Waldo Kühn

NOTES ON WEIGHT LOSS AND

HEALTHY AGING

Cover picture by: CDC/ Mary Anne Fenley. Source: Public Health Image Library

Published on SRIBD 2020

 INDEX

1. Introduction 2

2. Controlling type 2 diabetes without meds 4

3. Hormone replacement therapy 7

4. Healthy ageing: What else can be done

9
 Collagen

 Amino acid supplementation

 Other supplements

 Why we age

5. Food notes
30

2
 INTODUCTION

I have struggled with obesity all my life. When I got to my late forties I was weighing over 160
kilograms. By that time I had lost and regained weight several times. I also suffer from depression
and emotional eating has been a problem, especially during nights when I struggled to fall asleep.

Despite my morbid obesity and age I have managed to stay in fairly good health – which I attribute in
part to a variety of nutritional supplements I am regularly taking. I have high blood pressure and
type 2 diabetes. Both conditions are being carefully monitored and managed with prescription
medication. Otherwise my lipid profile is actually not bad (all things considered), my kidney function
is good and, most importantly, all parameters are improving as my weight loss progresses.

My cardiologist once told me during a routine check-up that unless I lost some serious weight I was
going to suffer a lot when I get old. Obesity and associated diabetes and hypertension aggravate
most of the health issues that sneak up on all of us as we age: wear and tear, poor circulation and
oxygenation, poor wound healing, weakened immune system, auto-immune problems, impaired
functioning of organs and associated co-morbidities, eyesight, hearing and so on. Most of these
issues are inevitable, but can definitely be delayed. Other issues like cancer and neurological
diseases are more difficult to prevent, but medical science is slowly progressing.

While this presentation documents my personal journey, I also have a medical background (trained
in laboratory medicine) so it is based on reasonable educated conclusions I have drawn from hours
of reading and comparing reputable scientific material.

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CONTROLLING TYPE 2 DIABETES AND LOSING 10 KILOGRAMS (20 LBS.) IN THREE MONTHS

Glucose is the body’s major source of energy. When we take in food the liver turns carbohydrates
into glucose. This causes a spike in insulin production by the pancreas. Insulin binds to glucose in
order to facilitate its uptake into the cells of the body, where it is used to produce energy in the form
of ATP. Excess glucose is stored as glycogen molecules in the liver, and to a lesser extent in muscle
tissue and smaller amounts elsewhere. There is a limit to how much glycogen can be stored, so
insulin also signals for enzymes that convert excess glycogen to fat, to be stored inside fat cells
throughout the body (together with dietary fat). Fat (triglyceride molecules) is a more energy-dense
molecule than glycogen and the body uses it as a long term reserve – so it does not convert into
energy as readily as glycogen does. When we take in too much energy the pancreas secretes
increasing amounts of insulin to try to take the excess glucose out of the blood, and send it into the
above-mentioned reserves.

High levels of circulating glucose are actually toxic! Glucose binds to protein molecules creating
glycated molecules.1. These cross-linked protein molecules can no longer fulfil their vital functions in
the body, and become the starting point for further pathological conditions. Since these products
form in the blood, it is not surprising that the circulation system is one of the most severely affected.
The walls of blood vessels are made from collagen; and collagen is severely affected by glycation.
The collagen protein molecule is heavily reliant on amino-acid cross-linking to form a robust
structural matrix that forms the basis for: blood vessel walls, heart valves, skin, bones, tendons and
ligaments, cartilage, muscles, organs, gut, gums and even teeth. 2.

Glycation causes blood vessels to stiffen and harden, affecting blood pressure control and oxygen
supply to tissues by destroying the fine capillary beds that interface blood and tissues. Nerve tissue
in the extremities of the body is among the first to die, manifesting as tingling sensations and lack of
feeling in fingers and toes. Due to inadequate blood supply to these areas, even small wounds do
not heal well and become very susceptible to infections. Glycation also gums up antibodies (which
are also proteins) and makes signalling by immune first-responders inefficient. Wounds heal poorly
because collagen is the major molecule responsible for wound healing. Untreated diabetic wounds
usually see massive tissue death, gangrene and septicaemia; necessitating amputation of septic
areas in order to save the rest of the body.

Prolonged high circulating glucose causes cell receptors to become less responsive to insulin. The
pancreas will make more insulin and eventually the insulin-producing cells may burn out – requiring
lifelong treatment with insulin. The body deals with prolonged high glucose and poor cellular
response to insulin, by dumping excess glucose into the urine along with other metabolic waste.
When the point has been reached where the body has resorted to pour glucose into the urine, a
diagnosis of diabetes can be made if glycosuria is detected during a medical check-up. Getting rid of
glucose in this way requires extra water, which explains constant thirst experienced by diabetes
sufferers. Medically, when circulating levels of glucose in the blood exceed 11.1 mmol/l (160-180
mg/dl), called the renal threshold for glucose, diabetes is also diagnosed. It is at this level that
glucose spills over into the bladder. The kidneys are however also poisoned by glucose. In fact,

4
glucose levels exceeding the renal threshold is a sign that the kidneys cannot cope with all the
glucose in the blood it is filtering. Glucose in the urine and high blood pressure are the first
indicators that the kidneys are in trouble. Protein in urine (>20mg/l) is the first indicator of damage
to the filtering units of the kidneys. The process of damage can still be reversed at this stage, but
from that point renal disease follows insidiously and eventually can no longer be stopped.
Management then requires dialysis which is expensive and physically and emotionally taxing.

Now, the idea that carbohydrate intake cause a spike in blood glucose and a resultant spike in insulin
production, which in turn activates an increased conversion of glucose into fat, has led to the whole
idea of the carbohydrate free diet (ketogenic diet), where you can feast on protein and fat but stay
away from starches and sugars. The American cardiologist Robert Atkins was the first to capture the
popular imagination with this concept. The general medical consensus is that the benefits of this
type of diet are not permanent.3, 4, 5.
Counterpoint: Some medical professionals are adamant that the ketogenic diet is the way to go:
https://youtu.be/8GUIBNKnT1M
Ketosis: When we restrict our intake of energy and glucose starts to decrease, insulin decreases and
its counter-hormone, glucagon then freely acts to initiate breakdown of glycogen into glucose
(glycogenolysis) and mobilize triglycerides from fat stores to get broken down for energy
(gluconeogenesis and β-oxidation).This generates acetyl-coenzyme A which enters the citric acid
cycle (Krebs cycle) to generate ATP. A portion of acetyl-coenzyme A gets converted into ketones,
which the brain can use for fuel. In the total absence of insulin (like when type I diabetics do not take
their insulin) this process can develop into life-threatening keto-acidosis.

Everybody agrees that there is only one sure way to burn off excess fat: You have to take in less
energy than what your body is used to metabolizing, thereby forcing it to dig into its fat reserves to
obtain that energy. The only way to keep it off is to continue eating sparingly (and exercise.) It is not
pleasant, but sometimes unpleasant is the only way. Also, you can get used to it. But you will have to
be a bit tenacious. Importantly, it must not be a diet, but a lifestyle change that you need to
acclimatize yourself to.

Philosophical approach to food: Does ethical eating make you a more disciplined eater? In the Bible
there is a scripture along the lines of: Let me put a knife to my throat if I am a glutton. I find the
emotional trauma associated with industrial-scale slaughter very off-putting. (We know that animals
can sense fear and made to wait in line while those in front are getting butchered. I do understand
that, like modern hunting, stock farming is about management of artificially created populations.
Hunting is perhaps more ethical than cattle trucks.) Vegan eating is very difficult for me, as I find
myself surrounded by an abundance of relatively cheap high quality animal products. I can replace
some meat-based foods with soy. But meat is everywhere, packaged and prepared well and
presented alluringly in shops and on fast food menus. When you have had a hard and emotionally
taxing day, food is a reward. The body appreciates animal-based foods because it is nutritionally
packed with the stuff that builds us up. Dairy goes well with coffee (my current staple) Dairy is an
excellent dietary source of calcium (calcium supplements hold a risk of kidney stones and heart
disease32.). Yoghurt (without added sugar) is a very healthy high-protein food. But the dairy industry
is also quite unethical. There are alternatives, but they are more expensive, and are not as abundant
as dairy on supermarket shelves. I think my food future lies somewhere in the middle: using more
non-animal products and fewer animal products.

5
To date I have lost about ten kilograms in three months. I was in hospital three times in about 18
months: first for high blood pressure which required monitoring; then for a wound under my big toe
that would not heal and got infected. With my last hospital visit which lasted a week, I was put on a
diet of about 8 400 kilojoules (2 000 calories). Realizing that I had lost a few kilograms, I decided to
follow on the momentum. I started to focus on restricting myself to around 1 900 calories. I probably
went over a bit, but on average kept to that. Motivation to exercise was a real problem: my weight,
often feeling depressed and a low free testosterone level conspired against exercise. My sedentary
job was a problem as well. So, initial results were disappointing. I had been on depo-testosterone
injections prior, and had lost a lot of weight through being motivated to exercise. (At first, I had lost
only small amounts. Then, I lost 19 kilograms in 3 months. Then things stabilized. However, when my
prescription ran out I made the mistake of not having it renewed until a few years had gone by.)

I decided it was time to have my levels looked at again. My lab result showed very low testosterone
levels. My thyroid hormones are normal.

Having been diagnosed with type 2 diabetes, I regularly monitor my blood sugar and am taking
metformin. I began to notice something: When my calorific intake was strictly controlled and
remained under 8 000 kilojoules (1 900 calories) for two days and more, my blood sugar was always
normal. WHAT I ate did not matter; it was HOW MUCH I ate that made the difference. Then I forced
myself to go down to 6 000 kilojoules (1 400 cal.) a day. Initially the cheating days were many. But
now exceeding 8 000 kilojoules was cheating in my mind. Previously, exceeding 11 000 kilojoules
was cheating for me. But it remained difficult. Obviously I replaced cane sugar with sucralose and
tried to favour low-GI nutrient-dense foods like whole-wheat toast with tuna over high-GI food like
white bread and sweets, which cause sudden glucose spikes in the blood. You may think that 1 400
calories a day is very low. (My dietician reckons 1 700 cal. will be more achievable.) So far, I manage
quite comfortably. I generally only eat when I’m feeling hungry; having something in the morning for
energy, at lunch at work for the afternoon slump, and a larger meal when I get home. I have my
cheating days, but don’t feel guilty about them. I just go back to my routine. The benefits of this
lean-mean approach far outweigh any discomfort.

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 HORMONE REPLACEMENT THERAPY

I have just gone back on depo-testosterone therapy. I do not think any of the female hormones
possess the invigorating and metabolically constructive effect that testosterone does. Human
growth hormone (HGH) has similar effects, but with side-effects like fluid retention, carpal tunnel
syndrome, high blood sugar levels and heart disease, which makes non-therapeutic supplementation
risky. (https://youtu.be/ZWjKakabNQY) Not many doctors are willing to prescribe it for healthy older
people simply to top up naturally declining levels (levels decline rapidly with age.) There are
supplemental amino-acid mixes (HGH secretory supplements) that claim to stimulate production of
HGH by the pituitary gland, but evidence that it does anything is scant. There is however well-
documented evidence that fasting, as well as weight training and deep sleep do increase HGH levels.
HGH prevents breakdown of protein for use as a source of energy during fasting, so that fat reserves
instead get depleted first. It also increases muscle mass.

More information on testosterone therapy: Article: Dandona P, Rosenberg MT. A practical guide to
male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64(6):682–696.
doi:10.1111/j.1742-1241.2010.02355.x

Estrogen and progestin supplementation for women: Estrogen alone or in combination with
progesterone can relieve symptoms of perimenopause such as vaginal atrophy, reduced sexual
pleasure and general quality of life (like quality of sleep). 12. The Woman’s Health Initiative Study
published in 2002 on combination therapy with estrogen and progesterone found a relative
increased risk for breast cancer (cumulative effect with years of therapy), cardiovascular disease,
thromboembolic events and stroke. It also confirmed the positive effects of therapy: risk for hip
fractures and clinical vertebral fractures were reduced by one third. Endometrial cancer risk was
unaffected. Risk of colorectal cancer was reduced. Total cancer risk was not reduced. Critics of the
study pointed out that it used a very specific combination and dosage of conjugated equine
estrogens and medroxyprogesterone acetate. It is therefore far from certain that the study’s findings
apply to lower dosages or other hormone formulations. Following these results, the US Food and
Drug Administration proposes HRT only for vaginal dryness and hot flashes. Due to positive effects
on bone, it may also be used exceptionally for the prevention of osteoporosis when other
treatments are considered inappropriate.

Bioidentical estradiol administered transdermally, with skin patches or vaginal gels, avoid the “first
pass” liver metabolism of the synthetic oral preparations used in the study, thus minimizing the
induction of clotting factors in the liver. It appears to decrease risk for thromboembolism and
appears to be associated with better lipid profiles. Transdermal preparations of estrogen are
associated with lower occurrence of carotid atherosclerotic plaque formation. 13.

Despite it being considered a weak estrogen, oral estriol has a proliferative effect on endometrial
tissue, exposing women to a higher risk for endometrial cancer. Vaginally applied estriol does not
have the same proliferative effect. Moreover, studies on the effect of estriol on breast tissue in
humans have been inconsistent.12.

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Progesterone counters estrogen’s proliferative effect on endometrium. Synthetic progestins appear
to have different affinity for receptors than natural. In general, bioidentical progesterone appears to
be safer and more effective than synthetic preparations in terms of thromboembolic events, breast
cancer risk, possible better effect on blood pressure, cardiovascular safety, sleep quality and positive
effect on bone density (in animal studies). Data on oral administration vs. other routes of
administration for bioidentical progesterone is unclear.

“Preliminary studies seem to support a better safety profile of bioidentical hormones, but this
should be confirmed by large-scale studies. Also, further studies are necessary that directly compare
synthetic hormones with bioidentical hormones, in terms of efficiency and safety.” 12.

More information: https://youtu.be/uEZpg0n7jcY and https://youtu.be/lmS4aJmblVY

Dehydroepiandosterone (DHEA): This is a prohormone produced in the adrenal glands and

converted to androgens and estrogens in target tissue. Levels decrease drastically with ageing. A
positive relationship between DHEA levels and muscle strength, muscle mass, better mobility and
lower risk for falls in the elderly have been described. DHEA levels have been positively linked with
bone mass density in both men and women. Lower levels of DHEA have been linked to higher risk for
erectile dysfunction in men and decreased sexual responsiveness in women.

Short-term studies on DHEA showed a good safety profile with limited side-effects and did not show
any significant effect on hormone-dependant tumours such as breast and prostate tumours. 12.

Melatonin: 5-Methoxy-N-Acetyltryptamine is produced in the pineal gland in the brain in the dark.
Production decreases as it gets light. It regulates our body clock.
Supplements are most commonly used for insomnia, to improve quality of sleep in the elderly, for
jet lag, to adjust sleep-wake cycles in shift-change disorder and for blind people to take at bed-time.
Taking melatonin may aid sleep in people taking beta-blockers (Beta blocker-induced insomnia.)
Slow-release formulations taken at bedtime seem to decrease blood pressure in people suffering
from hypertension. Immediate-release formulations do not have the same effect.
Taking daily melatonin for 8 weeks seems to reduce pain and painkiller use in women suffering from
endometriosis. It also reduces pain during menstruation, during intercourse and going to the
bathroom.
Melatonin is more likely to be helpful in older people with much lower natural levels than in younger
people in improving quality of sleep. In young people immediate-release supplements may supress
natural production.
High dose supplementation may reduce some side-effects of chemotherapy and possibly improve
survival time when taken with chemotherapy. 29.
Applying melatonin gel to skin before sun-exposure can prevent sunburn in people with sensitive
skin, but not in people with less sensitive skin.
Taking melatonin for 4 weeks has been shown to reduce pain in people suffering from
temporomandibular disorders which affect the jaw-joint and muscle.

Possible side effects include headache, short-term feelings of depression, daytime sleepiness,
dizziness, stomach cramps, and irritability. 28.

8
 HEALTHY AGEING: WHAT ELSE CAN BE DONE?

Collagen: I have previously mentioned how important collagen is in almost all tissues of the body.
Can we maintain healthy collagen? The answer is: perhaps. The complexity of protein metabolism
makes supplementation a complex issue. Collagen synthesis relies mostly on one type of cell: the
fibroblast. These cells unfortunately decrease as we age. Collagen synthesis occurs through
transcription-translation of DNA, linking amino-acids in accordance with the genetic code of the
individual. Every third amino acid is always l-glycine. So this is by far the most abundant constituent
of collagen. Alanine is also abundantly present. L-alanine is available from animal protein. L-proline is
a very important and abundant constituent. L-lysine, while constituting a small percentage of the
overall makeup of collagen is also important. L-proline and l-lysine become hydroxylated post-
translationally (after incorporation in pre-pro-collagen) by the enzymes prolyl-hydroxylase and lysyl-
hydroxylase. Vitamin C is an essential co-factor in this process. Scurvy, a disease of weakened
collagen is caused by inadequate vitamin C intake. Hydroxylysine units also undergo glycosylation
(addition of monosaccharides), and ultimately, through action of lysyl oxidase (with copper as co-
factor) link up the tropo-collagen units into collagen fibres.

Can supplementation of the abovementioned amino-acids increase collagen production? Amino-acid

metabolism is very complex. Glycine is abundant, but the body makes l-glycine from l-serine which it
derives in turn from the glycolysis-intermediate 3-phosphoglycerate and l-glutamate. One study
found that increased concentrations of glycine, proline and lysine in cell culture medium increased
production of type II collagen by chondrocytes. The authors suggest a daily intake of as much as 10
grams of l-glycine would be necessary in order to treat osteoarthritis through increased production
of type II collagen.14. According to an article6, l-proline supplementation does not significantly
increase l-proline levels and the body derives most of its proline via complex interplays between the
citric acid cycle and urea cycle involving: l-glutamate (increased dietary intake – wheat and soy
protein are good sources16. – does not however appear to increase l-proline levels), l-arginine, l-
citrulline and l-ornithine (via intermediates like pyrolline-5-carboxylate and glutamate-5-
semialdehyde.) L-citrulline supplementation appears to increase l-arginine, which may lead to
increased l-proline levels via l-ornithine production in the urea cycle. 6. One study found that a
combination of branched chain amino acids (BCAA – valine, leucine and isoleucine) with l-glutamine
and l-proline improved skin collagen formation in mice. 7. L-lysine is an essential amino acid.
Nutritional deficiency of l-lysine leads to connective tissue disorders due to poor collagen formation.
Although it constitutes a small overall content in collagen, its importance in the structural integrity
of the fibre makes it very important, and supplementation may be worthwhile. It is well known that
lack of vitamin C results in poorly developed collagen. There is limited data indicating that vitamin C
supplementation may have a positive effect on healing of injuries. 8. Mineral supplementation
including copper, manganese, iron and zinc also has benefits if deficiencies exist.

Another structural protein fibre found with collagen in connective tissues is elastin. While collagen
lends tensile strength, elastin provides elasticity. It is abundant in tissues that require a degree of
stretchiness, notably skin, arterial vessel walls, lung tissue, ligaments, bladder wall etc. It has a fairly

9
similar amino-acid make-up as collagen, with lots of l-glycine, l-alanine and l-proline. It also contains
l-valine (a branched chain amino acid.)

Amino-acid supplements: Are they really necessary and which are most important?

I have already pointed out that l-lysine supplements may be worth spending money on if you want
to follow a long-term regimen to age well. Roles include giving tensile strength to collagen, as well as
fatty acid transport into mitochondria – being a precursor to l-carnitine. It is abundant in animal
protein and legumes, but cereals are a poor source, so vegans may need to supplement, as do
people who do not get regular balanced high protein meals. Nutritional requirement is slightly more
than 2 grams per day for a healthy 70 kg person. The body breaks down the lysine it does not need.

The other amino acid I think may hold value for older people is l-tyrosine. This amino-acid builds
hormones that we really need for optimal functioning as we age, but which decline with ageing. Not
only is it the building block of thyroid hormones which regulates metabolism; it is also the building
block for the catecholamines: epinephrine (adrenaline) and norepinephrine (noradrenaline), as well
as the neuropeptide dopamine. (Co-factors in production pathways include iron, vitamin B6 and
vitamin C.) Recommended dietary intake for l-tyrosine is 2.3 grams a day for a healthy 70 kg person.
This value is for a combination of both l-tyrosine and l-phenylalanine (the precursor to l-tyrosine in
metabolism) combined. Deficiencies of catecholamines and of dopamine provide a similar,
overlapping range of symptoms including: lethargy, lack of drive, concentration difficulty, depression
and somatic anxiety (physical manifestations of anxiety.) 9. Severe dopamine deficiency further causes
symptoms like muscle spasms and loss of balance as with Parkinson’s disease, but this is a severe
neurological disorder treated with prescription medication.

WebMD lists the potential benefits, side-effects and importantly, drug-interactions of l-tyrosine
supplements. Take note if you are taking thyroid medication or levodopa:

https://www.webmd.com/vitamins/ai/ingredientmono-1037/tyrosine

Other supplements: The following supplements are important to consider in my opinion. I have
taken information from an authoritative source, the Linus Pauling Institute of Oregon State
University.10.

Vitamin C: Linus Pauling was an influential scientist who won the Nobel Prize for Chemistry in 1954.
In addition to his work in atom theory, he did ground-breaking work in biochemistry. In the 1970s he
became involved in vitamin C research, notably a controversial experiment to use mega dose
infusions of vitamin C to treat cancer. The Mayo Clinic disputed his findings in their own subsequent
research and since then, periodic attempts have been made (even to this day) to try to lend
credence to the idea, but evidence is still lacking.

Vitamin C acts as an antioxidant, protecting molecules like DNA from damage induced by free
radicals and reactive oxygen species. It also protects immune cells from self-inflicted damage by
reactive molecules which they generate to kill microorganisms. It is an essential cofactor in many
reactions including biosynthesis of collagen, l-carnitine (see later) and neuropeptides, activation of
oxytocin and regulation of gene expression. Observational studies indicate that higher levels of
circulating vitamin C are associated with lower risks of hypertension, cardiovascular disease and
stroke. Some studies suggest vitamin C may be a useful adjunct to existing medical treatment to

10
reduce myocardial injury and arrhythmia following procedures or surgery in patients with
cardiovascular disease. Vitamin C also enhances intestinal absorption of non-heme iron.

It is a water-soluble vitamin and high amounts (more than 500 milligrams a day) should not be taken
if you have impaired kidney function. Very high amounts (more than 2 000 milligrams a day) have
been shown to cause increased blood levels of oxalate and may possibly increase risk of kidney
stones. There is a fat-soluble esterified version available (ascorbyl-palmitate) which will put less
strain on kidneys. Another reason not to overdo things with vitamin C is that we do need low levels
of free radicals in our blood for vascular tone (endothelial NO-production) and immune function.

Vitamin E: A group of eight fat-soluble variants: four tocopherols and four tocotrienols. They have
the designations: α, β, γ and δ. This vitamin has benefits and claimed benefits. α (alpha)-tocopherol
is the most active form in the body. Most research therefore focus on α-tocopherol. Critics say the
problem with studies that use large supplemental doses of this form, is that it outcompetes the
other forms found in the diet of test subjects for absorption by the liver and binding to transport
proteins. They point out that vitamin E does not exist in nature as pure α-tocopherol, but instead in
various mixes with the other forms. Some researchers claim the γ-(gamma) form has the most health
benefits, and that large studies completely ignore it. 11. For instance, some human and animal studies
have found an inverse incidence between plasma levels of γ-tocopherol and incidences of heart
disease and prostate cancer. It is also the dominant form of vitamin E in the North-American diet.

Synthetic vitamin E (all-racemic vitamin E, also labelled dl-α-tocopherol, as opposed to natural d-α-
tocopherol) is a mix of eight stereoisomers of which only some have biological activity. I have not
been able to find a lot of information on whether natural is better than synthetic. I have pointed out
the debate about using only α-tocopherol vs. a mix of tocopherols and tocotrienols as they occur in
nature. The artificial vitamin is only a chemical mixture of synthetic isomers of α-tocopherol.

Benefits of α-tocopherol as listed by Linus Pauling Institute:

Fat-soluble anti-oxidant: Quenches chains of free radical molecules in lipid cell membranes. So it
prevents the membrane structures of cells from being damaged by highly reactive molecules. It also
prevents plasma lipid oxidation, which would have resulted in fatty deposits forming on the insides
of blood vessels (atherosclerosis formation.)
Alpha-tocopherol likely supports some aspects of cell-mediated immunity.
Severe vitamin E-deficiency, as caused by lipid malabsorption and genetic disorders affecting vitamin
E-transport, results in: neurological disturbances, muscle weakness and damage to the retina of the
eye.
Limited clinical evidence suggests that supplemental vitamin E may be beneficial for managing age-
related macular degeneration and fatty liver disease secondary to type 2 diabetes mellitus.
Supplemental α-tocopherol was shown to slow cognitive decline in cognitively impaired subjects in
some, but not in all, clinical studies.
Randomized controlled trials do not support a preventative role for supplemental α-tocopherol for
chronic diseases like cardiovascular disease, cancer and cataracts.

Current RDA is 15 mg/day.

Plant seed, notably sunflower, almond and hazelnuts and vegetable oils are good sources. Other
sources include tomato, avocado, spinach, asparagus, Swiss chard, and broccoli.

11
High doses of supplemental α-tocopherol may interfere with the vitamin K-dependant blood clotting
cascade, increasing risk of bleeding for persons on anticoagulant medication.
Upper safe limit (tolerable upper intake level) is set at 1 000 mg/day.10.
Vitamin A: Fat-soluble vitamin found in animal-products (dairy, liver and fish oils) as retinol and in
fruits and vegetables as pro-vitamin A carotenoids. The three active forms in the body are retinol,
retinal and retinoic acid. Vitamin A is involved in the specialization of virtually all cells in the body.
Thus, it plays in important role in foetal development, as well as normal immune functions, eye
development and vision. Vitamin A deficiency is the leading cause of preventable blindness in the
developing world. Deficiency is associated with increased susceptibility to infections, as well as
thyroid and skin disorders.
Prophylactic supplemental vitamin A is associated with a significant decrease in childhood mortality
in areas at high risk for vitamin A deficiency.
Vitamin A supplementation is widely recommended for children over 6 months of age who are
infected with measles while affected by malnourishment, immune deficient or are at risk of measles
complications.
Retinoic acid and analogues are used for treatment of acute promyelocytic leukaemia and various
skin diseases.

The recommended dietary allowance (RDA) is 700 micrograms of retinol activity equivalents (μg
RAE)/day for women and 900 μg RAE/day for men. Overconsumption of vitamin A is highly toxic and
especially contraindicated in pregnancy as it can lead to severe birth defects. The tolerable upper
intake level (UL) for vitamin A in adults is set at 3 000 μg RAE/day. The UL does not apply to vitamin
A derived from carotenoids.10.

Vitamin D: A fat-soluble vitamin that regulates calcium homeostasis and is vital for bone health.
While it can also be obtained from dietary sources or supplements, vitamin D3 (cholecalciferol) is
synthesized in the human skin from 7-dehydrocholesterol upon exposure to ultraviolet-B (UVB)
radiation from sunlight. It is metabolized into its active form in the liver (25(OH)-calcidiol) and
kidneys (1,25(OH)-calcitriol).

Roles: Maintains calcium and phosphate homeostasis and is vital for bone health.
Severe vitamin D deficiency causes rickets in children (characterized by soft and deformed bones)
and osteomalacea in adults.
Secondary hyperparathyroidism due to insufficiency of vitamin D causes skeletal breakdown and can
precipitate osteoporosis.
Vitamin D can regulate cell differentiation and growth through binding to vitamin D-receptors found
on almost all cells. Through binding to receptors on cells, activated vitamin D can regulate the
expression of hundreds of genes involved in skeletal and other biological functions.
Vitamin D also exhibits many non-skeletal effects, particularly on the immune, endocrine, and
cardiovascular systems.
Observational studies have reported associations between low sun exposure, poor vitamin D status,
and increased risk of developing colorectal and breast cancer. Randomized controlled trials are
needed to evaluate whether cancer prevention may benefit from vitamin D supplementation. 10.
Evidence from observational studies suggests an inverse relationship between vitamin D levels and
onset of type 2 diabetes mellitus.

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Various observational studies have found an inverse relationship between vitamin D levels and
susceptibility and severity of certain autoimmune diseases including type 1 diabetes mellitus, lupus
erythematosus, multiple sclerosis and rheumatoid arthritis. Supplemental vitamin D may have a role
in management of eczema and Crohn’s disease.
2022 Update: Auto-immune attenuation affirmed: https://youtu.be/ezuyfGLph4Q. (51)

A systematic review and meta-analyses of 31 observational studies on maternal vitamin D status and
pregnancy outcomes have indicated that vitamin D insufficiency may be associated with gestational
diabetes mellitus and preeclampsia in pregnant women. Low maternal serum vitamin D levels were
also associated with small-for-gestational age infants and low-birth-weight infants. Safety and
benefits of vitamin D supplementation during pregnancy both need to be evaluated in clinical
trials.10.
People over 71 years of age require an increased recommended daily intake: 800 IU (20 micrograms
per day) for both sexes. (US Food and Nutrition Board) Food sources include fish, egg yolks and
fortified foods.10.

Excessive intake of vitamin D can cause hypercalcemia, kidney damage and weakened bones. 39.
It activates both major bone cells involved in calcification: Osteoclasts remove calcium from bone
(resorption) in order to maintain blood calcium homeostasis. Vitamin D also stimulates the other cell
type, osteoblasts, to produce osteocalcin, which puts calcium into bones. Osteocalcin needs vitamin
K2 (MK-7) to be activated. So, vitamin D supplementation needs to be accompanied by vitamin K-
supplementation (both Vitamin K1 and K2-7 in balance because they have different functions and
may compete for binding to carriers.) 27.

Vitamin K: A fat-soluble vitamin consisting of a range of vitamers. Vitamin K1 (phylloquinone) is

synthesized by plants and the predominant form in dietary sources (leafy green vegetables.)
Vitamin K2 (menaquinone) is primarily synthesized by gut bacteria and found in animal livers. It
consists of a range of forms designated MK-2 to MK-14.
Vitamin K3 (menadione) is a synthetic provitamin that needs to be converted to MK-4 to be active. It
is used in stock farming.

Functions: Vitamin K is an essential co-factor in the activation of various proteins involved in: blood
coagulation (K1 and K2), bone metabolism, prevention of mineralization of blood vessel walls – a
process that increases with ageing – (through activation of Ca++- binding vitamin K2-7-dependant
proteins) and proteins involved in regulation of various cell-functions.
Vitamin K deficiency causes excessive bleeding. New-born babies are given vitamin K injections to
prevent risk of possible intracranial bleeding. 10.

The adequate intake (AI) level for vitamin K is set at 90 μg/day for women and 120 μg/day for men.
The body can recycle vitamin K molecules for repeated use. 10.

2022 update: Vitamin K2 plus vitamin D failed to slow progression of existing aortic valve
calcification in a large randomised controlled trial: https://youtu.be/HfSplBjB514. (52)

Vitamin B-complex: Consists of a range of water-soluble vitamins with an array of functions in the
body, generally related to carbohydrate and protein metabolism and nervous system. I will discuss
the individual vitamins separately:

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Vitamin B1: The activated from is thiamine pyrophosphate. It functions as a co-factor in various
enzymatic processes involved in carbohydrate metabolism, branched chain amino-acid metabolism
and fatty-acid metabolism.

Severe thiamine deficiency causes beriberi, a disease affecting multiple organ systems, including the
central and peripheral nervous systems.
Wernicke-Korsakoff Syndrome is a neurological disorder secondary to thiamine deficiency.
Thiamine deficiency and decreased thiamine-dependant enzymatic activity are associated with
Alzheimer’s disease.
Hyperglycaemia in diabetic patients leads to increased urinary loss of thiamine by impairing
reuptake by the kidneys. In turn, thiamine deficiency appears to impair functioning of the pancreas,
exacerbating hyperglycaemia.10.

Vitamin B2: Riboflavin is the precursor to the co-enzymes flavin adenine dinucleotide (FAD) and
flavin mononucleotide (FMN). They act as electron-carriers in a number of redox reactions involved
in energy production and various metabolic processes.

Riboflavin deficiency can affect multiple pathways in the metabolism of vitamin B6, folate, niacin,
and iron.
Riboflavin deficiency has been linked to preeclampsia during pregnancy. Risk of preeclampsia (onset
of hypertension with proteinuria in pregnancy) has been linked to deficiency in the MTHFR C677T
gene responsible for production of FAD-dependant methylenetetrahydrofolate reductase (a key
folate-metabolizing enzyme.) Thus, low riboflavin status may interfere with the metabolism of
folate, particularly in individuals homozygous for the MTHFR C677T gene variant. These individuals
exhibit a higher risk of cardiovascular disease. Emerging evidence from intervention trials supports a
protective role for riboflavin against hypertension in individuals with the MTHFR 677TT genotype.

Vitamin B3: Dietary precursors to nicotinamide adenine dinucleotide (NAD), including nicotinic acid,
nicotinamide and nicotinamide riboside, are collectively known as niacin or vitamin B3.
NAD+ can be phosphorylated (NADP) and reduced (NADH and NADPH). NAD functions in oxidation-
reduction (redox) reactions (notably mitochondrial energy production) and non-redox reactions.
(NAD can also be produced from the essential amino-acid tryptophan via the kynurenine pathway.)
NAD is the sole substrate for PARP enzymes (poly-ADP ribose polymerase) and sirtuins involved in
DNA expression and repair activities. Thus, NAD is critical for genomic stability. Several studies
suggest a possible role for niacin in prevention in some cancers.
At pharmacologic doses, nicotinic acid improved lipid profiles of patients with a history of vascular
disease yet failed to reduce recurrent cardiovascular events or mortality.

Niacin deficiency causes pellagra, a disease affecting the skin, digestive system and nervous system.
It can lead to death if left untreated.
Causes of niacin deficiency include inadequate oral intake, poor bioavailability from un-limed grains,
defective tryptophan absorption, metabolic disorders, and the long-term use of chemotherapeutic
treatments.
The most prominent side-effect of pharmacological doses of niacin is skin flushing. The co-
administration of laropiprant — a prostaglandin D2 receptor-1 antagonist — helps reduce nicotinic
acid-induced skin flushing.10. Very high doses of niacin means that excess will be excreted. In this

14
process it becomes methylated to the extent that the body’s methyl supply can become depleted.
Methyl groups are necessary to activate many processes in the body. It has been recommended that
high doses of niacin are taken with methyl donors like choline and trimethyl-glycine (TMG).
However, the role of methylation in both the promotion, as well as suppression of tumours, is
complex and only beginning to be understood. For instance, genes involved in formation, as well as
those involved in suppression of malignancies can be influenced by methylation of DNA. 47, 48, 49.

Nicotinamide riboside and NMN: Probably not worth the expense. https://youtu.be/hggLOXhFRxc

Folate: Water-soluble vitamin also known as vitamin B9 or folacin. The biologically active form is 5-
methyl-tetrahydofolate. Folate is critical in the metabolism of nucleic acid precursors and several
amino-acids, as well as in methylation reactions (methylation of DNA plays a role in gene expression
and is critical for cell differentiation and repair.)

Severe deficiency of either folate or vitamin B12 causes megaloblastic anaemia, characterized by
formation of poorly functioning blood cells.
Inadequate folate status during early pregnancy increases the risk of congenital anomalies.
Introduction of mandatory folic acid-fortification of refined grains in the US and elsewhere has led to
a decrease in the incidence of neural tube defects in newborns.
Folate deficiency and elevated concentrations of homocysteine in the blood are associated with
increased risk of cardiovascular disease. Although folic acid supplementation has been proven
effective to control circulating homocysteine concentrations, the effect of homocysteine lowering on
the incidence of cardiovascular disease is still debated.
Low folate status has been linked to increased cancer risk. Trials looking into effect of high dose
folate have not found any effect on cancer incidence. Prospective cohort studies have reported an
inverse association between folate status and colorectal cancer risk, especially among men. The
relationship between folate status and cancer risk is however complex and requires further
research.10.
Folate is essential for brain development and function. Low folate status and/or high homocysteine
concentrations are associated with cognitive dysfunction in aging (from mild impairments to
dementia). Whether supplemental B-vitamins, including folic acid, will have long-term benefits in
maintaining cognitive health is not yet known.
Several autosomal recessive disorders affecting folate transport and metabolism can be treated with
high doses of synthetic folinic acid. 10.

Many new vitamin supplements contain the bio-active form of folate: L-5-methyl-tetrahydrofolate.
(Conversion from folic acid to functional 5-methyl-tetrahydrofolate in the body is not very efficient.)

Vitamin B6: Vitamin B6 (pyridoxine, pyridoxal and pyridoxamine forms) is a water-soluble vitamin.
Dietary sources include fish, poultry, nuts and fortified foods.
Its activated co-enzyme form, pyridoxal-5 ’-phosphate is involved in over 4% of all enzymatic
biochemical processes. That is a lot of biochemical processes! Vitamin B6 and pyridoxal-5'-
phosphate are essential to over 100 enzymes mostly involved in protein metabolism.
Although supplementation with vitamin B6 and other B vitamins has not been associated with
improved cognitive performance or delayed cognitive deterioration in the elderly, recent studies
suggest that vitamin B6 might help reduce the risk of late-life depression.

15
Pharmacologic doses of vitamin B6 are used to treat seizures in rare congenital errors of vitamin B6
metabolism.
Supplemental vitamin B6 appears to be useful for treatment of carpal tunnel syndrome.
Supplemental vitamin B6 may relieve symptoms of morning sickness in pregnant women.

Several medications, including anti-tuberculosis drugs, anti-parkinsonians, nonsteroidal anti-

inflammatory drugs, and oral contraceptives, may interfere with vitamin B6 metabolism.
Excessive supplementation of vitamin B6 (more than 100 mg/day) can cause nerve damage and skin
lesions.10.

Vitamin B12: Vitamin B12 (cobalamin) is a large complex molecule containing a metal ion, cobalt, in
its structure. Dietary sources are animal products and fortified foods. Its bio-active forms in the body
are methylcobalamin and 5-deoxyadenosylcobalamin.
It plays essential roles in folate metabolism and synthesis of the citric acid cycle-intermediate
succinyl-coenzyme A.
A common cause of vitamin B12 deficiency is an autoimmune vitamin B12 malabsorption syndrome
called pernicious anaemia, characterized by destruction of cells lining the stomach, low stomach acid
and autoantibodies against the vitamin B12 transport protein, intrinsic factor.
Other common causes for vitamin B12 deficiency are alcoholism and impaired absorption in the
elderly (over 60 years of age) due to atrophy of the stomach lining.
A vegan diet is also a risk factor for deficiency.
Prolonged use of certain medications, such as inhibitors of stomach acid secretion, can adversely
affect vitamin B12 absorption.

Vitamin B12 deficiency causes megaloblastic anaemia and neurological defects.

The preservation of DNA integrity is dependent on folate and vitamin B12 availability.
Poor vitamin B12 status has been linked to increased risk of breast cancer in some, but not all,
observational studies. There is a need to evaluate whether supplemental vitamin B12, along with
folic acid, could help reduce breast cancer incidence. 10.
Low maternal vitamin B12 status has been associated with an increased risk of neural tube defects,
but it is not known whether vitamin B12 supplementation could help reduce the risk of NTD.
Vitamin B12 is essential for the maintenance of the myelin sheath around neurons and for the
synthesis of neurotransmitters.
Vitamin B12 and folate lower homocysteine levels. While hyperhomocysteinemia may increase the
risk of cognitive impairment, it is not clear whether vitamin B12 deficiency contributes to the risk of
dementia in the elderly.

Vitamin B5: Water-soluble pantothenic acid is an essential nutrient. It is found in a wide range of
dietary sources, including: animal organs (liver and kidney), fish, shellfish, milk products, eggs,
avocados, legumes, mushrooms and sweet potatoes. Dietary deficiency is rare.
It is a precursor to acetyl-coenzyme A, which is essential to many vital biochemical processes in
carbohydrate, protein and lipid metabolism.
Evidence from limited intervention studies suggests than pantothenic acid or its alcohol analogue
pantothenol can improve healing of skin wounds. Further larger studies are warranted. 10.
High-dose of pantethene has been shown to lower serum cholesterol and lipid concentrations.

16
Little or no toxicity has been associated with dietary or supplemental pantothenic acid. Thus, no
upper safe limit has been set. Recommended adequate daily intake is 5 mg/day (The Food and
Nutrition Board of the US Institute of Medicine). 10.

Biotin: Water-soluble compound generally considered a B-complex vitamin. It is a cofactor to

enzymes in intermediary metabolism (five carboxylase enzymes require biotin for their activity
including acetyl-CoA carboxylases and pyruvate-CoA carboxylase.)
It is a regulator of gene expression.
Symptoms of frank biotin deficiency include hair loss, dermatitis, and skin rash, ataxia, seizures, and
other neurologic dysfunctions.
Biotinidase deficiency is a rare hereditary disorder that impairs biotin absorption and recycling,
resulting in secondary biotin deficiency
Animal studies have shown that biotin sufficiency is essential for normal foetal development.
Whether marginal biotin deficiency during pregnancy increases the risk for congenital anomalies in
humans is currently an area of concern and investigation.
Biotin is used in the treatment of an inherited disorder of thiamine transport, called biotin-
responsive basal ganglia disease, and is currently being tested in trials to limit or reverse functional
disabilities in individuals with multiple sclerosis.
Biotin is an essential nutrient. Biotin is widely found in food, and good dietary sources include egg
yolk, liver, whole-grain cereal, and some vegetables.
Long-term anticonvulsant therapy can interfere with biotin uptake, necessitating increased dietary
requirements.
The recommended adequate intake (AI) of biotin is set at 30 micrograms (μg)/day in adults. Biotin
requirements are likely increased during pregnancy and breast-feeding 10.

Minerals:

Calcium: “Calcium is the most abundant mineral in the human body. About 99% of the calcium in
the body is found in bones and teeth, while the other 1% is found in the blood and soft tissue.
Calcium concentrations in the blood and fluid surrounding the cells (extracellular fluid, also called
interstitial fluid) must be maintained within a narrow concentration range for normal physiological
functioning. The physiological functions of calcium are so vital to survival that the body will stimulate
bone resorption (demineralization) to maintain normal blood calcium concentrations when calcium
intake is inadequate. Thus, adequate intake of calcium is a critical factor in maintaining a healthy
skeleton. Calcium is a major constituent of bones and teeth and also plays an essential role as second
messenger in cell-signalling pathways.”10.
Ca++ is essential for muscle contraction, normal heart rhythm and blood clotting.
The recommended dietary allowance (RDA) for calcium is 1 000 mg/day-1 200 mg/day for adults. 10.

Magnesium: The second most abundant intracellular cation after potassium. Mg ++, free ionic portion
(the rest is bound in the skeleton, soft tissue – primarily muscle – and to blood proteins) is a cofactor
for hundreds of enzymes. Magnesium is involved in energy production, nucleic acid and protein
synthesis, ion transport, cell signalling, and also has structural functions.

17
“About half of the US adult population may have insufficient magnesium intakes to support
nutritional adequacy”10.
Severe magnesium deficiency can impede vitamin D and calcium homeostasis. Deficiency is caused
by alcoholism, old age and gastrointestinal and renal disorders.
“Inadequate dietary intakes and/or low serum concentrations of magnesium have been associated
with increased risk of cardiovascular disease, osteoporosis, and metabolic disorders, including
metabolic syndrome, hypertension, and type 2 diabetes mellitus. Preliminary studies have shown
that magnesium improved insulin sensitivity in individuals at risk for type 2 diabetes mellitus.
Randomized controlled trials have also investigated the role of magnesium supplementation in the
prevention of complications following stroke or heart surgery.” 10.
It is administered for the prevention of seizures in pregnant women with preeclampsia or eclampsia.
It is presently being investigated for management of hypertension, type 2 diabetes mellitus, asthma
and pain.
Dietary sources rich in magnesium include green leafy vegetables, unrefined grains, legumes, beans,
and nuts. The upper tolerable level (UL) for supplemental magnesium is 350 mg/day. (More info.)
Excess magnesium supplementation can result in diarrhoea and low blood pressure. “Some of the
later effects of magnesium toxicity, such as lethargy, confusion, disturbances in normal cardiac
rhythm, and deterioration of kidney function, are related to severe hypotension. As
hypermagnesaemia progresses, muscle weakness and difficulty breathing may occur. Severe
hypermagnesaemia may result in cardiac arrest.” 10.

Potassium: Potassium homeostasis is tightly controlled both inside and outside of cells. It is essential
for normal physiological functioning. It functions as an electrolyte involved in maintaining an ionic
gradient between the cell and extracellular fluid.
“Low potassium concentration in blood (hypokalaemia) can result in muscular paralysis or abnormal
heart rhythms and can be fatal. Hypokalaemia is usually due to excessive loss of potassium as with
prolonged vomiting or diarrhoea, use of diuretics, or with kidney disease.” 10.
Increasing dietary potassium intake may help lower blood pressure.
Evidence from observational studies reported that higher dietary intake was associated with lower
risk of kidney stones and lower risk for stroke.

Adequate dietary intake is between 2.6-3.4 grams a day. Good dietary sources of potassium include
fruit and vegetables, some nuts and seeds, and dairy products. The kidneys are efficient at
maintaining optimal levels of potassium through excretion and reabsorption from filtrate.

Phosphorus: “Phosphorus is an essential structural component of cell membranes and nucleic acids
but is also involved in several biological processes, including bone mineralization, energy production,
cell signalling through phosphorylation reactions, and regulation of acid-base homeostasis.” 10.
Dietary phosphorus insufficiency is uncommon and only seen in cases of near total starvation or rare
inherited disorders involving renal loss. Supplementation in healthy people is not necessary.

Zinc: Mineral with catalytic, regulatory and structural roles in the body. Zinc plays important roles in
growth and development, immune function, neurotransmission, vision, reproduction, and intestinal
ion transport.

18
Dietary zinc deficiency is quite common in the developing world, affecting an estimated 2 billion
people. Causes include diets rich in phytate and low intake of animal-based foods. Other causes for
zinc deficiency include chronic alcoholism and malabsorption syndromes.
Zinc deficiency has been associated with impaired growth in children, complications with pregnancy
and poor immune function.
“Current evidence suggests that supplemental zinc may be useful in the management of chronic
conditions, such as age-related macular degeneration, diabetes mellitus, Wilson’s disease, and
HIV/AIDS.”10.
Recommended dietary allowance (RDA) for adult men is 11 mg/day and for women, 8 mg/day.
Long-term consumption of zinc in excess of the tolerable upper intake level (UL) of 40 mg/day for
adults can result in copper deficiency. Otherwise high doses of supplemental zinc are well tolerated
over limited periods, such as when used to shorten the duration of common cold symptoms.
Good dietary sources are meat, eggs and seafood. Grains and legumes are not good dietary sources
due to their high phytate content.

Copper: An essential cofactor in several oxidation-reduction reactions. Copper enzymes regulate

various physiologic pathways, such as energy production, iron metabolism, connective tissue
maturation, and neurotransmission.
Copper deficiency can result from inadequate dietary intake, malabsorption syndromes and
excessive zinc intake. Symptoms include blood cell deficiencies, bone and connective tissue
abnormalities and neurological disorders.
“Marginal copper imbalance has been linked to impaired immune function, bone demineralization,
and increased risk of cardiovascular and neurodegenerative diseases. However, the use of more
precise indicators of nutritional copper status needs to be considered for future research.” 10.
Good sources are organ meats, shellfish, nuts, seeds and whole-grain products.

Selenium: A trace-element which mainly functions is as part of the selenocysteine moiety in several
enzymes: glutathione peroxidases, iodothyronine deiodinases and others.
Selenium deficiency results in impaired anti-oxidant protection. Diseases of deficiency include
Keshan cardiomyopathy and Kashin-Beck osteoarthropathy.
Current RDA is set at 55 μg/day for all people. (US Institute of Medicine.)
Bio-availability from food sources like grains is affected by the selenium content of the soil it was
grown in. Sources include Brazil nuts, grains, seafood, organ meats, poultry and dairy products.
“Because some evidence suggests that high serum selenium concentrations may have adverse
effects on glycaemic control, individuals with high selenium status and/or those at risk for type 2
diabetes mellitus should avoid taking selenium supplements” 10.

Iodine: This trace-element forms part of the thyroid hormones which are essential for regulation of
metabolism, growth and development and reproductive function.
Iodine deficiency results in a range of conditions of varying severity from goitre (enlargement of the
thyroid gland) to cretinism (a form of mental retardation). Deficiency during pregnancy can lead to
hypothyroidism (both maternal and foetal), miscarriage or preterm birth and neurological
impairments in offspring.
The recommended dietary allowance (RDA) for iodine intake is 150 micrograms (μg)/day in adults,
220 μg/day in pregnant women, and 290 μg/day in breast-feeding women. 10.

19
Current protocol in case of radiation emergencies calls for distribution of potassium iodide
supplements in order to out-compete incorporation of environmental radioactive iodine ( 131I) into
the thyroid gland, which would cause thyroid cancer.
Sources are seafood and seaweed, dairy, grains, eggs and poultry. More than 120 countries have
introduced programs of salt-fortification to correct iodine deficiency in populations.

Iron: Functions are as follows:

Iron-dependant hemoproteins: globin-heme responsible for oxygen transport and storage, heme-
enzymes involved in electron transfer (cytochromes) and/or with oxidase activity (peroxidases,
cytochrome P450 oxidases, myeloperoxidase, catalase and others), Fe-S cluster proteins with redox
activity involved in energy production (NADH dehydrogenase and others) and enzymes involved in
DNA replication and repair (DNA polymerases and helicases).
The body stores and recycles iron and only little is excreted. Uptake is regulated (hepcidin) if stores
are sufficient.
“Iron deficiency is the most common nutritional deficiency worldwide, affecting primarily children,
women of childbearing age, pregnant women, frequent blood donors, and individuals with certain
medical conditions.”10.
Iron deficiency causes microcytic anemia and associated symptoms like fatigue, rapid heart rate and
palpitations.
Anemia of inflammation results when proteins involved in iron homeostasis, hepcidin and ferritin,
increase in response to inflammatory cytokines. Absorption of dietary iron is suppressed and stores
are sequestered, becoming unavailable for erythropoiesis.
Iron deficiency in children has been associated with poor cognitive development and behavioural
problems.

Toxic iron deposition in organs (notably in hereditary hemochromatosis) is associated with

cardiomyopathy, liver cancer and type 2-diabetes. Individuals who do not have genetic disorders of
iron metabolism are also at risk for chronic diseases, due to high heme iron intake and/ or loss of
iron homeostasis.
“Iron supplementation may cause gastrointestinal irritation, nausea, vomiting, diarrhoea, or
constipation, and interfere with the absorption and efficacy of certain medications, including
antibiotics and drugs used to treat osteoporosis, hypothyroidism, or Parkinson’s disease
symptoms.”10.
“Since hereditary hemochromatosis is not uncommon and the effects of long-term dietary iron
excess on chronic disease risk are not yet clear, men and postmenopausal women who are not at
risk of iron deficiency should take a multivitamin/mineral supplement without iron. A number of
multivitamins formulated specifically for men or those over 50 years of age do not contain iron.” 10.

Manganese: Plays an important role in several physiological processes as a constituent of some

enzymes and co-factor in some enzymatic reactions, with roles in metabolism of carbohydrates,
amino acids and cholesterol, formation of healthy cartilage, bone and wound healing (manganese
activates prolidase (proline dipeptidase) which releases l-proline from peptides and degraded
collagen for new collagen formation).
Manganese superoxide dismutase is a vital antioxidant enzyme that protects mitochondria from
injury by oxygen free radicals generated during mitochondrial production of ATP.

20
Dietary intake of manganese appears to be sufficient in humans.
“In the US, estimated average dietary manganese intakes range from 2.1 to 2.3 mg/day for men and
1.6 to 1.8 mg/day for women. People eating vegetarian diets and Western-type diets may have
manganese intakes as high as 10.9 mg/day. Rich sources of manganese include whole grains, nuts,
leafy vegetables, and teas. Foods high in phytic acid, such as beans, seeds, nuts, whole grains, and
soy products, or foods high in oxalic acid, such as cabbage, spinach, and sweet potatoes, may slightly
inhibit manganese absorption. Although teas are rich sources of manganese, the tannins present in
tea may moderately reduce the absorption of manganese. Intake of other minerals, including iron,
calcium, and phosphorus, have been found to limit retention of manganese.” 10.
Manganese toxicity is a major industrial hazard caused by chemical exposure and inhalation of
manganese dust in smelters and welding. It causes severe neurological disorders.

Other micronutrients usually included in mineral supplements: Molybdenum (involved as a co-factor

in breakdown of spent nucleotides, metabolism of sulphur-containing amino-acids and detoxification
of some drugs and toxins) and chromium (thought to play a role in insulin sensitivity, but still
uncertain).

Other supplements:

Omega-6 and Omega-3 fatty acids: Both omega-6 and omega-3 fatty acids are important structural
components of cell membranes, serve as precursors to bioactive lipid mediators, and provide a
source of energy.
The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
exert an anti-inflammatory effect.
DHA supplementation during pregnancy may reduce the risk of early premature birth and very low
birth weight (Under 1.5 kilograms or 3 pounds 5 ounces.)
DHA is important for visual and neurological development. However, supplementation during
pregnancy or early infancy does not appear to have any significant effect on children's visual acuity,
neurodevelopment, and physical growth.
Long-chain omega-3 PUFA supplementation may be useful to reduce mortality in patients with
prevalent coronary heart disease and in those with heart failure without preserved ventricular
function.
Increasing EPA and DHA intake may benefit individuals with type 2 diabetes mellitus, especially
those with elevated serum triglycerides. However, evidence from large-scale randomized trials is
insufficient to support the use of omega-3 PUFA supplements for cardiovascular disease prevention
in people with type 2 diabetes.10.
It is not clear whether supplementation with marine-derived omega-3 supplements can slow down
cognitive decline.
Replacing saturated fat with omega-6 fatty acids has been shown to improve cholesterol, but have
not shown cardiovascular benefits in healthy people and those at risk for type 2 diabetes mellitus.

Supplement fact: Salmon-sourced Omega-3 supplements contain saturated animal fats as well. Krill
oil extracts contain marine Omega-3 fatty acids in the form of phospholipids.

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Choline: Most dietary choline is sourced from phospholipids (phosphatidylcholine). It is involved in
many processes including methylation reactions, neurotransmitter production, cell-signalling
molecules (platelet activating factor and others), protection of cells against osmotic stress (betaine),
transport of lipids, and synthesis of phospholipids (phosphatidylcholine and sphingomyelin) that
make up cell membranes and the myelin sheaths of neurons.
Choline deficiency causes muscle damage and non-alcoholic fatty liver disease.
“The need for choline is probably increased during pregnancy. Case-control studies examining the
relationship between maternal choline status and risk of neural tube defects (NTDs) have given
inconsistent results. It is not yet known whether periconceptual choline supplementation could
confer protection against NTDs.”10. “Animal studies have shown that choline is essential for optimal
brain development and influences cognitive function in later life. However, in humans, there is not
enough evidence to assert that choline supplementation during pregnancy improves offspring’s
cognitive performance; or that it helps prevent cognitive decline in older people.” 10.
“Recent intervention studies have found that supplementation with citicoline (a choline derivative)
may be useful to limit neurologic damage in stroke patients and improve retinal function in some
glaucoma patients. It remains unclear whether citicoline could be used in the treatment of
dementias and in head trauma patients.” 10.
“Choline is involved in the regulation of homocysteine concentration in the blood through its
metabolite betaine. There is currently no convincing evidence that high choline intakes could benefit
cardiovascular health through lowering blood homocysteine. Besides, elevated blood concentrations
of trimethylamine N-oxide (TMAO) generated from choline may increase the risk of cardiovascular
events.”10.
The non-profit advocacy group for promotion of breast feeding, Le Leche League, recommends
supplemental lecithin (a source of phospholipids) for blocked milk ducts. (Lecithin is an emulsifying
agent that makes fats soluble in water.)15.
De novo choline synthesis in humans is not sufficient to meet metabolic needs. Dietary sources
include eggs, soy beans, meat, poultry, fish, cruciferous vegetables, peanuts, and dairy products.
Lecithin is added to many foods as an emulsifying agent.

Excessive consumption of choline (≥7,500 mg) has been associated with blood pressure lowering,
sweating, fishy body odour, and gastrointestinal side effects. The tolerable upper intake level (UL)
for adults is 3 500 mg/day.10. Soy lecithin is produced by extraction with toxic solvents like hexane,
whereas sunflower lecithin is extracted by cold-press. Sunflower lecithin is therefore a better choice.

L-carnitine: Obtained from dietary sources (animal sources) and synthesized from l-lysine. Healthy
individuals including vegans can synthesize enough l-carnitine to prevent deficiency. It is produced in
the liver and kidneys and concentrates in tissues that use fatty acids as a fuel source, like muscle and
cardiac muscle. Its role is conjugation of fatty acids for transport into mitochondria for β-oxidation.
Haemodialysis removes l-carnitine and its precursors from circulation and impaired synthesis of l-
carnitine in the kidneys of patients in end-stage renal disease place them at risk for deficiency.
“Routine administration of L-carnitine to people with end-stage renal disease undergoing
hemodialysis is not recommended unless it is to treat carnitine deficiency.” 10.
Supplemental propionyl-l-carnitine shows promise for treatment of intermittent claudication in
peripheral arterial disease.

22
There is evidence that supplemental l-carnitine and acetyl-l-carnitine (separately or in combination)
can increase sperm cell motility, with the most dramatic effects seen in patients with lowest sperm
cell motility. L-carnitine is concentrated in the epididymis, where sperm cells mature and acquire
their motility.
“The roles of L-carnitine supplementation as an adjunct to standard medical therapy in myocardial
infarction, heart failure, angina pectoris, Alzheimer's disease, and HIV infection require further
research.”10. Studies in rats suggest supplemental acetyl-l-carnitine may be beneficial in preventing
age-related declines in metabolism and memory. Acetyl-l-carnitine in combination with alpha-lipoic
acid improved mitochondrial energy production and anti-oxidant protection of mitochondria in rats.
It is not known if it can have the same effects in humans.
There is little evidence that supplemental l-carnitine can improve athletic performance.
“If you choose to take carnitine supplements, the Linus Pauling Institute recommends acetyl-l-
carnitine at a daily dose of 500 to 1,000 mg.” 10.
L-carnitine has been shown to raise TMAO (as do meat and fish.) TMAO is likely pro-inflammatory
and atherogenic (formative role in atherosclerosis). 30.

Coenzyme Q10: A fat-soluble compound (ubiquinone – oxidised state and ubiquinol – the reduced
form) which can be made endogenously and obtained from dietary sources. It plays a central role in
mitochondrial oxidative phosphorylation and production of ATP. It also functions as an anti-oxidant
in lipid membranes and lipoproteins.
Levels of coenzyme Q10 in tissues decline with age.
There is some evidence to suggest that coenzyme Q10 supplementation may be a useful adjunct to
conventional medical therapy for congestive heart failure and in patients undergoing coronary artery
bypass graft surgery.
There are currently no proven therapeutic benefits of coenzyme Q10 supplementation in diabetes
mellitus, neurodegenerative diseases, inherited ataxias, or breast cancer.
Coenzyme Q10 supplementation does not appear to improve athletic performance.
Coenzyme Q10 supplementation is generally safe but may decrease efficacy of warfarin treatment.
Supplementation has been shown to be safe at up to 1 200 mg/day. During pregnancy (from 20
weeks gestation) supplementation with two 100 mg doses per day was found to be safe.
“Because reliable data in lactating women are not available, supplementation should be avoided
during breast-feeding”10.
The use of cholesterol-lowering medications called statins can decrease circulating coenzyme Q10
concentrations. However, there is no evidence that this causes any adverse side effects in statin-
treated patients.10.

Ubiquinol as an anti-oxidant: https://youtu.be/um2XJZCRF1g

Alpha lipoic acid: Also known as thioctic acid, it is produced endogenously and obtained from the
diet. Levels in dietary sources are low and bound to protein, thus not bio-available. It is a cofactor for
several important mitochondrial multi-enzyme complexes that catalyse reactions related to the
breakdown of amino acids and energy production (cofactor in conversion of pyruvate to acetyl-
coenzyme A). It can scavenge reactive oxygen free radicals and nitrogen free radicals in vitro. In vivo
anti-oxidant activity is unknown. Tissue concentrations achieved from oral supplementation are low,
and lipoic acid is rapidly eliminated from cells. It may play a role in the regeneration of other anti-

23
oxidants by acting as a reducing agent for them. “Both lipoic acid and dihydrolipoic acid have been
found to inhibit copper- and iron-mediated oxidative damage in the test tube and to inhibit excess
iron and copper accumulation in animal models. Lipoic acid may also be helpful as an adjunct
treatment against heavy metal toxicity. No clinical trial has examined the use of lipoic acid as a
chelating agent in mercury toxicity, yet it has proven to be effective in several mammalian
species.”10.
Lipoic acid has been found to increase glutathione levels in cultured cells and supplemental lipoic
acid has increased glutathione levels in aged rats.
Lipoic acid may improve cellular uptake of glucose and modulate activity of various cell signalling
molecules and transcription factors.
“Available evidence suggests that treatment with intravenous or oral lipoic acid may help reduce
symptoms of diabetic peripheral neuropathy. It is important to note that many of the studies
examining the efficacy of lipoic acid for the treatment of diabetic neuropathy have been conducted
by one German research group and funded by the manufacturer of lipoic acid in Germany.” 10.
A clinical trial to assess impact of supplemental lipoic acid on loss of mobility and changes in brain
volume in patients with multiple sclerosis is currently underway.
Supplemental lipoic acid may show benefits in weight control in patients with high body-mass index.

“Lipoic acid occurs naturally in food covalently bound to protein, whereas supplements contain
unbound (free) lipoic acid. If you choose to use supplements, the Linus Pauling Institute
recommends a daily dose of 200 to 400 mg/day for generally healthy people.” 10.
Synthetic lipoic acid exists as a racemic mix of the R- and S-enantiomers. Studies have shown that S-
LA has lower biological activity than R-LA, and interferes with the actions of R-LA through
competitive inhibition. There are LA supplements with pure R-LA or a higher R-LA to S-LA ratio, but
they are quite expensive.

Glutathione: A tripeptide which functions as an anti-oxidant and recycles anti-oxidant vitamins C

and E. It is required for the biosynthesis of leukotrienes and prostaglandins (inflammatory
mediators). It facilitates conjugation of drug chemicals in the liver to facilitate their excretion or
further metabolism. (A phase II detoxification enzyme.)

Bioavailability of supplemental glutathione is poor because peptidases break it down in the

alimentary canal and absence of a transporting molecule across cell membranes. Levels may be
increased by increased uptake of its building block amino acids – notably l-cysteine (egg yolks are a
good source) as well as l-glycine. N-acetyl cysteine (NAC) increases glutathione.

Carotenoids: Fat-soluble yellow, orange and red plant pigments. The most common ones are:
α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene.
Only α-carotene, β-carotene, and β-cryptoxanthin can be converted into retinol in the body. They
are known as provitamin A carotenoids.
Dietary lutein and zeaxanthin are selectively taken up into the macula of the eye. They protect it
from damage caused by UV radiation by absorbing up to 90% of the blue light frequencies.
“Observational studies have suggested that diets rich in lutein and zeaxanthin may help slow the
development of age-related macular degeneration (AMD). Randomized controlled trials found that

24
lutein and zeaxanthin supplements could improve visual acuity and slow the progression to
advanced AMD in subjects with AMD.”10.
“Evidence is lacking to suggest a role for lutein and zeaxanthin in the management of other eye
conditions, including cataracts, diabetic retinopathy, and retinopathy of maturity.” 10.
The best sources for lutein and zeaxanthin are leafy green vegetables and other green and yellow
vegetables. Cooked kale and spinach are good sources. The best animal source is egg yolks.

High doses of supplemental β-carotene have not been able to reduce incidence of cardiovascular
disease or cancer in large randomized controlled trials.
Two randomized controlled trials found that high-dose β-carotene supplements increased the risk of
lung cancer in smokers and former asbestos workers.
“Although the reasons for the increase in lung cancer risk are not yet clear and several mechanisms
have been proposed. The US Preventive Services Task Force estimated that the risks of high-dose β-
carotene supplementation outweigh any potential benefits for cancer prevention and recommended
against supplementation, especially in smokers or other high-risk populations.” 10.

Recent meta-analyses of observational studies showed an inverse relation between lycopene intake
and incidence of prostate cancer. To date, most small scale intervention studies found little to no
benefit of lycopene supplements decreasing the incidence or severity of prostate cancer in high risk
patients.

Creatine monohydrate: Creatine is a tripeptide obtained from meat and produced endogenously.
Supplementation improves muscle mass and strength in people over fifty when combined with
resistance training.
It increases muscle mass in the following ways: Upregulation of proteins involved in osmolarity
(swelling of muscle cells) and myogenesis-pathway factors (muscle development and repair.) 31.
Supplementation in combination with resistance training can therefore slow down sarcopenia – age-
related decrease in muscle mass and strength, which is also associated with reduced bone mass and
low-grade inflammation. Studies on the ability of creatine supplementation to increase bone density
have shown mixed results.
Phosphocreatine regenerates ATP in muscle tissue to supply short bursts of energy.

Supplementation with 5 grams per day in frail elderly subjects did not adversely affect liver and
kidney functions during the study.31.
“Future research should objectively examine the safety and long-term effects of creatine
supplementation on properties of muscle, bone and inflammation in various aging and disease-state
populations.”31.

Hydrolyzed collagen supplements: Hydrolysed collagen is basically gelatine broken into smaller
peptides with hydrochloric acid or caustic soda or enzymatically. At least some of the l-proline in
those peptides is hydroxyproline. But they contain l-proline as well. (During collagen production in
fibroblasts and chondrocytes, l-proline is built into new collagen, not the hydroxylated form. It is
only converted to hydroxyproline after the initial chains have been made. The same goes for l-
lysine.) However, the formed tropocollagen units are then linked up in the interstitial tissue (lysyl
oxidase), and I think this is where the ingested supplemental peptides can be useful and actually add

25
to existing collagen. Some studies have shown that absorbed peptides can end up in tissues like
bone.26. Studies that showed improvements in test subjects used more than 10 grams of hydrolysate
per day.

Hyaluronic acid: Looks promising but still too early to be sure. It is a key component of connective
tissue which is why there are many HA skin serums on the market. Safety is still being investigated.

Aspirin: Regular aspirin use has been shown to be able to slightly reduce incidence of ischaemic
heart disease and ischaemic stroke due to its anti-platelet effects. Aspirin use can lower the risk for
colorectal cancer in high risk groups as was shown in a small study of people with Lynch syndrome –
an inherited disorder which places them at increased risk for colorectal cancer. 25. However, potential
benefits need to be weighed against the high risk of gastric bleeding of regular aspirin usage,
especially in elderly people (over 70) and people at high risk for bleeding.
2021 Update: Aspirin may cause more problems than it solves in older people:
Aspirin and Cancer in Older People - National Cancer Institute

D-ribose: A 5-carbon sugar produced naturally and available as a supplement. Supplemental D-

ribose may relieve symptoms of fibromyalgia, chronic fatigue syndrome and congestive heart
failure.33, 34. It may increase ATP production in ischaemic tissue. 35, 36. It is included as part of a
preservative for platelets in blood transfusion. 37.
I think it may worsen gout through increased 5’-phosphoribosyl-1-pyrophosphate (PRPP) production
and probably not do much else in healthy tissue. It has a hypoglycaemic effect and should not be
used in combination with diabetes medicine (See WebMD.) 34.

Taurine: An amino acid-like sulfonic acid obtained in small amounts from the diet (mainly meat and
fish) and produced endogenously from cysteine in humans. It is involved in the formation of bile
salts which are necessary for absorption of fat soluble nutrients. It functions as an anti-oxidant in
detoxification of highly reactive hypochlorite and hypobromite. It is necessary for normal skeletal
muscle function, osmotic regulation and regulation of Ca ++-exchange across cell membranes. It may
act as an inhibitory neurotransmitter and neuroprotectant. 42. It is concentrated in heart muscle,
retina, brain and blood platelets. In cats (which cannot make taurine endogenously), taurine-
deficiency can lead to retinal degeneration and eventually blindness.
Supplementation may improve heart function and symptoms in patients with moderate to severe
heart failure.40. Early research shows that taking 1.5-4 grams of taurine daily for up to 3 months
improves liver function in people with hepatitis. 40.

Supplements appear to be safe. Excess taurine is excreted by the kidneys. Evidence regarding safety
of supplementation in pregnancy and breast feeding is limited. It is found naturally in human breast
milk. Taurine is added to infant formulas because premature infants cannot yet produce it and cow’s
milk does not have adequate amounts. It is not certain whether addition of taurine to infant
formulas is really necessary or beneficial.41, 43. Some energy drinks have high amounts of taurine but
come with increased risk for heart arrhythmia due to their high caffeine content.

Beta-alanine: A non-essential amino-acid that has been shown to be able to increase levels of the
dipeptide carnosine in muscle tissue, to a greater extent than carnosine supplements are capable of.

26
Carnosine is found in red meat. It is absent in plant diets. It may attenuate muscle fatigue in some
types of strenuous exercise.44, 45. Some research suggests that carnosine can attenuate glycation of
proteins. Carnosine appears to be able to delay onset of cell senescence in fibroblasts in vitro. 46.
Supplementation with carnosine appears to be safe but can cause side-effects like itchiness, skin
rash, feelings of tiredness and vivid dreams. (WebMD)

Note: All supplements should be kept out of reach of children. Some of them are quite
dangerous when taken in excessive doses.

27
 WHY WE AGE

Some of the theories of why we age as found on Wikipedia:

Theories on ageing: 1. Programmed factors

Methylation of DNA: The genetic code of an individual is carried in their DNA. As computer code is
occurs in combinations of 1’s and 0’s, genetic code occurs as subsets of nucleotides called genes.
The nucleotides (technically nucleosides in this form – not relevant here) in DNA are adenine (A),
guanine (G), cytosine (C) and thymine (T). DNA is a double-stranded molecule, the nucleotides in
each strand being linked via hydrogen bonds to those of the opposite strand. The whole mechanism
by which the code gets transcribed (read) to be translated into actual proteins, is based on
complimentary binding – that means that A and T always link up and G and C always link up. So the
two strands of DNA are complementary – the one forms as a mirror of the other. This is also how the
genetic code is transcribed to daughter cells when a cell divides: the two DNA strands unzip, and a
complementary strand is aligned unto each of the unzipped strands through the action of the
enzyme DNA polymerase. The result of the process is two identical copies of double stranded DNA
molecules – one for each daughter cell. When the code is translated into proteins, the two DNA
strands unzip from each other and a strand of messenger RNA (mRNA) forms complimentary to a
DNA strand. mRNA becomes a template for construction of a protein. mRNA is essentially the same
as a DNA strand, except that it exists as a single strand, the nucleotide sugar is ribose instead of
deoxyribose, and thymine is replaced by a different nucleotide, namely uracil. So the RNA chain that
forms on the DNA strand has an A complimentary to each T on the DNA, and a U to complimentary
to each A on the DNA. G still gets a C and C a G. Each sequence of three nucleotides (called a codon)
codes for a specific amino-acid. So a gene consists of a series of codons.
A specific cytosine base can become methylated by the action of one enzyme from a group of DNA
methyltransferases. A methyl group on a C-base prevents G from binding to it. Methylation of Cs in
the introduction sequence to a gene (called the promotor), stops transcription factors from forming
a template of that gene. Therefore it can no longer be expressed. This is important for the
differentiation of different types of cells with different functions. Sometimes a methylated cytosine
undergoes deamination, which changes the molecule into a thymine. Previously the RNA template
would have had a G to complement the C. Now it will have an A instead. This is one way in which a
mutation occurs. The extent of methylated residues in DNA correlates with age in an individual.
Senescent cells: When cells can no longer function due to DNA damage, they undergo apoptosis
(self-destruction). Sometimes such cells do not undergo apoptosis. The accumulation of such cells is
associated with chronic states like kidney failure and diabetes.
Gene variants: A variation of a gene called FOXO3A is found in centenarians worldwide. FOXO3A is a
sirtuin gene. Roles of sirtuins in mammals are: Transcription silencing (de-acetylase enzymes),
mitochondria regulation, insulin-signalling, tumorigenesis, apoptosis, cell proliferation and survival,
tissue regeneration, differentiation, stress response. 17.
Calorific restriction: leads to extended lifespan in some species.
Telomere shortening: Telomeres are sequences at the ends of DNA helices which hold them
together, similar to the plastic caps at the ends of shoe laces. With each cell division they shorten.
The enzyme telomerase opens up these regions for the double helix to unfold, in order to be

28
replicated. Some mice do not have telomerase and possess longer telomeres than humans, yet do
not live very long. A study following a thousand participants over ten years found that a third did not
exhibit shortening of telomeres.
Antagonistic pleiotropy: The theory holds that certain traits are advantageous for early survival and
natural selection, but also cause senescence in later life. I think a good example would be
methylation of DNA which is necessary for normal development and functioning of an organism, but
eventually impairs cell division.
Autoimmunity kills off the organism: However, completely immunodeficient mice living in
pathogen-free laboratories still age.
Regulation of energy homeostasis: In 2011 it was shown that acetylation levels of AMP-activated
protein kinase in yeast cells change with age, and that preventing this change slowed their ageing.
Transforming growth factor-beta: stops formation of subcutaneous fat, causing skin to become
wrinkled and saggy.

Theories on ageing: 2. Damage-related factors

DNA damage: It has been argued that intrinsic causes of DNA damage are the most important
drivers of ageing. Abnormal expression of genes is caused by:
1. Genetic damage: Aberrant structural alterations of DNA.
2. Mutations: Changes in DNA sequence.
3. Epimutations: Methylation of gene promotor regions and structural changes to supporting
histones, which makes binding sites inaccessible for binding of polymerases.
DNA damage cause cells to stop dividing or apoptose, affecting large reserves of stem cells.
Genetic instability: Dogs annually lose approximately 3.3% of the DNA in their heart muscle cells.
Humans annually lose 0.6% of the DNA in their heart muscle cells. The ratio is consistent with the
ratio between the maximum lifespan of dogs to humans (more or less 1:6). Similar comparative
ratios hold for DNA loss from lymphocytes and brain cells.
Accumulation of metabolic waste: A build-up of waste products in a cell presumably interferes with
its metabolism. An example is lipofuscin which is formed by a complex reaction that binds fat to
proteins. Granules increase in size with ageing.
Ageing yeast cells over-accumulate some proteins.
Upregulation of autophagy (a process whereby cells get rid of waste) can enhance clearance of toxic
intracellular waste associated with neurodegenerative diseases, and has been demonstrated to
enhance lifespans of yeasts, worms and primates. Autophagy was upregulated in obese mice placed
on caloric restriction, exercise and a low fat diet. It was not however by the expected AMP-activated
protein kinase pathway.
Wear and tear theory: Damage that accumulate with time.
Accumulation of errors in DNA: Errors due to mismatching and damage are missed by proofreading
and correction mechanisms, and accumulate in the genetic code.
[Incidence of several cancers increases dramatically with ageing. The 50-74 age-group has 50% of all
cancers in the UK, while the 75+ age-group has 36% of all cancers diagnosed in the UK. The cancer
incidence in the latter group is much higher though, and the lower 36% value is due to the smaller
size of the 75+ population group. The major cancers in both groups are: Males: prostate, lung and
bowel cancer. Females: breast, lung and bowel cancer. The information was from 2011. 20.]
Cross-linkage: Cross-linkage affects the functioning of molecules (as I discussed in the first chapter.)

29
Mutations in mDNA: Mutations in mitochondrial DNA leads to defective mitochondrial respiration.
Free radical theory: Damage caused by highly reactive metabolites, notably free radical oxygen
molecules like superoxide and the hydroxyl radical.
DNA oxidation: Caloric reduction reduces formation of oxidised DNA in rats and may be the reason
for extended lifespan associated with caloric restriction.

Male-pattern baldness and ageing stem cells: Male baldness with ageing was first associated with a
single X-linked gene, thus an inherited trait from maternal side; as well as hormonal changes
(Influence of dihydrotestosterone – a metabolite of testosterone formed by 5α-reductase, which is
also implicated in benign prostatic enlargement and prostate cancer.) Since then more genes have
been found that are associated with the phenomenon.
A 2011 study found that as we age, stem cells in the scalp lose their ability to differentiate into hair
follicle cells.18, 19.

Dental health and heart disease: Gum disease (periodontitis) is associated with increased risk for
heart disease.38. It increases the risk of streptococci entering the blood stream and depositing inside
atherosclerotic plaques and heart valves, creating areas of chronic inflammation.

Epigenetics: https://youtu.be/kp1bZEUgqVI

More information on gene silencing: https://youtu.be/t5jroSCBBwk

Dr David Sinclair: https://youtu.be/IEz1P4i1P7s

UPDATE: Resveratrol – faulty research: https://youtu.be/JAFnD27ffqE

How enzymes work: https://youtu.be/yk14dOOvwMk

Sleep and health: https://youtu.be/pLROS6DT8Yo

Risk calculator: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate

Calorie calculator: https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/calorie-

calculator/itt-20402304

L-tryptophan scare: https://youtu.be/y3LlDJPGEK4

30
 FOOD NOTES

MSG: Monosodium glutamate has been implicated in so-called Chinese restaurant syndrome
(headaches and other symptoms after eating Chinese food) and food allergies. Several studies have
failed to show any real negative health effects. A 1995 report from the Federation of American
Societies for Experimental Biology for the US Food and Drug Administration (FDA) concluded that
MSG is safe when "eaten at customary levels". 21.
Food Standards Australia New Zealand (FSANZ) MSG technical report concludes, "There is no
convincing evidence that MSG is a significant factor in causing systemic reactions resulting in severe
illness or mortality. The studies conducted to date on Chinese restaurant syndrome (CRS) have
largely failed to demonstrate a causal association with MSG. Symptoms resembling those of CRS may
be provoked in a clinical setting in small numbers of individuals by the administration of large doses
of MSG without food. However, such effects are neither persistent nor serious and are likely to be
attenuated when MSG is consumed with food. In terms of more serious adverse effects such as the
triggering of bronchospasm in asthmatic individuals, the evidence does not indicate that MSG is a
significant trigger factor."21.
The umami flavour that MSG brings to food enhances savoury notes. This means that less salt is
required to enhance flavour. The sodium content of MSG is only a third of that of table salt.
Glutamate is important as a neurotransmitter involved in cognitive functions like learning and
memory, precursor to GABA and constituent of many proteins. The body can produce its own
glutamate, so it is not an essential dietary amino acid.

Red wine and resveratrol: The alcohol and polyphenol flavonoids in red wine may help to protect
against cardiovascular disease, when consumed in moderation. 22.
Polyphenols in red wine, particularly resveratrol, can function as anti-oxidants. It may protect the
endothelial cells lining blood vessels, reduce low density lipoprotein (LDL – the “bad cholesterol”)
and prevent blood clots. Studies on resveratrol are mixed with some showing no benefits.
“More research is needed to determine if resveratrol lowers the risk of inflammation and blood
clotting.”22.
Red wine contains more resveratrol than white wine because most resveratrol is found in grape
skins, which are fermented for longer with red wine than with white. Red and purple grape juices
may have similar health benefits. Resveratrol is also found in varying amounts in peanuts,
blueberries and cranberries. Resveratrol supplements appear to be safe but absorption is poor.
Alcohol: Moderate amounts of alcohol may improve HDL (“good cholesterol”) and protect blood
vessel linings against damage caused by high levels of LDL. It may also help decrease formation of
blood clots and improve endothelial function. 22.
The negative aspects of alcohol consumption are well known.

Green tea: A 2010 trial of a concentrated extract of the polyphenol epigallocatechin gallate (EGCG)
on patients with chronic lymphocytic leukaemia showed a drop in leukemic cell count and reduction
in size of lymph nodes in some of the participants. 23.

31
“Although only a comparative phase III trial can determine whether EGCG can delay progression of
CLL, the benefits we have seen in most CLL patients who use the chemical suggest that it has modest
clinical activity and may be useful for stabilizing this form of leukemia, potentially slowing it down,”
says Tait Shanafelt, M.D., a Mayo Clinic hematologist and lead author of the study. 23.
A systematic review of toxicological evidence from studies with green tea extracts showed that
concentrated extracts can cause liver injury. No harmful effects were seen with consumption of
green tea beverages.24.

Cruciferous vegetables: Isothiocyanates (like sulphorophane), Indole-3-carbinol (I3C) and its

metabolite 3,3'-diindolylmethane (DIM) have been extensively investigated for their potential role in
suppression of tumours. I3C, DIM and isothiocyanates appear to be able to modulate the expression
and activity of phase II detoxification enzymes responsible for clearing of exogenous chemical
substances (drugs, toxins, carcinogens) and hormonal metabolites. 10.
“Although high intakes of cruciferous vegetables have been associated with a lower risk for cancer,
there is insufficient evidence that exposure to isothiocyanates through cruciferous vegetable
consumption decreases cancer risk.”10.
“Some experts have cautioned against the widespread use of I3C and DIM supplements for cancer
prevention in humans until their potential risks and benefits are better understood.” 10.

Dr Rhonda Patrick on health benefits of broccoli sprouts: https://youtu.be/0UqxC2RDF64

Turmeric: The active polyphenols in turmeric are called curcuminoids. Curcumin is poorly absorbed.
It appears to have anti-inflammatory properties. Limited evidence points to possible anti-cancer
activity. Trials to access safety and efficacy as an adjunct to treatment of several cancers are
underway.10.
More information:
https://youtu.be/FtwDSU6caH8

Omega-6 to Omega-3 PUFA ratio: The Western diet has a ratio of around 15:1 for omega-6
polyunsaturated fatty acid vs. omega-3 polyunsaturated fatty acid intake. This ratio contributes to
the high incidence of heart disease and other chronic diseases associated with the Western diet, in
contrast to the traditional Mediterranean diet. Cooking oils are the major source of omega-6. An
ideal ratio would be around 4:1 for omega-6 to -3.
EPA and DHA are the most important omega-3 fatty acids. The best way to obtain them is through
krill oil supplements. Flaxseed oil contains the omega-3 fatty acid, alpha-linolenic acid (not to be
confused with the omega-6 fatty acid, alpha-linoleic acid.) Alpha linolenic acid needs to be converted
to EPA and DHA in the body. The conversion process is not very efficient. Alpha linolenic acid
becomes rancid fairly quickly due to oxidation (oxygen attacks the unsaturated carbon-carbon
double bonds to form toxic aldehydes, ketones and carboxylic acids) and forms toxic polymers when
heated. Omega-9 monounsaturated fatty acid-oils (canola and olive oil) are considered a healthier
substitute for omega-6 cooking oils. They can be heated, but not repeatedly.

Diet soda: The landmark Nurses' Health Study found a correlation between heavy consumption of
diet sodas and weakened kidney function, even after factors like obesity and blood pressure had
been accounted for.50.

32
Diet sodas had mostly been sweetened by aspartame and acelfame-K by the time of the study.

The picture below shows a fatty plug that was flushed from a vein harvested for grafting in a patient,
suffering from familial hypercholesterolemia, during his bypass surgery. Photo: W. Kühn.

33
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“I’m running out of time to live, running out of love to give, running out of life within, God help me.”
Rebecca St. James.

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