a "cure to aging"?

Vitami

L-glutathione

vitamin B1

vitamin B

vitamin B12 vitamin C

vitamin B1 vitamin D vitamin E

folic acid

L-glutathione

chromium picolinate

coenzyme Q10

DHEA

Melatonin bioflavonoids

Rutin Acetylsaliclyic acid

α-lipoic acid

β-carotene

potassium

selenium zinc

magnesium

garlic

ginger

Gingko biloba cod liver oil flaxseed oil ginseng reen tea extract

coenzyme Q10

Gingko biloba

Melatonin

vitamin B1

vitamin B6



folic acid

L-glutathione

chromium picolinate

Coenzyme

DHEA

Melatonin

bioflavono


α-lipoic acid

β-carotene

potassium selenium zinc

magnesium

garlic

ginger

cod liver oil

flaxseed oil

green tea extract

coenzyme Q10 bioflavonoids

Melatonin

vitamin B1

vitamin B6 vitamin B3



folic acid

n-acetyl cysteine L-glutathione

chromium picolinate

coenzyme Q10

DHEA

Melatonin

bioflavonoids


α-lipoic acid

β-carotene

potassium

selenium zinc

magnesium

garlic

ginger


coenzyme Q10

Gingko biloba

bioflavonoids

Melatonin

vitamin B1

vitamin B12 Vita

vitamin D vitamin E

folic acid L-glutathione

coenzyme Q10

DHEA

Me

bioflavonoids


ic acid β-ca

otassium magne

garlic ginger

Gingko biloba cod liver oil flaxseed oil ginseng

coenzyme Q10

Gingko biloba

bioflavonoids

Melatonin L-glutathione

Melatonin

Acetylsaliclyic acid

β

β


β-carotene DHEA

ginseng Mela

Flaxseed

complex dietary supplement

DSP

a “cure” to aging?

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

Introduction 1

Compound profiles

Vitamin B1 ● ● ● ● ● ● 3

Vitamin B3 ● ● ● ● ● ● 5

Vitamin B6 ● ● ● ● ● ● 7

Vitamin B12 ● ● ● ● ● ● 9

Vitamin C ● ● ● ● ● ● 11

Vitamin D ● ● ● ● ● ● 13

Vitamin E ● ● ● ● ● ● 15

Folic acid ● ● ● ● ● ● 17

N-acetyl cysteine ● ● ● ● ● ● 19

L-glutathione ● ● ● ● ● ● 21

Acetyl L-carnitine ● ● ● ● ● ● 23

Chromium picolinate ● ● ● ● ● ● 25

Coenzyme Q10 ● ● ● ● ● ● 27

DHEA ● ● ● ● ● ● 29

Melatonin ● ● ● ● ● ● 31

Beta-carotene ● ● ● ● ● ● 33

Bioflavonoids ● ● ● ● ● ● 35

Rutin ● ● ● ● ● ● 37

Acetylsalicylic acid ● ● ● ● ● ● 39

Alpha-lipoic acid ● ● ● ● ● ● 41

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List of Compounds

Potassium ● ● ● ● ● ● 43

Selenium ● ● ● ● ● ● 44

Zinc ● ● ● ● ● ● 45

Magnesium ● ● ● ● ● ● 46

Garlic ● ● ● ● ● ● 47

Ginger ● ● ● ● ● ● 49

Gingko biloba ● ● ● ● ● ● 51

Cod liver oil ● ● ● ● ● ● 53

Flax seed oil ● ● ● ● ● ● 55

Ginseng ● ● ● ● ● ● 57

Green tea extract ● ● ● ● ● ● 59

How compounds interact 61

Interaction diagram 64

Conclusion 65

References 66

iii

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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.

Introduction

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 anti-

aging 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 anti-

aging 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

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].

3

Quick Facts:

Properties: Polar, amino acid

derivative

Molar Mass: 300.821 g/mol

Figure 1: thiamin

Metabolism:

Thiamin is found in humans as

thiamin phosphate derivatives:

monophosphate (ThMP), thiamin

triphosphate (ThTP)and thiamin

py rophospa te ( 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 dehydro-

genase, alpha-ketoglutarate

dehydrogenase, and branched

chain keto acid dehydrogenase.

All of the above enzymes are

Dose: 0.72 mg/day | anti-carcinogenic | antioxidant | neuroprotective

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].

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].

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

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

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

Vitamin B3

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].

Quick Facts:

Properties: Water soluble

Molecular Mass: 123.1 g/mol

Figure 1: Pyridoxol Phosphate

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.


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].

5

6

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 oesop-

hageal cancers) when in combination

with antioxidant [9].

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.

Related Compounds:

Folic acid (page 17), Chromium

picolinate (page 25)

Vitamin B6

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].

Quick Facts:

Properties: pyridine ring, polar


Figure 1: Pyridoxol Phosphate

Metabolism:

Vitamin B6 has been found to play

a key role in protein metabolism,

neurotransmiter synthesis, hemo-

globlin 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

Dose: 0.72 mg/day | anti-carcinogenic | neuroprotective

include the decarboxylation of 3,4-

dihydroxyphenylalanine (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.

7

8

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.

Vitamin B12

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]

Quick Facts:

Properties: Polar, contains cobalt

Also contains: 1355.37 g/mol

Figure 1: Vitamin B12 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’-deoxyaden-

osylcobala-min (AdoB12), and methyl-

cobalamin (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

Dose: 0.72 mcg/day | anti-carcinogenic | anti-inflammatory | antioxidant |

| neuroprotective

9

enzyme that regenerates meth-

ionine 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].

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 anti-

carcinogenic 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)

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, S-

adenosylhomosysteine is SAH and Homocysteine is HCY.

10

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.

Vitamin C

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 anti-

carcinogenic agent [4].

Quick Facts:



Figure 1: L-Ascorbic Acid

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 co-

substrate in peptide amidation and

tyrosine metabolism [3].

Vitamin C acts on dioxygenases by

reducing the active centre metal

ion involved in the previous

Dose: 3.6 mg/day | anti-carcinogenic | anti-inflammatory | antioxidant |

| neuroprotective

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 mito-

chondria, vitamin C deficiency can

result in fatigue and lethargy. Last,

deficiency can result in mood

changes, attributed deficiency in

dopamine hydroxylation [3].

reactions, attributed to vitamin C’s

redox potential. This ability is

hypothesized to also help with the

gastrointestinal absorption of dietary

iron [4].

11

12

Figure 2: Pathway

for certain Vitamin C

oxidization [2]

in immune cells in high

concentrations, consumed rapidly

when infections occur. Vitamin C is

said to help phagocytes with the

production of lymphocytes [6].

Moreover, Vitamin C acts as an

antihistamine and an anti-

inflammatory agent by preventing

high histamine levels [7]. What’s

more epidemiologic studies in

humans have found evidence that

vitamin C acts as a cancer pre-

venting agent [4].

Many clinical and epidemiological

studies have suggested that vitamin

C could help in the prevention and

maintenance of cardiovascular

disease, cancers, and cataracts [5].

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 co-

antioxidant and pays a large role in

Related Compounds: Vitamin D (page 13), Vitamin E (page 15), Acetyl L-

carnitine (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.

Vitamin D

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].

Quick Facts:

Properties: Non-Polar

Figure 1: Calcitrol

Metabolism:

Vitamin D in its consumed and

produced form is inactive, and is

metabolized in the body to

become various derivatives, of

which the most significant is

calcitrol. [1]

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]

Dose: 2.5 IU/day | anti-carcinogenic | antioxidant | insulin-sensitive |

| neuroprotective

13

Vitamin D contributes to the

mechanisms of calcium balance,

immunity, insulin secretion, imm-

unity, blood pressure regulation

and cell regulation. When levels

of calcium are low, the parathyroid

hormone is secreted which

increased the production and

function of calcitrol, which,

through gene regulation, increases

intestinal absorption of dietary

niacin and increases the reabsorp-

tion of calcium in the kidneys [3].

Similarly, vitamin D affects the rate

of insulin secretion when there is

increased insulin demand [4].

There has also been considerable

evidence that vitamin D plays a

role in the suppression of auto-

immune disorders [5]. Research

also indicates that VDR regulates

the expression of renin, in the

angiotensin-renin system, which

contributes to blood pressure

regulation. [6]

Effects: Extreme deficiency in

vitamin D causes Rickets, an illness

characterized by inadequate

mineralization of calcium in weight-

bearing 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

14

Figure 2: Pathway for the creation of Vitamin D3 in the skin [3]

transcription regulation, its regular

consumption has been shown to

reduce rates of colorectal, breast

and prostate cancer. [7]

Vitamin D’s role in the reninangio-

tension 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]

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.

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

Vitamin E

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]. Quick Facts:

Properties: Non-polar

Molar Mass: 430.71 g/mol

Figure 1: α-tocopherol

Dose: 1.44 IU/day | anti-carcinogenic | antioxidant | neuroprotective

Metabolism:

Vitamin E includes four toco-

pherols and four tocotrienols, all

derived from 6-chromanol. Of the

eight types, α-tocopherol, is

preferentially absorbed in humans.

Vitamin E acts as a “chain-

breaking” 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].

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 glut-

amate and stroke induced neurodeg-

eneration [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

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].

Figure 2: The eight forms of vitamin E

16

Related Compounds: Vitamin C (page 11), Coenzyme Q10 (page 27), Beta-

carotene (page 33), Alpha-lipoic acid (page 41), Selenium (page 44)

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].

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.

Folic Acid

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].



Figure 1: Pyridoxol Phosphate 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 trans-

ferring single carbon units for amino

acids, for example, changing homo-

cysteine 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


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 homo-

cysteine requires a folate coenzyme

which requires a enzyme that uses

B12 and another that uses B6 [4].

17

Cancer arises from DNA damage and

inappropriate expression of critical

genes. Since folate plays a role in

nucleotide synthesis and methylation,

folate plays a role in both DNA repair

and expression. Studies have found

that lower folate levels are correlated

to cervical, lung brain pancreas breast

and colorectal cancer. [7]

Folic acid’s role in nucleotide

synthesis and methylation could also

contribute normal brain function. In a

Canadian study, low folate levels were

associated with an increase in short-

term memory problems. Studies have

also found that folic acid may be

associated with Alzheimer's disease

and vascular dementia. [8]

18

Figure 2: The two steps of converting Folate into THF

Effects:

Folate deficiency has been

associated with higher levels of

homocysteine, which is an

indicator of a risk of cardiovascular

disease, since homocysteine con-

tributes to a degradation of arterial

walls. Studies on Finnish males also

found that those with a higher folic

acid intake had a 55% lower risk

for an acute coronary event. [5]

Folate deficiency also causes

anaemia, since folate contributes

to rapid blood cell division [6].

Related Compounds:

Vitamin B1 (page 3), Vitamin B3

(page 5), Vitamin B6 (page 7)

Vitamin B12 (page 9)

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.

N-acetyl cysteine

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 detoxifi-

cation 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].

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].

Dose: 7.2 mg/day | antioxidant

19

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.

Figure 1: structure of NAC

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

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].

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

Related Compounds:

L-glutathione (page 21)

20

Figure 2: Functions of NAC in glutathione synthesis.

L-glutathione

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].

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 C-

terminal 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

Quick Facts:

Molecular Formula: C10H17N3O6S

Linear tripeptide make of L-

glutamate, L-cysteine and glycine.

Most important antioxidant

Water-soluble

Found in almost all cells with

highest concentration in liver cells.

Figure 1: structure of GSH [1]

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 peroxi-

dase 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].


[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

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

41)

22

Figure 2: GSH synthesis and utilization in animals. [2]

Acetyl L-Carnitine

Description:

Acetyl L-carnitine (ALCAR) is a

common dietary supplement that

helps the body turn fat into

energy. It is an acetyl form of L-

carnitine with the acetyl group

replacing the hydroxyl group. It is

also used as a medication for

various neurological disorders like

Alzheimer's disease and age-

related memory loss due to its

ability to cross the blood-brain

barrier. [1]

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].

Dose: 14.4 mg/day | antioxidant | neuroprotective

23

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.

Figure 1: structure of ALCAR

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]

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].

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].


[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

Related Compounds:

Vitamin C (page 11), Alpha-lipoic

acid (page 41), Cod liver oil (page

53), Flax seed oil (page 55).

24

Figure 2: functions of ALCAR as

a reservoir for acetyl groups.

Chromium Picolinate

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].

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.

Dose: 1.44 mcg/day | insulin-sensitive

25

Quick Facts:

Molecular Formula: Cr(C6H4NOs)3

It is used to supply the trace

mineral chromium in the body

This supplement has been

advertised to promote weight loss

and muscle building.

Figure 1: structure of chromium

picolinate [1].

Metabolism/ function:

Chromium picolinate is a more

bioavailable form of chromium

because it is more easily absorbed

than the mineral salt form. Vitamin

C is thought to promote

chromium absorption. In natural

foods, chromium is found in its

biologically active form, which is

Related Compounds:

Vitamin B3 (page 5), Vitamin C

(page 11)

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,

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.

26

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]

Coenzyme Q10

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.

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].

Dose: 0.44 mg/day| antioxidant

27

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)

Figure 1: structure of Coenzyme Q10 [1].

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].

Effects:

Antioxidant – since CoQ10 is an

energy carrier, it gets oxidized or

reduced easily, serving as an anti-

oxidant. CoQ10 also inhibits lipid

peroxidation by preventing the

formation of peroxyl radicals. It

reduces the level of perferryl

radicals, thus inhibiting both the

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].


[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.

Related Compounds:

Vitamin E (page 15)

28

Figure 2: Eukaryotic electron transport chain.

Inner membrane space

Coenzyme Q10

Dehydroepiandrosterone

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].

Dose: 0.15 mg/day

29

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.

Figure 1: structure of DHEA [1].

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].

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].

Effects:

Natural DHEA levels peak in early

childhood and fall as age

increases. This observation

suggests that DHEA supple-

mentation 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

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].


[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.

Related Compounds:

none

30

Figure 2: DHEA synthesis and its related hormones

Melatonin

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.

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].


31

Quick Facts:

Molecular Formula: C13H16N2O2

A hormone produced by the pineal

gland in the brain.

Water soluble

It regulates body’s circadian rhythm

Figure 1: structure of melatonin [1].

Metabolism:

Melatonin is synthesized from L-

tryptophan. Tryptophan circula-

ting in the blood is taken up by

pinealoctyes and converted to

melatonin. Melatonin is then

metabolized by the liver and

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].

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

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].


[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.

Related Compounds:

none

32

Figure 2: Melatonin

synthesis [3].

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.

Beta-carotene is cleaved symmetrically into 2 retinal molecules by beta-

beta-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].

Dose: 50.0 IU/day | antioxidant

33

Quick Facts [1]:

Chemical Formula: C40H56

Molecular Weight: 526.8726 g/mol

Properties: Hydrophobic, non-polar

Figure 1: Beta-carotene

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].

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

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).

Related Compounds:

Vitamin B12 (page 9), Vitamin E

(page 15), Gingko biloba (page

51)

34

Figure 2: Cleavage of beta carotene into retinal.

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

Bioflavonoids

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, antho-

cyanidins, isoflavones, dihydro-

flavonols, and chalcones [2].

35

Quick Facts:

Major groups: flavonoids,

isoflavonoids, and neoflavonoids,

derived from 2-phenylchromen-4-

one (flavones), 3-phenylchromen-

4-one and 4-pneylcoumarin,

respectively [1]

Properties: Hydrophobic, polar

Figure 1: general chemical structures

of flavonoids (A), isoflavonoids (B),

and neoflavonoids (C). [1]

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 resistance-

associated 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].

A

B C

Dose: 4.32 mg/day | anti-coagulant | anti-inflammatory | antioxidant

Effects:

Bioflavonoids have been shown to

have antibacterial, antiviral, anti-

inflammatory, anti-allergic, and

vasodilatory effects. It inhibits lipid

peroxidation and platelet

aggregation. Generally, they also

act as antioxidants, free radical

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.

Related Compounds:

Rutin (page 38), Gingko biloba

(page 51), Green tea extract

(page 59)

36

Figure 2: Pathways of

transport and metabolism of

flavonoid glucosides (FG).

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.

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].

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

37

Quick Facts:

Chemical Formula: C27H30O16

Molecular weight: 610.5175 g/mol


Figure 1: Structure of rutin.

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 low-

density lipoprotein [1].

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.

Related Compounds:

Bioflavonoids (page 35), Green tea extract (page 59)

38

Figure 2: Conversion of quercetin to quercetin glucuronide (A) and

quercetin 3-sulfate (B).

A

B

Acetylsalicylic acid

Description:

Acetylsalicyclic acid (ASA),

also known as aspirin, is a

drug that is often used as an

analgesic to relieve minor

pain and has anti-

inflammatory 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].

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].

Dose: 2.50 mg/day | anti-coagulant | anti-inflammatory

39

Quick Facts:

Chemical Formula: C9H8O4



Figure 1: Chemical structure of ASA

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

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.


[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.

Related Compounds:

Vitamin C (page 11),

Magnesium (page 46), Ginger

(page 49), Cod liver oil (page 53),

Flax seed oil (page 55)

40

Prostaglandin G2

Arachidonic acid

Thromboxane A2

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

Prostacyclin

cyclooxygenase

Aspirin

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-bismethylthio-

hexanoic acid, and 2,4-bis-methylthio-butanoic acid, which suggests that

LA is metabolized through β-oxidation and S-methylation.

Alpha-lipoic Acid

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.

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].

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

41

Quick Facts:

Chemical Formula: C8H14O2S2



Figure 1: R-enantiomer of alpha-

lipoic acid.

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 ARE-

mediated gene transcription [3].

LA can also activate protein kinase

signalling pathways to phos-

phorylate Nrf2, promoting the

transcription of genes in response

to Phase II detoxification (fig. 2)[3].

References: [1] National Centre for Biotechnology Information. PubChem: Thioctic acid.


[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.

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)

42

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

LA Keap1

SH HS

Keap1

SH HS

Protein kinase

Nrf2

ARE Phase II genes

P

Potassium

Description:

Potassium is an alkali metal that

rapidly oxidizes in air, like sodium.

Potassium occurs naturally as ionic

salts and in plants [1]. Deficiency of

potassium

43

Quick Facts:

Chemical properties: alkali metal


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].

Dose: 0.36 mg/day | insulin-sensitive

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].

References: [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).

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

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].

Selenium

Description:

Selenium is a non-metal that has

been recognized to be essential to

the diet of humans [3]. Selenium can

be found in vegetables, fish, shellfish,

red meat, grains, eggs, chicken, and

44

Quick Facts:

Chemical properties: non-

metal


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].

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.

Related Compounds:

Vitamin E (page 15)

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].

Zinc (chelated)

Description:

Zinc, in its chelated form, is the

organic form of an essential trace

mineral found in food [1]. Animals

and humans absorb and digest

mineral chelates better than their

inorganic

45

Quick Facts:

Chemical properties: divalent

organic mineral


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

properties, able to protect

against the accelerated aging

of the skin and muscles in the

body [3]. It was also found

ound

that zinc may delay the progression of

age-related macular degeneration and

vision loss [4]. Zinc also contributes to

the immune system by being used in

granulocytes, a type of white blood

cells that helps protect the body

against infections [2].

References: [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.

Related Compounds:

Magnesium (page 46)

inorganic mineral form. Zinc is said to be chemically similar to magnesium

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].

Magnesium

Description:

Magnesium is an alkaline metal that

acts as a cofactor to many enzymes,

including those involved in DNA

replication and maintenance [1]. The

metal is the fourth most common

46

Quick Facts:

Chemical properties: Divalent,

alkaline earth metal


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.

Dose: 0.72 mg/day | anti-carcinogenic | anti-coagulant | antioxidant

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.

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.

Related Compounds:

Acetylsalicylic acid (page 39),

Potassium (page 43), Zinc (page 45)

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].

Garlic

Description:

Garlic, from the plant Allicum

sativum, is a common ingredient

used in many cultures for flavour

and its medicinal properties,

including anti-tumourgenesis, car-

dioprotection, and antithrombosis

[1,2]. Garlic can be consumed in

many ways: fresh, powdered, and

extracted in oil [1].

S-allyl cysteine, as well as ajoene and allicin, are known inhibitors of ADP-

induced 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 non-

organosulfur 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

Quick Facts:

Key compound: S-allyl cysteine

Properties: amino acid derivative,

hydrophobic and non-polar

Also contains: adenosine, allicin

Figure 1: S-allyl cysteine

Metabolism:

Garlic’s anti-coagulent effects is

expected to be a result of

inhibition of the platelet GPIIb-IIIa

receptor, responsible for ADP-

induced platelet aggregation [2].

Dose: 21.6 mg/day | anti-carcinogenic | anti-coagulant

Garlic’s anti-coagulant effects are

most studied, inhibiting platelet

aggregation through its

organosulfur compounds. Certain

garlic extracts also reduce

cholesterol biosynthesis [1,4].

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].

Related Compounds:

Gingko biloba (page 51)

48

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

Dose: 7.2 mg/day | anti-carcinogenic | antioxidant | anti-coagulant |

| anti-inflammatory

Ginger

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].

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-3-

ol and 1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-one (or 6-paradol) [4].

49

Quick Facts:

Key compounds: 6-shogaol,

gingerols

Properties: phenolics

Also contains: sesquiterpenes,

monoterpenes [2]

Figure 1: 6-shogaol (top) and

10-gingerol (bottom)

Metabolism:

Ginger contains many phenolics

that produce anti-inflammatory

and antioxidant effects [3]. These

compounds can be inter-

converted and may also change

when cooked or heated. 6-

shogaol has been shown to induce

apoptosis in certain cancer cells,

while 10-gingerol may inhibit cell

growth, producing anti-

tumourgenic effects [3].

Effects:

In addition to its anti-tumourgenic

effects, ginger is an antioxidant

[4]. Ginger has also been shown to

have anti-inflammatory benefits

[3].

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].

Related Compounds:

Acetylsalicylic acid (page 39)

50

Figure 2: Main metabolites of 6-shogaol [5]

6-s

ho

gao

l 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

5-methoxy-1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-one

1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-ol

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

3’,4-dihydroxylphenyl-decan-3-one

1-(4’-hydroxy-3’-methoxyphenyl)-decan-3-one apoptosis

Dose: 1.44 mg/day | neuroprotective | antioxidant | anti-coagulant

Gingko Biloba

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].

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].

51

Quick Facts:

Key compounds: ginkgolides,

bilobalides

Properties: terpene trilactones

Also contains: terpenoids,

flavonoids, carotenoids

Figure 1: Common ginkgolides [2].

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.

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.

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].

Related Compounds:

Beta-carotene (page 33),

Bioflavonoids (page 35), Garlic

(page 47), Ginseng (page 57)

52

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

Both are flavonoids and act as antioxidants [3].

Cod Liver Oil

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.

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.

Dose: 5.04 mg/day | anti-coagulant | anti-inflammatory

53

Quick Facts:

Key compounds: Omega-3 fatty

acids [eicosapentaenoic acid (EPA)

and docosahexaenoic acid (DHA)]


Also contains: Vitamin A , Vitamin D

Figure 1: EPA and DHA

Metabolism:

Like other fatty acids, EPA and

DHA can be broken down as a

source of energy or incorporated

into the phospholipid bilayer.

Because omega-3 fatty acids

contain more double bonds than

Effects:

While usually taken for its anti-

inflammatory 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].

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 anti-

coagulants 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.


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

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

Related Compounds:

Vitamin D (page 13), Acetyl L-

carnitine (page 23), Acetylsalicylic

acid (page 39), Alpha-lipoic acid

(page 41), Flax seed oil (page 55)

54

lipoxygenases

eicosapentaenoic

acid (EPA)

(20:5(n-4))

arachidonic

acid (AA)

(20:4(n-6))

TXA2

TXA3

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

(series-2 thromboxanes)

inflammatory response

induces platelet aggregation

(series-3 thromboxanes)

anti-inflammatory response

inhibits platelet aggregation

Flax Seed Oil

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].

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

Quick Facts:

Key compound: α-linolenic acid

Properties: Omega-3 fatty acid,

hydrophobic and non-polar

Also contains: linoleic acid, oleic

acid, palmitic acid, stearic acid

Figure 1: α-linolenic acid (ALA)

(18:3(n-3))

Metabolism:

Flax seed oil contains many fatty

acids than can be broken down by

fatty acid oxidation or

incorporated into cell membrane

phospholipids. As an omega-3

fatty acid, ALA contains more

double bonds than most fatty and

Dose: 21.6 mg/day | anticarcinogenic | antioxidant | anti-inflammatory

| anti-coagulant

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).

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 anti-

coagulant effects. The oil also acts

as an antioxidant by suppresses

inflammatory mediators in blood

sera and reduced oxygen radical

production [3].

References: [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].

Related Compounds:

Acetyl L-carnitine (page 23),

Acetylsalicylic acid (page 39),

Cod liver oil (page 53)

56

Figure 2: Conversion of ALA (found in flax seed oil) to

EPA (found in cod liver oil).

Ginseng

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.

57

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.

Dose: 86.4 mg/day | anti-carcinogenic | antioxidant | anti-inflammatory

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].

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.


[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].

Related Compounds:

Gingko biloba (page 51)

58

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

Green Tea Extract

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].

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.

59

Quick Facts:

Key compound: catechins, including

epigallocatechin gallate (EGCG)

Properties: family of polyphenol

Also contains: flavonoids

Figure 1: Green tea’s most common

catechin: epigallocatechin gallate

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.

Dose: 7.2 mg/day | antioxidant | anti-coagulant

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].

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].

Related Compounds:

Vitamin B1 (page 3), Bioflavonoids

(page 35), Rutin (page 37)

60

Figure 2: Potential pathways for EGCG metabolism.

(metabolite 5: 5-(3,5-dihydroxyphenyl)-4-hydroxyvaleric acid.)

EGCG

EGC

gallic acid

metabolite 5

How Compounds Interact

While each of the 31 compounds have their unique roles in the anti-

aging 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.

61

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 L-

glutathione.

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.

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 B-

vitamins 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 anti-

coagulant 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 β-

carotene 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 anti-

aging properties. Chromium also complexes with picolinate, an

artificial derivative of Vitamin B3. This interaction is shown with a

gray dotted line.

62

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 one-

way 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.

63

Interaction Diagram

Vit

am

in B

1

Legend

Is a type of / converts to...

Acts synergistically with...

Helps to break down...

Complexes with ...

Inhibits...

64 Helps to regenerate/

synthesize/absorb ...

Conclusion

65

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.

References

The following references were used in the introduction. All compound-

specific 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 age-

related 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

66

Vitami

L-glutathione

vitamin B1

vitamin B



folic acid

L-glutathione

chromium picolinate

coenzyme Q10

DHEA

Melatonin bioflavonoids


α-lipoic acid

β-carotene

potassium

selenium zinc

magnesium

garlic

ginger


coenzyme Q10

Gingko biloba

Melatonin

vitamin B1

vitamin B6



folic acid

L-glutathione

chromium picolinate

Coenzyme

DHEA

Melatonin

bioflavono


α-lipoic acid

β-carotene

potassium selenium zinc

magnesium

garlic

ginger

cod liver oil

flaxseed oil

green tea extract

coenzyme Q10 bioflavonoids

vitamin B1

vitamin B6 vitamin B3



folic acid

n-acetyl cysteine L-glutathione

chromium picolinate

coenzyme Q10

DHEA

Melatonin

bioflavonoids


α-lipoic acid

β-carotene

potassium

selenium zinc

magnesium

garlic

ginger


coenzyme Q10

Gingko biloba

bioflavonoids

Melatonin

vitamin B1

vitamin B12 Vita

vitamin D vitamin E

folic acid L-glutathione

coenzyme Q10

DHEA

Me

bioflavonoids


ic acid β-ca

otassium magne

garlic ginger

Gingko biloba cod liver oil flaxseed oil ginseng

coenzyme Q10

Gingko biloba

bioflavonoids

Melatonin L-glutathione

Melatonin


β

β


β-carotene DHEA

ginseng Mela

Flaxseed

selenium

magnesium

green tea extract

coenzyme Q10 flaxseed oil


bioflavonoids DHEA Gingko biloba

a "cure to aging"?

Documents

compound profiles vitamin

acetylsalicylic acid

glutathione coenzyme

alphalipoic acid

flax seed oil

antiaging effects

list of compounds potassium

synthetic compounds