A "Cure to Aging"?

Melatonin Acetylsaliclyic acid Acetylsaliclyic acid bioflavonoids coenzyme Q10 Gingko biloba magnesium vitamin B1 flaxseed oilMelatonin cod liver oil coenzyme Q10 Rutin vitamin C DHEA Flaxseed vitamin B12β-carotene gingerAcetylsaliclyic acid folic acid chromium picolinate reen tea extract

ginseng

complex dietary supplement vitamin B α-lipoic acid zinc

vitamin Epotassium Gingko biloba

selenium vitamin D vitamin B1 DHEA magnesium bioflavono L-glutathione garlic

DSP

flaxseed oil

β-caroteneginsengMela L-glutathione Melatonin cod liver oil coenzyme Q10 Rutin vitamin C DHEA bioflavonoids gingerAcetylsaliclyic acid vitamin B12β-carotene Coenzyme

vitamin B1

Melatonin

green tea extract chromium picolinatefolic acid

a “cure” to aging? vitamin E Vitami vitamin Dpotassium vitamin B1 selenium bioflavonoids coenzyme Q10 vitamin B6

L-glutathione garlic

zinc

ginger

α-lipoic acid garlic

vitamin B1

β Gingko bilobamagnesium flaxseed oil Melatonin coenzyme Q10 Rutin vitamin Cβ

ginseng

coenzyme Q10

cod liver oil DHEA bioflavonoids

gingerAcetylsaliclyic

Melatonin

acid vitamin B12 β-carotene folic acid

reen tea extract chromium picolinate Melatonin cysteine vitamin B3 vitamin B6n-acetyl α-lipoic acid L-glutathione potassium Gingko biloba vitamin E garlic zinc

vitamin B1vitamin Dselenium bioflavonoids folic acid

Gingko bilobamagne flaxseed oilMe otassiumvitamin B1 cod liver oil bioflavonoids coenzyme Q10 Rutin Vita ic acidDHEA vitamin D L-glutathione

Gingko biloba

ginseng

L-glutathione

Melatonin

vitamin E Acetylsaliclyic acid vitamin B12β-ca

Biochemistry 3D03 Metabolism “Your Way” Project McMaster University © 2012 Authors: Shanthiya Baheerathan, Qian Feng, Vivian Shan, Austin Yan Prepared for: Dr. Michelle MacDonald, TA: Rabia Mateen

Preface Aging is the inevitable process of continuous growth and change in an organism’s lifetime. Recently, research by Dr. Rollo et al. at McMaster University suggested a possible “cure� to aging. A dietary supplement (DSP) developed by him in 2003, composed of thirty-one natural and synthetic compounds, showed anti-aging effects in mice. This booklet presents a detailed review of the individual ingredients in the DSP and the pathways through which each ingredient is metabolized. By looking at how the metabolic pathways of each ingredient interact with each other, and with other chemicals and enzymes in the body, this booklet provides insights into the mechanisms through which the dietary supplement works to accomplish its anti-aging effects.

i

Table of Contents

ii

Anti-inflammatory

Antioxidant

Neuroprotective

Insulin-sensitive

Vitamin B1 Vitamin B3 Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin E Folic acid N-acetyl cysteine L-glutathione Acetyl L-carnitine Chromium picolinate Coenzyme Q10 DHEA Melatonin Beta-carotene Bioflavonoids Rutin Acetylsalicylic acid Alpha-lipoic acid

Anti-coagulant

Compound profiles

1

Anti-carcinogenic

Introduction

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

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3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41

Anti-coagulant

Anti-inflammatory

Antioxidant

Neuroprotective

Insulin-sensitive

Potassium Selenium Zinc Magnesium Garlic Ginger Gingko biloba Cod liver oil Flax seed oil Ginseng Green tea extract

Anti-carcinogenic

List of Compounds

● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ● ● ●

43 44 45 46 47 49 51 53 55 57 59

How compounds interact

61

Interaction diagram

64

Conclusion

65

References

66

iii

Introduction Aging has been a very active area of research because many age-related deterioration problems and pathologies affect millions of patients worldwide. Neurological diseases such as Alzheimer’s and Parkinson’s diseases have been associated with age-related cognitive declines, while aging is also related to many cancers [1]. These diseases are incurable and significantly affect one’s quality of life. Thus, it is very important to understand the process of aging in order to develop possible interventions to alleviate some of its detrimental consequences.

It has been postulated that mitochondrial decay plays a significant role in aging due to the accumulation of reactive oxygen species as by-products of the electron transport chain [2].

This makes the mitochondria a victim of its own by-products. As the damage accumulates, many different cellular processes are disrupted, including detoxification, cell repair systems, DNA replication, and osmotic balance. Higher processes like cognitive function are also affected by the accumulation of oxidative damage [3].

There are various dietary supplements sold over the counter that claim to have anti-aging properties. Some of these supplements, such as vitamins, N-acetyl cysteine and glutathione, work as antioxidants to scavenge reactive oxygen species in order to reduce mitochondrial damage [4, 5]. Instead of studying each individual supplement, Dr. David Rollo et al. took a novel approach in which they developed a complex dietary supplement (DSP) made of 31 ingredients that are commonly available. A list of these ingredients can be found on the Table of Contents on the previous two pages.

1

The DSP was designed to target five key mechanisms of aging, including oxidative stress, inflammation, mitochondrial function, insulin resistance, and membrane integrity. Using models of transgenic growth-hormone mice that expressed accelerated aging properties, Dr. Rollo et al. demonstrated in 2003, 2010 and 2011 that the complex DSP markedly improved learning, extended longevity, prevented age-related motor function decline, and increased cognitive ability [6, 7, 8].

Despite the benefits of the complex dietary supplement shown in mice, there is currently no sufficient explanation on how the cocktail of supplements work together to achieve its antiaging properties, especially in regards to the mechanisms on how the compounds function and interact. To attempt to answer this question, this booklet shows an investigation into the molecular mechanisms of each of the 31 supplements listed in the DSP, and draws many connections between the DSP’s individual components.

Pages 3 to 60 of this booklet provide an information page for each compound in the DSP, featuring a basic description of the compound, its metabolic pathways and significance, and its effects and functions in the body, especially in relation to antiaging properties. Each compound is also labelled with a combination of tags that represent six categories of potential anti-aging roles: anti-carcinogenic, antioxidant, anti-inflammatory, anti-coagulant, neuroprotective, and insulin-sensitive. The dosage provided at the top of each page refers to the daily dose that was used in the studies by Dr. Rollo et al. for each mouse. Page 61 to 64 details potential compound metabolism connections and has an interaction map on page 64 that summarizes the possible interactions between each of the compounds. These links provide insights into the mechanisms through which the DSP works to achieve its anti-aging properties.

2

Vitamin B1 Dose: 0.72 mg/day | anti-carcinogenic | antioxidant | neuroprotective Description: Thiamin is a water soluble B vitamin. The vitamin is found in the germ layers of cereal grains, yeast, nuts and meat. Known to play a critical role in energy metabolism, B1 needs to be replenished daily [1].

No Tolerable Upper Intake level has been derived for thiamin, but up to 50 mg has been consumed without any adverse effects [2].

Metabolism: Thiamin is found in humans as thiamin phosphate derivatives: monophosphate (ThMP), thiamin triphosphate (ThTP)and thiamin pyrophospate (ThDP), and Adenosine thiamin Triphosphate (AThTP) [3]. ThDP, the more well known derivative, is a coenzyme for many enzymes that catalyze the transfer of two carbon units, and for the dehydrogenation of 2-oxoacids. ThDP is required as a coenzyme for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and branched chain keto acid dehydrogenase.

All of the above enzymes are 3

Figure 1: thiamin

Quick Facts: Properties: Polar, amino acid derivative Molar Mass: 300.821 g/mol required for carbohydrate metabolism and neurotransmitter production.

ThDP is also a coenzyme for Transketolase, which catalyzes critical reactions, needed for the synthesis energy ribonucleotides, nucleotides, and NADPH [1,3].

ThTP is thought to be a neuroactive form of thiamin, but recently, it has been found that it can metabolize certain proteins and was found to play a role in cell signaling [4]. ThMP does not have any known functions but was found to be lower in Alzheimer’s patients [3]. AThTP’s role is completely unknown [3].

Figure 2: Pathway for ThDP, ThMP, AThTp production [3].

Effects: Beriberi and Wernicke Korsakoff syndrome result due to low ThDP levels, causing decreased activity in enzymes. An increased intake of thiamin will diminish the effects of both the diseases [3]. Increased thiamin intake has been connected to a lower incidence of tumor proliferation [5], and has a protective effect against Alzheimer’s disease [4]. Thiamin has also been found to decrease depression [4]. Moreover, it acts as an antioxidant [6] and a anti-carcinogenic agent [7].

Related Compounds: Folic acid (page 17), Green tea extract (page 59)

References:

[1] Conner R.; Straub G.; Ind. Eng. Chem Anal Ed 1941. 13 (6): 385-388.

[2] Dipalma JR.; Ritchie DM.; Ann. Rev. Pharmacol Toxicol 1966. 17:133-148 .

[3] Lonsdale D. ; Evid. Based Complement Alternat. Med. 2006. 3(1):49-59 .

[4] Ba A.; Cell Mol Neurobiol. 2008. 28(7)923-31.

[5] Bettendorff L.; Wins P.; The Febs Journal 2009. 276: 2917-2925.

[6] Basu TK.; Dickerson JWT.; Oncology. 1976. 33:250-252.

[7] Heseker H.; Kubler W.; Pudel V.; Westenhoffer J. Annals of New York Academy Of Sciences 1992. 669: 352-357.

4

Vitamin B3 Dose: 0.72 mg/day | anti-carcinogenic | antioxidant | neuroprotective Description: Niacin is a water soluble vitamin of the B complex, and it said to be involved in DNA repair, and the production of several hormones [1]. Too much niacin may lead to dermatological conditions such as skin flushing and itching, dry skin and skin rashes. B3 can be found in most animal products and some fruits and vegetables, seeds and fungi. Niacin can also be synthesized from tryptophan by the body [2]. This vitamin has been found to be toxic at doses greater than 3 g/day [3].

Metabolism: There exist different forms of Vitamin B3, the two most common: nicotinamide and niacin. While the two derivatives are very similar, nicotinamide does not have the same lipid modifying effects as niacin.

Both compounds are able to be converted to NAD, and NADP in vivo. Almost 200 enzymes use niacin coenzymes: NAD and NADP as acceptors and donators of electrons in redox reactions.

5

Figure 1: Pyridoxol Phosphate Quick Facts: Properties: Water soluble Molecular Mass: 123.1 g/mol

NAD is used in energy producing reactions that involve the catabolism of carbohydrates, fats, proteins and alcohols. NADP is involved in anabolic reactions, and the synthesis of macromolecules such as fatty acids and cholesterol.

NAD is also involved in non-redox reactions, and NAD acts as a substrate for two classes of enzymes that separate niacin from NAD and transfer ADP-ribose to proteins. This process is hypothesized to act in cell signaling by working on G-proteins [4].

Figure 2: The NAD molecule, the molecule in red is vitamin B3.

Effects: Early stages of niacin deficiency slows down metabolism, while severe deficiency leads to pellegra [5].

Niacin also binds to and inhibits the G-protein-coupled receptor that helps with fat breakdown.

This fat that breaks off adipose tissue is called very low density lipoproteins make low density lipoproteins. Niacin indirectly influences the increase in HDL concentrations of the blood. For this reason, niacin has been

prescribed to those who are at risk for heart disease [6]. Studies have even shown that niacin is more effective than Exetimibe, an anticoagulant [7].

Increased niacin intake has also shown reduced inflammation and increased flexibility in arthritis patients [8].

Finally, niacin has been found to be anticarcinogenic (for oral and oesophageal cancers) when in combination with antioxidant [9].

Related Compounds: Folic acid (page 17), Chromium picolinate (page 25)

References: [1] Shibata K; Toda S; Bioscience, Biotechnology, and Biochemistry 1997. 7: 1200-1202.

[2] Godsmith G.; American Journal of Clinical Nutrition 1958. 6:479-486.

[3] Knip M; Douek IF; Moore WP; Diabetologia. 2000. 43 (11): 1337–45.

[4] Jacobson E; Jacobson M; Methods in Enzymology. 1997 280-221-230 [5] Malfait P; Moren A; Dillon JC; Brodel A; Begkoyian G; Etchgorry MG; Malenga G; Hakewill P; Int. J. Epidemiol. 1993. 22(3): 504-511.

[6] Ganji SH; Kamanna VS; Kashyap ML; The Journal of Nutritional Biochemistry. 2002. 14: 298-305.

[7] Allen JT; Villines TCl Stanek EJ; Devine PJ; Griffen L; N Engl J Med 2009. 361: 2113-2122 [8] Scalagrino R; Pasquariello; Reumatismo. 1964. 16:333-337.

[9] Cheung MC; Zhao XQl Chait A; Albers JL; Arteriosclerosis, Thrombosis and Vascular Biology. 2001.

21:1320-1326.

6

Vitamin B6 Dose: 0.72 mg/day | anti-carcinogenic | neuroprotective Description: A water soluble vitamin and a part of the vitamin B family. This vitamin is found in meats, whole grains, vegetables, nuts and bananas [1]. Over-consumption of this vitamin as a supplement may cause neurological problems [2].

Metabolism: Vitamin B6 has been found to play a key role in protein metabolism, neurotransmiter synthesis, hemogloblin synthesis and gene expression. The vitamin has three different forms: pyridoxine, pyridoxal, and pyridoxamine, which are all converted to Pyridoxal phosphate (PLP). The active form, PLP, is a coenzyme which helps with decarboxylation, transamination, racemization, and elimination [3].

Important PLP-dependent steps of the synthesis of neurotransmitters

7

Figure 1: Pyridoxol Phosphate Quick Facts: Properties: pyridine ring, polar Molecular Mass: 169.18 g/mol include the decarboxylation of 3,4dihydroxyphenylalanine (DOPA) to dopamine, and the conversion of tryptophan to both nitric acid and serotonin.

Moreover, since PLP has electron sink properties, PLP binding enables the amino acid for further reactions.

PLP also increases hemoglobin's affinity for oxygen. [4]

Effects: Deficiency of B6 is uncommon, but borderline deficiency causes anaemia, reduced immune function, increased risk for cancer (colorectal, pancreatic, gastric, lung, prostate and breast), and decreased cognitive function [1, 5].

Low synthesis rates of the carbon compounds and subsequently DNA and RNA synthesis can be attributed to many of the effects of low B6 levels.

Figure 2: Conversion of Vitamin B6 derivatives to PLP. Studies have demonstrated that a deficiency in the B6 vitamin is correlated with thymic atrophy and lymphocyte depletion; this is especially the case for the elderly [6].

Related Compounds: Folic acid (page 17)

Moreover, decreased B6 intake in the elderly has been noted to be significantly correlated with better memory performance and cognitive test scores [6]. Studies have also demonstrated that B6 intake acts as a preventative factor against colon cancer by a reduction of oxidative stress and nitric oxide production [5].

References:

[1] Abbot R; British Food Journal 1997. 99(2):43-49.

[2] Bender DA; European Journal of Clinical Nutrition 1989. 43(5); 278-309.

[3] Merril AH; Henderson MJ; Annals of the New York Academy of Sciences 2006. 585:110-117.

[4] John RA; Bhiochem Biophys Acta. 1995. 1248(2):81-96.

[5] Zhang SM; Cook NR; Albert CMl Gaziano M; JAMA 2008. 300(17):2012-2021 [6] Rall LC; Nikbin DVM; Nutrition Reviews 1993. 51(8):217-225.

8

Vitamin B12 Dose: 0.72 mcg/day | anti-carcinogenic | anti-inflammatory | antioxidant | | neuroprotective Description: Vitamin B12 is a water soluble vitamin, which is a part of the vitamin B family.

It helps with the normal functioning of the brain and nervous system [1]. It also plays a role in DNA and fatty acid synthesis. It is the largest known vitamin and can be found in liver, cheese, meat, milk and fortified foods.

It is a common ingredient in energy drinks. It has low toxicity, but it should be noted that those who are allergic to cobalamin should avoid this supplement. [2] Metabolism: Vitamin B12 consists of a group of vitamers that all that contain cobalt and corrin ring molecules and have vitamin activity [3]. B12 participates in isomerase, methyltransferase and dehalogenase reactions. In humans, the B12 vitamin consists of: 5’-deoxyadenosylcobala-min (AdoB12), and methylcobalamin (MeB12). AdoB12 is a cofactor of methylmalonyl Coenzyme A (MUT), a key isomerase in the TCA cycle.

MeB12 is a cofactor of methyltetrahydrofolate, and homo cysteine methyltransferase (MTR), the 9

Figure 1: Vitamin B12 Quick Facts: Properties: Polar, contains cobalt Also contains: 1355.37 g/mol enzyme that regenerates methionine from homocysteine [4].

Effects: This vitamin is reported to boost energy levels and speed up the metabolism. Vitamin B12 helps iron function and it also helps the body absorb carotene and vitamin A [6].

Figure 1: A simplified schematic of the folate-dependent methionine cycle, vitamin B12 acts as a cofactor. Where, 5-methyltetrahydrofolate is 5-Ch3-THF, tetrafolate is THF, adenosylmethionine is SAM, Sadenosylhomosysteine is SAH and Homocysteine is HCY. Moreover, there is evidence that suggests that B12 promotes absorption of nutrients in the intestines [6]. In mice, B12 has been seen to act as an anticarcinogenic agent [7]. High B12 levels in aging populations has shown to act as a neuroprotectant [8]. Finally, high dosages of vitamin B12 has been associated with suppression of T-Cells and the body’s allergic reaction. [9] Related Compounds: Folic acid (page 17), Beta-carotene (page 33), Potassium (page 43) References:

[1] Bottigleiri T; Nutrition Reviews 1996. 54(12)-382-390.

[2] Louis W. S; Victor Hl N Engl J Med. 1965. 272:340-246.

[3] Roth JR; Lawrence JG; Bobik TA; Annual Review of Microbiology. 1996. 50: 137-181 [4] Hines C; Arch Intern Med 1978. 138(4):619-621.

[5] Swanon VL; Wheby MS; Bayless; Am J Pathol 1966. 49:167-191.

[6] [Vilter RW; Will JJ; Wright T; Rullman D; American Journal of Clinical Nutrition 1963. 12:130-142 [7] Ebbing M; Bonaa KH; Nygard Ol Arnesen E; JAMA 2009. 302(19): 2152-2153.

[8] Gonzailez MG, Ascension M; Petrzik K; British Journal of Nutrition 2009. 86: 313-321 [9] Chandra R.K. The Lancelet 1992. 320: 1124-1127.

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Vitamin C Dose: 3.6 mg/day | anti-carcinogenic | anti-inflammatory | antioxidant | | neuroprotective Description: Vitamin C, also called ascorbic acid, is a water-soluble vitamin. This vitamin can be attained from citrus fruit, broccoli and tomatoes.

Vitamin C is needed for the repair and growth of the body, as it helps make collagen [1]. This vitamin also acts as an anti-oxidant [2], a neuroprotective [3] and anticarcinogenic agent [4].

Metabolism: L-ascorbic acid has many co-factor functions in the synthesis of collagen, carnitine, tyrosine, and neurotransmitters.

Carnitine synthesis’ essential dioxygenases also require vitamin C for maximal activity. [1] This vitamin is also used as a cofactor for the synthesis of catecholamine, to convert dopamine and norepinephrine [2].

Vitamin C also acts as a cosubstrate in peptide amidation and tyrosine metabolism [3].

Vitamin C acts on dioxygenases by reducing the active centre metal ion involved in the previous 11

Figure 1: L-Ascorbic Acid Quick Facts: Properties: Water soluble Molecular Mass: 176.12 g/mol reactions, attributed to vitamin C’s redox potential. This ability is hypothesized to also help with the gastrointestinal absorption of dietary iron [4].

Effects: Deficiency in vitamin C can result in weaker collagenous structures, which causes tooth loss, joint pain, bone and connective tissue disorders, and slow wound healing, all indicative of an aging process [1].

Also, since carnitine is required for fatty acid transport into the mitochondria, vitamin C deficiency can result in fatigue and lethargy. Last, deficiency can result in mood changes, attributed deficiency in dopamine hydroxylation [3].

Figure 2: Pathway for certain Vitamin C oxidization [2]

Many clinical and epidemiological studies have suggested that vitamin C could help in the prevention and maintenance of cardiovascular disease, cancers, and cataracts [5].

in immune cells in high concentrations, consumed rapidly when infections occur. Vitamin C is said to help phagocytes with the production of lymphocytes [6].

Although Vitamin C has been found to behave as a pro-oxidant, it mostly behaves as an antioxidant, scavenging reactive oxygen species, reactive oxygen and nitrogen species. Vitamin C also acts as a coantioxidant and pays a large role in

Moreover, Vitamin C acts as an antihistamine and an antiinflammatory agent by preventing high histamine levels [7]. What’s more epidemiologic studies in humans have found evidence that vitamin C acts as a cancer preventing agent [4].

Related Compounds: Vitamin D (page 13), Vitamin E (page 15), Acetyl Lcarnitine (page 23), Chromium picolinate (page 25), Acetylsalicylic acid (39), Alpha lipoic acid (page 41) References:

[1] Libby P; Aikawa M; Circulation 2002. 105:1396-1398 [2]Carr A; Balz F; Americal Journal of Clinical Nutrition 1999. 69(6): 1086-1107.

[3] Pace A; Antonella S; Mauro P; Bove L; American Society of Clinical Oncology 2003. 21(5): 927-931.

[4] Chen LH; Boissonneault GA; Glauert HP; Anticancer Research. 1988. 8(4):739-48 [5] Valero MP; Fletcher AE; Stavola BL De; The Journal of Nutrition 2002. 132:1299-1306.

[6] Noroozi M; Angerson WJ; Lean ME; American Journal of Climical Nutrition 1998. 67:1210-1218.

[7] Hemila H; British Journal of Nutrition 1991. 67:3-16.

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Vitamin D Dose: 2.5 IU/day | anti-carcinogenic | antioxidant | insulin-sensitive | | neuroprotective Description: Vitamin D is a fat soluble vitamin which can be synthesized by humans in the skin or it can be obtained from the diet from alfalfa, and different mushrooms [1].Too much vitamin D intake could be toxic to the body, however since most of North America is deficient in the vitamin, toxicity is unlikely [2].

Vitamin D contributes to the mechanisms of calcium balance, immunity, insulin secretion, immunity, blood pressure regulation and cell regulation. When levels of calcium are low, the parathyroid hormone is secreted which Figure 1: Calcitrol increased the production and function of calcitrol, which, Quick Facts: through gene regulation, increases Properties: Non-Polar intestinal absorption of dietary niacin and increases the reabsorpMetabolism: tion of calcium in the kidneys [3].

Vitamin D in its consumed and Similarly, vitamin D affects the rate produced form is inactive, and is of insulin secretion when there is metabolized in the body to increased insulin demand [4]. become various derivatives, of which the most calcitrol. [1]

13

significant

is

More than 50 genes are known to be regulated by calcitrol. It bonds with the transcription factor, vitamin D receptor (VDR), which in combination with retinoic acid X receptor modulate transcription in the nucleus. [1]

There has also been considerable evidence that vitamin D plays a role in the suppression of autoimmune disorders [5]. Research also indicates that VDR regulates the expression of renin, in the angiotensin-renin system, which contributes to blood pressure regulation. [6]

Figure 2: Pathway for the creation of Vitamin D3 in the skin [3] Effects: Extreme deficiency in vitamin D causes Rickets, an illness characterized by inadequate mineralization of calcium in weightbearing bones.

Similarly other calcium and bone related illnesses result as a lack of vitamin D. Increased intake of vitamin D helps in the maintenance of bones. [4] Since some of the genes regulated by vitamin D have been found to induce cell differentiation through

transcription regulation, its regular consumption has been shown to reduce rates of colorectal, breast and prostate cancer. [7] Vitamin D’s role in the reninangiotension system also contributes to its ability to maintain hypertension.

[6] Studies have shown that vitamin D acts as a membrane antioxidant and acts to suppress autoimmune disorders. [5]

Related Compounds: Vitamin C (page 11), Cod liver oil (page 53) References:

[1] Lehmann B; Meurer M; Dermatologic Therapy 2010. 23:2-12.

[2] Hanley D; Davison S; The Journal of Nutrition 2006. 135:332-337.

[3] Rhoten WB; Bruns EM; Endocrinology 1985. 117(2):674.

[4] Norman AW; Frankel JBl Heldt Am; Grodsky GM; Science 1980. 209:823-825.

[5] Cantorna MT; Mahon BD; Exp Biol Med 2004. 229: 1139-1142.

[6] Li Y[C; Journal of Cellular Biochemistry 2002. 88(2):327-331.

[7] Garland CF; Garland FC; Journal of Public Health 2005. 96:252-261.

14

Vitamin E Dose: 1.44 IU/day | anti-carcinogenic | antioxidant | neuroprotective Description: Typically found in wheat germ oil and sunflower oils [1], vitamin E is a fat-soluble antioxidant.

Recently it has been shown to have anti-carcinogenic properties along with its antioxidant properties [2].

Metabolism: Vitamin E includes four tocopherols and four tocotrienols, all derived from 6-chromanol. Of the eight types, α-tocopherol, is preferentially absorbed in humans.

Vitamin E acts as a “chainbreaking” antioxidant by preventing the propagation of free radical reactions involved in cancer, cardiovascular disease, diabetes and aging [3]. α-tocopherol has been shown to regulate expression scavenger receptors which remove foreign substances from the body [4].

Figure 1: α-tocopherol Quick Facts: Properties: Non-polar Molar Mass: 430.71 g/mol Moreover, vitamin E has also been found to regulate the connective tissue growth factor (GTGF), which promotes endothelial cell growth. The previous actions of Vitamin E may be the reason why Vitamin E also regulates the activity of protein kinase C (PKC), which helps muscle growth [5]. α-tocotrienol, another derivative of vitamin E, has been shown to help with resistance to stroke-induced brain injury. The vitamin acts on molecular checkpoints to protect against glutamate and stroke induced neurodegeneration [6].

Effects: Vitamin E deficiency is known to cause spinocerebellar ataxia, peripheral neuropathy, ataxia and other neurological and immunological diseases. It’s neuroprotective effect may be attributed to it’s role as a molecular check point. [6]

15

Figure 2: The eight forms of vitamin E Its anti-coagulant role can be attributed to its role in circulation.

For this reason, Vitamin E cannot be used with warfarin due to possibly inhibitory effect caused by megadoses of vitamin E [7].

Research has also indicated that the anti-carcinogenic action of selenium is slowed down by a vitamin E deficiency, especially when the organism was under high oxidative stress. Vitamin E’s role as an antioxidant contributes to it’s role as an anti-carcinogen [2].

Related Compounds: Vitamin C (page 11), Coenzyme Q10 (page 27), Betacarotene (page 33), Alpha-lipoic acid (page 41), Selenium (page 44)

References:

[1] McLaughlin PJl Weihrauch JL; Journal of the American Dietetic Association 1979. 75(6):647-65.

[2] Burton GW; Traber MG; Annual Review of Nutrition 1990. 10:357-382.

[3] Herrera E; Barbas C; J. Physiol. Biochem 2000. 57(1):43-56.

[4] Brigellus RF; Traber MG; FASEB 1999. 13:1145-1155.

[5] Angelo A; Gysin R; Kempna P; Annals of New York Academy of Sciences 2004. 1031: 86-95.

[6] Kontush A; Schekatolina S; Annals of the New York Academy of Sciences 2004. 1031: 249-262.

[7] Rim[m EB; Stampfer MH; Ascherio A; Giovannuci E; Colditz GA; Willett WC; N Engl J Med 1993.

328:1450-1456.

16

Folic Acid Dose: 0.01 mg/day | anti-carcinogenic | antioxidant | neuroprotective Description: Folic acid is a water soluble B-complex vitamin, often called Vitamin B9. It is found in foods such as leafy vegetables, asparagus, legumes and yeast [1]. Although toxicity from this vitamin is very rare, an upper limit of 1 mg for men and 0.8 mg for women is suggested [1]. In the body, it is changed into folate [2].

Metabolism: Vitamin B9 is involved in a reaction the transfers one-carbon units. The vitamin acts as an acceptor and a donor of a carbon unit. Specific nucleic acid reactions that require this type of transfer include the synthesis of DNA from thymidine and purines, the synthesis of methionine and consequently, adenosylmethionene, and finally, it is used for the methylation of DNA. [2] Folic acid also plays a role in transferring single carbon units for amino acids, for example, changing homocysteine to methionine. Homocysteine degrades disulfide bridges and lysine amino acid residues, which degrades major structural components of the artery [3]. To carry out this reaction, NADPH first needs to reduce folic 17

Figure 1: Pyridoxol Phosphate Properties: Water soluble Molecular Mass: 441.4 g/mol acid two times. The pathway begins with folate (a derivative of folic acid) which is reduced to dihydrofolate (DHF) and tetrahydrofolate (THF), NADPH is required for this synthesis THF is the acceptor of the 1-carbon group [3].

Some reactions of the folic acid metabolism is heavily reliant on other reactions. The reaction that converts methionine to homocysteine requires a folate coenzyme which requires a enzyme that uses B12 and another that uses B6 [4].

Figure 2: The two steps of converting Folate into THF Effects: Folate deficiency has been Cancer arises from DNA damage and associated with higher levels of inappropriate expression of critical homocysteine, which is an genes. Since folate plays a role in indicator of a risk of cardiovascular nucleotide synthesis and methylation, disease, since homocysteine con- folate plays a role in both DNA repair tributes to a degradation of arterial and expression. Studies have found walls. Studies on Finnish males also that lower folate levels are correlated found that those with a higher folic to cervical, lung brain pancreas breast acid intake had a 55% lower risk and colorectal cancer. [7] for an acute coronary event. [5] Folic acid’s role in nucleotide Folate deficiency also causes synthesis and methylation could also anaemia, since folate contributes contribute normal brain function. In a to rapid blood cell division [6].

Canadian study, low folate levels were associated with an increase in shortRelated Compounds: term memory problems. Studies have Vitamin B1 (page 3), Vitamin B3 also found that folic acid may be (page 5), Vitamin B6 (page 7) associated with Alzheimer's disease Vitamin B12 (page 9) and vascular dementia. [8] References:

[1] Chanarin I; Anderson BB, Mollin DL; British Journal of Haematologyi 1958. 4(2):156-166 [2] Stokstad E; Koch J; Physiol Rev 1967. 46:83-116.

[3] Appling DR; FASEB 1991. 5:2645-2651.

[4] Fenech MF; Dreosti IV; Rinaldi JR; Carcinogenesis 1997. 18(7): 1329-1336.

[5] Voutilainen S; Rissanen THl Virtanen J; Lakk T; Circulation 2001. 103:2674-2680.

[6] Morris MS; Jacques PF; Rosenberg IHl Selhub J; American Journal of Clinical Nutrition.85(1):193-200.

[7] Giovannucci E; Stampfer MJ; Colditz GA; JNCI 1993. 85(11)-875-883.

[8] Clake R; Smith DA; Jobst KA; Refsum H; Lesley S; Ueland PM; Arch Neurol. 1998. 55:1449-1455.

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N-acetyl cysteine Dose: 7.2 mg/day | antioxidant Description: N-acetyl cysteine (NAC), the acetylated variant of L-cysteine, is a common antioxidant supplement. It is converted in the body into metabolites capable of stimulating glutathione (GSH) synthesis, promoting detoxification and acting directly as free radical scavengers. NAC is also often used as a drug for respiratory illnesses. The structure of NAC is shown in Figure 1 [1].

Figure 1: structure of NAC Quick Facts: Molecular Formula: C5H9NO3S NAC is an acetylated variant of amino acid L-cysteine.

Water soluble Cysteine is found in high protein foods but NAC is not.

Metabolism: The acetyl group on NAC makes it more water-soluble than cysteine.

Thus it is easily absorbed and distributed throughout the body upon oral ingestion. Inside the body, NAC gets converted to cysteine and participates in glutathione (GSH) synthesis.

The functions of NAC in GSH synthesis is highlighted in Figure 2.

Glutathione is synthesized from cysteine and glutamate. NAC functions in this pathway by supplying the cysteine that’s required for GSH synthesis. As the GSH concentration in the cell falls, glutamate cysteine ligase is first released from feedback inhibition to promote the ligation of cysteine and glutamate. To keep up with the supply of cysteine, exogenously supplemented NAC is de-acetylated into cysteine. NAC also cleaves the disulfide bond of plasma cysteine. The free cysteine then enters the cell to participate in GSH synthesis [2].

19

Figure 2: Functions of NAC in glutathione synthesis.

Effects: NAC acts as an antioxidant by scavenging Reactive Oxygen Species (ROS) in situations where ROS level is increased. It does so through 3 mechanisms.

1) increase levels of GSH (one of the most important antioxidant in the body) [3].

Related Compounds: L-glutathione (page 21)

2) NAC directly reacts with ROS such as HOCl and H2O2 etc. [4].

3) NAC regulates the expression of numerous genes through inhibiting the activation of some transcription factors. It prevents apoptosis and promotes cell survival by activating extracellular signal-regulated kinase pathway, a concept useful for treating certain degenerative diseases. It also modifies the activity of several proteins by its reducing activity [5].

References:

[1] Image from Wikimedia Commons.

[2] Raftos, J. E., Kuchel, P. W. et al. The International Journal of Biochemitry & Cell Biology. 2007. 33, 9, 1698-1706.

[3] Kerksick, C.; Willoughby, D. J. Int. Soc. Sports. Nutr. 2005. 2(2), 38-44.

[4] Aruoma, O. I.; Butler, J.. et al. Free Radical Biology & Medicine. 1989. 6, 595-597 [5] Zafarullah, M., Li, W. Q., Sylvester, J.; Ahmad, M. Cellular and Molecular Life Scicences. 2003. 60, 6-20

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L-glutathione Dose: 0.36 mg/day | antioxidant

Description: L-glutathione (GSH) is one of the most important antioxidants in the body. It is found in almost all cells in all organisms. It is structurally a tripeptide and the sulfhydryl (SH) group on the cysteine serves as a proton donor and is responsible for its biological activity [2].

GSH is not absorbed easily by the gastrointestinal track of humans upon oral administration. Thus, intravenous injections of GSH is preferred to increase intracellular GSH level [3].

Figure 1: structure of GSH [1] Quick Facts: Molecular Formula: C10H17N3O6S Linear tripeptide make of Lglutamate, L-cysteine and glycine.

Most important antioxidant Water-soluble Found in almost all cells with highest concentration in liver cells.

Metabolism: GSH reduces disulfide bonds formed within cytoplasmic proteins into cysteine and gets oxidized into glutathione disulfide (GSSG). In glutathione synthesis, γ-glutamyl-cysteine is first formed from glutamate and cysteine through γ-glutamyl-cysteine synthetase. Then, glycine is added to the Cterminal of the γ-glutamyl-cysteine. It is worth noting that NAC is a precursor in GSH synthesis by serving as a reservoir for cysteine.

Additionally, glycolysis pathway is also involved in step 17 of GSH synthesis.

Refer to Figure 2 for a detailed diagram of GSH synthesis [4].

21

Figure 2: GSH synthesis and utilization in animals. [2] Effects: GSH scavenges free radicals and other ROS (e.g., hydroxyl radical, lipid peroxyl radical, peroxynitrite, and H2O2) directly. Indirectly, it reduces ROS through enzymatic reactions by donating electrons and oxidizing to GSSG [5].

Additionally, glutathione peroxidase catalyzes the GSH-dependent

reduction of H2O2 and other peroxides. GSH also assists in the storage and transport of cysteine, the synthesis of leukotrienes and prostaglandins, the regulation of intracellular redox, signal transduction and expression, apoptosis, immune response, and cytokine production [5]. Lastly, the GSSG/GSH ratio rises with aging in the liver, kidney, and brain [6].

Related Compounds: N-acetyl cysteine (page 19), Alpha lipoic acid (page 41) References:

[1] Image from Wikimedia Commons.

[2] Lu, S. C. Curr. Top. Cell Regul. 2000. 36:95-116.

[3] Witschi, A.; Reddy, S.; Stofer, B.; Lauterburg, B. H. European Journal of Clinical Pharmacology, 1992.

43, 6, 667–9.

[4] Griffith, O. W. Free Radic. Biol. Med. 1999. 27, 922-935.

[5] Fang, Y. Z.; Yang, S.; Wu, G. Nutrition 2002. 18, 872-879 [6] Jones, D. P. Methods Enzymol. 2002. 348:93-112

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Acetyl L-Carnitine Dose: 14.4 mg/day | antioxidant | neuroprotective Description: Acetyl L-carnitine (ALCAR) is a common dietary supplement that helps the body turn fat into energy. It is an acetyl form of Lcarnitine with the acetyl group replacing the hydroxyl group. It is also used as a medication for various neurological disorders like Alzheimer's disease and agerelated memory loss due to its ability to cross the blood-brain barrier. [1] Metabolism: When ALCAR is exogenously administered, it is rapidly removed from the plasma and taken up by many tissues in the body such as kidney, heart, brain and liver. [2]

Figure 1: structure of ALCAR Quick Facts: Molecular Formula: C9H17NO4 An acetylated form of L-carnitine.

Naturally in plants and animals.

Water soluble and can cross the blood-brain barrier.

Endogenous ALCAR is synthesized intra-mitochondrially in many tissues including brain, liver, heart, kidney and muscle. It is formed by carnitine acetyltransferase that combines L-carnitine with an acetyl group from CoA. Once formed, ALCAR is transported across the inner mitochondrial membrane by carnitine acetyltranslocase (CarAT) into the cytoplasm to serve as a source of acetyl groups. It also provides acetyl groups for the production acetylcholine, which is a neurotransmitter. It is worth noting that Vitamin C is essential for the synthesis of ALCAR precursor L-carnitine.

Refer to Figure 2 [3].

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Effects: ALCAR functions physiologically as transport between the mitochondria and cytoplasm for long-chain fatty acid. Thus it plays a role in cellular energy production and in removing toxic accumulation of fatty acids from mitochondria [4].

ALCAR especially benefits the brain because it promotes the production of neurotransmitter acetylcholine and its ability to cross the blood-brain barrier when supplemental exogenously. It has been shown to clinically benefit cognitive abilities, memory and mood [5].

Related Compounds: Vitamin C (page 11), Alpha-lipoic acid (page 41), Cod liver oil (page 53), Flax seed oil (page 55).

Figure 2: functions of ALCAR as a reservoir for acetyl groups.

In anti-aging research, ALCAR has been shown to play a role in preventing mitochondrial damage.

It was shown that when given to old mice, ALCAR greatly improves mitochondrial function. with the mice exhibiting phenotypes of increased short term memory and cognitive function. When given in high doses, ALCAR also lowered oxidative stress in mice [6].

References:

[1] Image from Wikimedia Commons.

[2] Rebouche C. J. Ann. N. Y. Acad. Sci. 2004, 1033, 30–41.

[3] Hendler, S.S. & Rorvik, D., eds. Acetyl-L-carnitine, L-carnitine. PDR for Nutritional Supplements.

Montvale, Medical Economics Company, Inc., 2001, p 9-11, 255-259 [4] Carta A, Calvani M, Bravi D, Bhuachalla SN. Ann NY Acad Sci. 1993, 95, 324-326.

[5] White HL, Scates PW. Neurochem Res. 1990,15, 597-601.

[6] Hagen, T. M; Ames, B. N et al. PNAS. 2002. 99, 4, 1870-5

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Chromium Picolinate Dose: 1.44 mcg/day | insulin-sensitive Description: Chromium picolinate is a dietary supplement used to treat chromium deficiency. Chromium is a trace mineral found in foods like brewer’s yeasts and eggs etc. It is the active ingredient in Glucose Tolerance Factor (GTF), which plays a role in controlling blood glucose level by enhancing the function of insulin [2].

Figure 1: structure of chromium picolinate [1].

Metabolism/ function: Quick Facts: Chromium picolinate is a more Molecular Formula: Cr(C6H4NOs)3 bioavailable form of chromium It is used to supply the trace because it is more easily absorbed mineral chromium in the body than the mineral salt form. Vitamin This supplement has been C is thought to promote advertised to promote weight loss chromium absorption. In natural and muscle building. foods, chromium is found in its biologically active form, which is the active component of the hormone-like Glucose Tolerance Factor (GTF).

The GTF complex is composed of one trivalent chromium surrounded by two nicotinic acid (Vitamin B3) and amino acids, shown in figure 2 [3]. GTF works as a cofactor of insulin because it enhances the function of insulin.

After a meal, as blood glucose levels begin to increase, insulin is secreted from the pancreas. Insulin lowers blood glucose level by promoting glucose update into the cell. It is believed that GTF plays a role in enhancing insulin’s function by initiating the attachment of insulin to the insulin receptor. GTF and insulin also promote the use of amino acids for protein synthesis and the improvement in phagocytic ability of white blood cells [4].

Chromium may also play a role in cholesterol metabolism and nucleic acid metabolism.

25

Figure 2: The structure of Glucose Tolerance Factor (GTF). The trivalent chromium forms a complex with two nicotinic acid (Vitamin B3) and three amino acids. The amino acid moieties, cysteine, glutamic acid and glycine, render the salt water soluble. [3] Effects: Chromium picolinate helps to maintain the body’s chromium level to avoid chromium deficiency. However, the amount of chromium required by the body is not yet known [5].

Since insulin has an anabolic effect on skeletal muscle through promoting protein synthesis, Related Compounds: Vitamin B3 (page 5), Vitamin C (page 11)

Chromium is advertised to promote muscle building, though research has not shown this effect[4]. It is claimed that chromium picolinate can increase average life span based on some limited animal data. A study by Dr. Evans showed that high levels of chromium picolinate increased longevity in rat [6]. Overall, this supplement is a very controversial in terms of the efficacy of its advertised effects.

References:

[1] Image from Wikimedia commons.

[2] Tuman, R. W; Doisy, R. J. Diabetes. 1977, 26, 9, 820-826.

[3] Steele, N. C., Althen, T. G.; Frobish, L. T. J. Anim. Sci. 1997, 45, 1341-1345.

[4] Mertz, W. Physio. Rev. 1969, 49, 2.

[5] Stearns, D. M. Biofactors, 2000, 11, 3, 149–62.

[6] Evans, G. W. J. Inorganic Biochemistry, 1992, 46, 4, 243-250.

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Coenzyme Q10 Dose: 0.44 mg/day| antioxidant Description: Coenzyme Q10, or ubiquinone, is a naturally-occurring compound found in almost very cell in the body. It plays a role in aerobic energy production in the form of ATP as it is a part of the electron transport chain (ETC) in the inner mitochondrial membrane.

Coenzyme Q10 is often taken as a supplement with cardiovascular benefits and anti-aging properties.

Figure 1: structure of Coenzyme Q10 [1].

Quick Facts: Molecular Formula: C59H90O4 Oil soluble Present in most eukaryotic cells, primarily in the mitochondria It is part of the electron transport chain (ETC)

Metabolism: Exogenous Coenzyme Q10 is absorbed from the small intestinal tract. The absorption follows the same process as that of lipids and its uptake mechanism is similar to that of Vitamin E [2].

Coenzyme Q10 is synthesized in the mitochondria and endoplasmic reticulum from tyrosine (or phenylalanine) and acetyl-CoA. Tyrosine is converted to hydroxybenzoate through multiple steps while acetyl-CoA is converted to farnesyl,-PP (FPP). Afterwards, hydroxybenzoate and FPP are combined to from Coenzyme Q10 [3].

Coenzyme Q10 functions as an electron carrier in the electron transport chain. In ETC, electrons are passed through a series of compounds starting from NADH and ends with oxygen in order to create a proton gradient across the inner mitochondrial membrane. CoQ10 shuttles electrons from enzyme complex I and enzyme complex II to complex III in this process.

Refer to Figure 2 for the process of electron transport chain [4].

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Coenzyme Q10 Inner membrane space

Figure 2: Eukaryotic electron transport chain.

Effects: Antioxidant – since CoQ10 is an energy carrier, it gets oxidized or reduced easily, serving as an antioxidant. CoQ10 also inhibits lipid peroxidation by preventing the formation of peroxyl radicals. It reduces the level of perferryl radicals, thus inhibiting both the Related Compounds: Vitamin E (page 15)

initiating and propagation of lipid peroxidation. CoQ10 can also effectively regenerate vitamin E from α-tocopheroxyl radicals [5].

Anti-aging – CoQ10 is often used in skincare products to slow down cutaneous aging. Its anti-aging mechanism is based on lowering oxidative stress and slowing down mitochondrial decline. It has been to shown to prolong lifespan in C.elegans and rats [6].

References:

[1] Image from Wikimedia Commons.

[2] Ochiai A.; Itagaki S.; Kurokawa T.; Kobayashi M.; Hirano T.; Iseki K. Yakugaku Zasshi . 2007, 127, 8, 1251–4.

[3] Bentinger, M.; Tekle, M.; Dallner, G. Biochem. Biophys. Res. Commun. 2010, 396, 1, 74–9.

[4] Forster, M. J. et al. Free Radic. Biol. Med. 2006, 1, 41, 480-7 [5] Tappel, A. L. et al. Clinical Biochemistry. 2000, 33, 4, 279-284.

[6] Furukawa, S. et al. Mech. Ageing Dev. 2004, 125, 1, 41-6.

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Dehydroepiandrosterone Dose: 0.15 mg/day Description: Dehydroepiandrosterone (DHEA) is an endogenous hormone made mostly by the adrenal gland in the body. It serves as precursor for male and female sex hormones (androgens and estrogens respectively). DHEA is widely used to treat systemic lupus erythematosus, adrenal deficiency, and depression. It has been shown that DHEA levels decreases with age [2].

Metabolism/ synthesis: DHEA is converted in the body to become sex hormones, androgens and estrogens. Like all steroid hormones, DHEA is synthesized from cholesterol. Refer to Figure 2. for DHEA synthesis [2].

Figure 1: structure of DHEA [1].

Quick Facts: Molecular Formula: C19H28O2 19-carbon endogenous steroid hormone. oil soluble Mainly produced by the adrenal gland and it is the most abundant circulating steroids.

Effects/ functions: Systemic lupus erythematosus – SLE is an autoimmune disorder where the body’s immune system attacks its own tissue. DHEA supplementation has been to shown to improve the quality of life for people with lupus, enhancing mental function and boosting bone mass.

Adrenal insufficiency – with adrenal insufficiency, the adrenal gland does not make enough DHEA or cortisol. DHEA supplementation has been shown to improve mood, fatigue and well-being [3].

29

Figure 2: DHEA synthesis and its related hormones Effects: Natural DHEA levels peak in early childhood and fall as age increases.

This observation suggests that DHEA supplementation slows the aging process. Studies have shown that DHEA supplementation improves immune functions by increasing levels of interleukin-2. It also showed to increase insulin growth factor (IGF) that regulates blood Related Compounds: none

glucose metabolism. It also helps to protect bone mineral density in women.

Although all these benefits suggest the anti-aging properties of DHEA, other research have shown that no differences were seen for people who took DHEA and those who did not in terms of insulin sensitivity, body composition and physical performance. Thus the anti-aging effects of DHEA remain inconclusive [4].

References:

[1] Image from Wikimedia commons.

[2] Schulman, Robert A., Dean, Carolyn. DHEA is a common hormone produced in the adrenal glands, the gonads and the brain. Solve it with supplements. New York City, Rodale, Inc., p.100.

[3] Crosbie, D; Black, C, McIntyre, L, Royle, PL, Thomas, S. Dehydroepiandrosterone for systemic lupus erythematosus. Cochrane database of systematic reviews,2007, 4.

[4] Arlt, W. 2004, 18, 3,363–80.

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Melatonin Dose: 0.01 mg/day | antioxidant Description: Melatonin is an endogenous hormone produced by the pineal gland in the brain in response to environmental light/dark cycles [2]. Its main function is to help regulate other hormones and to maintain the body’s circadian rhythm.

Melatonin levels decreases with increasing age.

Figure 1: structure of melatonin [1].

Quick Facts: Metabolism: Molecular Formula: C13H16N2O2 Melatonin is synthesized from LA hormone produced by the pineal tryptophan. Tryptophan circulagland in the brain. ting in the blood is taken up by Water soluble pinealoctyes and converted to It regulates body’s circadian rhythm melatonin. Melatonin is then metabolized by the liver and excreted to bile as hydroxymelatonin conjugated with sulfate or glucuronide. The production of melatonin is light dependent. During the day when light is abundant, the level of melatonin is decreased, while at night, melatonin level is increased, promoting sleep. Refer to Figure 2 for melatonin synthesis [3].

Effects: Circadian rhythm – The main function of melatonin is to regulate the sleep-wake cycle. At night when melatonin level is high due to lack of night, melatonin promotes sleep through chemically causing drowsiness.

Melatonin acts on the target cell mostly indirectly through its G-protein coupled receptors that modulate several intracellular messengers such as cAMP, cGMP and [Ca2+] [4].

31

Figure 2: Melatonin synthesis [3].

Melatonin is also a powerful antioxidant as it can easily cross the blood-brain barrier and cell membrane.

It can directly scavenge OH, NO and oxygen Related Compounds: none

radicals.

Interestingly, once melatonin is oxidized upon reacting with free radicals, it can not get reduced again. In the GI track, melatonin mostly functions to deal with stress such as irritants and toxins [5]. Melatonin has been implicated in aging because its level decreases with age [6].

References:

[1] Image from Wikimedia commons.

[2] Sudgen, D. Experientia, 1989, 45, 922-931.

[3] Bubenik, G. A. et al. J Physiol Pharmacol. 2007, 6, 23-52.

[4] Moore, R. Y. Annu Rev Med. 1997, 48, 253-266.

[5] Calvo, J. R. et al. Biol. Signals. Recept. 2000, 9, 134-59.

[6] Bondy, S. C. et al. J. Pineal Res. 2004, 36, 165-70.

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Beta-Carotene Dose: 50.0 IU/day | antioxidant

Figure 1: Beta-carotene Description: Beta-carotene is a pigment that can be found in plants and fruits, particularly those that are orange and yellow, such as carrots and squash [6]. Beta-carotene is the biological precursor to vitamin A, which is biologically useful to the body.

Metabolism: Beta-carotene can be found readily available from natural sources and will be converted to vitamin A for biological processes.

It is first absorbed by the lymphatic system of the body and the absorption depends on dietary fat and bile concentration in the gastrointestinal tract [1].

Quick Facts [1]: Chemical Formula: C40H56 Molecular Weight: 526.8726 g/mol Properties: Hydrophobic, non-polar

Beta-carotene is cleaved symmetrically into 2 retinal molecules by betabeta-carotene-15,15’-dioxygenase in the presence of alpha-tocopherol (Fig. 2)[3,4]. Retinal can then be converted to other forms of vitamin A. Retinal can be converted into a transportable form of vitamin A, retinol, by retinol dehydrogenases and alcohol dehydrogenases [5]. Retinol is also known as the alcohol form of vitamin A. Another form of vitamin A is retinoic acid, which also acts as an important signalling molecule and hormone in vertebrate animals. Retinal is converted to retinoic acid by retinal oxidase [5].

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Alpha-tocopherol + beta-beta-carotene15,15’-dioxygenase

Figure 2: Cleavage of beta carotene into retinal.

Effects: The body absorbs 22% of dietary beta-carotene into the lymphatic system which is then transferred into the liver [1]. Beta carotene can act as an antioxidant by quenching singlet oxygen and other radicals [2]. To be cleaved Related Compounds: Vitamin B12 (page 9), Vitamin E (page 15), Gingko biloba (page 51)

into retinal, the process requires alpha-tocopherol, also known as vitamin E [4].

Retinal, retinol, and retinoic acid, compounds that have vitamin A activity, also known as retinoids have hormone-like effects in developing bone. They also act as immunostimulants and are essential for vision and reproduction. [5]

References: [1] National Centre for Biotechnology Information. PubChem: Beta Carotene. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=573 (accessed Mar 19, 2012).

[2] Sies, H.; Stahl, W. Am J Clin Nutr. 1995. 62: 1315S-1321S. [3] Biesalski, H.K.; Chichili, G.R.; Frank, J.; von Lintig, J.; Nohr, D. Vitam Horm. 2007. 75: 117-30.

[4] Lakshman, M.R. J Nutr. 2004. 134: 241S-245S. [5] Napoli, J.L.; Race, K. R. J Biol Chem. 1988. 263: 17372-7 [6] United Sates Department of Agriculture. Agricultural Research Service: Nutrient lists. http://www.ars.usda.gov/Services/docs.htm?docid=17477 (accessed Mar 19, 2012).

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Bioflavonoids Dose: 4.32 mg/day | anti-coagulant | anti-inflammatory | antioxidant Description: Bioflavonoids are a class of plant secondary metabolites, organic compounds which do not contribute directly to the growth, development, or reproduction of plants [9]. Secondary metabolites are often used for medicines, flavourings, or recreational drugs.

Bioflavonoids are comprised of three major classes: flavonoids, isoflavonoids, and neoflavonoids.

The classes can be further branched into flavanols, flavones, flavanones, catechins, anthocyanidins, isoflavones, dihydroflavonols, and chalcones [2].

A

B

C

Figure 1: general chemical structures of flavonoids (A), isoflavonoids (B), and neoflavonoids (C). [1] Quick Facts: Major groups: flavonoids, isoflavonoids, and neoflavonoids, derived from 2-phenylchromen-4one (flavones), 3-phenylchromen4-one and 4-pneylcoumarin, respectively [1] Properties: Hydrophobic, polar

Metabolism: Many flavonoids occur naturally as flavonoid glycosides (FG), which are absorbed into the small intestine epithelial cells by sodium-dependent glucose transporter 1 (SGLT1)(Fig.2)[4]. The efficiency of this absorption is suppressed by the efflux of FG by apical transporter multidrug resistanceassociated protein 2 (MRP2)[5]. FG could also gain entry to the intestinal epithelial cells by being hydrolyzed by broad-specific β-glucosidase enzyme (BSβG)[7]. Lactase phloridzin hydrolase (LPH) was found to also be able to hydrolyze FGs in the brush border of the small intestine [6]. A study subject ingested an onion meal with quercetin glucosides and quercetin was found in plasma afterwards, suggesting that FGs are processed before entering the blood plasma for circulation [8].

35

Figure 2: Pathways of transport and metabolism of flavonoid glucosides (FG).

Effects: Bioflavonoids have been shown to have antibacterial, antiviral, antiinflammatory, anti-allergic, and vasodilatory effects. It inhibits lipid peroxidation and platelet aggregation. Generally, they also act as antioxidants, free radical

Related Compounds: Rutin (page 38), Gingko biloba (page 51), Green tea extract (page 59)

scavengers and chelators of divalent cations. As antioxidants, they inhibit the initiation stage of lipid peroxidation and/or accelerate the termination stage to help prevent atherosclerosis and cancer. Regular consumption of flavonoids in red wine, dark chocolate, or green tea have been proposed to decrease risk of coronary heart disease.

References: [1] IUPAC. Goldbook: Flavonoids. http://goldbook.iupac.org/F02424.html (accessed Mar 19, 2012).

[2] Cook, N.C.; Samman, S. J Nutr Biochem.1995. 7: 66-76.

[3] Walle, T. Free Radical Biol & Med. 2004. 7: 829-837.

[4] Hollman,P.C.H. et al. M.B. Am J Clin Nutr. 1995. 62: 1276-1282.

[5] Walgren, R.A.; Karnaky Jr. K.J.; Lindenmayer, G.E.; Walle, T. J Pharmacol Exp Ther. 2000. 294: 830– 836.

[6] Day, A.J. et al. FEBS Lett. 2000. 468: 166–170.

[7] Day, A.J. et al. G. FEBS Lett. 1998. 436: 71–75.

[8] Moon, J. H.; Nakata, R.; Oshima, S.; Inakuma, T.; Terao, J. Am J Physiol Regulatory Integrative Comp Physiol. 2000. 279: R461–R467.

[9] Manach, C.; Morand, C.; Demigné, C.; Texier, O.; Régérat, F.; Rémésy, C. FEBS Lett. 1997. 409: 12-16.

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Rutin Dose: 0.72 mg/day | anti-coagulant | anti-inflammatory | antioxidant

Figure 1: Structure of rutin.

Description: Rutin is the flavonoid glycoside form of the flavonol quercetin. It is also known as quercetin rutinoside. It can be found naturally in buckwheat, asparagus, mulberry, onions, cranberries, green tea, and the Brazilian fava d’anta fruit.

Quick Facts: Chemical Formula: C27H30O16 Molecular weight: 610.5175 g/mol Properties: Hydrophobic, polar

Metabolism: Similar to the metabolism of flavonoids outlined on page 35, the metabolism of rutin, a flavonoid glucoside, follows the same process. In comparison to quercetin, rutin is absorbed more slowly than its aglycone counterpart because it must first be hydrolyzed by the gastrointestinal tract for uptake. Quercetin is hydrolyzed to quercetin glucuronide and/or sulphate conjugates by β-glucuronidase/quercetin-3-sulfate 3’sulfotransferase, respectively for transport in the blood plasma [6].

37

A

B Figure 2: Conversion of quercetin to quercetin glucuronide (A) and quercetin 3-sulfate (B).

Effects: Rutin and quercetin have been shown to be able to inhibit platelet aggregation [3][4]. They also have anti-inflammatory activity [5]. Like other flavonoids, rutin and quercetin act as antioxidants and free-radical scavengers. In addition, they can inhibit cytotoxicity of oxidized lowdensity lipoprotein [1].

Related Compounds: Bioflavonoids (page 35), Green tea extract (page 59)

References:

[1] Walle, T. Free Radic Biol & Med. 2004. 7: 829-837.

[2] Manach, C.; Morand, C.; Demigné, C.; Texier, O.; Régérat, F.; Rémésy, C. FEBS Lett. 1997. 409: 12-16.

[3] Cook, N.C.; Samman, S. J Nutr Biochem.1995. 7: 66-76.

[4] Navarro-Núñez, L.; Lozano, M. L.; Palomo, M.; Martínez, C.; Vicente, V.; Castillo, J.; Benavente-García, O.; Diaz-Ricart, M.; Escolar, G.; Rivera, J. J Agric Food Chem. 2008. 56: 2970-6.

[5] Guardia, T.; Rotelli, A. E.; Juarez, A.O.; Pelzer, L. E. Farmaco. 2001. 56: 683-7.

[6] Day, A. J.; Mellon, F.; Barron, D.; Sarrazin, G.; Morgan, M. R.; Williamson, G. Free Radic Res. 2001. 35: 941-52.

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Acetylsalicylic acid Dose: 2.50 mg/day | anti-coagulant | anti-inflammatory Description: Acetylsalicyclic acid (ASA), also known as aspirin, is a drug that is often used as an analgesic to relieve minor pain and has antiinflammatory and antipyretic effects to reduce fever [1]. It was discovered in August of 1897, by German chemist Felix Hoffmann in a pharmaceutical laboratory of Friedrich Bayer & Co [7].

Salicylic acid may be consumed in one’s diet and can also be synthesized endogenously [3].

Figure 1: Chemical structure of ASA Quick Facts: Chemical Formula: C9H8O4 Molecular weight: 180.157 g/mol Properties: Hydrophobic, polar

Metabolism: Acetylsalicyclic acid acts in the arachidonic acid cascade by restricting the conversion of fatty acid into prostaglandin G2, and subsequently thromboxane A2, by irreversibly inactivating the cyclooxygenase enzyme COX-1 and alternating the enzymatic activity of cyclooxygenase enzyme COX-2 (Fig. 2)[8]. Prostaglandins are a group of lipids that are typically more than 20 carbons long and have a 5-carbon ring. They act as autocrine or paracrine hormones that control pain transmission to the brain, regulation of temperature, and inflammation. Downstream of prostaglandins are thromboxanes A2 and prostacyclin. It has been found that thromboxanes A2 has an effect in platelet function and low doses of aspirin will increase bleeding time and reduce thrombosis [8].

39

Aspirin

cyclooxygenase

Arachidonic acid

Thromboxane A2

Prostaglandin G2

Prostacyclin

Figure 2: Arachidonic acid cascade and aspirin [8].

Effects: ASA has mostly been known as a medication for pain and fever, as mentioned earlier. Aspirin also has the effect of inhibiting platelet aggregation [2]. With intake of regular low doses, it can help prevent heart attacks and Related Compounds: Vitamin C (page 11), Magnesium (page 46), Ginger (page 49), Cod liver oil (page 53), Flax seed oil (page 55)

has been recommended for people with known cardiac disease to prevent strokes. In individuals without cardiovascular diseases, there is little benefit of low doses of aspirin and increased risk of hemorrhagic stroke and gastrointestinal bleeding [4]. More recently, research suggests that aspirin could play a role in cancer prevention [6].

Aspirin may inhibit the absorption of vitamin C, and breakdown fatty acids such as those in cod liver oil [5].

References:

[1] National Centre for Biotechnology Information. PubChem: Aspirin. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2244 (accessed Mar 21, 2012).

[2] Lewis, H. D. Jr. et al. N Engl J Med. 1983. 309: 396-403.

[3] Paterson, J. R. et al.. J Agric Food Chem. 2008. 56:11648-52.

[4] Antithrombotic Trialists' (ATT) Collaboration, Baigent, C. et al. Lancet. 2009. 373: 1849-60.

[5] Loh, H. S.; Watters, K.; Wilson, C. W. J Clin Pharmacol. 1973. 13: 480-6.

[6] Sneader, W. BMJ. 2000. 321:1591-4.

[7] Ghooi, R. B.; Thatte, S. M.; Joshi, P. S. Med Hypotheses. 1995. 44:77-80.

40

Alpha-lipoic Acid Dose: 0.72 mg/day | antioxidant | anti-inflammatory Description: Alpha-lipoic acid (LA) is a chiral organosulfur compound derived from octanoic acid [1]. It can exist as R-(+)-lipoic acid (RLA) and S-()-lipoic acid (SLA), but only the R enantiomer is found in nature, biosynthesized by the cleavage of linoleic acid and acting as a coenzyme of several enzymes [1].

It can be found readily available as a nutritional supplement at local pharmacies.

Figure 1: R-enantiomer of alphalipoic acid.

Quick Facts: Chemical Formula: C8H14O2S2 Molecular weight: 206.326 g/mol Properties: Hydrophobic, non-polar

Metabolism: Research suggests that LA is taken up by monocarboxylate and Na+dependent multivitamin transporters [3]. After gastrointestinal uptake, LA accumulates in skeletal muscle, the liver, and the heart. In vivo studies reveal that LA is subject to β-oxidation is rapidly reduced to dihydrolipoic acid (DHLA) [3]. Research has found that the most common metabolites of LA found in the body after ingestion include bisnorlipoic acid, tetranorlipoic acid, 6,8-bismethylthio-octanoic acid, 4,6-bismethylthiohexanoic acid, and 2,4-bis-methylthio-butanoic acid, which suggests that LA is metabolized through β-oxidation and S-methylation.

Effects: In vitro studies have found LA, and its reduced form DHLA, to be antioxidants and radical scavengers [7]. LA and DHLA create a potent redox couple which make them potent antioxidants. It has been found that DHLA and LA scavenge a variety of reactive oxygen species. Both DHLA and LA may scavenge hydroxyl radicals and hypochlorous acid, and LA will terminate singlet oxygen [3]. LA also has anti-inflammatory effects by inhibiting the NFκB pathway [7].

41

LA

Protein kinase

SH

HS

P

Keap1 Keap1

SH ARE

Nrf2

HS Phase II genes

Figure 2: Pathway of activating Phase II detoxification response [3].

DHLA is also able to regenerate other endogenous antioxidants such as vitamins C, E, and glutathione (GSH) [5]. LA and DHLA are also metal-chelators of Cu2+, Zn2+, and Pb2+[6]. DHLA prevents Cu(II)-mediated oxidation of LDL and chelation of iron and copper in the brain, reducing the risk of Alzheimer’s by decreasing the free radical damage [2].

LA has been proposed to modulate GSH levels through transcription factor Nrf2, reversing the age-related decline of GSH levels caused by deficits in AREmediated gene transcription [3].

LA can also activate protein kinase signalling pathways to phosphorylate Nrf2, promoting the transcription of genes in response to Phase II detoxification (fig. 2)[3].

Related Compounds: Vitamin C (page 11), Vitamin E (page 15), L-gluathione (page 21), Acetyl L-carnitine (page 23), Zinc (page 45), Cod liver oil (page 53) References:

[1] National Centre for Biotechnology Information. PubChem: Thioctic acid. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6112 (accessed Mar 22, 2012).

[2] Bush, A. I. Neurobiol Aging. 2002. 23: 1031–1038.

[3] Shay, K. P.; Moreau, R. F.; Smith, E. J.; Smith, A. R.; Hagen, T. M. Biochim Biophys Acta. 2009. 1790: 1149-60.

[4] Raddatz, G.; Bisswanger, H. J Biotechnol. 1997. 58:89-100.

[5] Biewenga, G. P.; Haenen, G.R.; Bast, A. Gen Pharmacol. 1997. 29: 315–331.

[6] Ou, P.; Tritschler, H. J.; Wolff, S. P. Biochem Pharmacol. 1995. 50: 123–12.

[7] Packer, L.; Witt, E. H.; Tritschler, H. J. Free Radic Biol Med. 1995. 19: 227–250.

42

Potassium Dose: 0.36 mg/day | insulin-sensitive Description: Quick Facts: Potassium is an alkali metal that rapidly oxidizes in air, like sodium. Chemical properties: alkali metal Molecular Mass: 39.10 g/mol Potassium occurs naturally as ionic salts and in plants [1]. Deficiency of potassium of potassium may lead to hypokalemia, muscle weakness, decreased reflex responses, respiratory paralysis, and cardiac arrthymia [2]. Potassium can typically be consumed through red meat, chicken, fish, potatoes, squashes, dried apricots, as well as nuts [3].

Metabolism: Potassium is an important electrolyte in the body for carbohydrate metabolism, helping to convert glucose to glycogen in the liver [2]. It also participates in the synthesis of protein from amino acids [3]. Magnesium helps maintain potassium in the cell, but sodium-potassium balance is controlled stringently [2].

Effects: Potassium ions are crucial for nerve impulse transmission in humans and animals [1].

Highly selective potassium ion channels are crucial for hyperpolarization of neurons, in order to conduct an action potential [1]. Research has suggested that intake of

greater than 4.7 g of potassium per day is related to vasodilation in humans and animals, and potassium has an effect in insulin secretion and action [3]. In a study of spontaneous hypertensive rats, it was found that oral administration of potassium overload reduced blood pressure, improved glucose metabolism and enhanced insulin sensitivity [2].

Related Compounds: Vitamin B12 (page 9), Magnesium (page 46) References:

43

[1] Minor, D. L. Jr. Curr Opin Struct Biol. 2001. 11: 408-14.

[2] Slonim, A. D.; Pollack, M. M. Pediatric critical care medicine: Potassium. Lippincott Williams & Wilkins: Philadelphia, 2006.

[3] National institute of Health. MedLine Plus: Potassium in Diet. http://www.nlm.nih.gov/medlineplus/ency/article/002413.htm (accessed Mar 23, 2012).

Selenium Dose: 1.08 mg/day | antioxidant Description: Quick Facts: Selenium is a non-metal that has Chemical properties: nonbeen recognized to be essential to metal the diet of humans [3]. Selenium can Molecular Mass: 78.96 g/mol be found in vegetables, fish, shellfish, red meat, grains, eggs, chicken, and and garlic [2]. It is considered to be a trace mineral, meaning the body only needs small amounts of it [1]. Too much selenium can call selenosis, inducing hair loss, nausea, fatigue, and mild nerve damage [2].

Metabolism: Selenium is an essential component of the catalytic centre of glutathione peroxidase, which reduces hydroperoxides and is involved in antioxidant protection of cells [1]. Other selenoenzymes and specific selenoproteins, such as iodothyronin 5’-deiodinase and thioredoxin reductase, all contain selenium to be functional enzymes. It is important to note that selenoenzymes and selenoproteins contain selenium in the form of selenocysteine (SeCys) [1].

Effects: The selenoenzymes, also called antioxidant enzyme, play a role in preventing cell damage and may prevent certain cancers and cardiovascular diseases [2].

Related Compounds: Vitamin E (page 15)

Together with vitamin E, research has suggested the two can work together in cancer prevention [1]. Studies have suggested that selenium intake has a relationship with prevention with cancer but selenium deficient diets have not been found to cause cancers [1].

References:

[1] Combs, G. F. Jr.; Gray, W. P. Pharmacol & Therapeutics. 1998. 79: 179-192.

[2] National institute of Health. MedLine Plus: Selenium in Diet. http://www.nlm.nih.gov/medlineplus/ency/article/002414.htm (accessed Mar 24, 2012).

[3] McConnell, K. P.; Smith, J. C. Jr.; Higgins, P. J.; Blotcky, A. J. Nutr Res. 1981. 1: 235-241.

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Zinc (chelated) Dose: 0.14 mg/day | antioxidant Description: Quick Facts: Zinc, in its chelated form, is the Chemical properties: divalent organic form of an essential trace organic mineral mineral found in food [1]. Animals Molecular Mass: 65.38 g/mol and humans absorb and digest mineral chelates better than their inorganic mineral form. Zinc is said to be chemically similar to magnesium inorganic due to their common oxidation state of +2 [1]. Zinc can be found in oysters, red meat, seafood, fortified breakfast cereals, beans, nuts, and whole grains [2].

Metabolism: Zinc is an essential mineral for the health of humans and animals because many enzymes require zinc in their catalytic centre, such as alcohol dehydrogenase [3]. In the human body, zinc interacts with a wide range of organic ligands, serve as structural ions in transcription factors for gene expression, and play roles in the metabolism of RNA and DNA. A notable structural role it plays is in “zinc fingers�[3].

Effects: Zinc is said to have antioxidant that zinc may delay the progression of properties, able to protect age-related macular degeneration and against the accelerated aging vision loss [4]. Zinc also contributes to of the skin and muscles in the the immune system by being used in body [3]. It was also found granulocytes, a type of white blood ound cells that helps protect the body Related Compounds: against infections [2].

Magnesium (page 46)

References:

45

[1] Brown, T. F.; Zeringue, L. K. J Dairy Sci. 1994. 77: 181-189.

[2] National institute of Health. Office of Dietary Supplements: Zinc. http://ods.od.nih.gov/factsheets/Zinc-QuickFacts/ (accessed Mar 26, 2012).

[3] Valko, M.; Morris, H.; Cronin, M. T. Curr Med Chem. 2005. 12: 1161-208.

[4] Age-Related Eye Disease Study Research Group. Arch Ophthalmol. 2001. 119: 1417-36.

Magnesium Dose: 0.72 mg/day | anti-carcinogenic | anti-coagulant | antioxidant Description: Quick Facts: Magnesium is an alkaline metal that Chemical properties: Divalent, acts as a cofactor to many enzymes, alkaline earth metal including those involved in DNA Molecular Mass: 24.31 g/mol replication and maintenance [1]. The metal is the fourth most common mineral in the body, and its deficiency results in heart, kidney, and brain problems [2,3]. Magnesium is usually consumed through green leafy vegetables, nuts, legumes, and drinking hard water [3].

Metabolism: As a divalent element, Mg2+ is able to interact with ligands and enzymes as cofactors, while competing with calcium in other metabolic pathways [3].

Many of these enzymes are DNA replication enzymes, including telomerases [1]. The activity of these enzymes, that reduces cancer risk, involves extending the ends of DNA strands in a Mg2+-dependent reaction.

Effects: Magnesium’s diverse roles in the cell make it an antioxidant and an anti-tumourgenic agent [1]. Its abilities to extend telomeres and reduce cancer risks has also been referred to as anti-aging effects.

Related Compounds: Acetylsalicylic acid (page 39), Potassium (page 43), Zinc (page 45)

Magnesium supplements have also been used to treat heart and kidney problems, but are also used to treat asthma [3]. In vivo experiments showed that magnesium administered through intravenous infusion increased blood-clotting time [2]. The reduction of platelet aggregation was further pronounced in the presence of acetylsalicylic acid [2].

References:

[1] Rowe, W.J. Clin Interv Aging. 2012. 7: 51-54.

[2] Stanger, M.J.; Thompson, L.A.; Young, A.J.; Lieberman, H.R. Nutrition Reviews 2012: 70(2): 107-117.

[3] Swaminathan, R. Clin Biochem Rev. 2003. 24(2): 47-66.

46

Garlic Dose: 21.6 mg/day | anti-carcinogenic | anti-coagulant Description: Garlic, from the plant Allicum sativum, is a common ingredient used in many cultures for flavour and its medicinal properties, including anti-tumourgenesis, cardioprotection, and antithrombosis [1,2]. Garlic can be consumed in many ways: fresh, powdered, and extracted in oil [1].

Metabolism: Garlic’s anti-coagulent effects is expected to be a result of inhibition of the platelet GPIIb-IIIa receptor, responsible for ADPinduced platelet aggregation [2].

Figure 1: S-allyl cysteine Quick Facts: Key compound: S-allyl cysteine Properties: amino acid derivative, hydrophobic and non-polar Also contains: adenosine, allicin

S-allyl cysteine, as well as ajoene and allicin, are known inhibitors of ADPinduced platelet aggregation [2]. Ajoene, while not found directly in garlic, can be produced from allicin. Figure 2 shows the complex relations between many of garlic’s compounds and metabolites. Yet, despite the central role of allicin, which is derived from S-allyl cysteine, some researchers argue that many of garlic’s bioactive ingredients are still to be identified as nonorganosulfur compounds [3].

Effects: The consumption of garlic is related to reduced oxidation by radicals. These antioxidant effects include the inhibition of lipid oxidation, thus not only reducing oxidation damage but also providing cardiovascular benefits [4].

47

Figure 2: Derivatives of garlic organosulfur compounds [2].

Garlic’s anti-coagulant effects are most studied, inhibiting platelet aggregation through its organosulfur compounds. Certain garlic extracts also reduce cholesterol biosynthesis [1,4].

Related Compounds: Gingko biloba (page 51)

Lastly, garlic also has hypoglycaemic effects that may help diabetics. Tests in mice showed that garlic oil lowered blood glucose levels and increased the activity of insulin [4]. These effects have been proposed to be caused by allicin.

References:

[1] Stanger, M.J.; Thompson, L.A.; Young, A.J.; Lieberman, H.R. Nutrition Reviews 2012. 70(2): 107-117.

[2] Rahman, K.; Billington, D. J Nutrition 2000. 130(11): 2662-2665.

[3] Amagase, H. . J Nutrition 2006. 136(3): 716S-725S. [4] Borek, C. . J Nutrition 2001. 131(3): 1010S-1015S. Figure 1: Image from Wikimedia Commons. Figure 2: Image cropped from [3].

48

Ginger Dose: 7.2 mg/day | anti-carcinogenic | antioxidant | anti-coagulant | | anti-inflammatory Description: Ginger, or Zingeber officinale, has been taken for a wide range of therapeutic effects, from nausea to low cholesterol [1]. Ginger can be dried, ground, or fresh, and is often used in Asian cuisines. Much of the research on ginger and its bioactive components is controversial, studies of the role of ginger in diabetics and ovarian cancer cells have indicated potential health benefits [3].

Metabolism: Ginger contains many phenolics that produce anti-inflammatory and antioxidant effects [3]. These compounds can be interconverted and may also change when cooked or heated.

6shogaol has been shown to induce apoptosis in certain cancer cells, while 10-gingerol may inhibit cell growth, producing antitumourgenic effects [3].

Quick Facts: Key compounds: 6-shogaol, gingerols Properties: phenolics Also contains: sesquiterpenes, monoterpenes [2]

Figure 1: 6-shogaol (top) and 10-gingerol (bottom)

6-shogaol is metabolized into several products that induce cell death. A study using mice showed the production of several metabolites; two of these were linked to apoptosis: 1-(4’-hydroxy-3’-methoxyphenyl)-decan-3ol and 1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-one (or 6-paradol) [4].

49

1-(4’-hydroxy-3’-methoxyphenyl)-4-decen-3-ol 5-cysteinyl-1-(4’-hydroxy-3’-methoxyphenyl)-4-decen-3-ol 5-N-acetylcysteinyl-1-(4’-hydroxy-3’-methoxyphenyl)-4-decen-3-ol

6-shogaol

3’,4-dihydroxylphenyl-decan-3-one 5-methoxy-1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-one 5-methylthio-1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-one 5-methylthio-1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-ol 5-cysteinyl-[6]-shogaol 5-glutathiol-[6]-shogaol 5-cysteinylglycenyl-1-(4’-hydroxy-3’-methoxyphenyl)-4-decen-3-ol 1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-ol 1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-one

apoptosis

Figure 2: Main metabolites of 6-shogaol [5] Effects: In addition to its anti-tumourgenic effects, ginger is an antioxidant [4]. Ginger has also been shown to have anti-inflammatory benefits [3].

Related Compounds: Acetylsalicylic acid (page 39)

The cardioprotective role of ginger is disputed. Ginger has been reported to have blood-thinning properties, though these effects have not been confirmed in vitro and has not been shown to augment the affects of other blood thinners [1]. Another study in diabetic rats showed that ginger reduced blood sera cholesterol by 44% [2].

References:

[1] Stanger, M.J.; Thompson, L.A.; Young, A.J.; Lieberman, H.R. Nutrition Reviews 2012. 70(2): 107-117.

[2] Al-Amin, Z.M.; Thomson,M.; Al-Qattan, K.K.; Peltonen-Shalaby, R.; Ali, M. Brit J Nutr 2006. 96: 660-666.

[3] Levy, A.S.A.; Simon, O.; Shelley, J.; Gardener, M. BMC Pharmacology 2006: 6:12-19.

[4] Peng, F. et al. Fitoterapia 2012. January 10 [Epub ahead of print].

[5] Chen et al. Drug Metabolism & Disposition 2012. January 13 [Epub ahead of print].

Figure 1: Image cropped from [4]. Figure 2: Adapted from [5].

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Gingko Biloba Dose: 1.44 mg/day | neuroprotective | antioxidant | anti-coagulant Description: Ginkgo Biloba is derived from a tree, and has been used in Asian medicines for centuries. Its medical ingredients are found in its leaves, and includes over forty flavonoids (pg. 38) and terpene trilactones, notably ginkgolides and bilobalides [1,2]. Ginkgo biloba seeds also contain nutrients and compounds with potential therapeutic benefits. The plant can be found in tablet or powdered form, and is commonly included in multivitamins [1].

Metabolism: Gingkolides are steroid compounds that can be derived from each other. Figure 1 shows many common ginkgolides that have hydroxyl groups in various locations. The biosynthesis of ginkgolides C is from the addition of hydroxyl groups from simpler ginkgolides.

Figure 1: Common ginkgolides [2].

Quick Facts: Key compounds: ginkgolides, bilobalides Properties: terpene trilactones Also contains: terpenoids, flavonoids, carotenoids

Many compounds result from ginkgolide metabolism, including bilobalide, shown in Figure 2 [3]. The collective group of flavonoids and related compounds have many antioxidant properties that involved interacting with reactive oxygen species. Ginkgolide metabolites also interfere with platelet formation, thus having anti-coagulant effects [1].

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Figure 2: Bilobalide (right) is derived from ginkgolides (left).

Both are flavonoids and act as antioxidants [3].

Effects: Taking ginkgo biloba and blood thinners like warfarin and aspirin has led to a cases of hemorrhages [1]. Ginkgo biloba has also been shown to interact with antiplatelet agents, garlic, and ginseng.

Related Compounds: Beta-carotene (page 33), Bioflavonoids (page 35), Garlic (page 47), Ginseng (page 57)

Ginkgo biloba is taken for its antioxidant and neuroprotective properties [1]. Its extract induces antioxidant mechanisms that reduce oxygen radicals [3].

Consuming gingko biloba has also been shown to improve memory and treat Alzheimer’s, tinnitus, dementia and schizophrenia [4].

Though no mechanism has been elucidated, gingko’s antioxidant role is suspected to provide its neuroprotective benefits [3].

References:

[1] Stanger, M.J.; Thompson, L.A.; Young, A.J.; Lieberman, H.R. Nutrition Reviews 2012: 70(2): 107-117.

[2] ]WHO. WHO monographs on selected medicinal plants. Geneva: World Health Organization 1999.

[3].Briskin, D.P. American Society of Plant Physiologists 2000. 124(2): 507-514.

[4] Sierpina, V.S.; Wollschlaeger, B.; Blumenthal, M. Am Fam Physician 2003. 68(5): 923-926.

Figure 1: Image cropped from [2]. Figure 2: Image cropped from [3].

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Cod Liver Oil Dose: 5.04 mg/day | anti-coagulant | anti-inflammatory Description: Cod liver oil has been used as medicine as early as 1789, mainly as a treatment for rickets or rheumatism [1]. The oil is extracted from the fresh liver of any fish in the genus Gadus, and is known for its omega-3 fatty acids, and its high Vitamin A and D content [2]. Omega-3 fatty acids are associated with cardiological benefits.

Figure 1: EPA and DHA

Quick Facts: Metabolism: Key compounds: Omega-3 fatty Like other fatty acids, EPA and acids [eicosapentaenoic acid (EPA) DHA can be broken down as a and docosahexaenoic acid (DHA)] source of energy or incorporated Properties: Hydrophobic, non-polar into the phospholipid bilayer.

Also contains: Vitamin A , Vitamin D Because omega-3 fatty acids contain more double bonds than the fatty acids usually incorporated in phospholipids, EPA and DHA help to increase cell membrane fluidity and affect the structure of lipid rafts. EPA and DHA also interact with several membrane proteins, including G-protein coupled receptors like rhodopsin and ion channels [3].

Omega-3 fatty acids interfere with the body’s fatty acid metabolic activities, usually competing with other fatty acids to inhibit certain pathways. For example, EPA and DHA compete with normally abundant arachidonic acid (AA) in the formation of thromboxanes by lipoxygenases [3]. The anticoagulant and anti-inflammatory properties of cod liver oil are related to the decrease in thromboxane-2 production needed for platelet aggregation [4]. The competing pathways of thromboxane production by omega-3 fatty acids is shown in Figure 2.

53

TXA2

arachidonic acid (AA) (20:4(n-6))

lipoxygenases eicosapentaenoic acid (EPA) (20:5(n-4))

(series-2 thromboxanes) inflammatory response induces platelet aggregation

TXA3

(series-3 thromboxanes) anti-inflammatory response inhibits platelet aggregation

Figure 2: Competing pathways for thromboxane production [6].

Effects: While usually taken for its antiinflammatory effects, cod liver oil involves the intake of fatty acids that are also be broken down as a source of energy, leading to potential weight gain [5].

Related Compounds: Vitamin D (page 13), Acetyl Lcarnitine (page 23), Acetylsalicylic acid (page 39), Alpha-lipoic acid (page 41), Flax seed oil (page 55)

Cod liver oil has been shown to have some anti-coagulant effects, though observations have been disputed in various studies.

Frequent consumers of fish oils have longer bleeding times, indicating that platelet aggregation has been inhibited [6].

These anti-coagulant effects are significantly increased when cod liver oil is taken with other anticoagulants like acetylsalicylic acid (page 42).

References:

[1] Rajakumar, K. Pediatrics 2003: 112(2):e132-135.

[2] Terkelsen, L.H.; Eskild-Jensen, A.; Kjeldsen, H.; Barker, J.H.; Hjortdal, V.E. Scand J Plast Reconstr Hand Surg 2000: 34:15-20.

[3] Mozaffarian, D.; Wu J.H.Y. J Nutrition 2012; 142: 614S-625S. [4] De Caterina, R.; Basta, G. European Heart Journal Supplements 2001; 3: D42-D49.

[5] Stanger, M.J.; Thompson, L.A.; Young, A.J.; Lieberman, H.R. Nutrition Reviews 2012: 70(2): 107-117.

[6] Green, M. MBJ 2011; 343:d7505.

Figure 1: Image cropped from [3]. Figure 2: Images from Wikimedia Commons, Adapted from [4].

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Flax Seed Oil Dose: 21.6 mg/day | anticarcinogenic | antioxidant | anti-inflammatory | anti-coagulant Description: Also known as linseed oil, the oil from flax seed is high in omega-3 fatty acids, notably α-linolenic acid (ALA). Flax seed, made of 35% oil, has been shown to have antioxidant and anti-apoptotic effects, and has therapeutic benefits similar to fish oils [1].

More than half of its oils are represented by ALA by mass [2].

Figure 1: α-linolenic acid (ALA) (18:3(n-3))

Metabolism: Quick Facts: Flax seed oil contains many fatty Key compound: α-linolenic acid acids than can be broken down by Properties: Omega-3 fatty acid, fatty acid oxidation or hydrophobic and non-polar incorporated into cell membrane Also contains: linoleic acid, oleic phospholipids. As an omega-3 acid, palmitic acid, stearic acid fatty acid, ALA contains more double bonds than most fatty and can increase cell membrane fluidity and affect the structure of lipid rafts.

ALA is a precursor for other omega-3 fatty acids, like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Thus, flax seed oil carries many benefits of various fatty acids that can be generated from its ALA, including the anti-inflammatory and anti-coagulant effects of EPA and DHA. [3].

Figure 2 shows the conversion of ALA to EPA [3,4]. The pathway involves elongases and desaturases to lengthen the 18:3(n-3) ALA fatty acid to a 20:5(n-3) EPA fatty acid. With two more elongases, another desaturase, and a process termed peroxisomal oxidation, the EPA fatty acid can be converted to DHA (22:6(n-3)).

55

Figure 2: Conversion of ALA (found in flax seed oil) to EPA (found in cod liver oil).

Effects: Consumption of flax seed oil has been linked to higher ALA levels and increase EPA and DHA concentrations, the main omega-3 fatty acids of cod liver oil (pg. 53).

Related Compounds: Acetyl L-carnitine (page 23), Acetylsalicylic acid (page 39), Cod liver oil (page 53)

References:

Flax seed oil with UVC radiation leads to a decrease in glutathione in the skin, lens of the eyes, and blood serum, though apoptosis was lower with flax seed oil than without [2]. Flax seed oil decreases platelet aggregation and increases bleeding time for its anticoagulant effects. The oil also acts as an antioxidant by suppresses inflammatory mediators in blood sera and reduced oxygen radical production [3].

[1] Tuluce, Y.; Oxkol, H.; Koyuncu, I. Toxicology and Industrial Health 2011. 28(2): 99-107.

[2] Prasad, K. J Cardiovasc Pharmacol. 2009. 54(5): 369-377.

[3] Barcelo-Coblign, G et al. Am J Clin Nutr. 2008. 88(3):801-989.

[4] King, M.W. “Omega-3, and -6 Polyunsaturated Fatty Acid Synthesis, Metabolism, Functions. Last updated March 10, 2012. themedicalbiochemistrypage.org/omegafats.php (accessed March 22, 2012).

Figure 1: Image from Wikimedia Commons. Figure 2: Image adapted from [4].

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Ginseng Dose: 86.4 mg/day | anti-carcinogenic | antioxidant | anti-inflammatory Description: Radix Ginseng, or the root of the perennial herb Panax ginseng, is commonly used in China and South Korea as a herbal remedy reported to be anti-carcinogenic, anti-inflammatory, and antioxidant [1,2]. American ginseng (P. guinquefolius) has also grown in popularity, and each species has its unique effects [3]. Most studies have analyzed the effects of Asian ginseng, usually consumed as powders, teas, tablets, or extracts, and will be the focus of the information below.

Quick Facts: Key compounds: more than 40 different triterpene saponins (ginsenosides, panaxosides) Properties: hydrophobic steroid glycosides with hydrophilic R groups Figure 1: General ginsenoside molecule (R1, R2, and R3 are variable) G-Rg1 : R1 = -OH; R2 ,R3 = -O-Glc Metabolism: Shown above in Figure 1, ginsenosides and related panaxosides are complex compounds involved in many metabolic pathways. Few specific mechanisms have been deduced, though studies by Tawab et al. Have studied ginsenoside breakdown in humans [4].

The most common type of ginsenoside in Panax ginseng is G-Rg1 which is broken down into G-Rh1 and G-F1 in the digestive tract for distribution in the body [4]. These simpler ginsenosides are further metabolized by intestinal bacteria into many products including compound-K, which has apoptotic properties providing ginseng with anticarcinogenic benefits [5].

This mechanism, starting with ginsenoside Rb1, is shown in Figure 2.

57

Figure 2: Breakdown of ginsenoside Rb1 to compound K [6].

Effects: Ginseng has been shown to increase blood-clotting time and may inhibit platelet-activating factors, while many studies suggest that ginseng also has roles in the immune system, psychological functions, and may benefit diabetics [1,2].

Related Compounds: Gingko biloba (page 51)

Ginseng has also been taken for many therapeutic, but unconfirmed benefits, treating impotence, liver disease, tuberculosis, and hypothermia.

Ginseng’s blood thinning effects have been disputed: while some discourage consumption with blood-thinner warfarin, other studies show that ginseng may not directly interfere with warfarin and may even inhibit its activity.

References:

[1] Kiefer, D.; Pantuso, T. Am Fam Physician 2003: 68(8): 1539-1542.

[2] WHO. WHO monographs on selected medicinal plants. Geneva: World Health Organization 1999.

[3] Stanger, M.J.; Thompson, L.A.; Young, A.J.; Lieberman, H.R. Nutrition Reviews 2012: 70(2): 107-117.

[4] Tawab, M.A. et al. Drug Metabolism and Disposition 2003, 31(8): 1065-1071.

[5] Cho, S.H.; Chung, K.S.; Choi, J.H.; Kim, D.H.; Lee, K.T. BMC Cancer 2009. 9:449.

[6] Quan, L.H. Braz. J. Microbiol. 2011. 42(3): 1227-1237.

Figure 1: Adapted from [4]. Figure 2: Adapted from [6].

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Green Tea Extract Dose: 7.2 mg/day | antioxidant | anti-coagulant Description: Green tea is one of the world’s most consumed drinks, noted for its antioxidant properties [1]. The drink has also been associated with reducing cardiovascular disease and cancer risks. Its extract is full of bioflavonoids (pg. ___) and contains catechins, a compound found in many teas.

Green tea specifically contains epigallocatechin gallate (EGCG), which is unique to green tea [1].

Metabolism: Green tea contains many compounds involved in many pathways, generating several antioxidant compounds.

Two potential metabolic pathways for EGCG are shown in Figure 2.

Figure 1: Green tea’s most common catechin: epigallocatechin gallate Quick Facts: Key compound: catechins, including epigallocatechin gallate (EGCG) Properties: family of polyphenol Also contains: flavonoids

The top pathway, showing the degradation of EGCG to epigallocatechin (EGC), then to “metabolite 5” (5-(3,5-dihydroxyphenyl)-4-hydroxyvaleric acid) was developed from a model in mice [2]. Metabolite 5 was the most common metabolite found in the cecum and feces. The second pathway, leading to gallic acid (3,4,5-trihydroxybenzoic acid), was seen in pigs [3].

Gallic acid and its derivatives are antioxidant, acting as a free radical scavenger [4]. In mice, gallic acid has also been shown to have hepatoprotective effects.

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EGCG

metabolite 5

EGC gallic acid

Figure 2: Potential pathways for EGCG metabolism. (metabolite 5: 5-(3,5-dihydroxyphenyl)-4-hydroxyvaleric acid.)

Effects: EGCG inhibits stress-induced apoptosis by interfering with telomere attrition. Thus, green tea, especially in high concentrations, helps to reduce cell death during times of stress [1].

Related Compounds: Vitamin B1 (page 3), Bioflavonoids (page 35), Rutin (page 37)

Green tea catechins have been recognized for its benefits outside of antioxidant properties, including the reduction of blood cholesterol and sugar levels [2].

The consumption of green tea has also been related to reducing cardiovascular disease and breast, prostate, colorectal, and lung cancers [1].

References:

[1] Bandele, D.J.; Osheroff, N. Chem Res Toxicol. 2008. 21(4): 936-943.

[2] Takagaki, A.; Nanjo, F. J. Agric. Food Chem. 2010. 58(2): 1313-1321.

[3] van’t Slot, G.; Humpf, H.U. J. Agric. Food Chem. 2009. 57(17): 8041-8048.

[4] Rasool, M.K. J Pharm Pharmacol. 2010. 62(5): 638-643.

Figure 1: Image from Wikimedia Commons [3]. Figure 2:Adapted from [2,3].

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How Compounds Interact While each of the 31 compounds have their unique roles in the antiaging supplement, together they interact with networks of metabolic pathways to produce their intended effect. The diagram on page 64 shows many of these connections compiled from the individual interactions noted from pages 3-60, including synergistic properties, compounds that form complexes, and the direct conversion of some ingredients to others.

Ingredient Inter-conversion and Overlap Firstly, the nature of these ingredients result in many direct connections. For example, rutin and several compounds in gingko biloba belong to the group of bioflavonoids. These connections are indicated by the blue arrows, with a compound pointing towards the compounds with the broader group. As many extracts contain many compounds that represent other ingredients, such overlap is very common and increases the actual dose of these ingredients. An example is green tea extract, which contains Vitamin B1, rutin, and bioflavonoids.

Inter-conversion between compounds is also very common. Similar ingredients like cod liver and flax seed oils also contain omega-3 fatty acids that are in the same metabolic pathways. Other compounds, like N-acetyl cysteine, is a direct precursor to Lglutathione.

Synergistic Partnerships Many compounds are able to further the effects of other compounds, such as Vitamin C’s ability to increase the antioxidant properties of Vitamin E. The result is a combined effect greater than the sum of the effects of the individual compounds, not surprising as many of these compounds have similar properties. Synergy may be due to a compound increasing the absorption of another compound, or interacting with a pathway to significantly push a reaction forward.

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Synergistic interactions are shown with double-headed green arrows. As shown on page 64, many of the vitamins interact synergistically, notably the B-vitamins. The presence of folic acid is usually critical to the absorption of the other B-vitamin, while the Bvitamins acts as a cofactor to folic acid, making the presence of multiple B-vitamins necessary for their respective benefits.

Many of the extracts work together to produce an anti-inflammatory effect, notably ginseng, gingko biloba, and garlic. Ginger’s anticoagulant effects are extended when taken with acetylsalicylic acid.

Other synergistic partnerships include acetyl L-carnitine and α-lipoic acid, and magnesium and acetylsalicylic acid.

Increased Metabolic and Catabolic Activity Similar to synergistic partnerships, some compounds increase the efficacy of other compounds by assisting in their breakdown. Yet, these interactions are not synergistic because they are a one way relationship. For instance, Vitamin E is necessary for cleavage of βcarotene to Vitamin A, though β-carotene does not increase the efficacy of Vitamin E. Acetyl L-carnitine an acetylsalicylic acid increases the breakdown of fatty acids, including those found in cod liver and flax seed oils.

These are shown by the red-dashed lines.

Complexes A complex can be formed between Chromium and Vitamin B3. This type of interaction is similar to a synergistic one, because the presence of each component is important to its beneficial effects, but in this case, both compounds act together to achieve its antiaging properties. Chromium also complexes with picolinate, an artificial derivative of Vitamin B3. This interaction is shown with a gray dotted line.

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Inhibitors Inhibitory interactions are shown with a yellow line, with the diamond towards the inhibited compound. For example, the presence of ASA inhibits the activity of vitamin C, specifically by blocking its absorption, while potassium inhibits vitamin B12 absorption. While this interaction is explicit, inhibitory actions are likely to be found among many of the compounds involved in similar pathways. Because main structures are similar, compounds may compete for the same enzymes and decrease the activity of each individual ingredient.

Helps to Absorb or Regenerate Some compounds, like Coenzyme Q, are necessary for the absorption of another ingredient, like vitamin E. Like the “increased metabolic activity� arrows, these purple arrows indicate one way interactions. In contrast to catabolism, these compounds amplify the effect of another compound by aiding in its absorption of by regenerating spent metabolites. Regeneration of other compounds also significantly increase their beneficial effects, and may also be a oneway effect. An example of this type of relationship is the regeneration of vitamin C by alpha-lipoic acid.

Complex Interactions Lastly, given 31 compounds with varying individual effects yet similar metabolic pathways, various interactions occurring between two compounds are also possible. There are two examples: cod liver oil and acetylsalicylic acid both work together to achieve anti-coagulant properties, yet ASA also assists in the breakdown of cod liver oil among other fats. The chromium from chromium picolinate forms a complex with vitamin B3, while picolinate can be converted to itamin B3.

The complexities of these interactions indicate that the DSP may work in many different ways. The interaction diagram will only get busier as more metabolic pathways are elucidated, and more effects confirmed.

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Vitamin B1

Interaction Diagram

Legend Is a type of / converts to...

Complexes with ...

Acts synergistically with...

Inhibits...

Helps to regenerate/ synthesize/absorb ...

Helps to break down...

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Conclusion

The complex dietary supplement provides a promising future for the treatment and prevention of age-related declines.

This booklet helps to understand some of the complex interplay that exists between the metabolic pathways of each compound that may have contributed to the supplement’s overall combined anti-aging properties. As research continues on each of the individual compounds, more links can be drawn further understand how the anti-aging supplement achieves its benefits.

The next step is to determine whether reduced amounts of ingredients in the DSP will achieve similar effects and to identify the most optimal number and type of ingredients that should be included.

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References The following references were used in the introduction. All compoundspecific references are included in the footnotes from page 3 to 60, while the interaction pages are a summary of the interactions noted on the compound-specific pages. Reference [6] outlines the DSP. [1] Chen, P., Ratcliff, G., Belle, S. H., Cauley, J. A., DeKosky, S. T. and Ganguli, M. Patterns of cognitive decline in presymptomatic Alzheimer disease. Arch Gen Psychiatry. 2001. 58:853–858 [2] Miquel. J., Economos. A. C., Fleming. J. and Johnson. J. E. Mitochondrial role in cell aging Exp Gerontol. 1980. 15:575–591.

[3] Beckman, K. B. and Ames, B. N. The Free Radical Theory of Aging Matures.

Physiol Rev. 1998. 78:547–581.

[4] Aruoma, O. I., and Butler, J.. et al. The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radical Biology & Medicine. 1989. 6, 595-597 [5] Fang, Y. Z., Yang, S. & Wu, G. Free radicals, antioxidants, and nutrition. Nutrition, 2002,18, 872-879 [6] Lemon, J. A., Boreham, D. R. and Rollo, C. D. A dietary supplement abolishes agerelated cognitive decline in transgenic mice expressing elevated free radical processes. Exp Biol Med. 2003, 228, 7, 800-810.

[7] Aksenov, V., Long, J., Lokuge, S., Foster, J. A., Liu, J. and Rollo, C. D. Dietary amelioration of locomotor neurotransmitter and mitohondrial aging. Exp Biol Med. 2010, 235, 1, 66-76.

[8] Aksenov, V., Long, J., Liu, J, Szechtman, H., Khanna, P., Matravadia, S. and Rollo, C. D. A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice. AGE. 2011. 10.

1007

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Melatonin Acetylsaliclyic acid Acetylsaliclyic acid bioflavonoids coenzyme Q10 Gingko biloba magnesium vitamin B1 flaxseed oilMelatonin cod liver oil coenzyme Q10 Rutin vitamin C DHEA Flaxseed vitamin B12β-carotene gingerAcetylsaliclyic acid folic acid chromium picolinate reen tea extract

ginseng

vitamin B selenium green tea extract potassium Gingko biloba zinc vitamin E flaxseed oil selenium D vitamincoenzyme B1vitamin Q10 α-lipoic acid

L-glutathione garlic

magnesiumDHEA bioflavono Coenzyme flaxseed oil β-caroteneginsengMela vitamin B1 Acetylsaliclyic acid L-glutathione Melatonin cod liver oil coenzyme Q10 Rutin vitamin C DHEA bioflavonoids gingerAcetylsaliclyic acid vitamin B12β-carotene green tea extract chromium picolinatefolic acid vitamin B6 magnesium DHEA bioflavonoids L-glutathione ginger Gingko biloba vitamin Eα-lipoic garlic zinc acid garlicVitami

vitamin D vitamin B1 coenzyme Q10 bioflavonoids

selenium

potassium

vitamin B1

β Gingko bilobamagnesium flaxseed oil Melatonin coenzyme Q10 Rutin vitamin Cβ

ginseng

coenzyme Q10

cod liver oil DHEA bioflavonoids

gingerAcetylsaliclyic

Melatonin

acid vitamin B12 β-carotene folic acid

reen tea extract chromium picolinate Melatonin cysteine vitamin B3 vitamin B6n-acetyl α-lipoic acid L-glutathione potassium Gingko biloba vitamin E garlic zinc

vitamin B1vitamin Dselenium bioflavonoids folic acid

Gingko bilobamagne flaxseed oilMe otassiumvitamin B1 cod liver oil bioflavonoids coenzyme Q10 Rutin Vita ic acidDHEA vitamin D L-glutathione

Gingko biloba

ginseng

L-glutathione

Melatonin

vitamin E Acetylsaliclyic acid vitamin B12β-ca