Data Ebook Antiage Ebook v1 2621 en

NEW ADVANCES IN
ANTI-AGING NUTRITIONAL
SUPPLEMENTATION
WHAT IF AGING WERE NOT INEVITABLE?
CHARLES FEELGOOD
LINUS FREEMAN
ANGLIQUE HOULBERT
REVISED EXPANDED - UPDATED

NEW ADVANCES IN ANTI-AGING NUTRITIONAL
SUPPLEMENTATION
CONTENTS
THE ENGINEERING METHOD . . . . . . . . . . . . . . . . . . 7

The 7 deadly things . . . . . . . . . . . . . . . . . . . . . . . .9
Buying time . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1000 year life expectancy? . . . . . . . . . . . . . . . . . . . . 11
What can we do now? . . . . . . . . . . . . . . . . . . . . . . . 14
TELOMERASE ACTIVATORS . . . . . . . . . . . . . . . . . .16
What are telomeres? . . . . . . . . . . . . . . . . . . . . . . . . 16
What is telomerase . . . . . . . . . . . . . . . . . . . . . . . . 17
Recreating telomerase activity . . . . . . . . . . . . . . . . . 18
Is telomerase carcinogenic? . . . . . . . . . . . . . . . . . . . 19
Which substances activate telomerase? . . . . . . . . . . . 21
Astragaloside IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Cycloastragenol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Other nutrients involved in maintaining telomeres . . . . 30
Magnesium ascorbyl-phosphate . . . . . . . . . . . . . . . . . . . . . . . . 30
L-carnosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2 New advances in anti-aging nutritional supplementation

Extract of Terminalia chebula . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Extract of green tea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Extract of palm oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Extract of purslane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Marine omega-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
MITOCHONDRIAL BIOGENESIS . . . . . . . . . . . . . . . .34
What are mitochondria? . . . . . . . . . . . . . . . . . . . . . 34
How can we optimise mitochondrial function? . . . . . . . . . . . . . . . 34
Is it possible to boost mitochondrial biogenesis? . . . . . . . . . . . . . . 35
Codename PQQ . . . . . . . . . . . . . . . . . . . . . . . . . 35
PQQ activates certain genes . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Multiple applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Optimal mitochondrial defence against oxidative stress . . . . . . . . . 36
Neuroprotection and improved cognitive function . . . . . . . . . . . . 37
Cardioprotection and improved energy levels . . . . . . . . . . . . . . . 38
Combining PQQ with synergistic nutrients . . . . . . . . . . . . . . . . . . 38
CALORIE RESTRICTION MIMETICS . . . . . . . . . . . . . .43
A key development in longevity research . . . . . . . . . . . . . . . . . . 44
Expression of longevity genes activated by calorie restriction . . . . . 45
Benefits to human health of calorie restriction . . . . . . . . . . . . . . . 46
Research into alternatives to calorie restriction . . . . . . . . . . . . . . . 46
Resveratrol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
The reason behind the paradox! . . . . . . . . . . . . . . . . . . . . . . . 47
Multi-faceted activity for optimal cardio-protection . . . . . . . . . . . . 50
Oustanding anti-cancer weapon . . . . . . . . . . . . . . . . . . . . . . . . 51
Significant neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Last, but not least, powerful anti-ageing properties . . . . . . . . . . . . 54
How can we boost the effects of resveratrol? . . . . . . . . 56
Pterostilbene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Quercetin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Fisetin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Polydatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Polyphenols from pine bark extract . . . . . . . . . . . . . . . . . . . . . . 57
Niacinamide, a first-generation tool in genetic anti-aging therapy . . . 58

Oxaloacetate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
What is oxaloacetic acid? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
How does a lack of oxaloacetate affect metabolism? . . . . . . . . . . . 59
What are the benefits of oxaloacete supplementation? . . . . . . . . . . 60
Oxaloacetate mimics and reproduces the effects of calorie restriction 61
Also an anti-diabetic substance . . . . . . . . . . . . . . . . . . . . . . . . . 63
Generalized protection against cancer . . . . . . . . . . . . . . . . . . . . 64
To recap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
A closer look at thecimportance of the NAD+/NADH . . . . . . . . . . . 65
Berberine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Un activateur de lAMPK qui peut remplacer la metformine . . . . . . . 67
STEM CELL ACTIVATORS . . . . . . . . . . . . . . . . . . . .71
Stem cell pioneers receive Nobel prize . . . . . . . . . . . . . . . . . . . . 73
Fucoidan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Astragaloside IV . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Polygonum multiflorum . . . . . . . . . . . . . . . . . . . . . . 76
Extract of wild blueberry . . . . . . . . . . . . . . . . . . . . . 77
Beta 1.3/1.6 glucan . . . . . . . . . . . . . . . . . . . . . . . . 77
L-carnosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Vitamin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Vitamin D3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
The immortality gene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
OTHER PROMISING SUBSTANCES . . . . . . . . . . . . . .81
Saikosaponin A . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Centrophenoxine . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Apple polyphenols . . . . . . . . . . . . . . . . . . . . . . . . . 89
Epimedium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
L-theanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Reishi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Selegiline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
IN CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . 97
Bibliography and resources . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

NEW ADVANCES IN ANTI-AGING
NUTRITIONAL SUPPLEMENTATION
Since the beginning of time, man has sought to extend his lifespan and pro-
long the energy of youth. Various religions and alchemists have taken up
the mantle, offering the promise of eternal life. But today, it is science-led
anti-ageing nutrition and medicine that is signaling an optimistic future for
human life expectancy. Not so long ago, doctors believed that the principal
factors governing ageing were chronic stomach poisoning and degeneration
of the immune system.
But preventive nutrition and anti-ageing medicine have moved far beyond these common, sim-
plistic explanations, and are beginning to open the door to the real and foreseeable possibility
of longevity way beyond what is currently considered feasible. For now, of course, it remains
just a possibility there are many hurdles to be overcome But certain studies are showing
considerable promise, such as the work of English bio-gerontologist Aubrey de Grey, whose
anti-aging strategy sets him apart from his peers
Until de Grey, only two schools of thought really existed on how to delay ageing:
1 The first consists of slowing down the process whereby damage linked to the bodys
degeneration causes disease, and delaying the point at which disease becomes serious
and ultimately fatal. However, by definition, this is a very short-term strategy since
damage is accumulating all the time and it becomes increasingly difficult to combat
such cumulative damage - especially since that fatal threshold is reached all too soon.

2 The second approach focuses on delaying the process through which metabolism
causes damage. This essentially involves a cleansing of the metabolism, and can mar-
ginally delay the age at which disease develops. But of course, it can only postpone
aging and any damage already sustained before treatment is initiated continues to
accumulate and develop. For this approach to be truly effective, it also requires a much
more sophisticated scientific understanding of metabolism than we currently enjoy,
particularly if we want to prevent exposure to potentially harmful side-effects.
Such limitations have led Aubrey de Grey to adopt a third strategy which he terms
engineering.
Dr Aubrey de Grey
Biogerontologist

THE ENGINEERING METHOD
Originally a computer science specialist, de Grey has taken an approach more akin to that of an
engineer than a doctor. Even if he considers aging to be a disease, and a fatal one at that, his aim
is to repair rather than cure.
According to de Grey, the reason it is so difficult to medically treat aging is because the process
of metabolism is exceptionally complex and our current level of knowledge, including at a cel-
lular level, is simply not sophisticated enough. As a consequence, age-related diseases are not
yet adequately controlled, and for now at least, standard approaches to anti-aging treatments
are not very promising. That is why de Grey is focusing on neither metabolism nor pathology,
but on the damage that links the two.
What do we mean by damage?

Damage is the result of metabolism-induced chemical reactions. It appears and accumulates
continually, even before we are born, but results in disease only when we are near the end of
life. For example, a 40 year old man can still run and think more or less as he did at 20, but his
life expectancy is considerably shorter because of damage that has accumulated: in a few years,
he will start to see the consequences of such damage. It is this knowledge that forms the basis
of the engineering method.
What are the principles of this method?

It focuses not on influencing metabolism or disease, but on the damage which links these two
processes. By concentrating on repairing the damage that accumulates throughout life, Aubrey
de Grey believes it is possible to maintain it below the point at which it becomes pathogenic.

Of course, this would be easier if the damage didnt need to be completely repaired in order to
achieve the desired outcome that is, if partial repair were enough to prolong life until scientific
progress allows more complete repair. Obviously, the engineering method is conceptually quite
different from the other two approaches. Nevertheless, its originator who is not short of critics
who think him somewhat eccentric maintains his approach is actually much more feasible
than the other two.
Why is this method likely to be effective?

1 Because it intervenes early enough to have an effect before deterioration has
taken hold.
2 Because it does not involve metabolism, our current understanding of which is still
relatively poor.
3 Because, as it specifically does not affect metabolism, it significantly reduces the
potential side-effects of treatment.

The 7 deadly things
n a sense, the engineering method offers anti-aging science a way of bypassing current igno-
rance. Indeed, its sole objective is to enable those who want to, to live long enough to benefit
from the advances science will achieve in a few decades time.
Perhaps its greatest advantage, however, is that without being overly simple, it is the least com-
plex approach. It condenses the question of damage repair into 7 deadly factors.
These are the seven types of damage accumulated over a lifetime which contribute to
aging and eventually become pathogenic.
What are the seven types of damage?
1 Carcinogenic nuclear and epigenetic mutations: these are cancer-causing changes to

nuclear DNA and the proteins which bind to the DNA.
2 Mitochondrial mutations: these are mutations to mitochondrial DNA (mitochondria are
the cells energy centres) which impair the cells ability to function.
3 Intracellular aggregates: these are the waste products of various molecules, particu-
larly proteins, which cannot be eliminated and clog up our cells. They are associated with
atherosclerosis and neurodegenerative diseases such as Alzheimers.
4 Extracellular aggregates: these are similar to the waste products above but accumulate
between the cells.
5 Cell loss: when cells have exhausted their ability to self-replicate (the Hayflick limit),
they die and are irreplaceable. This weakens the bodys organs, particularly the heart,
as well as the immune system, and leads to a number of diseases including Parkinsons
disease.
6 Cell senescence: this is where cells are no longer able to divide but do not die either.
They become dangerously dysfunctional, secreting harmful substances, leading in parti-
cular to diabetes.
7 Extracellular crosslinks: these are cross-link proteins which in excess, can make tissue
rigid and cause a number of problems including eye health disorders.

Aubrey de Grey believes that specifically targeting these seven types of deadly damage with
cell therapy, immunity boosters, enzymes such as telomerase, etc, offers a greater possibility of
significantly extending life expectancy than the metabolism or pathology approach, neither of
which are currently wholly understood and which could have infinite permutations!
Buying time
Thus Aubrey de Grey believes not in biological immortality but in bio-technological immorta-
lity taking an engineers approach, and applying a strategy of extensive repair to prevent the
accumulation of damage. Holding back aging in this way would seem possible insofar as it is a
much less complex approach than trying to reverse aging once it has appeared like trying to
keep a boat from sinking once its sprung a leak.
Furthermore, even incomplete repair might be enough to achieve the desired result which
would not be the case with incomplete reversal of aging.
Improvements can thus afford to be modest since it is only a question of prolonging life until
such time as it is possible to truly extend life for longer. Betting on the future in this way may
seem unwise to some but since aging inevitably blights everyones future, why not at least try
it? After all, scientific and technical advances are being made all the time in most technologies.
Aubrey de Grey cites the example of aviation which took centuries to evolve, but once func-
tionality was achieved, progress accelerated rapidly over the last century. The same sort of
chronology applied to IT and infection control amongst many others. So its not unreasonable
to believe that, once treatments capable of extending life expectancy by 30 or 50 years have
been developed for people in their fifties, this same population will be able to benefit, in 30 or
50years time, from more effective repair techniques which are likely to further extend lifespan
by 50 years, etc. This is the philosophy behind the engineering method.

Aubrey de Greys view
If youre already 100 years old, we wont be able to give you back 30 or 50 years of extra life because you will
already be too weak to withstand treatment which is experimental rather than proven. If youre 80, we wont
be able to do much for you. But if youre 50, it will be rather like jumping off a cliff with a jet-pack on your back
a jetpack that you turn on halfway through your fall. This metaphorical jetpack will slow your descent and
with a bit of luck, youll avoid a nasty crash at the bottom - instead of falling to the ground, youll start to climb
again. In other words, youll begin to rejuvenate biologically and be less prone to age-related diseases. And if
youre aged 30 when you start treatment, you wont even get near the ground
1000 year life expectancy?

But when is all this likely to become a reality? Well, Aubrey de Grey can only talk in terms of
hopes rather than certainties but he believes that the first person to reach 150 years old is pro-
bably already alive now, and in their fifties. And the first person to reach 1000 years old is pro-
bably only 10 years younger than that - though he does admit that this is extremely speculative.
Perhaps the first 150 year-old has not yet been born it really depends on whether luck, or
funding for the necessary scientific research, proves forthcoming.
De Grey says quite seriously that he will need an investment of 100 million dollars a year for
around 10 years to achieve rejuvenation in mice and its no secret that he has already succee-
ded in attracting significant funding.
Such rejuvenation would consist of taking a healthy strain of mice, allowing them to live to the
age of 3 with no special diet or medication, and then applying the engineering method, in order
to treble what would normally be their remaining one year of life, taking their life expectancy
to 6 years. With regard to humans, theres a 50% chance of similarly doubling life expectancy in
a 50 year-old, and it is envisaged this could be achieved 15 years after it is successfully realised
in mice.
He concedes that if luck is not in their favour, it could obviously take more than 100 years, but
there is a 50/50 chance it might be achieved in just 15 years!

So who is Aubrey de Grey?
Dr Aubrey de Grey works in the department of genetics at Britains Cambridge University. The focus
of his work in biogerontology, the study of the bodys aging process, is the development of a genuine
treatment for aging. He has developed a potential repair programme, called Strategies for Engineered
Negligible Senescence (SENS), which divides the problems of aging into seven key types of damage
and identifies detailed approaches for treating each of them. One of the principal aspects of the SENS
approach is its focus on indefinite life extension through maintaining good health, even with imperfect
repair processes; repair only needs to be sufficiently effective to maintain damage below pathogenic
levels. Dr Grey calls this Longevity escape velocity these ideas are described in detail in his book
Ending Aging, published in 2007.
What methods already exist?

Anti-aging enthusiasts currently have to satisfy themselves with adopting an almost ascetic
lifestyle - avoiding drugs or a harmful lifestyle, taking as much exercise as possible and watching
their diet closely.
Many choose to supplement their diet with scientifically-supported nutrients that have demons-
trable health benefits. Indeed, several aging mechanisms can be significantly slowed down by
taking the right supplements:
These include a top quality* multivitamin, to provide a daily or even several times daily
dose of all the substances essential for a healthy body and for reducing the risk of cancer. Indeed,
a new study 1 has recently confirmed the benefits of a multivitamin in reducing cancer risk. The
multivitamin complex used in the study comprised all the water- and fat-soluble vitamins, the
main minerals and oligo-elements (magnesium, zinc, selenium, iodine, manganese, chromium,
molybdene, boron) as well as two essential carotenoids lycopene and lutein. These nutrients
* Click here for Daily 3

act together to compensate for any gaps in the diet. Corroborating earlier findings, this study
showed that taking a daily multivitamin and mineral complex is the only way of providing the
body on a daily, or several-times-daily, basis with all the elements it needs for optimal func-
tion and is the perfect complement to the diet. Daily multivitamin supplementation thus pro-
vides essential health protection to ensure optimum well-being for the whole family.
1 Regular antioxidant supplementation to prevent the body from rusting.
Click here for Antioxidant Synergy
2 Glycation control, to prevent caramelisation of tissues caused by sugars and high

GI foods.
Click here for Anti-Glycation Formula
3 Control of chronic inflammation which affects most people in old age.
Click here for InflaRelief Formula
4 Last but not least, hormone supplementation to control age-related hormone

decline.
Click here to access our hormone supplements at Super-Nutrition.com
References
J . Michael Gaziano, MD, MPH; Howard D. Sesso, ScD, MPH; William G. Christen, ScD; Vadim Bubes, PhD;
Joanne P. Smith, BA; Jean MacFadyen, BA; Miriam Schvartz, MD; JoAnn E. Manson, MD, DrPH; Robert
J.Glynn, ScD; Julie E. Buring, ScD. Multivitamins in the Prevention of Cancer in Men - The Physicians
Health StudyII Randomized Controlled Trial. JAMA.2012;():1-10. doi:10.1001/jama.2012.14641.

What can we do now?
Classic nutritional supplements can the-

refore help to slow down the aging pro-
cess but unfortunately they cannot stop
it altogether.
While Aubrey de Greys work undoub-
tedly represents a very important
methodological advance, recent years
have seen a scientific tsunami sweep
through the worlds of biology, phar-
macy and nutrition. Alongside de Greys
work, hundreds of articles have been
published that re-examine accepted
wisdom on the relatively limited lifes-
pan of the human species. Very many of
these studies involve applied research:
there are researchers who look and
researchers who find.
The good news is that the arsenal of anti-aging weapons available today is greater than ever
before we already have a number of products, almost all in nutritional supplement form, which
can address this issue. They are available to everyone right now, to help fight the 7 deadly
things identified by Aubrey de Grey and ultimately reverse, not just slow down, the infernal
mechanism which leads first to degeneration, and eventually the grave!
These substances fall into several categories:
1 Telomerase activators
The identification of these substances represents a major breakthrough. Telomerase enables
production and growth of telomeric DNA. Located at the tips of chromosomes, telomeres enable
cells to reproduce, but when they become too short the cells die. With telomerase activators,
however, cells can hopefully surpass the Hayflick limit and continue to reproduce, enabling us
to avoid one of the most seemingly inescapable mechanisms of aging.

2 Generators of new mitochondria
Mitochondria are the cells energy powerhouses. As we age, they become fewer in number and
those that remain lose their efficacy, producing more and more waste products. This leads to
a considerable loss of energy, persistent physical and cognitive problems and accelerated cell
degeneration.
This major deficit in energy is involved in the majority of age-related degenerative diseases.
However, a nutrient has just been discovered that not only helps improve the function of exis-
ting mitochondria, but also increases their numbers - it facilitates their biogenesis by activating
genes which control their reproduction, even within senescent cells.
3 Calorie restriction mimetics

The work of Dr Roy Walford has shown that strict calorie restriction, though not malnutrition, is
the safest and most scientifically-sound way of significantly extending lifespan - by around 20%
in most mammals (and by almost 100% in some less complex species). It has even been suppor-
ted in humans by the findings of the Biosphere experiment in which Walford personally parti-
cipated. Calorie restriction has a positive effect on the majority of the seven types of damage
highlighted by Aubrey de Grey.
By activating certain genes and inhibiting others, calorie restriction significantly slows down
the aging process. However for most of us, it requires too much willpower and is difficult to
keep to long-term. Researchers have thus been investigating substances that mimic the effects
of calorie restriction by influencing longevity genes in the same way. We will explore a number
of these identified and tested substances.
4 Stem cell activators

Research into stem cells is raising significant hopes in the world of medicine and in the fight
against aging and age-related diseases.
Recent studies have shown that certain nutrients and plant extracts can stimulate and increase
natural production of bone marrow stem cells.

TELOMERASE ACTIVATORS
One of the keys to delaying cellular aging, and thus increasing life expec-
tancy, can be found at the very heart of our cells, specifically in the telomeres
that form the tips of our chromosomes. A journey through our cells and
genetic inheritance
What are telomeres?
Found in the nucleus of cells, telomeres are the tips of double-stranded DNA. Their purpose is to
protect the genome from losing data when cell division shortens chromosomes. Unfortunately,
telomeres get progressively shorter, particularly when inflammation or stress is present, so that
by the age of 80, our telomeres will be two to three times shorter than at birth.
Indeed, telomeres shorten with each and every cell division and so their replication is always
incomplete. The greater the frequency of cell division, or the more oxidative stress is present,
the more the telomeres shorten. At a particular point, when the telomere reaches a critical size,
the cell becomes senescent. Until now, this has been an inevitable mechanism of aging.

As many studies have shown, this progressive telomere shortening is closely linked to a number
of age-related diseases (cardiovascular disease, infectious diseases, etc) and is also predictive of
premature death in older individuals.
The telomere can thus be considered an important biological clock, eventually signalling the
onset of aging in the body.
There is, however, an enzyme called telomerase which reverses the process of telomere degra-
dation. Telomerase enables production and growth of telomeres as well as DNA repair.
What is telomerase?
Telomerase is a nucleoprotein enzyme which catalyses the production and growth of telomeric
DNA and stimulates the repair of DNA damage.
Telomerases role begins right at the beginning of embryonic development. It is then, when
the rate of cell division is extremely high, that this enzyme is at its busiest. Consisting of protein
and RNA, telomerase continually repairs the chromosome tip during foetal development, thus
maintaining the telomeres integrity.
However, things start to deteriorate as early as birth! Levels of telomerase begin to fall and
continue decreasing until adulthood. From this point, more telomerase becomes available in
sex cells and stem cells, although it has almost disappeared from somatic cells.
That said, the stem cells activate as much telomerase as is necessary for tissue regeneration, but
this last vestige of activity is clearly not enough to prevent the general decline in telomerase at
the end of life, especially when the body is frequently under stress. Indeed, stress results in an
increased requirement for cell renewal and thus a greater number of cell divisions.
As a result, the turnover in telomeres is much faster and aging becomes apparent much ear-
lier. The increase in telomere shortening when telomerase is deficient has been confirmed by a
number of studies. They have all shown that the immediate consequence of this shortening is a
drastic reduction in cell lifespan.

Thus there is clearly a direct link between low levels of telomerase, loss of telomeres and cell
senescence, and eventually, the aging of tissues and the bodys many consequent dysfunctions.
More specifically, studies have shown that the more telomeres shorten, the higher the risks of
atherosclerosis, hypertension, cardiovascular disease, Alzheimers disease, infections, diabetes,
fibrosis, metabolic syndrome and cancer. Not to mention mortality!
Indeed, in a study conducted on 150 subjects aged over 60, those with the shortest telomeres
were shown to have an 8-fold higher risk of dying from an infectious disease and a 3-fold higher
risk of dying from a heart attack because telomeres that are too short prevent immune cells
from reproducing fast enough to fight potential infections.
Recreating telomerase activity

Even though adult somatic cells no longer produce telomerase, they do still contain its compo-
nents. And it seems forced expression of one of these components, the catalytic subunit (hTRT),
is enough to to reconstitute telomerase activity.
By introducing this hTRT gene into primary human cells, telomeres can be lengthened and
cell growth can be significantly modified.
A study conducted for more than a year on treated vascular, retinal and foreskin cells, showed
that telomerase-producing cells continued to divide while unproductive cells became senes-
cent.
Another study on mice genetically modified to be totally lacking in telomerase showed that
they aged at an accelerated rate, became infertile and developed diabetes, osteoporosis and
neuro-degenerative diseases, and therefore died at a very young age.
Furthermore, reactivating telomerase for one month in another group of the same type of mice
produced astonishing results:
A return to normal fertility;
Recovery of the spleen, liver and kidneys;
Reversal of the effects of aging in the brain.
In these mice, the brains had grown and the neurons had become active again.
This has led many scientists to suggest that any substance that increases telomerase activity
might be able to treat age-related diseases.

Is telomerase carcinogenic?
Given that telomerase lengthens telomeres and makes cells virtually immortal, an obvious
question is what is its effect on cancer cells? Or, worse still, could it turn healthy cells into can-
cer cells? We know that a tumour is a proliferation of cells that have become immortal and
are reproducing very actively. A cancer cell is therefore different from a normal cell because of
its immortality. Because of the potentially catastrophic effects of using telomerase to combat
aging, new studies were carried out, the results of which were published in 1999. Happily, they
provided unequivocal evidence that such concerns were groundless. In a publication 1, Dr Woo-
dring Wright confirms that, the addition of telomerase in human cell culture does not cause cells to
develop into cancer cells. It seems that even when human cells are multiplied many, many times
beyond their life expectancy (more than 200) it does not result in cancer cells.
DrWoodring Wright

Cells treated with telomerase simply retain all their properties and youthful health and are not
affected by any chromosome abnormalities.
A study on mice similarly demonstrated the absence of any malignant tumours, all of which
indicates that cancerization of cells is due to other mutations that have nothing to do with
telomerase. The latter simply enables cells to continue multiplying healthily as they do in the
embryo. Furthermore, according to Dr de Pinho 2, telomerase should, on the contrary, prevent
normal cells from becoming cancerous, in as much as it prevents damage to DNA.
References
1 I nhibition of human telomerase in immortal human cells leads to progressive telomere shorte-
ning and cell death. Herbert B., A.E. Pitts, S. I. Baker, S. E. Hamilton, W. E. Wright, J. W. Shay, D. R. Corey,
Proc. Natl. Acad. Sci. USA, 1999; (96/25): 14276-14281.
2 DePinho R. A. et al. ,Telomerase activation reverses tissue degeneration in aged telomere-deficient
mice. Nature 469, 102-106, January 2010. Published online 28 November 2010.

Which substances activate telomerase?
A number of molecules studied and used in humans for several years have been clearly shown
to stimulate telomerase, increasing their numbers, and lengthening them appreciably. As a
consequence, they are able to reverse certain aging mechanisms by postponing the cell death
thought to be inevitable after a certain number of divisions. These molecules are likely to be just
the first of a growing list over the coming years.
The two most promising come from a plant that has featured in traditional Chinese medicine for
thousands of years: the dried root of astragalus (Astragalus membranaceus). This plant has been
traditionally used as a tonic and stimulant of the immune system:
it increases the number of stem cells in bone marrow and lymphatic tissue and pro-
motes their development into active immune cells;
it switches immune cells from a resting state to an active one;
it produces immunoglobulins;
it stimulates macrophages;
it activates natural killer cells and T-lymphocytes;
it stimulates endogenous interferon production and maximises its effects against
viral infections;
it increases resistance to the immune-suppressive effects of chemotherapy drugs;
and finally, it stimulates production of interleukin-6 and tumour necrosis factor.
The numerous studies conducted on this plant have highlighted its many exceptional pro-
perties; in addition to immune-stimulant benefits, it also has antioxidant, anti-inflammatory,
anti-fibrotic, and neuro-protective properties, as well as cardio-protective properties, due to its
ability to inhibit the formation of oxidised lipids in the myocardium, increase vasodilation, and
reduce blood clotting. It also has beneficial, cardiotonic effects in angina pectoris.

Whats more, no side-effects have been reported to date, either from the various studies, or
from several years use in humans. Most significant though, according to recent studies, is astra-
galus extracts ability to affect telomerase activation in keratinocytes, fibroblasts and immune
cells in culture. To be more precise, researchers noted a significant decrease in the percentage
of short telomeres, rather than an increase in average telomere length. Given the necessity to
prevent telomeres from shortening below the critical point at which cell senescence results, this
is a very promising start!
In addition to the benefits of the whole plant, researchers are particularly interested in its active
compounds to which most of its properties are attributed. A highly complex and costly process
has enabled two active substances to be isolated and concentrated from this plant that have a
similar chemical structure and amazing anti-aging properties:
Astragaloside IV, a glycoside studied extensively in Chinese and European research

centres, and
Cycloastragenol, a saponin comprising a group of oil glycosides.

Astragaloside IV
Among the active compounds of this plant are astragalosides, numbered I to VIII, including
astragaloside IV. This natural substance is present in minute quantities in the root of the astra-
galus plant it is often undetectable in whole plant capsules.
Astragaloside IV, recognised for its immune-stimulant, anti-bacterial and antioxidant proper-
ties, is without doubt one of the most effective anti-aging substances currently available. It is
one of the rare supplements that can activate telomerase, slow down telomere shortening and
even lengthen the shortest telomeres.
It stimulates stem cell proliferation

Mesenchymal stem cells (MSC) are multipotent stromal stem cells that can differentiate into a
variety of cell types 1 including:
osteoblasts (bone cells);
chondrocytes (cartilage cells);
adipocytes (fat cells).
In vitro research has shown astragaloside IV can stimulate MSC proliferation. Given ongoing
research into the use of stem cells for treating a range of diseases, this opens up huge possibili-
ties for a number of therapeutic applications.
It is cardioprotective
Studies conducted on astragaloside IV, show that it can:
reverse endothelial dysfunction caused by hyper-aminoacidaemia (presence of
excessive amino acids in the urine), which is strongly associated with cardiovascu-
lar problems;
considerably reduce the severity of heart attacks (as shown in dogs subjected to
coronary ligature in vivo);
improve post-ischaemic cardiac function and reperfusion arrhythmia in rat hearts
in vitro.
Its also worth noting that the cardio-protection afforded by astragaloside IV was accompanied
by a significant increase in coronary flow both in vivo and in vitro 2.

Astragaloside IV not only increases the endogenous antioxidant activity of superoxide dismu-
tase (SOD) as demonstrated in vivo, but reduces homocysteine-induced endothelial dysfunc-
tion. In addition, pre-treatment with SOD had a similar effect to that of astragaloside IV, ie, a
reduction in homocysteine-induced endothelial dysfunction4.
In a study on rats, hypertrophy of the left ventricle decreased following administration of astra-
galoside IV, as did other measurable factors.
In another animal study, over-activity of the reninangiotensin system in rats with hypertension
and induced cardiac hypertrophy was inhibited by treatment with astragaloside IV.
It prevents breast cancer

Analysis of the effects on breast cancer cell proliferation of various concentrations of injections
of astragalus, astragaloside IV and formononetin showed this substance was effective at inhibi-
ting proliferation of certain breast cancer cells. These effects varied according to the concentra-
tion of active product 7.
It is beneficial in Parkinsons disease

The cell-regenerative mechanism of astragaloside IV may also be beneficial in treating Parkin-
sons disease, which is known to be caused by progressive degeneration of dopamine neurons.
Oxidative stress and degeneration of these brain cells is thus involved in the development of
Parkinsons disease.
Astragalus is traditionally recognised for treating neurodegenerative diseases and for its ability
to protect dopamine neurons in Parkinsons disease.
When researchers examined the in vitro effect of astragaloside IV on 6-hydroxydopamine
(6-OHDA), they noted that - in a dose-dependent manner - it reduced the latters damaging
effects on dopamine neurons.
6-OHDA is a neurotoxic amine, naturally present in urine, which can destroy dopamine and
noradrenergic neurons. It is often used in laboratory tests to induce Parkinsonism in animals in
order to trial anti-Parkinsons drugs.
The neuro-protective effects of astragaloside IV, specifically on dopamine neurons, suggest it
has real therapeutic potential for the treatment of Parkinsons disease8.

In brief, astragaloside IV has the following properties:
Immunostimulant
Generates more active immune cells, immunoglobulin and macro-
phages;
Activates T lymphocytes and natural killer cells;
Increases production of T and B lymphocytes, and antibodies 3;
Increases stem cells in the spinal cord and encourages their develop-
ment into active immune cells.
Anti-inflammatory
Reduces inflammation of the airways in chronic asthma.
Anti-bacterial
Acts, in vitro, against Shigella dysenteriae, Streptococcus haemolyticus,
Diplococcus pneumoniae and Staphylococcus aureus.
Anti-viral
Inhibits replication of certain viruses;
Produces interferon and maximises its effect against viral infections.
Antioxidant
In vitro, inhibits 40% of lipid peroxidation.
Cardioprotective
Has beneficial effects on congestive heart failure and angina pectoris;
Aids recovery following cardiovascular problems.
Neuroprotective
Improves treatment of neurodegenerative diseases;
Protects dopamine neurons from the degeneration which causes Par-
kinsons disease;
Protects against the toxic effects of chemotherapy.
Antiglycation
Prevents the neuropathic complications of diabetes.
Click here for a certified astragaloside IV formulation

References
1 S evimli-Gr C., Onbalar I., Atilla P., Gen R., Cakar N., Delilolu-Grhan I., Bedir E. In vitro growth
stimulatory and in vivo wound healing studies on cycloartanetype saponins of Astragalus genus.
J. Ethnopharmacol. 2011 Apr 12;134(3):844-50.
2 W ei-Dong Zhang, Hong Chen, Chuan Zhang, Run-Hui Liu, Hui-Liang Li, Hong-Zhuan Chen. Astragaloside
IV from Astragalus membranaceus Shows Cardioprotection during Myocardial Ischemia in vivo
and in vitro. Planta Med 2006; 72(1): 4-8.
3 Wang YP, Li XY, Song CQ, Hu ZB. Effect of astragaloside IV on T, B lymphocyte proliferation and peri-
toneal macrophage function in mice. Acta Pharmacol. Sin. 2002 Mar;23(3):263-6.
4 Q iu LH, Xie XJ, Zhang BQ. Astragaloside IV improves homocysteine-induced acute phase endothe-
lial dysfunction via antioxidation. Biol. Pharm. Bull. 2010; 33 (4): 641-6.
5 Tan Y. F., Yin X. C., Xiong Y. J., Wang Y. (Stem cell factor secretion by bone mesenchymal stem cells
stimulated with astragaloside IV). Zhongguo Dang Dai Er Ke Za Zhi. 2010 Apr;12(4):290-2.
6 S hi H., Ma C., Liu Y., Zhou J., Hu Z., Wu D., (Inhibitory effect on activated reninangiotensin system by
astragaloside IV in rats with pressure-overload induced cardiac hypertrophy). Zhongguo Zhong
Yao Za Zhi. 2009 Dec; 34(24):3242-6.
7 Deng Y., Chen H. F. (Effects of Astragalus injection and its ingredients on proliferation and Akt phos-
phorylation of breast cancer cell lines). Zhong Xi Yi Jie He Xue Bao. 2009 Dec.; 7(12): 1174-80.
8 C han W. S., Durairajan S. S., Lu J. H., Wang Y., Xie L. X., Kum W. F., Koo I., Yung K. K., Li M. Neuroprotec-
tive effects of AstragalosideIV in 6-hydroxydopamine-treated primary nigral cell culture. Neuro-
chem. Int. 2009 Nov.; 55(6):414-22. Epub 2009 May 4.

Cycloastragenol
Astragaloside IV is not the only active principle of the astragalus plant. Cycloartane-type sapo-
nins are also important constituents of astragalus root, to which are attributed astragalus
wound-healing properties, one of its uses in traditional medicine.
Saponins are amphipathic glycosides, ie both hydrophilic and lipophilic. Cycloastragenol, tested
in vivo and in humans for several years, seems to be the most powerful of the saponins in terms
of anti-aging treatments.
An excellent telomerase activator

As described earlier, all human somatic cells divide a finite number of times; cells approaching
this endpoint are termed senescent. At this point, they stop dividing and die this is called the
Hayflick limit. Shortening of telomeres is thus believed to be one of the principal mechanisms
of cell aging and so there is much to be gained from the discovery of telomerase inducers that
can help delay the onset of cellular aging.
With this in mind, nutraceutical research has been investigating resveratrol and cycloastragenol
for their ability to improve the function of T cells in vivo, and has evaluated their effects on:
cell proliferation;
telomerase activity levels;
surface marker levels;
cytokine secretion by CD4 and CD8 T lymphocytes.
Research shows that cycloastragenol produced a slight increase in telomerase activity and the
proliferative capacity of T cells CD4 and CD8. The results suggest that these substances can inhi-
bit the appearance of CD4 and CD8 and cell senescence 2. In addition, researchers noted that
the saponin is not cytotoxic for cancer cells, but that it increases proliferation of lymphocytes3.
Just as for astragaloside IV, it is important to check the certificate of analysis when selecting a
cycloastragenol product.
Cycloastragenol is already known across the Atlantic as the main ingredient in TA-65 from Telo-
merase Activation Sciences (TA Sciences), a product taken by thousands of people since its
launch in 2005.

But TA65 is not easy to obtain as it is exclusively distributed through a franchised network
of doctors at a cost of between $2,000 and $4,000 for six months treatment. While TA Sciences
have not revealed the exact composition of TA65, competitor analysis shows cycloastrage-
nol and astragaloside IV to be the only detectable ingredients. (One capsule of TA65 contains
around 5mg of cycloastragenol and 20mg of astragaloside IV).
It is reasonable to assume, therefore, that the much less expensive generic cycloastragenol
may be just as effective.
Studies on subjects taking TA65 have shown not only an increase in T-lymphocyte numbers,
and improvements in immune function and bone density, but also and most significantly, a
lengthening of the shortest telomeres through telomerase activation.
Cycloastragenol thus constitutes a powerful anti-aging weapon that can repair DNA damage
because it:
stimulates telomerase levels;

reduces the number of the shortest telomeres;
activates T-lymphocytes.
The chemical structure of cycloastragenol is fairly similar to that of astragaloside IV. However,
its low molecular weight means it crosses the intestinal barrier easily and because it is optimally
absorbed, increased efficacy is achieved at a lower dose. Daily supplementation with cycloas-
tragenol, in combination, or alternating, with astragaloside IV, can help control the aging pro-
cess and naturally extend life expectancy, given that the spectrum of activity of these two sup-
plements is obviously wider when they are combined.
As for astragaloside IV, you could not realistically ingest a sufficient quantity by taking astraga-
lus plant capsules as they only contain a tiny amount. You would need to consume hundreds of
whole plant capsules and tens of 50:1 extract capsules, the most potent available, to obtain the
amount of cycloastragenol shown to be effective.
It is therefore vital to take a concentrated, purified nutritional supplement.
The dose should also be calculated according to age. Cycloastragenols efficacy seems to be
dose-dependent and people with the shortest telomeres who are usually older achieve the
most effective and rapid results with higher doses, 25mg to even 50mg a day. While those in
their thirties can therefore rely on 10mg a day, 70 year-olds should be taking between 25 and
50mg a day.

A cautionary note
The pharmacology and pharmokinetics of cycloastragenol have recently aroused much interest
in the scientific community due to cycloastragenols ability to regulate telomerase in cells. But
cycloastragenol also has a modulatory effect on lymphocytes inasmuch as it modifies the pro-
perties of telomerase. It should be noted that telomerase plays a role in the activity of 85-95%
of cancer cells. However, telomerase does not cause cancer, a fact already demonstrated by
DrWoodring Wright.
Click here for a certified cycloastragenol formulation.
References
1 A ndrews, W. West, M. Report: Turning on Immortality: The Debate Over Telomerase Activation. Life
Extension Magazine. August 2009.
2 Valenzuela H. F., Fuller T., Edwards J., Finger D., Molgora B., Cycloastragenol extends T cell prolifera-
tion by increasing telomerase activity. J. of Immun. 2009, 182, 90.30.
3 V erotta L., Guerrini M., El-Sebakhy N. A., Assad A. M., Toaima S. M., Radwan M. M., Luo Y. D., PezzutoJ.M.,
Cycloartane and oleanane saponins from egyptian astragalus spp. as modulators of lymphocyte
proliferation. Planta Med. 2002 Nov.; 68 (11): 986-94.

Other nutrients involved
in maintaining telomeres
Promising new studies continue to confirm the benefits of some other nutrients and phytonu-
trients in maintaining telomeres.
To recap, telomeres are the fine protective tips at the end of our chromosomes. Every time our
cells divide, DNA has to replicate but with each cell division, telomeres get shorter and the lifes-
pan of the cell decreases. As mentioned, this telomere shortening is directly linked to cellular
aging and the development of a host of age-related diseases.
Telomerase is an enzyme that can lengthen the shortest telomeres. Recent studies show that
telomerase significantly affects the shortest telomeres rather than average telomere length. In
fact it is the percentage of short telomeres that is the best marker of senescence and even
mortality. Cycloastragenol and astragaloside IV have been shown to stimulate telomerase and
lengthen the shortest telomeres representing a massive advance though they have little or
no effect on average telomere length. It is therefore strongly recommended that these subs-
tances be combined with other nutrients and phytonutrients to complement and boost their
action.
Researchers have identified a number of substances likely to help mitigate this telomere shorte-
ning, in some cases significantly so, with genuine, consistent and confirmed effects.
Magnesium ascorbyl-phosphate (Asc2P)
This is a rare and stable form of vitamin C which is able to penetrate into cells. In vitro stu-
dies have shown that introducing it into human vascular endothelial cells prevents up to
62% of telomere shortening, via suppression of intracellular oxidative stress, whereas the
natural form of vitamin C, ascorbic acid, has no effect. In addition, this form of vitaminC
prevents the cell from widening, a valuable marker of cell senescence.

L-carnosine
Also called beta-alanine-L-histidine, this di-peptide is a natural molecule found in skele-

tal muscle and in the brain. It is recognised for its anti-glycation and antioxidant proper-
ties, and has also been shown in culture particularly in lung fibroblasts - to counteract
telomere damage and shortening by around 32%, and substantially lengthen lifespan.
Extract of Terminalia chebula
Extract of the fruit of this plant, standardised to 30% tannins, has demonstrated cyto-pro-
tective effects against oxidative stress (particularly UVB-associated oxidative damage), as
well as inhibitory effects on cell aging, in a study conducted at the College of Pharmacy
of Chungnam University, Korea. Compared with non-treated controls, telomere shorte-
ning was 45% lower.
Extract of green tea
Extract of green tea standardised in polyphenols, especially EGCG (Epigallocatechin gal-

late), is recognised for its ability to lengthen telomeres in humans. A large-scale Chinese
study carried out at the University of Hong Kong, involving over 2000 subjects aged 65
and over, showed that consuming at least 700 ml/day of green tea led to an average
lengthening in telomeres of over 46%, which equates to an extension in human lifespan
of five years.
Extract of palm oil
Tocomax, a standardised extract of palm fruit oil, provides d-gamma tocotrienols - vita-
min E isomers that boost the action of tocopherols. An in vitro study has demonstrated
the protective effect of d-gamma tocotrienol against oxidative stress and its potential
to produce significant increases in telomere length by modulating telomerase activity.
In this study, cells were exposed for 24 hours to gamma tocotrienol, before and/or after
two hour exposure to hydrogen peroxide. At the doses used in this study, the telomere
length of treated cells was over 16% longer than controls.

Extract of purslane
Extract of purslane (Portulaca oleracea) was investigated in a study in which three-month

old mice were given sub-cutaneous injections of the extract for a two-week period at
doses of 2.5 mg/kg/24 hrs. The results highlighted several benefits in the purslane-
treated mice, as compared with controls: improvements in learning and memorising,
neuro-protective effects, increased SOD levels and in particular, an increase of over 27%
in the activity of telomerase and telomeres of brain cells. In vivo administration of purs-
lane produced a slowing down in telomere shortening of between 24 and 57%, after only
two weeks use.
Click here for a formulation to preserve average telomere length
Marine omega-3
According to a study published in Brain, behaviour and immunity, supplementing with

marine omega-3 for just four months was associated with lengthening of telomeres in
immune cells.
A number of earlier studies have shown that telomeres are very sensitive to oxidative
stress and that telomere length is a valuable marker of biological aging.
A team led by Professor Jan Kiecolt-Glaser of Ohio University and Elizabeth Blackburn, a
pioneer in the field of telomere research, conducted a study involving 106 overweight
adults. Each was assigned to one of three groups: the first received 2.5g/day of omega-3,
the second 1.25g/day and the third was blindly given a placebo.
The study showed that after four months, levels of F-isoprostanes, a marker of oxidative
stress, were markedly lower in the two groups supplemented with omega-3 fatty acids.
No difference was observed in telomerase, but an improved omega-6/omega-3 ratio

was associated with longer telomeres, suggesting that a better ratio between these two
groups of fatty acids can directly affect cellular aging.

Inflammation markers were also 10-20% lower for the two omega-3 supplemented
groups, while markers increased by 36% in the control group. This observation strongly
suggests inflammation is a parameter that directly influences telomere length.
Supplementation with marine omega-3 over a four-month period notably increased ave-
rage telomere length, thus affecting one of the key processes of cellular aging. These
results confirm those of an earlier study, published in 2010, which showed that high cir-
culating levels of omega-3 were able to slow down cellular aging in coronary patients.
Click here for a Marine Omega 3 formulation
References
J anice K. Kiecolt-Glaser, Elissa S. Epel, Martha A. Belury, Rebecca Andridge, Jue Lin, Ronald Glaser,
William B. Malarkey, Beom Seuk Hwang, Elizabeth Blackburn. Omega-3 fatty acids, oxidative stress,
and leukocyte telomere length: a randomized controlled trial. Brain, Behavior, and Immunity. Avai-
lable online 23September 2012, ISSN 0889-1591, 10.1016/j.bbi.2012.09.004.

MITOCHONDRIAL BIOGENESIS
What are mitochondria?
Mitochondria are the cells powerhouses they enable cells to function at full capacity. A young
persons cells contain a great many mitochondria between 2,000 and 2,500 per cell but as
we age, levels of mitochondria decrease and those that remain become less effective and pro-
duce more waste products. The result is a huge loss of energy, which is implicated in the majo-
rity of age-related degenerative diseases: physical and cognitive problems, accelerated cell
breakdown, cardiovascular problems.
This mitochondrial dysfunction has been
definitively linked to almost all deadly
diseases of aging, Alzheimers disease, type2
diabetes, heart failure, etc. Scientists have
clearly noted greater evidence of mitochon-
drial damage in the brain cells of men aged
70+ compared with those of 40 year-olds.
The health and function of mitochondria, the
cells powerhouses, are now considered so
important that many scientists believe that
mitochondrial longevity is synonymous
with aging body longevity.
How can we optimise mitochondrial function?

In 2002, a famous study by Dr Bruce Ames (Emeritus Professor of Biochemistry at the University
of California) demonstrated that the synergy of acetyl-L-carnitine and R-lipoic acid optimised
mitochondrial function and thus slowed down the aging process. We now know that certain
other nutrients, such as resveratrol and coenzyme Q10 also improve the function of existing
mitochondria and thus have a beneficial effect on longevity.
Is it possible to boost mitochondrial biogenesis?

Improving the function of existing mitochondria is one thing, but increasing numbers of mito-
chondria, in senescent cells in other words, enabling mitochondrial biogenesis by activating

the genes that control their reproduction, protection and repair that would be an exceptional
advance!
And it is indeed possible with PQQ (pyrroloquinoline quinone). Intense aerobic exercise or
severe calorie restriction are currently the only other ways of achieving such results. By boosting
and generating new mitochondria, this anti-aging nutritional supplement ensures the longe-
vity of each and every cell.
Code name PQQ

One of the most significant advances in the field of mitochondrial
bioenergetics
PQQ is ubiquitous in the natural world, particularly in all plant species. The fact that it is found
in cosmic dust has led some experts to hypothesize that PQQ played a central role in the evo-
lution of life on Earth itself 2. It is a powerful growth factor in plants, bacteria and higher forms
of life 5, 6. Neither humans nor the bacteria that colonise the human digestive tract are able to
synthesise PQQ 3.
Studies show that when animals are deprived of dietary PQQ, they suffer stunted growth, impai-
red immunity, compromised reproductive capability, decreased numbers of mitochondria in
tissue, lower rates of conception, and lower numbers of offspring and survival rates in young
animals 7, 8, 9. Unsurprisingly, reintroducing PQQ to their diet reversed these effects, restored
systemic function and simultaneously increased mitochondria and energy efficiency.
These findings have led researchers to include PQQ among those nutrients classed as essential4.
Whether it is classified as a new vitamin or a new coenzyme matters little in terms of its anti-
aging efficacy.
The most extraordinary finding relating to PQQ came in 2010, when researchers at a Californian
university noted that it not only protected mitochondria from oxidative damage but actually
stimulated their growth 1. In other words, it promotes generation of new mitochondria in senes-
cent cells.

PQQ activates certain genes
The Californian researchers also discovered that PQQ activated certain genes which regulate
mitochondrial reproduction, protection and repair and thus reversed cellular aging via three
exceptional molecules:
PCG-1a, or peroxisome proliferator activated receptor gamma coactivator-1 alpha, is a regula-

tor which directly stimulates genes that improve mitochondrial and cellular respiration, growth
and reproduction. This ability to up-regulate cellular metabolism has a positive effect on blood
pressure, cholesterol and triglycerides.
CREB, orCyclic adenosine monophosphate response element-binding, is a protein that plays a
key role in embryonic development and growth. It stimulates growth of new mitochondria, and
protects and repairs cell DNA.
DJ-1, which simply takes the name of the DJ-1 gene, is a protein involved in cell function and
survival. It is proving to be a powerful anti-stress-oxidant of the first order for brain health, par-
ticularly in preventing Parkinsons disease and other neurological disorders.
Multiple applications
PQQ thus powerfully combats mitochondrial dysfunction and degeneration and can generate
new mitochondria in aging cells. In addition, however, it protects the brain, heart and muscles
from aging and degeneration.
Optimal mitochondrial defence against oxidative stress

Like other engines of bioenergy production, the mitochondria are extremely vulnerable to
oxidative damage. The principal cause of mitochondrial dysfunction is oxidative stress and it
is at this mitochondrial level that PQQ delivers its anti-aging benefits. Due to its exceptional
stability 10, PQQ has been shown to be a powerful antioxidant weapon. It is significantly more
effective - between 30 and 5000 times more effective - at protecting mitochondrial DNA than
common antioxidants such as vitamin C.
In effecting large scale electron transfers, it neutralises the main free radicals which impair heal-
thy mitochondrial function, without sustaining any molecular breakdown. It has been shown
to be particularly effective at neutralising the ubiquitous superoxide and hydroxyl radicals 11.
PQQ thus offers greater benefits than conventional antioxidants in common use by consumers.
Its no surprise, then, that PQQ is exceptionally effective at combating degenerative diseases
associated with aging and decreased energy in the bodys two most important organs the
heart and brain.

Neuro-protection and improvement in cognitive function
PQQs health benefits to the whole central nervous system have been demonstrated by research.
It is particularly effective at protecting brain cells from post-ischemic oxidative damage, from
inflammation and from the free radical damage resulting from the sudden return of blood sup-
ply and nutrients to tissues 13. PQQ significantly reduces the extent of the brain area damaged14.
PQQ improves performance in memory tests 12 and interacts positively with the brains neuro-
transmitter system. In particular it protects neurons by modifying the NMDA, or N-mthyl-D-
aspartate, receptor site 15, 16 which is a powerful mediator of excitotoxicity the over-stimula-
tion of neurons which is associated with several neurodegenerative diseases 17, 18, 19. PQQ also
protects against neurotoxicity induced by mercury and other toxins 20.
Studies have shown that PQQ prevents the development of alpha-synuclein, a protein linked
to Parkinsons disease 21 and also protects nerve cells from oxidative damage by beta-amyloid
protein, associated with Alzheimers disease 22.
One study conducted in 2010 showed that PQQ could prevent the formation of beta-amyloid
molecular structures 23.
PQQ has also demonstrated ability to protect memory and cognition both in animals and
elderly humans 24, 25. The fact that it stimulates production and release of nerve growth factor
in cells and neurons 26 may partly explain why PQQ supplementation in elderly rats resulted in
a marked improvement in their memory function 24.
A recent double-blind, placebo-controlled study showed that a daily dose of 10-20mg of PQQ
significantly improved short term memory as well as concentration in young adults, compared
with a control group.
In another double blind, placebo-controlled study conducted in Japan in 2007, administering
20 mg PQQ supplementation a day to middle-aged volunteers produced improvements in
cognitive function 25 (the performance of the supplemented group was twice that of the pla-
cebo group), especially when subjects also took 300 mg/day of CoQ10. The study therefore
suggests a synergistic relationship between PQQ and coenzyme Q10 which enhanced perfor-
mance in memory tests. This combination can therefore be used to improve mental aptitude
and quality of life and to help slow down or prevent cognitive decline.
Cardioprotection and improvements in energy levels

Research has demonstrated that PQQ helped protect cardiac muscle cells against oxidative
stress. Animal research showed that supplementation with PQQ reduced the extent of damage
following stroke and heart attack 27, whether it was given before or after the event.

Researchers at the VA Medical Centre at the University of California San Francisco conducted
comparative tests between PQQ and Metoprolol, a betablocker, and concluded that PQQ was
superior to Metoprotol at protecting mitochondria against oxidative damage 28. Subsequent
studies by the same research team demonstrated that PQQ helped cardiac muscle cells to resist
oxidative stress 29. PQQ is thus undoubtedly cardioprotective.
In addition, since mitochondria are responsible for energy production, PQQ supplementation
should make physical exercise easier and more effective.
Combining PQQ with synergistic nutrients

As already mentioned, certain nutrients, such as acetyl-L-carnitine, R-lipoic acid, L-carnosine,
resveratrol and coenzyme Q10 help improve the function of existing mitochondria.
with acetyl-L-carnitine and R-lipoic acid

Acetyl-L-carnitine and R lipoic acid are undoubtedly the most effective of these synergistic
nutrients, as demonstrated in Dr Ames famous study. By facilitating the transport of fatty acids
into cell mitochondria, acetyl-L-carnitine facilitates the conversion of dietary fats into energy
and muscle. Acetyl-L-carnitine and L-carnitine have a particularly crucial role to play in the brain
as it requires large amounts of energy. Esters such as acetyl-L-carnitine appear to have unique
neuroprotective, neuromodulatory and neurotrophic properties which are particularly impor-
tant for countering the processes of various diseases 30.
At the end of the 1980s, it became clear that the various effects of acetyl-L-carnitine on the
health of neurotransmitters and brain cells had something in common they improved the
ability of cells to maintain and restore mitochondrial function despite advancing age. Research
has shown that acetyl-L-carnitine supplementation rejuvenates mitochondria with declining
structure and function due to the aging process.
With regard to alpha-lipoic acid, the body produces tiny amounts, and it is found in mitochon-
dria-containing foods such as red meat. It has been termed the universal antioxidant since
unlike other antioxidants, it crosses cell membranes and exerts its antioxidant action in both the
bodys lipid and aqueous environments, including the brain.
R-alpha lipoic acid is the most biologically active form of alpha-lipoic acid, naturally produced
by the body. It is the most important mitochondrial antioxidant. Numerous studies have looked
at it in combination with acetyl-L-carnitine to establish the synergistic effects of these two com-
ponents on mitochondrial function. The benefits observed in these studies include improve-

ments in memory, and in age-related hearing loss, as well as a reduction in oxidative damage. In
addition, alpha lipoic acid helps protect mitochondria from age-related structural deterioration
which invariably impair their function 31, 32, 33.
In his interview in the May 2010 issue of NutraNews, Dr Ames was clear: When we gave R-lipoic
acid combined with acetyl-L-carnitine, all the functions we were examining that had declined
with age were restored. The mitochondria produced fewer oxidants and the mitochondrial
membrane potential improved. Dr Ames demonstrated the involvement of this mitochon-
drial dysfunction in degenerative diseases, including cancer and neurological decline. He also
showed that combined administration of acetyl L-carnitine and R-lipoic acid enabled the effects
of calorie restriction to be mimicked and optimal mitochondrial function to be restored both in
the heart and brain.
It is therefore a good idea to complement the action of PQQ - the only nutrient capable of
generating new mitochondria - with these two nutrients, the most scientifically-supported for
maximising the function of existing mitochondria.
Click here to find PQQ in a certified Mitochondrial formulation
with CoQ10
In addition, it now appears that combining PQQ with coenzyme Q10 significantly enhances the
benefits of the former. This is not altogether surprising, given the key role played by CoQ10 as
a mitochondrial fuel for promoting cellular respiration and increasing production of adenosine
triphosphate (ATP).
Recent studies have highlighted improved cardiovascular and cognitive performance when
these two nutrients are taken in combination, as opposed to separately. This is not unusual in
that the heart and brain are the two organs that consume by far the most energy.
A Japanese study conducted in 2007 showed that PQQ, taken in daily doses of 20mg, improved
memory, attention and cognitive function. The performance of the PQQ-supplemented group
was twice that of the placebo group. Combining PQQ with 300mg of COQ10 further enhanced
performance in memory tests. Mental aptitude and quality of life can therefore be improved
in elderly people, and this combination can help prevent age-associated decline in cognitive
function.

Another study showed PQQ to be more active when taken with antioxidants and that when
combined with CoQ10, neurodegenerative parameters improved and the nerve growth fac-
tor neurotrophin was stimulated. Similarly, the PQQ/CoQ10 combination slows down cerebral
degeneration, reduces formation of amyloid plaque (one of the likely causes of Alzheimers
disease and dementia) and possibly also inhibits cerebral atrophy (age-related shrinking of the
brain). Taken together, PQQ and CoQ10 therefore improve antioxidant status and mitochondrial
health via complementary mechanisms. They also provide multi-faceted support to cardiovas-
cular and cerebral function. They improve mental status and quality of life in older people and
can be used to slow down or prevent cognitive decline in middle-aged individuals.
Click here to find PQQ + CoQ10
Soluble in water, PQQ does not accumulate in the body and does not lead to intolerance, even
at high doses. It can therefore be consumed by everyone who wishes to control one of the
major mechanisms of aging.
PQQ adds to the arsenal of recognised anti-aging weapons and can be used simultaneously,
or, as we have seen, alternated with telomerase activators (cycloastragenol, astragaloside IV),
as well as with the calorie restriction mimetics (resveratrol, oxaloacetate) covered in the next
chapter.

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CALORIE RESTRICTION MIMETICS
The work of Dr Roy Walford has shown that severe calorie restriction, but
not malnutrition, is the safest way of significantly extending lifespan - by
between 20% and 30% in most mammals and almost 100% in certain spe-
cies. Walfords research has been partly supported even in humans, by the
findings of the Biosphere II experiment in which he personally participated
Calorie restriction is the most scientifically-supported way of increasing lifespan in a monocellu-

lar organism or a mammal. Researchers have known for decades that reducing calorie intake by
up to 40% significantly slows down the aging process and increases life expectancy in labora-
tory animals including locusts and mammals. In rats, a 30% reduction in calorie intake resulted
in a 30% increase in longevity. Calorie restriction is also recognised as offering animals protec-
tion from cancer and other age-related diseases.

It has taken over 70 years for researchers to begin to unravel the mysteries of calorie restriction:
the effect of a strict hypocaloric diet that of a significant increase in life expectancy - was first
noted in rats as long ago as 1935 1. But it is only now that we are beginning to understand the
mechanisms behind this effect. These are essentially related to beneficial alterations in gene
expression, one of the bodys adaptive responses to reduced calorie intake.
This delay in aging postpones the development of degenerative diseases, while improving
biomarkers of aging, including metabolic rate, insulin sensitivity, cardiac health and cognitive
function2. Conversely, too high an intake of calories can have important negative consequences.
Eating more than the body needs overloads the blood with triglycerides, sugar, homocysteine
and pro-inflammatory chemicals, thus accelerating the aging process and the deterioration of a
number of biomarkers of health.
A key development in longevity research

In 1989, anti-aging researchers began an important study on calorie restriction using rhesus
monkeys. These were chosen because they have very similar biological characteristics of aging
to those of humans. The monkeys were split into two groups: half were fed normally, and half
were fed 30% fewer calories than normal. After 20 years, 30% of the control group had died from
age-related causes, compared with only 13% in the calorie-restricted group. In other words, the
risk of degenerative disease was reduced to almost a third of that of the control group. In addi-
tion, over the course of the studys 20 year-duration, all the health biomarkers measured were
better in the calorie-restricted group (reduced blood pressure and triglyceride levels, impro-
ved glycaemia and decreased cancer incidence). The calorie-restricted animals had lost weight
in terms of fat, but without suffering the loss of muscle mass observed in the control group.
Calorie restriction also inhibited reductions in cerebral volume, particularly in the areas which
control motor and cognitive functions 3. The calorie-restricted primates were more alert and in
better health than their normal-diet counterparts.

Expression of longevity genes activated by calorie restriction
The researchers showed that it is possible to modify the messages transmitted by the genes to
the body. This process of gene expression occurs when an internal or external stimulus activates
or inhibits certain genes (protective or harmful).
Researchers have identified a family of genes called sirtuins, which are present in the tissues of
almost all life forms from monocellular organisms to plants and mammals. An increasing body
of evidence suggests that sirtuins regulate energy metabolism, endocrine signalling and cer-
tain stress responses. Sirtuins are also activated by a wide range of signals in response to stress,
such as during periods of famine or calorie restriction, suggesting that they play a key role in the
physiology of mammals.
Sirtuins are also known to act as guardian genes, protecting cells and increasing their survival
rates. Sirtuins include a group of enzymes called deacetylases which slow down aging by affec-
ting a number of cell mechanisms such as DNA repair, resistance to oxidative stress or cell death.
Sirtuins action begins when external signals indicate a deterioration in environmental condi-
tions. Longevity genes are then stimulated to induce defensive changes at a cellular level, such
as slowing down metabolism and increasing cell respiration in order to help the body adapt to
a more effective programme of survival.
It has been shown that human sirtuin, SIRT1 for example, suppresses the enzyme P53, which is
usually involved in inhibiting tumour growth and promoting cell death (apoptosis). By suppres-
sing P53 activity, SIRT1 prevents the cycle of apoptosis and premature aging triggered when
cell DNA is damaged, thus giving the cells sufficient time to repair all the damage and prevent
unnecessary cell death.
It has also been shown that a second sirtuin, SIRT2, present in yeast, is activated when subjec-
ted to stress. It increases DNA stability and accelerates cell repair, while increasing total cell
lifespan4, 5.
In general, sirtuin activation increases sensitivity to insulin and lipolysis, decreases inflamma-
tion and plays a preventive role in neurodegenerative diseases and carcinogenesis. One study
showed that transgenic mice overexpressing SIRT1 presented the same phenotype as calorie-
restricted mice.

Benefits to human health of calorie restriction
For ethical and practical reasons, calorie restriction has not been studied extensively in humans.
However, limited observations suggest it does have beneficial effects. For example, inhabitants
of the Japanese island of Okinawa, whose diet is typically very low in calories, have exceptio-
nally long life expectancy 6.
Certain data suggest that calorie restriction slows down aging and reduces the risk of fatal
diseases in humans. Individuals whose calorie intake was reduced by 20% for between two
and six years lost body fat mass and saw markers of aging improve, including blood pressure,
cholesterol levels and blood sugar control 7. Even short periods of calorie restriction can tem-
porarily improve body temperature and insulin sensitivity, both markers of longevity 8. Clinical
studies have shown that brief periods of calorie restriction reduced the inflammation which
accompanies the development of a number of degenerative diseases. A more youthful heart
muscle performance was also observed; calorie restriction seems to increase the number of
mitochondria essential for energy production in the heart and skeletal muscle, reducing age-
associated increases in oxidative damage9, 10.
Research into alternatives to calorie restriction

Calorie restriction has a positive effect on most of the seven types of damage highlighted by
Aubrey de Grey. By activating certain genes and inhibiting others, calorie restriction consi-
derably slows down the aging process. Unfortunately, for most people, it requires too much
willpower and is very difficult to sustain. It is hard to imagine many people committing to a
lifelong draconian hypocaloric diet in order to extend their life expectancy. Fortunately, scien-
tific understanding of calorie restrictions mechanisms has enabled the isolation of natural or
synthetic substances capable of reproducing the formers benefits. A team of researchers at
Harvard University has begun to investigate other ways of modulating sirtuin activity that do
not require a reduction in calorie intake. After an initial process of study, these scientists have
noted several metabolites extracted from plants acting as sirtuin activators.
Among those identified, the two main substances are resveratrol and oxaloacetate which can
be combined with complementary substances such as quercetin and pterostilbene which add
to the effects of calorie restriction by inhibiting systemic inflammation, boosting mitochondrial
health and protecting brain and heart tissue from age-related deterioration.

Resveratrol
A potent plant-based antioxidant, resveratrol is an outstanding anti-aging substance. Grapes

are its main source, and thus it is found in red wine. Indeed it is thought to be responsible for
the effects of the well-known French paradox in which red wine appears to help maintain
cardiovascular health despite a relatively unhealthy diet containing high GI foods and/or foods
high in saturated or trans-saturated fat.
Resveratrol is therefore a phytonutrient if not the phytonutrient thats highly recommended
for maintaining and protecting cardiovascular health. But its benefits dont stop there studies
conducted on this substance have all reached the same conclusions:
Resveratrol is a proven, potent anti-cancer agent effective at combatting the deve-

lopment of various-stage cancer cells.
Resveratrol protects the brain from oxidative stress and thus the majority of neuro-
degenerative diseases.
Ultimately, then, it is an excellent, natural anti-aging substance.
The reason behind the paradox!
Resveratrol is a stilbene from the phytoalexin family. Its also a polyphenolic compound, from
the flavonoid group, and thus a powerful antioxidant. Many plants, particularly grapevines, pro-
duce this protective substance in response to pathogenic insults resulting from UV and ozone
exposure. Its worth noting here that resveratrol is concentrated in the leaves of the grapevine,
the grape skin and pips, and that its found in the fermentation of red wine but not in white.
It was Japanese scientists who originally began to take an interest in this substance in the 1980s
when a traditional remedy, Kojo-Kon, attracted their attention. This medicine contained a plant
called Polygonum cuspidatum, which was used to treat a range of disorders including allergies,
skin inflammation and hyperlipidaemia. They succeeded in isolating the plants active principle,
resveratrol 1. From 1985 onwards, studies increased and much more became known about the
metabolic properties of resveratrol.
Studies on leucocytes in rats demonstrated its ability to inhibit production of eicosanoids. These
include prostaglandins, thromboxanes and leukotrienes which are involved in inflammatory
reactions and platelet aggregation.

This discovery led to further research and it was then that people began to talk about the
French paradox the strange co-existence of a high-fat diet and a relatively low incidence of
cardiovascular disease among the French.
What was behind this paradox? Red wine consumption - or more specifically, red wine with
resveratrol. And so the link was rapidly identified. However, we still dont know precisely why
resveratrol mitigates the harmful effects of a high-fat diet and lowers the risk of cardiovascular
disease but it is thought that its antioxidant and anticoagulant properties play a part.
Resveratrol is a remarkable antioxidant weapon against free radicals in blood cells.

One study involved incubation of human blood cells with resveratrol and a substance that pro-
duced oxidative damage. Result: in a dose-dependent manner, resveratrol protected the cells
from any oxidative damage and prevented the triggering of cell death. Thus, mononuclear cells
in peripheral blood acquire antioxidant potency when treated with resveratrol2.
Resveratrol works in three different ways:
It competes with CoQ10 and reduces the oxidative chain complex III, the site where
reactive oxygen species are produced.
It destroys superoxide radicals which develop in the mitochondria.
It inhibits lipid peroxidation induced by Fenton reaction products during energy
production.

Resveratrol Calorie Restriction
SIRT 1
Cell effects General effects
Cell death
Inflammation
Cell repair
Lipolysis
cell survival Insulin

Prevention of sensitivity
Resistance to carcinogenesis
oxidative stress
Prevention of
neurodegenerative conditions
Free radicals
Increase
in lifespan

Multi-faceted activity for optimal cardio-protection
Cardio-protection was resveratrols first indication: it has a positive effect on a number of the
mechanisms behind cardiovascular disease. As an antioxidant, it stops peroxidation from
breaking down lipids, and, in a dose-dependent manner, prevents oxidised LDL from penetra-
ting the vascular wall.
In vitro, it was shown that treating parenchymal cells of the liver with resveratrol led to inhibited
secretion of esterified cholesterol secretion and triglycerides without changing intracellular
triglyceride levels.
As a result, its thought that resveratrol lowers hepatic secretion of VLDL which is converted into
LDL in the blood, thus blocking hepatic lipoprotein metabolism.
In addition, it has been demonstrated that supplementation with trans-resveratrol in healthy
individuals inhibits platelet aggregation in a dose-dependent manner 3.
Researchers also reported another, very powerful inhibitory effect on platelet synthesis of
thromboxane. A dose of ten micromoles of resveratrol was sufficient to produce a 60% inhi-
bition, a much better result than all other wine polyphenols or antioxidants. Thromboxane is
essential for the development of cardiovascular problems, as it participates in the process of
pathological coagulation, constricts the arteries, damages the endothelial wall of the blood ves-
sels and promotes the development of atheroma.
Conversely, resveratrol and some other antioxidants can stimulate production of prostacyclin, a
substance that prevents blood clot formation, keeps the arteries dilated and promotes healthy
endothelial walls. Prostacyclin also happens to be synthesised by healthy endothelial walls due
to an enzyme called prostacyclin synthase. Unfortunately, the work of this enzyme can be almost
wiped out by certain free radicals, particularly lipid peroxides or hydroperoxides. Production of
prostacyclin necessarily entails the reduction of hydroperoxides and lipid peroxidation. This is
where resveratrol comes into play, acting synergistically with certain other bioflavonoids, vita-
mins C and E and selenium. These nutrients act synergistically to reduce platelet aggregation,
maximise prostacyclin productionand minimise production of thromboxane and free radicals.
Finally, resveratrol also restores adequate nitric oxide levels. Nitric oxide is absolutely pivotal to
a healthy cardiovascular system, as it enables dilation of arteries and thus good circulation. A
high-fat diet reduces nitric oxide levels by a third. So here too, we can see how resveratrol sup-
plementation can prove extremely beneficial in reversing this unwelcome tendency.

Outstanding anti-cancer weapon
Cancer is perhaps the most promising area of resveratrol research, with an increasing number
of studies leading to a deeper understanding of this amazing substance.
Resveratrol is quite simply the most effective natural substance at stopping various stages of
the development of all types of cancer initiation, promotion and progression.
Resveratrol affects cancer both by blocking oestrogens and androgens as well as through gene
modulation; it can thus combat a number of cancers, in a preventive as well as curative capa-
city. Several recent studies show that resveratrol kills cancer cells whether or not they have the
tumour suppressor gene 4, or whether or not they are oestrogen receptor-positive or negative.
One of resveratrols mechanisms has been identified with the discovery that the body converts
this polyphenol into an anti-cancer agent capable of targeting and killing cancer cells. In par-
ticular, it showed how the enzyme cytochrome P450 found in various tumours metabo-
lises resveratrol into a phyto-oestrogen called piceatannol, which has anti-cancer properties.
The death of cancer cells triggered by piceatannol, and thus resveratrol, causes absolutely no
damage to normal cells 5.
In addition, it seems that resveratrol can also boost certain types of chemotherapy. Researchers
at the University of Notre-Dame discovered that resveratrol maximises the effects of vitamin D.
Vitamin D3 has the particular ability of being converted into a steroid that inhibits growth of
breast cancer cells.
In a very detailed study, Austrian scientists have demonstrated that resveratrol prevents cancer
cells from metastasizing to bone.
However, the best results have been recorded for cancers of the pancreas, breast and kidneys.
Results for colon and prostate cancer were also encouraging but on a smaller scale.
Another of resveratrols properties is that of reducing the harmful effects of the omega-6 fatty
acid, linoleic acid, an ingredient prominent in the Western diet that promotes the growth of can-
cer cells. Linoleic acid is actually converted into arachidonic acid, which in turn is converted into
hormone-like substances (such as prostaglandin E2 or leukotriene B4) that stimulate inflamma-
tory processes, and as result, the growth of cancer cells. Tests on rodents show the Western diet
alone is sufficient to cause colon cancer.
Japanese researchers have confirmed that resveratrol - at a dose easily available from supple-
mentation, blocked the growth-promoting effect of linoleic acid and inhibited the growth of
breast cancer cells.

In yet another study, the results of investigations into the effects of grape extract containing
resveratrol and quercetin, in which advanced human prostate cancer cells were transplanted
into rodents, led researchers to propose these two substances as a therapy for prostate cancer
in humans.
Meanwhile scientists at the University of Colorado studied the effects of grape seed extract
combined with natural cytokines on advanced prostate cancer cells. They concluded that this
combination might offer a more effective and less toxic alternative to chemotherapy in the cli-
nical treatment of prostate cancer.
Finally, another study looked at different types of advanced prostate cancer cells. Of the polyphe-
nols examined, resveratrol was found to be the most powerful against the cancer cells.
Powerful anti-inflammatory activity

Inflammation can sometimes be beneficial. It is the bodys response to injury or stress and helps
it fight bacteria. But it can also be a problem in certain disease: auto-immune diseases, cardio-
vascular problems, Alzheimers disease and cancer are among the diseases aggravated or even
caused by chronic inflammation.
Anti-aging medicine is thus focused on solutions to long-term prevention of even the mildest
chronic neurological inflammation.
Chinese scientists 6 have in particular demonstrated the efficacy of resveratrol in treating inflam-
mation caused by spinal cord injury. When injected immediately after injury, resveratrol is as
effective at curbing inflammation as prednisone, an anti-inflammatory drug, with the added
advantage of offering free radical protection.
British in vitro studies 7 have noted resveratrols ability to slow down the development of
inflammation in chronic obstructive pulmonary disorder (COPD). In this chronic, progressive
and irreversible respiratory disease, in which breathing ultimately becomes impossible, the
cells involved in the inflammatory process include macrophages which produce interleukins
and other immune-stimulant substances. These macrophages also produce substances that
extend cell life but unfortunately, generate increased inflammation and free radicals at the
same time. In this study, the researchers examined macrophages in samples of pulmonary fluid
from 15smokers and 15 other patients with COPD. They found that adding resveratrol to the
samples decreased interleukin production hugely by 94% in the macrophages of the smokers
and by 88% in those of the COPD patients. Resveratrol thus inhibits the release of inflammatory
cytokines in COPD and may thus constitute an effective treatment.

Significant neuroprotection
As a first-class antioxidant, its no surprise that resveratrol protects the brain from free radical
attack. But it also plays a role in the treatment of some quite specific diseases:
Cerebral congestion, which occurs when blood flow to the brain is impeded, depriving it
of oxygen and nutrients. Neurotransmitters are released that allow calcium to penetrate
neurons, thus flooding the brain with free radicals which can lead to cell death. Another
example is Alzheimers disease which is stimulated by oxidative damage to brain cells.
Alzheimers disease, which is promoted by oxidative damage to brain cells. According to

researchers at the University of Missouri, resveratrol protects the central nervous system
from oxidative stress and prevents oxidation of lipoprotein particles. Oxidised lipopro-
teins cause oxidative stress which initiates neuronal cell death. Over time, this unleashes
neurological inflammation and can even lead to Alzheimers disease.
Revealing a new mechanism used by resveratrol to neutralise the free radicals involved in the
inflammatory process, these studies conclude that the latter can be inhibited by supplementa-
tion with resveratrol and vitamins C and E. In addition, an abnormal peptide called beta-amy-
loid, responsible for considerable oxidative stress and the consequent death of numerous neu-
rons, has been detected in the brains of Alzheimers patients where it forms plaques that are
easily-recognizable during autopsy. Again, a study has confirmed the protective effect of resve-
ratrol on beta-amyloid toxicity in endothelial cells. The extract of black grape skin used in this
research reduced free radical production associated with beta-amyloid and protected epithelial
cell membranes from radical damage 8.
Finally, a study has confirmed the hypothesis that it is resveratrols powerful antioxidant acti-
vity that confers protection against Alzheimers disease. In this research, scientists tested the
effects of resveratrol on human neuroblastoma cells sensitive to oxidative stress generated by
beta-amyloid. Resveratrol significantly raised levels of glutathione, an intracellular free radical
neutraliser and eliminated the neurotoxicity caused by beta-amyloid 9. The combination of res-
veratrol with vitamins C and E protects the brain more effectively than any antioxidant taken
separately10.
Last, but not least, powerful anti-aging properties

Biomols research laboratories and scientists at Harvard Medical School 11 have recently demons-
trated that resveratrol activates a longevity gene in yeast, increasing its lifespan by 80%. This
increase is due to its calorie-restriction mimetic effects.

As we know, calorie restriction can increase lifespan in certain species by almost 100%, and by
at least 20-30% in mammals. Calorie restriction has a beneficial effect on gene expression. By
exerting a regulating action on factors of aging, including inflammation, metabolic function
and immune response, the genes are able to directly influence life expectancy. Calorie restric-
tion therefore promotes healthy cell function through a number of physiological pathways
including:
blocking inflammatory factors;

optimising fat and carbohydrate metabolism;
lowering glycemia;
supporting endothelial function;
inhibiting the development and spread of cancer.
In addition to mimicking all these effects, resveratrol also:
promotes insulin sensitivity;

stimulates mitochondrial function;
protects against the harmful effects of a high-fat diet.
Thus, in a similar way to calorie restriction, resveratrol activates longevity genes called sirtuins.
In order to test the power of resveratrol to activate sirtuins in humans, the researchers chose
yeast as being most closely-related to humans. They hypothesised that if resveratrol proved
able to modify the newly-identified target-genes to trigger sirtuin production, it would reflect
the proteins role in animals and confirm a link with lifespan extension, at least for yeast. The
yeast lived 60-80% longer than normal due to the resveratrol, even at low doses.
Subsequent experiments on human cells have revealed that resveratrol activated a similar
pathway, requiring the human gene, SIRT1. This ensured the survival of 30% of resveratrol-
treated human cells irradiated with gamma rays, compared to 10% of untreated cells.
Tests performed on flies and worms have proved convincing and tests on mice are ongoing.
From these studies, it appears that it is not so much the antioxidant potential of resveratrol that
activates the famous longevity gene, but its chemical structure. It seems resveratrol actually
accelerates the rate of the reaction known as desacetylation and the activation of certain
genes depend on this.

For example, genes in cancer cells that shouldnt be activated, are, and vice versa. Resveratrol
seems to work by controlling desacetylation which, by activating the longevity gene, extends
lifespan in cells or in the body.
We have described how it is the inability of senescent cells to perfectly replicate DNA in each
new cell that leads to aging, and ultimately death. It is at this senescence point that DNA starts
to make mistakes: fragments of DNA become active and reproduce, preventing cells from
behaving normally. Resveratrols main anti-aging benefit is that, by stimulating the longevity
gene, it reduces this DNA fragmentation by exactly 60%.
As we can see, the results are extremely promising! So much so, that the European Union has
awarded a grant to scientists researching the health benefits of resveratrol. This European pro-
ject, Marek Murias, will evaluate the antioxidant and anti-proliferation effects of resveratrol glu-
curonide and sulphate metabolites produced by the liver during resveratrol metabolism.

How can we boost the effects of
resveratrol?
As we have seen, resveratrol works well with certain other nutrients which enhance its effects.
A particularly favourable synergy occurs when resveratrol is combined with substances that
modulate gene expression, improve biomarkers of aging and boost disease-fighting mecha-
nisms.
The most interesting of these substances are pterostilbene and polydatin, two resveratrol deri-
vatives, as well as nutrients such as quercertin, fisetin and pinebark extract which add to this
synergy.
Pterostilbene
Pterostilbene has been used for centuries in ayurvedic medicine. Pterostilbene and resvera-
trol are both stilbenes, directly related in terms of structure, which perform similar, though not
identical, functions. Researchers have shown that they act synergistically to activate longevity
genes. Pterostilbene also mimics many of the effects of calorie restriction.
It also has a number of anti-inflammatory, antineoplastic and antioxidant properties and regu-
lates the genes involved in the development of cancer, atherosclerosis, diabetes and the inflam-
mation that is at the root of numerous diseases.
Its various properties therefore enable it, in conjunction with resveratrol, to help counter certain
effects of aging.
Polydatin
Polydatin is a glucoside of resveratrol: a molecule of resveratrol bound to a sugar molecule.

When polydatin enters the bloodstream, the resveratrol molecule separates from the sugar
molecule and the resveratrol glucoside is thus absorbed at a different rate to normal trans-res-
veratrol, therefore improving the bioavailability, half-life and potency of the resveratrol and pro-
longing and increasing its effect.
This synergy is further enhanced by combining the resveratrol, or its derivatives, with other
nutrients:

Quercetin
Quercetin is a powerful antioxidant and highly effective anti-inflammatory used to prevent car-
diovascular disease, metabolic syndrome and cancer. It may improve longevity simply by redu-
cing the impact of certain chronic diseases. But it also seems to have an effect independent of
this, with data suggesting it has a direct effect on extending life expectancy, at least in simple
laboratory organisms. Portuguese researchers have shown that, by increasing resistance to oxi-
dative stress, quercetin prolongs the life span of laboratory yeast cells in culture by 60% 12.
A team of German biologists have shown that feeding C.elegans worms a flavonoid-rich diet
improved their health and total longevity 13. They identified a total of four specific genes which
seemed to be activated by quercetin 14.
Other scientists have reported findings suggesting that quercetin may mimic certain effects of
calorie restriction on life expectancy.
Fisetin
Fisetin, a flavonoid extracted from Buxus sinica, has a stabilising effect on resveratrol by preven-
ting its breakdown. Most significantly, it sends a switch-on signal to carrier cells of the anti-
aging gene by ensuring protection of DNA and neurons, particularly during periods of oxidative
stress.
Polyphenols from pine bark extract
Pine bark extract from the Landes maritime pine contains very powerful antioxidants polyphe-
nols called oligoproanthocyanadins or OPCs. OPCs, polymers of catechin and epicatechin, are
able to neutralize all reactive oxygen species or free radicals. They also have a potent anti-inflam-
matory effect via a number of pathways:
they block activation of NF-kB in macrophages inhibiting production of adhesion
molecules;
they inhibit, in vitro, the activation of IL-1 pro-inflammatory cytokines. Ex-vivo,
they block the activity of COX 1 and 2.
In addition, they improve endothelial function, thus lowering the risk of cardiovascular disease,
and reduce venous insufficiency. Lastly, they help lower blood sugar levels and inhibit absorp-
tion of carbohydrates. They promote reductions in systolic pressure, improvements in the lipid
profile and normalization of platelet activity.

Niacinamide, a first-generation tool in genetic anti-aging therapy
Niacinamide, or nicotinamide, is one of two forms of vitamin B3, the other being niacin. Niaci-
namide is needed for hundreds of enzyme reactions. Research has demonstrated its beneficial
effects for a wide range of health problems, in particular, its ability to increase activity of the
anti-aging protein, SIR2p.
Click here for a synergistic formulation with resveratrol
References
1 H . Arichi et al (1982) Effects of stilbene components of the roots of Polygonum cuspidatum on
lipid metabolism. Chem. Pharm. Bull. 30, 1766-70.
2 Losa G.A. Resveratrol modulates apoptosis and oxidation in human mononuclear cells. Eur. J. Clin.
Invest. 2003 Sept.; 33(9): 818-23.
3 Pace-Asciak C.R. The red wine phenolics trans-resveratrol and quercetin block human platelet
aggregation and eicosanoid synthesis: implications for protection against coronary heart disease.
Clin. Chim. Acta, 1995; 235: 207-19.
4 Pozo-Guisado E. et al. The antiproliferative activity of resveratrol results in apoptosis in MCF-7 but
not in MDA-MB-231 human breast cancer cells. J. Steroids Biochem. Mol. Biol. 2003; 84: 149-57.
5 Potter G.A. et al. The cancer preventive agent resveratrol is converted to the anticancer agent
piceatannol by the cytochrome P450 enzyme CYP1B1. Br. J. Cancer. 2002 Mar. 4; 86(5):774-8.
6 Y ang Y. B. et al. Effects of resveratrol on secondary damage after acute spinal cord injury in rats.
Acta. Pharmacol. Sin. 2003; 24: 703-10.
7 Culpitt S. V. et al. Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macro-
phages in COPD, Thorax, 2003 Nov.; 58(11): 592-6.
8 R usso A. et al. Red wine micronutrients as protective agents in Alzheimers like induced insult.
LifeSci. 2003; 72: 2369-79.
9 Savaskan E. et al. Red wine ingredient resveratrol protects from beta-amyloid neurotoxicit. Geron-
tology 2003; 49: 380-3.
10 Chanvitayapongs S. et al. Amelioration of oxidative stress by antioxidants and resveratrol in PC12
cells. Neuroreport 1997; 8: 1499-502.
11 H owitz K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.
Nature. 2003 Sep. 11; 425 (6954): 191-6.
12 B elinha i. et al., Quercetin increases oxidative stress resistance and longevity in Saccharomyces
cerevisiae. J. Agric. Food Chem. 2007 March 21; 55(6): 2446-51.
13 P ietsch k. et al., Quercetin-mediated lifesspan in Caenorhabditis elegans is modulated by age-1,
Sek-1, daf-2 and unc-43. Biogerontology 2008 Nov. 29.
14 S aul n. et al., Quercetin-mediated longevity in Caenorhabditis elegans: is DAF-16 involved? Mech.
Ageing Dev. 2008 Oct.; 129(10): 611-3.

Oxaloacetate
A substance that can mimic calorie restriction and thus increase lifespan and
delay the appearance of age-related diseases.
What is oxaloacetic acid?
Oxaloacetic acid, or its ionic form, oxaloacetate, is naturally present in freshly-picked apples and
oranges. However, it is extremely unstable and does not last more than a day at room tempera-
ture.
Oxaloacetate is present in every cell of the body and its metabolites are directly involved in
mitochondrial energy production as it is an intermediate in the citric acid or Krebs cycle and in
gluconeogenesis. Oxaloacetic acid is therefore a dicarboxylic acid essential for metabolism.
The body produces oxaloacetate but, in certain cases, genetic mutations affect production
of pyruvate carboxylase, a mitochondrial enzyme that converts pyruvate into oxaloacetate,
making the body unable to produce enough oxaloacetate.
How does a lack of oxaloacetate affect metabolism?
When the body lacks oxaloacetate, it has three effects:

The citric acid cycle is interrupted, thus limiting the expression of energy to the body.
Since oxaloacetate is necessary for the first stage of gluconeogenesis which produces the fuel
needed by the body during fasting, its absence severely affects certain organs such as the heart
and brain, which need the glucose produced by gluconeogenesis.
One of the products of oxaloacetate breakdown is aspartic acid, which is needed for the urea
cycle; decreased levels of aspartic acid lead to increases in serum ammonia levels.
For these reasons, the prognosis for patients with decreased levels of oxaloacetate is somewhat
bleak and a lack of oxaloacetate is extremely harmful to the body9.

What are the benefits of oxaloacetate supplementation?
Oxaloacetic acid is a small molecule which, when taken orally as a soluble supplement, is dis-
tributed throughout the body via the bloodstream 10. It is naturally very unstable and does not
last more than a day at room temperature. The recent development of a complex process means
that oxaloacetate can now be stabilized and made totally bioavailable. This substance has also
just received one of very first patents within the framework of lifespan extension, for its efficacy
in mimicking the effects of calorie restriction. In this sense, it is similar to resveratrol although,
as we will see, it acts via different mechanisms.
The latest research demonstrates that oxaloacetate supplementation is extremely beneficial,

not only in mice, but also in humans since it improves a number of essential parameters and
provides considerable protection:
it significantly boosts antioxidant status. Oxaloacetic acids unique abilities are the
result of its capacity for transporting antioxidants into mitochondria, it being able
to cross the mitochondrial membrane easily 17;
it regulates glycaemia and improves insulin resistance;
it combats denaturation of nucleic acids in mitochondria;
at high doses, it protects mitochondrial DNA in cells of brain tissue 19. As it can cross
the blood-brain barrier, it thus protects the brain from certain damage;
it reduces toxicity from certain heavy metals in the cells of pancreatic islets and
neurons 31, 32;
it protects neurons from hydrogen peroxide 33 and free radicals 20, 21, 34, 35;
in combination with zinc, it ensures protection from DMLA for retinal pigment epi-
thelial cells;
it has a positive effect on arthritis and joint stiffness;
it blocks production of fat by the body;
it repairs DNA in skin cells and other tissue damaged by UV rays;
it improves endurance test results in mice;
it reduces certain symptoms of chronic alcoholism (weight loss, nausea, diarrhoea,
shaking), or those of a hangover following over-consumption of alcohol;
it has a positive effect on the digestive tract of rats and inhibits potential ulceration36;
it reduces apoptosis (programmed cell death);
it delays the appearance of most complications associates with age-related diseases;

it reduces incidence of primary or metastatic cancer and can be taken before, during
or after chemotherapy;
in particular, it regulates the expression of certain beneficial genes which are acti-
vated by calorie restriction, and extends lifespan of animal laboratories, notably
mice, by 25%7,8.
Oxaloacetate mimics and reproduces the effects of calorie restriction
Oxaloacetate is one of the most effective substances at reproducing the benefits of calorie res-
triction, so avoiding the need to actually reduce food intake. Calorie restriction - reducing food
intake by 30% to 50% - is the only recognized method of prolonging life in mammals.
It produces changes in metabolism and in the expression of genes which increase lifespan. It has
a beneficial effect on most biological parameters and delays the development of degenerative
diseases (dementia, Alzheimers, Parkinsons).In humans, it reduces the risk of atherosclerosis,
peaks in fasting blood sugar, systolic and diastolic blood pressure, triglycerides, LDL-cholesterol
and total cholesterol, and thus has a direct effect on reducing incidence of cardiac disease, kid-
ney disease, type 2 diabetes and cancer 1, 3.
The ability to mimic these effects through nutritional supplementation constitutes a major
advance in combatting the aging process and degenerative diseases. Calorie restriction is, of
course, very difficult to sustain on a daily basis. Therefore, any substance that can mimic its
effects has surely earned a place among the key advances in anti-aging nutrition.
Oxaloacete is one of the few products shown to increase the lifespan of male mice which, like
humans, do not live as long as females. Research showed that at the 50% mortality mark, oxa-
loacetate increased average lifespan by around 25% compared to controls.
In addition to these remarkable results, it was also reported that mice given oxaloacetate had
minimal inflammation and arthritis symptoms and a lower tendency to age-related curvature of
the spine. Furthermore, bone density was higher than in the control group suggesting efficacy
against osteoporosis. Further studies have shown that oxaloacetates activity is not restricted to
mice. Research on Drosophila melanogaster (the common fruit fly) has demonstrated an ave-
rage increase in lifespan of 20% following the addition of oxaloacetate to food. Similar results
were also obtained with the roundworm C. elegans.
While different species react in different ways and there is no absolute certainty over oxaloace-
tates effects in humans, it is nevertheless possible to make reasonably confident assumptions

regarding its effectiveness given the number of human studies currently being conducted by
the National Institute on Aging in the United States.
Oxaloacetate mimics the cell conditions that result from calorie restriction by restoring the
NAD+/NADH ratio. It crosses cell membranes without difficulty and is easily reduced into malate
by the enzyme malate dehydrogenase in cytosol. This reaction also converts NADH into NAD+,
increasing the NAD+/NADH ratio. This increase is related to the signalling effect which enables
the expression of beneficial genes, so imitating the effects of calorie restriction.
We dont fully understand all the reasons why calorie restriction leads to a longer life, but certain
of them have been identified:
activation of the protein adenosine monophosphate (AMP) 4;

increase in the ratio between nicotinamide adenine dinucleotide (NAD+) and its
reduced version (NADH) in the mitochondria 5.
protection of mitochondrial DNA6.
Therefore, supplementing with oxaloacetic acid offers one of the safest methods of mimicking
calorie restriction.
Also an anti-diabetic substance
The effects of oxaloacetic acid supplements have been tested on humans and animals.
Yoshikawa 10 first studied oxaloacetic acid for its potential in treating diabetes, having identified
it as the active ingredient of Euonymus alata extract, a traditional herb still used today for trea-
ting diabetes in Asian countries after hundreds of years use 23.
Yoshikawa showed that taking sodium oxaloacetate orally allowed it to pass into the bloodstream
within an hour and lowered fasting glucose levels in the bloodstream and urine to normal levels
in the majority of patients, without any side effects.
In animal studies, Yoshikawa showed that sodium oxaloacetate increased tissue absorption of
glucose by 300% in diabetic animals and by 180% in normal animals.
The anti-diabetic properties of oxaloacetic acid should be considered inasmuch as they provide
a safer means of mimicking calorie restriction than conventional methods. The most common
treatment of diabetes uses metformin which, while effective, carries a slight risk of lactic aci-

dosis which can be life-threatening. Whats more, using metformin to mimic calorie restriction
requires life-long use of the drug, increasing individual risk of lactic acidosis to over 1 in 1000.
Although such a risk may be acceptable within the context of calculating risk/benefit in dia-
betes treatment, the use of metformin as a calorie restriction mimetic for increasing longevity
cannot be justified.
This is why the use of oxaloacetic acid to mimic calorie restriction represents a safer option than
the long-term use of anti-diabetic drugs.
Generalized protection against cancer
A consensus exists that calorie restriction is very effective at reducing the incidence of cancer1.
Therefore, it is highly likely that calorie restriction mimetics may have the same effect. Could
an oxaloacetic acid supplement reduce the ability of certain types of cancer cells to reproduce,
without affecting normal tissue?
Research has clearly shown that, by introducing oxaloacetate to human lung cancer tissue in
vitro, the reproduction of cancer cells can be halted while normal cells remain unaffected
even six weeks after the oxaloacetic acid solution had been removed 26. Interestingly, the herb
alatus itself prevents the spread of certain types of cancer whilst maintaining low cytotoxicity.
Its mechanism of action seems to have inhibiting effects on matrix metalloproteinases (MMP)
which are involved in tumour metastasis 27. Of course, while these in vitro results are extremely
encouraging, they now need to be confirmed in vivo.

To recap
Supplementation with oxaloacetic acid successfully mimics some of the effects of calorie res-
triction observed in animals. Animal studies show an increase in lifespan and other significant
health benefits, including protection of mitochondrial DNA, the retina, and neuronal and pan-
creatic tissues. Human studies suggest a substantial decrease in fasting blood sugar and impro-
ved insulin resistance.
In addition, studies into chronic and acute toxicity point to very low toxicity for oxaloacetic acid,
similar to that of vitamin C.
As a calorie restriction mimetic, oxaloacetate induces a number of beneficial changes to gene
expression which considerably extend lifespan.
Following its evaluation, the American FDA has designated oxaloacetate an orphan
drug for the treatment of glioma (including glioblastoma). This designation is used to
encourage the development of natural substances which help fight orphan diseases and
which would not normally be developed due to the very small number of people affected
by these rare diseases.
In addition, oxaloacetate is currently the subject of clinical trials investigating its potential
in the treatment of Parkinsons disease. Results of these studies will be published shortly.

A closer look at the importance of the NAD+/NADH ratio
The by-products of oxaloacetate degradation in the body are well-documented and include
pyruvate, aspartic acid and malate. Once in the body, oxaloacetate (a water-soluble ion) can
react in a number of ways.
One such reaction is the conversion of oxaloacetate into L-malate, catalysed by the enzyme
malate hydrogenase. During this conversion, NADH is also converted into NAD+, considerably
increasing the NAD+/NADH ratio.
When calorie intake is cut, the body produces the glucose it needs from pyruvate, in a process
called neoglucogenesis. Studies on calorie-restricted animals show a change in the activity of
metabolic genes resulting in the production of enzymes responsible for neoglucogenesis 3.
Within this neoglucogenesis process, NADH is converted into NAD+ when biphosphoglyce-
rate is converted into 3-phosphoglyceraldehyde the result of which is an increase in the NAD+/
NADH ratio.
In studies on yeasts, the increase in this ratio was clearly associated with calorie restriction and
led to an increased lifespan 11, 12.
For human cells, prolonged lifespan is linked to increases in nicotinamide phosphoribosyltrans-
ferase and NAD+ precursors 14.
Energy levels and lifespan also seem to be linked with the activity of AMPK 5-adenosine mono-
phosphate-activated protein kinase, which is stimulated by the increase in the NAD+/NADH
ratio 15. AMPK activation also seems to be the underlying mechanism of metformin, an anti-
diabetic drug which has been suggested as a calorie restriction mimetic and which has been
shown to increase lifespan in mice 16. In order to achieve extended lifespan through calorie
restriction, AMPK must therefore be activated 4, as demonstrated by a control group of oxaloa-
cetate-supplemented animals which showed a significantly increased lifespan.except when
AMPK was not activated 7.
So, we can conclude that when oxaloacetate supplementation is administered, activation of
AMPK via an increase in the NAD+/NADH ratio leads to mimicking of calorie restriction.

In addition, when oxaloacetate supplementation was given, the increase in mitochondrial
NAD+ was demonstrated in the calorie restriction process and optimised the survival chances
of cells subjected to genotoxic stress 5. This penetrative effect of oxaloacetic acid into the mito-
chondria17 is also increased by ascorbic acid (vitamin C).
The passage of oxaloacetic acid through the mitochondrial membrane has been confirmed by
more recent studies 18. In particular, these show that in oxaloacetate-supplemented animals,
prolonged cell survival was due to increased levels of mitochondrial NAD+, and that the sup-
plement actually protected mitochondrial DNA 19. However, it is not known whether the latter
was due to the increase in levels of NAD+ in the mitochondria or the fact that oxaloacetic acid
is a powerful antioxidant 20, 21.
It may be that protecting mitochondria also contributes to the extension in lifespan of animals
supplemented with oxaloacetate.
Either way, it has been demonstrated that calorie restriction delays the cumulative effects of
mitochondrial DNA mutations 6. Animals with abnormal mitochondrial function clearly aged
prematurely 22.
The conclusion appears logical: maintaining and improving mitochondria through oxaloace-
tate supplementation is likely to increase lifespan.
Click here to find certified oxaloacetate

Berberine
An AMPK activator and substitute for metformin
Animal studies have clearly identified that substances which can curb the action of insulin can
increase life expectancy - calorie restriction works at this level too. All the synthetic and natural
substances that reduce insulinaemia and glycaemia also restrict the aging process.
In allopathic medicine, the drug most often prescribed to increase insulin receptor sensitivity
and inhibit glucose production by the liver (neoglucogenesis) is metformin. Recent studies
demonstrated that metformin blocked the action of certain genes which contribute to this
neoglucogenesis and activated other genes responsible for glucose metabolism, in exactly the
same way as calorie restriction.
Chinese and ayurvedic medicine utilise a number of plants that are still relatively unknown
in Western medicine. One such plant is Berberis vulgaris, or European barberry, the berries of
which contain a powerful plant alkaloid called berberin. Traditionally used for its immune-sti-
mulant, anti-fungal, and anti-bacterial properties, and its ability to control intestinal disorders,
this substance has emerged as an excellent mimetic of metformin.
Like calorie restriction, berberine induces mild to moderate stress at a cellular level which in the
long-term is beneficial. In fact, when a cell suffers temporary stress, it produces the metabolic
enzyme AMPK (Adenosine Monophosphate Kinase) which prioritises the prevention or repair
of cell damage over synthesis of proteins, fats or carbohydrates which require a lot of energy.
Therefore, all available energy is diverted to cell damage prevention and repair at the expense of
other functions which have to take second place. This change to survival mode forces the cells
to delay their non-essential functions and re-direct resources towards protection and repair.
In activating AMPK, berberine works at several levels:
by improving sensitivity to insulin, it facilitates intracellular glucose transport, enhancing

the bodys use of both sugar and insulin and thus reducing blood glucose levels;
by stimulating fatty acid metabolism in the mitochondria, it reduces levels of circulating
lipids in the blood: triglycerides and LDL-cholesterol;
by promoting extraction of glucose transporters from the circulation, it results in measu-
rable reductions in blood sugar levels;

And finally, by increasing production of GLUT 4, a glucose transporter present only in
muscles and fat cells, it leads to significant improvements in insulin sensitivity.
Such is the extent of berberines properties it can be compared with metformin. The most repre-
sentative studies focus on the efficacy of berberine versus metformin in patients with type II
diabetes 38, whether or not associated with dyslipidaemia 39.
With properties traditionally-recognised as beneficial to immunity, cardiovascular and intestinal
health, berberine also appears to be an excellent anti-aging nutritional supplement.
Research on berberine suggests the recommended daily amount to be between 1g and 1.5g
a day, spread over two or three doses, taken before the three main meals of the day. In order to
benefit fully from berberine supplementation, it should be taken for at least three months, as its
optimal activity is only apparent after two weeks regular use.
Apart from a few reported cases of mild, temporary constipation immediately after beginning
supplementation, berberine is completely free of side-effects.
To summarise, the main benefits of berberine supplementation are:
a significant reduction in glycaemia;

decreased levels of glycated haemoglobin (HbA1c);
rebalancing of circulating levels of insulin;
lower triglycerides, LDL-cholesterol and total blood cholesterol.
and, in particular, the ability to mimic calorie restriction, and thus increase life
expectancy.
Click here to find certified berberine

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25 Salpeter S. R., Greyber E., Pasternak G. A., Salpeter E. E. Risk of fataland nonfatal lactic acidosis with
metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch. Intern. Med.
2003; 163: 2594-602.
26 Farah I. O. Differential modulation of intracellular energetics in A549 and MRC-5 cells. Biomed. Sci.
Instrum. 2007; 43: 110-5.
27 C ha B. Y., Park C. J., Lee D. G., et al. Inhibitory effect of methanol extract of Euonymus alatus on
matrix metalloproteinase-9. J. Ethnopharmacol. 2003; 85: 163-7.
28 Wood J. P., Osborne N. N. Zinc and energy requirements in induction of oxidative stress to retinal
pigmented epithelial cells. Neurochem. Res. 2003; 28: 1525-33.
29 B ressler N. M., Bressler S. B., Fine S. L. Age-related macular degeneration. Surv. Ophthalmol. 1988;
32: 375-413.
30 Friedman D. S., OColmain B. J., Munoz B., e t al. Prevalence of agerelated macular degeneration in
the United States. Arch. Ophthalmol. 2004; 122: 564-72.
31 Chang I., Cho N., Koh J. Y., Lee M. S. Pyruvate inhibits zinc-mediated pancreatic islet cell death and
diabetes. Diabetologia 2003; 46:1220-7
32 B erry E. V., Toms N. J. Pyruvate and oxaloacetate limit zinc-induced oxidative HT-22 neuronal cell
injury. Neurotoxicology 2006; 27:1043-51.
33 Desagher S., Glowinski J., Premont J. Pyruvate protects neurons against hydrogen peroxide-induced
toxicity. J. Neurosci. 1997; 17: 9060-7.
34 O Donnell-Tormey J., Nathan C. F., Lanks K., DeBoer C. J., de la Harpe J. Secretion of pyruvate: an
antioxidant defense of mammalian cells. J. Exp. Med. 1987; 165: 500-14.
35 R oberts E., Simonsen D. G. Protection against hydrazine toxicity by alphaketoglutarate and oxalace-
tate: enhancement of arginine protection. Biochem. Pharmacol. 1965; 14: 351-3.
36 K uroda K., Akao M. Inhibitory effect of fumaric acid and dicarboxylic acids on gastric ulceration in
rats. Arch. Int. Pharmacodyn Ther. 1977; 226: 324-30.
37 W illcox B. J., Curb J. D., Rodriguez B. L. Antioxidants in cardiovascular health and disease: key les-
sons from epidemiologic studies. Am. J Cardiol. 2008; 101: 75D-86D.
38 Yin J., Xing H., Ye J., Efficacy ofberberinein patients with type 2 diabetes mellitus. Metabolism:
clinical and experimental. Metabolism.2008May;57(5):712-7.
39 Zhang Y., Li X., Zou D., Liu W., Yang J., Zhu N., Huo L., Wang M., Hong J., Ren G., Ning G., Treatment of
type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J. Clin. Endocrinol.
Metab.2008Jul.; 93(7):2559-65. Epub 2008 Apr.8.

STEM CELL ACTIVATORS
Research on adult and embryonic stem cells has raised considerable hope in
the field of medicine and the fight against aging and age-related diseases.
The use of embryonic stem cells is the subject of great ethical debate world-
wide and is not authorised in all countries - it is banned in France, for example.
Human stem cells were first isolated, cultivated and differentiated from embryos in 1998. There
are several types of stem cells which differ according to their source:
totipotent cells obtained in the first four days of growth of the embryo - they are
the only ones that allow the development of a human being;
pluripotent stem cells derived from the blastocyst, destined to produce all body
tissues;
multipotent stem cells present in the adult body, which differentiate into several
types of cells;
unipotent stem cells that produce only one type of differentiated cell.
Stem cells are naturally present in organs and enable cell regeneration. In certain tissues, cells
are constantly renewed. Their stem cells generate differentiated cells in order to replenish
cells when needed. Red blood cells, the bodys oxygen carriers, live for only 120 days and are
constantly replaced by new cells formed from stem cells in bone marrow. In the digestive sys-
tem, intestinal stem cells constantly differentiate into cells that line the intestine, thereby repla-
cing those that are sloughed off. Skin stem cells make skin while stem cells in the hair follicles
make hair. Stem cells produce a wide range of immune cells that differentiate into adult immune
cells in response to specific signals from hormone-like substances, levels of which increase with
infection and inflammation.

The role of haematopoietic stem cells in the treatment of haematological diseases has already
been proven. Bone marrow, peripheral blood and placenta cells are used in such cases. Stem
cells in the bone marrow help to regenerate all blood lines from bone marrow. This process is
the basis of bone marrow transplants performed following treatment of cancer by chemothe-
rapy that can destroy all blood lines. In such cases, bone marrow cells may come from a donor
compatible with the patient. They are taken from the iliac crest bones and stored pending com-
pletion of the chemotherapy. Released back into the patients blood stream, the cells re-colo-
nise the bone marrow restoring the creation of all blood lines.
Today, it is recognised that adult stem cells can be obtained from various sources such as the
central nervous system, skeletal muscle, the pancreas and even fat. In addition, scientists have
been able to isolate and culture adult stem cells much more easily than previously thought
possible. Recent studies have shown that, under certain conditions, and once re-implanted in
another organ, adult stem cells can acquire the characteristics of their new environment.
The natural activation of stem cells thus constitutes a promising advance in delaying the aging
process and increasing length and quality of life. In the coming years, stem cell therapy will
represent a significant advance in the fight against degenerative diseases for which conventio-
nal medicine can generally provide only short-lived or temporary results.
The injection of adult stem cells from bone marrow is currently authorised in some countries,
but is by no means widespread.
Hence the importance of the research conducted in recent years by certain scientists who, with
the use of nutrients and plant extracts, have been able to stimulate and increase the amount of
adult stem cells in bone marrow. For regeneration activity purposes, scientists have been par-
ticularly focusing their research on bone marrow as these cells evolve daily by producing new
lines of red blood cells, white blood cells and platelets. Mature cells are then released into the
bloodstream where they exert their full regenerative and vital functions.
The nutrients that studies have revealed to be the most active include folic acid, vitamin B12,
iron and other better- or lesser-known components such as fucoidan, Polygonum multiflorum
extract, wild blueberry extract and beta 1.3/1.6 glucan.

But what benefits can we expect from the use of stem-cell activating substances?
An increase in average life expectancy.

A reduction in the decline in immune function that results in increased susceptibi-
lity to infections, cancer and other chronic inflammatory diseases
An improvement in condition and in the pain associated with degenerative diseases
(macrophagic myofasciitis, Hunter syndrome, muscular dystrophy, Alzheimers,
Huntingtons and Parkinsons diseases as well as multiple sclerosis).
Stem cell pioneers win Nobel Prize
On October 9, 2012, Dr. John B. Gurdon of Cambridge University in England and Dr. Shinya Yamanaka of
Kyoto University in Japan were awarded the Nobel Prize in Medicine for their work on induced pluripo-
tent stem cells (or IPS cells).These two scientists have helped lay the foundations for regenerative medi-
cine with their concept of regenerating all human body tissues through the injection of pluripotent cells.
This new technology thus enables the mechanisms of aging to be targeted in advance. Through these
scientific advances, any somatic cell can be restored to an all-powerful pluripotent stem cell state, from
a sliver of skin, blood cells or a hair. Rejuvenated cells obtained in this way are identical in all respects to
those created decades earlier.
What was just the hope or vision of a few people will tomorrow become a
reality

Fucoidan
Recognised in Japan for its immune-stimulant and anti-cancer properties, fucoidan is extracted
from a type of algae, Laminaria japonica, part of the laminaria family. This sulphated polysac-
charide boosts the immune system, improving defence against different viruses and helping
protect the body by promoting apoptosis (programmed cell death) of cancer cells. People with
a high intake of fucoidan appear to live longer too, as demonstrated by the inhabitants of Oki-
nawa who eat brown seaweed on a daily basis.
Scientific research into fucoidan began in the 1970s and since then, it has been the subject of
almost 700 papers. The results of these studies, combined with anecdotal data from the long
history of fucoidan-rich algae consumption in Japan, Hawaii and Tonga, suggest that fucoidan
can relieve a great many health problems and increase life expectancy.
It activates the immune system
The immune systems first line of defence are NK cells natural killer cells. Research suggests
that when people in poor health increase their intake of gluconutrients, there is a sharp increase
in the number of their NK cells.
A number of polysaccharides have effects on different immune responses. One in vitro study
looked at fucoidans immune-modulatory effect. Mouse spleen lymphocytes became cyto-
toxic to tumor cells after culture with fucoidan. Macrophages treated with fucoidan exhibited
induced tumoricidal activity, increased phagocytosis, lysosomal enzyme activity and produc-
tion of nitrite, H2O2, tumour necrosis factor (TNF)-alpha and interleukin 6. The tumoricidal effect
of macrophages induced by fucoidan appeared to be mainly mediated by free radical and
cytokine production. These findings suggest that fucoidan is an activator of lymphocytes and
macrophages and that this property could contribute to its effectiveness in the immunopreven-
tion of cancer1.
It has anti-cancer effects
Fucoidan has shown a marked anti-cancer effect in animal models, whether injected into the
bloodstream or the peritoneal cavity, or administered orally. Specifically, a significant reduction
in cancer development was observed in mice and rats in which cancer cells had been implanted.
This effect has been noted in several animal cancer models, including leukaemia and breast

cancer. Fucoidan appears to act via two anti-cancer mechanisms: apoptosis which triggers the
death of certain types of fast-growing cancer cells and by directly destroying cancer cells wit-
hout affecting healthy cells.
Mice were fed for 10 days with food containing fucoidan, and then injected with leukaemia
cells. The mice were then given fucoidan-containing food for a further 40 days. Fucoidan inhi-
bited tumours by 65%. It seems to mediate tumour destruction through T lymphocyte and NK
cell responses2.
And in particular it promotes cell regeneration
As with other substances extracted from algae, certain concentrations of fucoidan have exhi-
bited the ability to stimulate bone marrow stem cells.
A clinical study in which healthy volunteers ingested 3g of fucoidan a day for 12 days demons-
trated a significant increase in the proportion of haematopoietic stem cells in peripheral blood.
No side effects were observed.
Other studies have shown that fucoidan led to an increase in alkaline phosphatase activity at
a molecular level, and improved expression of genes specific to osteogenesis and osteogenic
differentiation, thus promoting bone regeneration.
Therefore, by acting directly on the mobilisation of stem cells, fucoidan facilitates more effective
repair of damaged tissues, both in cardiovascular terms, following a heart attack, as well as in
the joints or vital organs.

Astragaloside IV
As we have seen already, astragaloside IV is already known for its telomere-lengthening effects.
The adaptogen plant Astragalus membranaceus from which astragaloside IV is extracted, has
been used for hundreds of years in traditio-
nal Chinese medicine, to increase vitality and
strength, amongst others.
Research shows this saponin stimulates the
immune system in various ways, in particu-
lar, by increasing stem cells in the spinal cord
and lymphatic tissue and encouraging them
to develop into active immune cells.
Astragaloside IV also supports proliferation
of mesenchymal stem cells, pluripotent tis-
sue stem cells that help form skeletal connec-
tive tissue such as bone and cartilage.
Polygonum multiflorum
Extract of Polygonum multiflorum or FO-TI, is recognised in Chinese medicine as an effective
blood tonic, and in particular as a major factor in longevity due to its ability to increase levels of
circulating superoxide dismutase (SOD) and monoamine oxidase.
Mouse studies conducted in Taiwan show that after daily administration of high-dose (200-
1000mg/kg) Polygonum multiflorum, significant improvements were noted in red blood cells,
and in particular, a higher percentage of hematocrit compared with a control group. This
research also shows that doses at this level stimulate proliferation of stromal and haematopoie-
tic stem cells in bone marrow.

Extract of wild blueberry
Studies have shown that extract of Vaccinium uliginosum standardized to 25% anthocyanidins
can prevent and reverse the age-related decline of certain cell functions. In particular, wild blue-
berry extract has been shown to increase neurogenesis in the brains of elderly laboratory rats.
Researchers experimented with neural tissue transplantation following cell damage caused by
neurodegenerative disease or brain injury. In general, transplanted tissue has very little chance
of survival, particularly in older recipients. But when animals were supplemented with blue-
berry extracts, the growth of the transplantation and cell organization were comparable to that
observed in younger recipients. Blueberry extracts may therefore confer their beneficial effects
by increasing proliferation of neural stem cells.
Beta 1.3/1.6 glucan

The majority of research into this oat-extract polysaccharide has highlighted its potent immune-
modulatory effects.
Recent studies have suggested that beta 1.3/1.6 glucan promoted hematopoiesis and boosted
the proliferation of stem cells, thus improving the repair of white cells in bone marrow. The pro-
tective action of beta 1.3/1.6 glucan against the harmful effects of radiation was demonstrated
in 1985 in research conducted by the US armed forces Institute of Radiobiological Research.
Myra D. Patchen and her team had exposed mice to lethal doses of radiation.
70% of mice given an oral dose of yeast-extracted beta 1.3/1.6 glucan following exposure to
radiation were completely protected against the harmful effects 3. Dr Patchen also suggested
that the use of beta 1.3/1.6 glucan should be considered as an effect way of restoring the
immune system and preventing infection following chemotherapy or radiotherapy treatment
for cancer. According to Patchen, beta 1.3/1.6 glucan acts as an antioxidant and may even pro-
tect macrophages against damage from radiation, toxins, heavy metals and free radicals.

Injecting beta-glucan into the peritoneum of mice which had been completely exposed to
Xrays significantly delayed their death, as well as the growth of tumours in animals with cancer.
Forty days after the radiation exposure, almost 30% of beta 1.3/1.6 glucan-treated mice were
still alive, compared with just 3% of the non-treated mice. The researchers discovered that beta-
glucan boosts the proliferation of stem cells, promoting the repair of white cells in damaged
bone marrow. A single dose of beta-glucan considerably increased the animals leucocytes and
lymphocytes. Furthermore, the activity of natural killer cells and killer cells activated by lympho-
kines increased significantly with repeated doses of beta-glucan. These mechanisms appear to
play a role in the prevention of secondary infections associated with irradiation. They probably
also help stop the growth of tumours in animals with cancer, by stimulating anti-tumour immu-
nity. These results suggest that beta-glucan may be a promising adjunct treatment for cancer4.
L-carnosine
L-carnosine, which acts on the maintenance of telomeres (see previous chapter) improves repli-
cative capacity of myoblast cultures. Certains myoblasts, called satellite cells, remain on the
periphery of muscle fibres, intervening in their repair when damaged. However, with increasing
age comes sarcopaenia (loss of muscle mass) and the satellite cells are no longer able to repair
the damage.
A study on myoblasts - the stem cells responsible for skeletal muscle formation - showed that
supplementing with L-carnosine increases their replicative capacity and also reduces the acti-
vity of beta-galactosidase.

Vitamin C
In recent years, scientists have discovered that adult cells can be reprogrammed into pluripo-
tent stem cells. A team of Chinese researchers recently demonstrated that in the course of such
reprogramming, large amounts of free radicals are released which might go some way to explai-
ning the ineffectiveness of this reprogramming process. They also showed that adding vitamin
C improved the production of completely reprogrammed stem cells and that other antioxidants
had no such effect. Vitamin C appears to act by accelerating changes in gene expression, thus
promoting more effective transition into a totally reprogrammed state5.
Vitamin D3
Over 90% of our vitamin D3 needs should in theory be met by exposure to the sun, but popula-
tions in Western countries, such as France, Belgium, the United States, Switzerland and Canada,
actually have inadequate levels of vitamin D, especially during the winter. We are now aware of
the risks associated with a lack of vitamin D3 but scientists are providing increasing evidence
of its fundamental role in cell division and differentiation and its effects on the immune system.
In fact, inadequate vitamin D levels are linked to almost all age-related problems, including
cancer, vascular disease and chronic inflammation.
Research suggests that doses of 5000 IU a day could offer multiple health benefits. This is also
the dose recommended by the Vitamin D Council.
Studies have also shown that vitamin D, combined with other natural substances, may have
effects on adult stem cells and as a result, increase neurogenesis and improve cognitive abi-
lity. Researchers therefore tested a synergistic combination of extracts of blueberry, green tea,
L-carnosine and vitamin D3. When this unique combination of substances was given to rats,
there was a clear decrease in oxidative stress but more significantly, it was shown to promote
the proliferation and migration of neural stem cells towards damaged brain cells (following a
stroke for example).
Click here for a formulation that naturally stimulated stem cell production

The immortality gene
For many years, German scientists have been focusing on the hydra (a freshwater polyp) which appears
to be immortal Indeed, if you cut a hydra in half, it quickly regenerates. Its ability to do so is linked to
its stem cells which do not age and can proliferate indefinitely.
Gene analysis has revealed that it is the long-recognised FoxO3 gene, associated with longevity in
centenarians, which is also found in the hydra. Whats more, when researchers inactivated this FoxO3
gene, they observed a significant decrease in the number of stem cells and less effective function of the
immune system.
These results show that the FoxO3 gene plays an important role in the aging process and offers hope in
the area of gene therapy and immortality.
References
A nna-Marei Boehm, Konstantin Khalturin, Friederike Anton-Erxleben, Georg Hemmrich, UlrichC. Klos-
termeier, Javier A. Lopez-Quintero, Hans-Heinrich Oberg, Malte Puchert, Philip Rosenstiel, Jrg Wittlieb,
Thomas C. G. Bosch., FoxO is a critical regulator of stem cell maintenance in immortal Hydra. PNAS
2012; published ahead of print November 12, 2012, doi:10.1073/pnas.1209714109.
1 C hoi E.M. et al., Immunomodulating activity of arabinogalactan and fucoidan in vitro. J. Med. Food,
2005 Winter, 8(4): 446-53.
2 The role of NK cells in antitumor activity of dietary fucoidan from Undaria pinnatifida sporophylls
(Mekabu), Planta Med. 2006 Oct. 20, Department of Pathology, School of allied health sciences,
Kitasato University, Kitasato Kanagawa, Japan.
3 P atchen M.L. et al., Glucan: mecanisms involved in its radioprotective effect, J. Leux Biol., 1987,
42:95-105.
4 Enhancement of radioprotection and anti-tumor immunity by yeast-derived beta-glucan in mice,
J. Med. Food, 2005 Summer, 8(2):154-8.
5 Cell Stem Cell, published on-line on December 24th 2009.

OTHER PROMISING SUBSTANCES
This chapter includes those substances difficult to place in a particular cate-

gory, but which research has already shown can extend lifespan in animals.
Given their safety and health benefits, we recommend they be included in
any anti-aging regime.
Saikosaponin A
This new genetic cell detoxifier could extend lifespan

by activating the P16 tumour-suppressing gene
Researchers are constantly and actively engaged in the quest to hold off the ravages of aging
and extend human lifespan. The latest advances in genetics are generating significant new opti-
mism 1.
Scientists have made a genetic breakthrough which they say could extend human lifespan and
even protect against cancer. Experiments on mice have shown that their lifespan could be pro-
longed by up to 45%, without developing cancerous tumours. This suggests that under certain
conditions, humans could live to almost 125 years, cancer-free, because the genes thought to
be responsible are naturally present and have identical roles - in both mice and humans.
Geneticists and cancer experts have reached the same conclusions on the identification and
role of these genes:
The telomerase gene boosts the immune system and in particular, lengthens the shortest
telomeres - the tips of chromosomes. It responds exceptionally well to astragaloside IV
and cycloastragenol.

The P53 gene (or tumour suppressor) is activated more specifically by resveratrol and
its derivatives.
The P16 gene, also a tumour suppressor gene, completes the picture by controlling
anarchic cell mitosis. Recently, it has been possible to use P16 gene concentration, which
increases in human tissue with age, in blood tests as a biomarker for cell aging.
Manuel Serrano, a Spanish researcher at the CNIO, told a conference: When P53 and P16 genes
were activated in mice, cancer incidence was reduced to practically zero. The Spanish scientists
concluded that the activation of three genes telomerase, P53 and the tumour-suppressor P16
represented a major contribution to the prevention and regression of tumours by apoptosis
(programmed cell death). They added: We do not think that the mice lived longer because they
didnt have cancer, but because these genes protected them against aging.
This is therefore the first time that scientists have been able to prolong lifespan in mice in this
way (by inserting an extra copy of the three genes), while protecting them from cancer. Until
now, the mice were aging without cancer, but their lifespan did not increase significantly. And
only calorie restriction enabled their life expectancy to be extended. These transgenic mice,
able to self-reproduce, have strengthened their new DNA model, thus creating a group of
supermice, with longer lifespans of 4.5 years compared with the average 3 year lifespan, and
that benefit from optimal protection against cancer.

When Western research meets traditional Chinese medicine
Bupleurum falcatum or buplevre, belongs to the Apiacaeae plant family and is used in traditional
Chinese and Japanese medicine. It is widely considered to be a cell detoxifier that helps fight
chronic infection and inflammatory conditions (particularly hepatitis). Bupleurum has recently
increased in popularity due to favourable results achieved in cancer treatment. Its active prin-
ciples are the saikosaponins A, B, C and D. Of these, it is the A form, a triterpenoid glycoside, that
activates the tumour-suppressing P16 gene, but it is extremely rare and expensive - you would
need to consume 50g of Bupleurum to obtain 4mg saikosaponin A. This new plant substance -
saikosaponin A has been specifically selected and isolated in order to activate the P16 tumour
suppressor gene 2.
A number of studies have demonstrated the immunosuppressive effects of saikosaponin A. It

significantly inhibits the proliferation and activation of T cells and induces apoptosis of can-
cer cells via mitochondria, making it a potential treatment for inflammatory and auto-immune
disease 3, 4.
One study combined saikosaponin A with astragaloside IV. It showed that treated mice lived
significantly longer than controls, however advanced their tumours. The Chinese researchers
also observed that mice with cancer whose diet had been supplemented with saikosaponin A
lived longer than healthy mice. This encouraging animal research has already led to the deve-
lopment of human application treatments in the oncology departments of a number of Chinese
hospitals.

Good combinations for boosting its effects
The benefits of saikosoaponin A are enhanced when it is combined, though not simultaneously,
with other anti-aging substances. Supplementation with saikosaponin A is recommended on a
non-continuous or alternating basis, ie, every other week, with astragaloside IV or cycloastrage-
nol, which activate the telomerase gene, and with resveratrol and its derivatives, which activate
the P53 gene.
Though it is still too soon to establish a strict administration protocol for this product, the fol-
lowing can be used as a basis:
Either a 4mg dose of saikosaponin A in the evening, and astragaloside IV and/or
cycloastragenol in the morning.
Or you can alternate these products every other day.
No adverse reaction has been observed to date.
Caution: as saikosaponin A is a vasodilator, comparable to niacin, it should not be taken by anyone using
coronary vasodilators, or by pregnant women or nursing mothers.
Click here to find certified saikosaponin A
References
1 M aria A. Blasco, Bruno M., Bernardes de Jesus: CNIO scientists successfully test the first gene therapy
against ageingassociated decline. Fundacin Centro Nacional de Investigaciones oncolgicas
Carlos III.
2 Wu W. S., Hsu H. Y.: Involvement of p-15(INK4b) and p-16(INK4a)geneexpression in saikosapo-
ninA and TPA-induced growth inhibition of HepG2 cells. Biochem Biophys. Res. Commun. 2001 Jul.;
13;285(2):183-7.
3 Sun Y., Cai T. T., Zhou X. B., Xu Q.: SaikosaponinA inhibits the proliferation and activation of T cells
through cell cycle arrest and induction of apoptosis. Int. Immunopharmacol. 2009 Jul.; 9(7-8):978-
83. doi: 10.1016/j.intimp. 2009.04.006. Epub 2009 Apr 16.
4 Yano H., Mizoguchi A., Fukuda K., Haramaki M., Ogasawara S., Momosaki S., Kojiro M. The herbal medi-
cine sho-saiko-to inhibits proliferation of cancer cell lines by inducing apoptosis and arrest at the
G0/G1 phase. Cancer Res.1994 Jan. 15;54(2): 448-54.

Centrophenoxine
To counter the effects of aging on the brain

Centrophenoxine, also known as meclofenoxate, was developed in 1959 and has been widely
used for over 30 years to combat cerebral problems associated with aging and changes in
memory.
Centrophenoxine is composed of two substances:
DMAE (dimethylethanolamine), a natural component of foods such as fish. It is also a

metabolite of choline, which is naturally present in the body.
PCPA, a synthetic compound similar to a variety of phytohormones called auxins. It is
also an analogue of pyroglutamic acid (PCA), naturally present in the brain.
These two substances are, amongst others, powerful antioxidants that can protect the brain
from free radical damage. Centrophenoxines therapeutic benefits have been particularly noted
in cases of cerebral atrophy, age-related brain damage, cerebral congestion, chronic alcoholism
or drug abuse.
Prevents mental deterioration
Clinical studies on geriatric patients showing symptoms of confusion, extreme weakness, dis-
turbances in memory or intellectual concentration, have revealed marked progress and impro-
vements in symptoms after just a few weeks treatment with centrophenoxine. Regular use can
thus prevent mental deterioration and improve memory performance in both healthy indivi-
duals and those suffering from dementia 3.
In a double-blind study of 50 elderly subjects suffering from moderate dementia, centrophe-
noxine stimulated memory significantly more than a placebo. It also produced general impro-
vements in patients condition 9.

A double-blind study on geriatric patients suggested that centrophenoxine increased the capa-
city to transfer new information to the secondary memory. Alongside this improved memory
function, ability to carry out daily activities was also enhanced. Patients expressed these bene-
ficial effects in terms of improved attention and a feeling of well-being.
Boosts energy production in the brain
Centrophenoxine stimulates brain function. It increases neuronal uptake of glucose and oxygen
as well as production of carbon dioxide, indicating increased brain energy (ATP) production.
Research on rats showed a steady increase in cerebral metabolic activity, even under hypoxic
conditions, and an increase in cortical electrical activity (a reflection of brain metabolic activity)
in almost 40% of adult or elderly animals.
Superior cholinergic
DMAE, the main constituent of centrophenoxine, is converted into choline by the liver by adding
a methyl group. Centrophenoxine thus supplies DMAE and choline to the brain. Choline, a simi-
lar substance to B group vitamins, comes from the diet (from liver, meat and eggs) and is pro-
duced in small amounts by the body. However, too little choline can be provided by the diet, as
a result of food processing and of following certain diets (vegetarian or vegan) and a low intake
of choline is not good for our health 4, 5.
Indeed, choline is essential for optimal brain function and is used to produce other substances
such as acetylcholine, a neurotransmitter crucial for memory, learning and mental concentration.
It also produces two essential components of the cell membrane phosphatidylcholine and
sphingomyelin. Choline insufficiency can sometimes lead to permanent auto-cannibalization,
membrane disruption, and cell death. Furthermore, a number of studies have associated exces-
sive neuronal choline auto-cannibalization over a lifetime with the development of Alzheimers
disease.
Therefore, centrophenoxine is probably the most effective way of increasing blood and brain
levels of choline and acetylcholine.

Powerful antioxidant
As we age, neuronal membranes normally become less fluid and more rigid due to hydroxyl
radical damage and cross-linked proteins. This decrease in fluidity impairs the ability of neu-
ronal membranes to conduct electrical impulses. Fluidity decreases as hydroxyl-induced lipid
peroxidation increases 6.
Maintaining a good level of phosphatidyl DMAE in neuronal cell membranes through regular
supplementation with centrophenoxine thus represents an effective strategy for:
combatting aging of the brain;

repairing or regenerating neuronal and synaptic cell membranes damaged by
hydroxyl radicals;
significantly increasing the fluidity of neuronal membranes7.
Ability to increase RNA synthesis
In general, production of total RNA, messenger RNA and proteins falls considerably with age.
Studies conducted on elderly rats showed that centrophenoxine significantly increased RNA
synthesis, producing almost the same levels as adult rats. RNA (derived from DNA in the cell
nucleus) allows cells to receive instructions from nuclear genes and make new proteins to
replace worn-out or hydroxyl radical-damaged proteins2.
It is highly effective at reducing certain cell waste products
According to data from animal studies, centrophenoxine is very effective at reducing levels of
lipofuscin 1. Lipofuscin is a residue consisting of fragments of membranes, damaged proteins
and fatty acids. It accumulates in cells in later life to the point where it sometimes accounts for
30% of their volume as shown in elderly animals. As cells store more lipofuscin, their function
becomes less effective and they can quickly die once a critical volume is reached. Lipofuscin
is sometimes called the aging pigment. It manifests as brown marks on the skin, called liver
spots or aging spots, usually on the hands and face.

Animal and human research has shown low levels of lipofuscin are correlated with healthy cell
function and low levels with unhealthy cells.
Long-term use of centrophenoxine in healthy, elderly animals led to a considerable reduction in

lipofuscin in the brain 8. Memory and learning capacity were restored to almost youthful levels.
In addition, their life expectancy was much longer than untreated animals. This study is the only
research to scientifically demonstrate that centrophenoxine extends lifespan in animals.
Centrophenoxine is therefore one of the few substances shown to increase longevity in labora-
tory animals. Its effects in reducing levels of lipofuscin, an intracellular metabolic waste product,
are unique and directly address one of the seven deadly things identified by Aubrey de Grey.
To recap, centrophenoxine
Significantly improves the memorising process, in particular, increasing the speed

at which memorised information can be used;
Improves the use and metabolism of glucose in the brain which benefits concentra-
tion and attention and contributes to a sense of well-being;
Is the only known agent shown to reduce the accumulation of lipofuscin, a toxin
associated with aging, in the cells of the brain, heart, lungs and skin. Cells affec-
ted by lipofuscin can no longer communicate and function properly. Patients with
Alzheimers disease have abnormally high levels of lipofuscin in the brain.
Click here to find certified centrophenoxine

References
1 C entrophenoxine: effects on aging mammalian brain, Nandy K., 1978, J. Am. Ger. Soc. 26, 74-81. A
survey of the available data on a new nootropic drug, Zs-Nagy et al., 1994, BCE-001 Ann. N. Y. Acad
sci. 717, 102-14.
2 Centrophenoxine increases the rate of total and mRNA synthesis in brain cortex of old rats: an
explanation of its action in terms of the membrane hypothesis of aging. Zs-Nagy et al., 1984, Exp.
Gerontol. Geriatr. 9, 17-30.
3 The differential effects of meclofenoxate on memory loss in the elderly, Marcer D. et al, 1977, Age
and ageing, 6, 123-31.6. Age-related change in the multiple unit activity of the rat brain parietal
cortex and the effect of centrophenoxine, Roy D. et al, 1988, Exp. Gerontol. 23, 161-74.
4 Choline: an important nutrient in brain development, liver function and carcinogenesis, Zeisel S.,
1992, J. Am. Coll. Nut. 1, 478-81.
5 Choline, an essential nutrient for humans, Zeisel S. et al., Faseb j. 5, 2093-98.
6 Alterations in the molecular weight distribution of proteins in rat brain synaptosomes during
aging and centrophenoxine treatment of old rats, Nagy K. et al., 1984, Mech. Age dev. 28, 171-176.
7 Fluidising effects of centrophenoxine in vitro on brain and liver membranes from different age
groups of mice. Wood et al. 1986, Life Sci. 39, 2089-95.
8 Effects of centrophenoxine on lipofuchsine pigment in the nervous system of old rats, Riga S. et
al., 1974, Brain Res. 72, 265-275.
9 Effects of centrophenoxine on body composition and some biochemical parameters of demented
elderly people. Fulop T. Jr. et al, 1990, Arch. Gerontol. Geriatr. 10, 239-51.
Apple polyphenols
Plant polyphenols offer tremendous promise for solving the problems associated with aging.
In three recent studies, apple polyphenols were shown to extend lifespan in laboratory animal
models (by up to 12%).
These findings seem to be explained by the activation of genes which stimulate endogenous
antioxidant defences and by the inhibition of other genes involved in premature death.
Epidemiological studies confirm a correlation between consumption of flavonoids in general,
and apple flavonoids in particular, and human longevity.

Phloridzin is one such polyphenol which is concentrated in apple peel. It is one of the chalcone
flavonoids, which reduces insulin resistance and is effective at countering glycation via a num-
ber of synergistic mechanisms.
Apples are also rich in chlorogenic acid, catechins, epicatechins and various tannins.
Apple polyphenols are also potent antioxidants with an ORAC value three times that of green
tea extract. Polyphenols combat free radicals, by increasing in particular the activity of the
endogenous antioxidant paraoxanase by over 20%.
As demonstrated in many studies, apple polyphenols have many applications. In terms of anti-
aging, they are of particular use as anti-cancer agents, almost halving the risk of colon cancer.
Click here to find apple polyphenols
Epimedium
Epimedium and its active substances are widely used to increase libido and promote good
sexual health. Researchers have recently been studying the effects of this plants flavonoids, par-
ticularly icariine and icariside II, its bioactive form in vivo, on the life expectancy of the C.elegans
worm. They found that icariside II increased lifespan by more than 20% by affecting intracellular
signalling molecules activated by insulin and IGF-1.
The researchers concluded that Given the extensive protective effects and safe long term use of
icariin and icariside II in humans, they may serve as promising anti-aging candidates in the future.
Click here to find epimedium
References
C
ai W. J., Huang J. H., Zhang S. Q., Wu B., Kapahi P., Zhang X. M., Shen Z. Y. Icariin and its derivative ica-
riside II extend healthspan via insulin/IGF-1 pathway in C. elegans. PLoS One.2011; 6(12): e28835.
doi: 10.1371/journal.pone.0028835. Epub 2011 Dec. 21.

L-theanine
Traditionally used to reduce feelings of stress and anxiety, L-theanine, derived from tea (Camellia
sinensis), is also proving to be a specific anti-aging amino acid. High concentrations of L-theanine
are already known to help reduce obesity, hypertension and cancer risk.
Studies on C. elegans worms suggest that this substance can extend life by between 3.6%
and 4.4%. According to the researchers, Taken together, these findings indicate that L-theanine
extends C. elegans lifespan suggesting that this compound may be worth evaluating in mammals
and humans in regard to prevention of aging.
Click here to find L-theanine
References
arse K., Jabin S., Ristow M., L-Theanine extends lifespan of adult Caenorhabditis elegans. Eur. J.
Z
Nutr.2012 Sep; 51(6):765-8. doi: 10.1007/s00394-012-0341-5. Epub 2012 Mar. 16.
Reishi
Reishi has been in medicinal use for over 2000 years; in ancient times it was known as the mus-
hroom of immortality with good reason. Recent decades have seen a focus on the analysis of
its various constituents. Research has confirmed that reishis many properties confer all-round
protection against the various diseases which challenge our longevity.
Among the hundreds of active components in reishi, researchers have identified three specific
substances that have powerful anti-aging effects:
Polysaccharides, which have anti-cancer effects due to their ability to prevent

abnormal blood vessel formation and to boost the immune system1, 2.

Triterpenes, which protect the liver, lower blood pressure and cholesterol, prevent
platelet aggregation that leads to heart attack and stroke, fight allergic responses
triggered by histamine, and also possess anticancer activity 2.
Ganoderma lucidum peptide which has powerful antioxidant properties3.
What makes this mushroom unique is its ability to act in many places at the same time, trigge-
ring important changes which contribute to increased longevity:
It protects cell DNA from the oxidative damage that contributes to aging and can-
cer 4;
It protects mitochondrial DNA and the mitochondria themselves from oxidative
damage that impairs their energy-producing ability and makes them ineffective,
another major cause of aging 5, 7;
It increases levels and activity of numerous intracellular antioxidant molecules,
thus reducing oxidation of cell membranes 8, 9;
It protects the kidneys from oxidative damage and therefore lowers the risk of kid-
ney failure 10;
It increases expression of a longevity gene, and extends life expectancy in several
species, from yeasts and primitive worms to mammals such as mice11,12,13, 14.
Researchers who have studied reishis effects in laboratory mice have clearly identified that it is
associated with an increase in animal lifespan of between 9% and 20%, which equates to 7-16
extra years in humans 13.
Its wide-spectrum properties prevent and treat many age-related diseases and therefore target
aging at its roots.

References
1 C heng K.C., Huang H.C., Chen J.H. et al., Ganoderma lucidum polysaccharides in human monocytic
leukemia cells: from gene expression to network construction. BMC Genomics. 2007;8:411.
2 Boh B., Berovic M, Zhang J., Zhi-Bin L. Ganoderma lucidum and its pharmaceutically active com-
pounds. Biotechnol. Annu. Rev., 2007;13:265-301.
3 Sun J., He H., Xie B.J., Novel antioxidant peptides from fermented mushroom Ganoderma lucidum.,
J. Agric. Food Chem. 2004 Oct. 20;52(21): 6646-52.
4 W achtel-Galor S., Choi S. W., Benzie I. F. Effect of Ganoderma lucidum on human DNA is dose
dependent and mediated by hydrogen peroxide. Redox Rep., 2005; 10(3): 145-9.
5 A jith T.A., Sudheesh N.P., Roshny D., Abishek G., Janardhanan K.K. Effect of Ganoderma lucidum on
the activities of mitochondrial dehydrogenases and complexI and II of electron transport chain
in the brain of aged rats. Exp. Gerontol., 2009 Mar., 44(3): 219-23.
6 C herian E., Sudheesh N.P., Janardhanan K.K., Patani G., Free-radical scavenging and mitochondrial
antioxidant activities of Reishi-Ganoderma lucidum (Curt: Fr.) P. Karst and Arogyapacha-Trichopus
zeylanicus Gaertn extracts. J. Basic Clin. Physiol. Pharmacol. 2009; 20(4): 289-307.
7 S udheesh N.P., Ajith T.A., Janardhanan K.K., Ganoderma lucidum (Fr.) P. Karst enhances activities of
heart mitochondrial enzymes and respiratory chain complexes in the aged rat. Biogerontology.
2009 Oct.;10(5):627-36.
8 W achtel-Galor S., Yuen J., Buswell J.A., Benzie I.F.F., Ganoderma lucidum (Lingzhi or Reishi): A Medi-
cinal Mushroom. In: Benzie I. F., Wachtel-Galor S., eds. Herbal Medicine: Biomolecular and Clinical
Aspects. 2nd ed. Boca Raton: CRC Press; 2011.
9 Sudheesh N.P., Ajith T.A., Ramnath V., Janardhanan K.K., Therapeutic potential of Ganoderma luci-
dum (Fr.) P. Karst. against the declined antioxidant status in the mitochondria of post-mitotic tis-
sues of aged mice. Clin. Nutr. 2010 Jun.;29(3): 406-12.
10 L ai K.N., Chan L.Y., Tang S.C., Leung J.C., Ganoderma lucidum extract prevents albumin-induced
oxidative damage and chemokines synthesis in cultured human proximal tubular epithelial cells.
Nephrol. Dial Transplant. 2006 May; 21(5):1188-97.
11 Weng Y., Lu J., Xiang L. et al., Ganodermasides C and D, two new anti-aging ergosterols from spores
of the medicinal mushroom Ganoderma lucidum. Biosci. Biotechnol. Biochem., 2011;75(4):800-3.
12 C huang M.H., Chiou S.H., Huang C.H., Yang W.B., Wong C.H., The lifespan-promoting effect of acetic
acid and Reishi polysaccharide. Bioorg. Med. Chem., 2009 Nov. 15;17(22): 7831-40.
13 Wu Z., Zhang Y., Tan N., Zhao C., Yang J., Zhu J. S., ReishiMax extends the life span of mice: a preli-
minary report. The FASEB J. 2011 April; 25(601.2).
14 Weng Y., Xiang L., Matsuura A., Zhang Y., Huang Q., Qi J., Ganodermasides A and B, two novel anti-
aging ergosterols from spores of a medicinal mushroom Ganoderma lucidum on yeast via UTH1
gene. Bioorg. Med. Chem. 2010 Feb.; 18(3): 999-1002.

Selegiline
Selegiline is a molecule from the amphetamine group, used since 1960 as an antidepressant
drug. These days, it is normally prescribed to treat Parkinsons disease, as an inhibitor of monoa-
mine oxydase B (IMAO B).
Animal research shows that selegiline constitutes an effective anti-aging treatment. In a study
published in a European medical journal in 1989, 132 same-age male rats were divided into
two groups. Beginning when the rats were aged 104 weeks, one group received an injection of
saline solution three times a week, and the other an injection containing selegiline three times
a week.
The rats that did not receive selegiline died at an average age of 147 weeks. After 164 weeks,
all non-treated rats had died, while all the treated rats remained alive and well. It was another
seven weeks before the first treated rat died and the last died at 226 weeks. The average lifespan
of selegiline-treated rats was 192 weeks an outcome considered remarkable by the resear-
chers since maximum lifespan for this type of laboratory rat is 182 weeks.
This increase in lifespan is due to selegilines inhibitory effects on monoamine oxydase, ena-
bling levels of dopamine to be maintained at over 30%. According to researchers, similar results
in extending lifespan could be achieved in humans. If the animal experiments translate directly
into a slowing down of the aging process, this would manifest in humans as a 24% increase in
maximum lifespan, with 25-30 more healthy years.
For the researchers, the health of the population could be maintained with 10-15mg deprenyl a
weekl starting at the age of 45 to combat aging of dopaminergic neurons. Prophylactic use of depre-
nyl seems to offer a reasonable prospect of improving the quality of life in the later decades, delaying
the time of natural death and decreasing susceptibility to age-related neurological diseases.

However, this research conducted by Dr Knoll is controversial and his views do not reflect cur-
rent mainstream opinion. In addition, the optimal dose of selegiline for extending lifespan is
unknown. Extrapolation from animal tests would seem to suggest it should be in the region of
5mg every other day or even 5mg just once a week, particularly for women.
References
K
noll J. Deprenyl Medication: A Strategy to Modulate the Age-Related Decline of the Striatal
Dopaminergic System. Journal of the American Geriatric Society. V.40., No.8, August, 1992, pp. 839-
847.
We are also aware of other highly promising substances, currently being studied in culture or in
animals, which will undoubtedly extend the range of available resources that can significantly
prolong lifespan.
Glaucarubinone
Glaucarubinone comes from Simaruba glauca, a small South American tree. Tests conducted on
C. elegans suggest this substance extends life expectancy in these worms by 2.7 days (nema-
todes only live for a few weeks), by acting directly on mitochondrial metabolism. These findings
are therefore very promising and the researchers believe it would be beneficial to evaluate this
substance in mammals and humans in the interests of preventing age-related diseases1.
Alpha-carotene
Like beta-carotene, this carotenoid is naturally present in carrots. A large-scale US study invol-
ving almost 50,000 participants showed that it halved the risk of mortality in individuals with
a high body mass index (30 or above). The benefits were particularly noted in terms of the risk
of death from cardiovascular disease, although the risk of all-cause mortality was also lower2.

L-carnosine
As we have seen in previous chapters, L-carnosine, which is also known as beta-alanine-histi-

dine, works by maintaining telomeres.
Tests on the bacteria Escherichia coli, exposed to high concentrations of glucose, showed that
L-carnosine provides protection from glycation and thus helps extend life expectancy 3. This
substance also extended the lifespan of male drosophila fruit flies by 20%4.
Click here to find L-carnosine
References
1 B ossecker A., Mller-Kuhrt L., Siems K., Hernandez M. A., Berendsohn W. G., Birringer M., Ristow M.
The phytochemical glaucarubinone promotes mitochondrial metabolism, reduces body fat, and
extends lifespan of Caenorhabditis elegans. Horm. Metab. Res. 2011 Apr.; 43(4): 241-3. doi: 10.1055/
s-0030-1270524. Epub 2011 Jan. 24.
2 Li C., Ford E. S., Zhao G., Balluz L. S., Giles W. H., Liu S. Serum alpha-carotene concentrations and risk
of death among US Adults: the Third National Health and Nutrition Examination Survey Follow-up
Study. Arch. Intern. Med., 2011 Mar. 28; 171(6): 507-15. doi: 10.1001/archinternmed.2010.440. Epub
2010 Nov. 22.
3 Pepper E. D., Farrell M. J., Nord G., Finkel S. E. Antiglycation effects of carnosine and other compounds
on the long-term survival of Escherichia coli. Appl. Environ. Microbiol., 2010 Dec.; 76(24):7925-30.
doi: 10.1128/AEM.01369-10. Epub 2010 Oct. 15.
4 Stvolinsky S., Antipin M., Meguro K., Sato T., Abe H., Boldyrev A. Effect of carnosine and its Trolox-
modified derivatives onlifespan of Drosophila melanogaster. Research Center of Neurology, Rus-
sian Academy of Medical Sciences, Moscow, Russia. Rejuvenation Res., 2010 Aug.; 13(4): 453-7. doi:
10.1089/rej.2009.1010.

IN CONCLUSION
Which of us hasnt dreamt of prolonging a healthy life or even seeking immor-
tality? What if this hypothetical dream were to soon become a reality? If the
time were to arrive when we could reverse the trend or at least stop the inevi-
table process of aging and be given a glimpse of eternity? Only time will tell,
but we have reason to be confident.
Across the centuries, there have always been men and women who have significantly impacted
on the development of human existence, people like Pasteur or Einstein who, through their
discoveries and theories, have upset the established order of things.
Today, that mantle has been taken up by a vanguard of scientists such as Aubrey de Grey, who
leads the SENS project (Strategies for Engineered Negligible Senescence), the aim of which is
to achieve radically-extended human life expectancy by combatting the seven main causes of
aging (nuclear and mitochondrial mutations, intra and extra cellular waste, loss of cells, cellular
senescence and excessive cross-links).
Another ongoing project, supported by the Dalai Lama and the futurist Ray Kurzweil, is Dmitry
Itskovs Avatar 2045, which aims to upload a human brain into an avatar, or humanoid robot.
Itskovs intention is to free people from disease, old age and death.
Far from being science fiction, these two projects are well funded and bring together extre-
mely competent teams. They are at last pointing to the possibility of significant extensions in
lifespan and of viewing aging as a disease that can be prevented and cured rather than an ine-
vitable process. They are thus allowing us to enter a new era, that of regenerative medicine
The battle to combat the ravages of aging and extend human lifespan is intensifying. The latest
advances in genetics have raised great hopes among scientists who have been doing research
in this area for years. Moreover, if knowledge in this field continues to grow exponentially while
constraints grow linearly, there is a good chance that human immortality will be possible within
fifteen to twenty years. The important thing is to stay in good shape until then
High-quality, scientifically-supported supplements can help you do this on a daily basis and you
now have at your disposal a whole arsenal of anti-aging nutraceuticals that affect every aspect
of the aging process: the production of new mitochondria which ensures the longevity of all the

bodys cells; the mimicking of caloric restriction in increasing life expectancy and slowing down
the onset of age-related diseases; telomere lengthening; the slowing down of aging of the brain
and the activation of tumour suppressor genes
So, happy aging
I dont want to achieve immortality through my work.

I want to achieve it through not dying.
Woody Allen
Bibliography and resources

Recommending reading
The Longevity Factor, Joseph Maroon (Atria Books).
How resveratrol and red wine activate genes for a longer and healthier life.
The immortality edge, Michael Fossel et Greta Blackburn (Wiley).

Realize the secrets of your telomeres for longer, healthier life.
Transcend, Ray Kurzweil et Terry Grossman (Rodale).

Nine steps to living well forever.
Abundance, Peter Diamandis et Steven Kotler. (Free Press - Simon & Schuster)
The future is better than you think.
Ending Aging, Aubrey de Grey et Michael Rae (St Martins Griffin).

The Rejuvenation Breakthroughs that Could Reverse Human Aging in our Lifetime.

Links
General
Holding back aging with natural nutrients
What if aging were not inevitable?
Questions to Aubrey de Grey
Interview with Aubrey de Grey
On telomerase, astragaloside IV and cycloastragenol

Astragaloside IV, a telomerase activator
Finding a formulation for maintaining telomere length
Certified form of astragaloside IV
Certified form of cycloastragenol
On mitochondria
Improving mitochondrial function (Bruno Lacroix)
Interview with Dr Bruce Ames (quoted in the section on PQQ)
Certified mitochondrial formulation with PQQ
PQQ nutrient of the year
Finding PQQ + Q10
On calorie restriction mimetics

Nutrients that mimic calorie restrictions effects on longevity
Resveratrol and human adipocytes (activation of the Sirt-1 gene)
Resveratrol slows down aging
Resveratrol activates a longevity gene
Certified form of resveratrol
Certified form of oxaloacetate
Oxaloacetate extends lifespan

Other promising substances
Click here for saikosaponin A
Centrophenoxine stimulates the brain and combats aging
Click here for centrophenoxine
Click here for apple polyphenols
Click here for epimedium
Click here for L-theanine
Click here for L-carnosine
You will find all the nutritional supplements mentioned in this book
in this Anti-Aging section
Engineering: the exacting, science-based activity of designing and producing works in accor-
dance with rigorous scientific rules. The principles on which engineering and its methodo-
logy are founded are highly logical.

Charles Feelgood is the pseudonym of a well-known French author
and specialist in natural health and nutritional supplementation.
Linus Freeman has been Managing Editor, since its creation in 1997,
of the newsletter NutraNews,
published by the Fondation pour le libre choix: nutranews.org
Anglique Houlbert is a Dietician/Nutritionist specialising

in nutritional supplementation for over 10 years.
She has also written several books on nutrition and health.
This e-book is published by the Fondation pour le libre choix

2006-2013 Fondation pour le libre choix All rights reserved.

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NEW ADVANCES IN

REVISED EXPANDED - UPDATED

THE ENGINEERING METHOD . . . . . . . . . . . . . . . . . . 7

2 New advances in anti-aging nutritional supplementation

3 New advances in anti-aging nutritional supplementation

4 New advances in anti-aging nutritional supplementation

5 New advances in anti-aging nutritional supplementation

6 New advances in anti-aging nutritional supplementation

What do we mean by damage?

What are the principles of this method?

7 New advances in anti-aging nutritional supplementation

Why is this method likely to be effective?

8 New advances in anti-aging nutritional supplementation

What are the seven types of damage?

1 Carcinogenic nuclear and epigenetic mutations: these are cancer-causing changes to

9 New advances in anti-aging nutritional supplementation

10 New advances in anti-aging nutritional supplementation

1000 year life expectancy?

11 New advances in anti-aging nutritional supplementation

What methods already exist?

* Click here for Daily 3

12 New advances in anti-aging nutritional supplementation

1 Regular antioxidant supplementation to prevent the body from rusting.

Click here for Antioxidant Synergy

2 Glycation control, to prevent caramelisation of tissues caused by sugars and high

Click here for Anti-Glycation Formula

3 Control of chronic inflammation which affects most people in old age.

Click here for InflaRelief Formula

4 Last but not least, hormone supplementation to control age-related hormone

13 New advances in anti-aging nutritional supplementation

Classic nutritional supplements can the-

These substances fall into several categories:

14 New advances in anti-aging nutritional supplementation

3 Calorie restriction mimetics

4 Stem cell activators

15 New advances in anti-aging nutritional supplementation

What are telomeres?

16 New advances in anti-aging nutritional supplementation

17 New advances in anti-aging nutritional supplementation

Recreating telomerase activity

18 New advances in anti-aging nutritional supplementation

19 New advances in anti-aging nutritional supplementation

20 New advances in anti-aging nutritional supplementation

21 New advances in anti-aging nutritional supplementation

Astragaloside IV, a glycoside studied extensively in Chinese and European research

22 New advances in anti-aging nutritional supplementation

It stimulates stem cell proliferation

23 New advances in anti-aging nutritional supplementation

It prevents breast cancer

It is beneficial in Parkinsons disease

24 New advances in anti-aging nutritional supplementation

Click here for a certified astragaloside IV formulation

25 New advances in anti-aging nutritional supplementation

26 New advances in anti-aging nutritional supplementation

An excellent telomerase activator

27 New advances in anti-aging nutritional supplementation

stimulates telomerase levels;

28 New advances in anti-aging nutritional supplementation

Click here for a certified cycloastragenol formulation.

29 New advances in anti-aging nutritional supplementation

Magnesium ascorbyl-phosphate (Asc2P)

30 New advances in anti-aging nutritional supplementation

Also called beta-alanine-L-histidine, this di-peptide is a natural molecule found in skele-

1 Carcinogenic nuclear and epigenetic mutations: these are cancer-causing changes to

1 Regular antioxidant supplementation to prevent the body from rusting.

2 Glycation control, to prevent caramelisation of tissues caused by sugars and high

3 Control of chronic inflammation which affects most people in old age.

4 Last but not least, hormone supplementation to control age-related hormone

3 Calorie restriction mimetics

4 Stem cell activators

Astragaloside IV, a glycoside studied extensively in Chinese and European research

stimulates telomerase levels;

Also called beta-alanine-L-histidine, this di-peptide is a natural molecule found in skele-

Extract of green tea standardised in polyphenols, especially EGCG (Epigallocatechin gal-

Extract of purslane (Portulaca oleracea) was investigated in a study in which three-month

According to a study published in Brain, behaviour and immunity, supplementing with

No difference was observed in telomerase, but an improved omega-6/omega-3 ratio

Resveratrol is a proven, potent anti-cancer agent effective at combatting the deve-

cell survival Insulin

Alzheimers disease, which is promoted by oxidative damage to brain cells. According to

blocking inflammatory factors;

promotes insulin sensitivity;