu-Gonzalez P, Garcia-Gonzalez MJ, et al. A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocaRdial Infarction undergoing primary Angioplasty The Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty (MARIA) trial: study design and rationale. Contemp Clin Trials. 2007 Jul;28(4):532-9. 47. Corbalán-Tutau MD, Madrid JA, Nicolás F, Garaulet M. Daily profile in two circadian markers "melatonin and cortisol" and associations with metabolic syndrome components. Physiol Behav. 2012 Jun 15. [Epub ahead of print] 48. Cagnacci A, Arangino S, Angiolucci M, et al. Potentially beneficial cardiovascular effects of melatonin administration in women. J Pineal Res. 1997;22:16-9. 49. Cavallo A, Daniels SR, Dolan LM, et al. Blood pressure-lowering effect of melatonin in type 1 diabetes. J Pineal Res. 2004;36:262-6. 50. Cagnacci A, Cannoletta M, Renzi A, et al. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens. 2005;18:1614-8. 51. Grossman E, Laudon M, Yalcin R, et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med. 2006 Oct;119(10):898-902. 52. Rechciński T, Trzos E, Wierzbowska-Drabik K, Krzemińska-Pakuła M, Kurpesa M. Melatonin for nondippers with coronary artery disease: assessment of blood pressure profile and heart rate variability. Hypertens Res. 2010 Jan;33(1):56-61. 53. Pawlikowski M, Winczyk K, Karasek M. Oncostatic action of melatonin: facts and question marks. Neuro Endocrinol Lett. 2002;23:S24-9. 54. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. 2008 Sep;7(3):189-203. 55. Lissoni P, Rovelli F, Malugani F, et al. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuroendocrinol Lett. 2001;22:45-47. 56. Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Reiter RJ. Melatonin uses in oncology: breast cancer prevention and reduction of the side effects of chemotherapy and radiation. Expert Opin Investig Drugs. 2012 Jun;21(6):819-31. 57. Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C, Rueda N. Breast cancer therapy based on melatonin. Recent Pat Endocr Metab Immune Drug Discov. 2012 May 1;6(2):108-16. 58. Song N, Kim AJ, Kim HJ,et al. Melatonin suppresses doxorubicin-induced premature senescence of A549 lung cancer cells by ameliorating mitochondrial dysfunction. J Pineal Res. 2012 Apr 4. doi: 10.1111/j.1600-079X.2012.01003.x. Epub ahead of print. 59. Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20. Epub 2012 Jan 24. 60. Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as adjuvant cancer care with and without chemotherapy: A systematic review and meta-analysis of randomized trials. Hepatobiliary Pancreat Dis Int. 2002 May;1(2):183-6. 61. Lissoni P, Barni S, Mandala M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in untreatable advanced hematologic malignancies. Eur J Cancer. 1999;35:1688-92. 62. Lissoni P, Bucovec R, Bonfanti A, et al. Thrombopoietic properties of 5-methoxytyrptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia. J Pineal Res. 2001;30:123-6. 63. Cerea G, Vaghi M, Ardizzoia A, et al. Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Res. 2003 Mar-Apr;23(2C):1951-4. 64. Berk L, Berkey B, Rich T, et al. Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119). Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):852-7. 65. Lissoni P, Brivio F, Fumagalli L, et al. Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res. 2008 Mar-Apr;28(2B):1377-81 66. Lissoni P, Fumagalli L, Paolorossi F, Rovelli F, Roselli MG, Maestroni GJ. Anticancer neuroimmunomodulation by pineal hormones other than melatonin: preliminary phase II study of the pineal indole 5-methoxytryptophol in association with low-dose IL-2 and melatonin. J Biol Regul Homeost Agents. 1997 Jul-Sep;11(3):119-22. 67. Bubenik G, Blask D, Brown G. Prospects of the clinical utilization of melatonin. Biol Signals Recept. 1998;7:195-219. 68. Zhang Z, Insena PF, Liang B, et al. Melatonin immune modulation and aging. Autoimmunity. 1997;26:43-53. 69. Srinivasan V, Maestroni G, Cardinali D, et al. Melatonin, immune function and aging. Immun Ageing. 2005;2:17. 70. Radogna F, Diederich M, Ghibelli L. Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol. 2010 Dec 15;80(12):1844-52. 71. Preiser JC. Oxidative stress. JPEN J Parenter Enteral Nutr. 2012 Mar;36(2):147-54. Epub 2012 Feb 1. 72. Hikichi T, Tateda N, Miura T. Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy. Clin Ophthalmol. 2011;5:655-60. 73. Baydas G, Canatan H, Turkoglu A. Comparative analysis of the protective effects of melatonin and vitamin E on streptozocin-induced diabetes mellitus. J Pineal Res. 2002 May;32(4):225-30. 74. Korkmaz A, Ma S, Topal T, Rosales-Corral S, Tan DX, Reiter RJ. Glucose: a vital toxin and potential utility of melatonin in protecting against the diabetic state. Mol Cell Endocrinol. 2012 Feb 26;349(2):128-37. 75. Gumustekin M, Tekmen I, Guneli E, et al. Short-term melatonin treatment improved diabetic nephropathy but did not affect hemorheological changes in diabetic rats. Pharmazie. 2007 Sep;62(9):693-8. 76. Aygün D, Kaplan S, Odaci E, Onger ME, Altunkaynak ME. Toxicity of non-steroidal anti-inflammatory drugs: a review of melatonin and diclofenac sodium association. Histol Histopathol. 2012 Apr;27(4):417-36. 77. Kaur C, Ling EA. Antioxidants and neuroprotection in the adult and developing central nervous system. Curr Med Chem. 2008;15(29):3068-80. 78. Bonnefont-Rousselot D, Collin F. Melatonin: action as antioxidant and potential applications in human disease and aging. Toxicology. 2010 Nov 28;278(1):55-67. 79. Hardeland R. Melatonin metabolism in the central nervous system. Curr Neuropharmacol. 2010 Sep;8(3):168-81. 80. Srinivasan V, Pandi-Perumal SR, Cardinali DP, et al. Melatonin in Alzheimer's disease and other neurodegenerative disorders. Behavioral and Brain Functions 2006;2:15. 81. Cardinali DP, Pagano ES, Scacchi Bernasconi PA, Reynoso R, Scacchi P. Melatonin and mitochondrial dysfunction in the central nervous system. Horm Behav. 2012 Feb 25. [Epub ahead of print] 82. Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer's disease. Neuro Endocrinol Lett 2002;23:20-3. 83. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 2003;70:334-41. 84. Pappolla MA, Chyan YJ, Poeggeler B, et al. Alzheimer beta protein mediated oxidative damage of mitochondrial DNA: prevention by melatonin. J Pineal Res. 1999;27:226-9. 85. Pappolla M, Bozner P, Soto C, et al. Inhibition of Alzheimer B-fibrillogenesis by melatonin. J Biol Chem. 1998;273:7185-8. 86. Pappolla MA, Soss M, Omar RA, et al. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neuro Sci. 1997;17:1683-90. 87. Bachurin S, Oxenkrug G, Lermontova N, et al. N-acetylserotonin, melatonin and their derivatives improve cognition and protect against beta-amyloid-induced neurotoxicity. Ann N Y Acad Sci. 1999;890:155-66. 88. Wang X. The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther. 2009 Winter;15(4):345-57. Review. 89. Van Someren EJ, Mirmiran M, Swaab DF. Non-pharmacological treatment of sleep and wake disturbances in aging and Alzheimer's disease: chronobiological perspectives. Behav Brain Res. 1993;57:235-53. 90. Dowling GA, Burr RL, Van Someren EJ, et al. Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease. J Am Geriatr Soc. 2008 Feb;56(2):239-46. Epub 2007 Dec 7. 91. Cardinali DP, Furio AM, Brusco LI. Clinical aspects of melatonin intervention in Alzheimer's disease progression. Curr Neuropharmacol. 2010 Sep;8(3):218-27. 92. Singer C, Tractenberg RE, Kaye J, et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep. 2003;26:893–901. 93. Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S. Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry. 2009;17:166-9. 94. Goel N, Stunkard AJ, Rogers NL, et al. Circadian rhythm profiles in women with night eating syndrome. J Biol Rhythms. 2009 Feb;24(1):85-94. 95. Rastmanesh R, de Bruin PF. Potential of melatonin for the treatment or prevention of obesity: An urgent need to include weight reduction as a secondary outcome in clinical trials of melatonin in obese patients with sleep disorders. Contemp Clin Trials. 2012 Jul;33(4):574-5. Epub 2012 Apr 5. 96. Wolden-Hanson T, Mitton DR, McCants RL, Yellon SM, Wilkinson CW, Matsumoto AM, et al. Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology. 2000;141:487-97. 97. Prunet-Marcassus B, Desbazeille M, Bros A, et al. Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity. Endocrinology. 2003;144:5347-52. 98. 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. Erratum in: Endocrinology 2002 Apr;143(4):1269. 99. Puig-Domingo M, Guerrero JM, Reiter RJ, et al. Thyroxine 5'-deiodination in brown adipose tissue and pineal gland: implications for thermogenic regulation and role of melatonin. Endocrinology. 1988 Aug;123(2):677-80. 100. Torres-Farfan C, Valenzuela FJ, Mondaca M, et al. Evidence of a role for melatonin in fetal sheep physiology: direct actions of melatonin on fetal cerebral artery, brown adipose tissue and adrenal gland. J Physiol. 2008 Aug 15;586(16):4017-27. 101. Tan DX, Manchester LC, Fuentes-Broto L, Paredes SD, Reiter RJ. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev. 2011 Mar;12(3):167-88. 102. Ginter E, Simko V. Brown fat tissue - a potential target to combat obesity. Bratisl Lek Listy. 2012;113(1):52-6. 103. Nduhirabandi F, Du Toit EF, Blackhurst D, Marais D, Lochner A. Chronic melatonin consumption prevents obesity-related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet-induced obesity. J Pineal Res. 2011 Mar;50(2):171-82. doi: 10.1111/j.1600-079X.2010.00826.x. Epub 2010 Nov 15. 104. Ramírez-Fernández MP, Calvo-Guirado JL, de-Val JE, et al. Melatonin promotes angiogenesis during repair of bone defects: a radiological and histomorphometric study in rabbit tibiae. Clin Oral Investig. 2012 Feb 11. Epub ahead of print. 105. Kotlarczyk MP, Lassila HC, O'Neil CK, et al. Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res. 2012 May;52(4):414-26. 106. Seabra MLV, Bignotto M, Pinto LR Jr, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29:193–200.