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LLOYD WRIGHT’S ANTI AGING
Scientific Backgrounder
Douglas Laboratories Inc. All Rights Reserved
XTRA-CELL LLOYD WRIGHT’S ANTI AGING™
Table of Contents
Scientific Review ___________________________________________________ 3
An aging world_____________________________________________________________3
What is aging? _____________________________________________________________4
Why do we age? ____________________________________________________________4
Immunity as a key to aging _________________________________________________4
Hormones as a key to aging _________________________________________________6
Free radicals as a key to aging
____________________________________________8
Proteolytic activity as a key to aging _________________________________________11
Conclusion ________________________________________________________________13
References_________________________________________________________________13
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Scientific Review
An aging world
With
the
new
millennium, population
aging
has
been
emerging as a preeminent phenomenon.
The combined effects of
lowered fertility rates,
improved health care
and longevity, better
educational
and
nutritional status, and
sustained
economic
development,
are
causing a dramatic
increase in the numbers
and proportions of older
inhabitants throughout
the world. By the year
2030, the proportion of
people aged 65 and over
is expected to be 13% or
more in most countries.
As the World War II baby-boomers begin to reach their elder years by 2010, we should see a
dramatic increase in the annual percent growth of elderly population in both developed and
developing countries. From 2010, this growth rate should remain level until the year 2030 when it is
predicted to drop to eventually follow the steadily declining growth rate of the general population.
Because the proportion of older people is increasing, there is a new pressure to better comprehend
their needs as a group. Understanding the dynamics of aging requires an adequate description of
the underlying physiology and biology.
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What is aging?
Aging is a continuous process resulting from the accumulation of little random changes affecting
structural and functional elements within the body. At a molecular level, damages accumulate with
time on DNA, proteins and lipids as they overcome the intrinsic repair mechanisms of the body. This
build-up of molecular changes eventually affects physiological processes leading to the point where it
may even compromise the general homeostasis of the body. As a consequence, we tend to become
more vulnerable to environmental stress and age-related diseases as we grow old. Aging is also
associated with a slower metabolism, a decrease in the number of active cells and an increase in
their mutation rate.
Why do we age?
Although genetic disorders and gene mutations may contribute to premature aging, aging itself is
not a genetically programmed process. Instead, it appears to arise indirectly through evolutionary
neglect. In other words, the natural selection pressure applies until an organism actively starts
reproducing itself and wanes thereafter. According to the theory of natural selection, genes that
confer a better chance for survival and procreation will be passed along through generations while
those that cut life short will not have that chance. But what if the deleterious trait only manifests
itself in later life? Likely, it will be transmitted to the offspring. This is well illustrated by
Huntingdon disease, a genetically programmed degeneration of neurons in the brain that only
strikes when people are in their 30s or 40s, a time when most already had their children. Could it be
that aging itself is a late onset disorder beyond the control of natural selection (Partridge and Gems,
2000; Rose, 1991)? If this is really the case, then there might be a chance to cancel the program of
body aging (Skulachev, 2010).
Artificial selection experiments, done on the tiny drosophila, support the evolutionary theory of
aging. When eggs laid by older flies were selectively picked for further development and the process
repeated over several generations, it was possible for researchers to double the lifespan of these flies.
Interestingly, long-lived flies were revealed to be "superflies" that remained
vigorous longer and resisted environmental stress better (Rose and
Nussbaum, 1994). These results suggest that aging might be postponed by
increasing the force of selection at later ages. Of course, applying such an
approach to human is unthinkable given the ethical problems that it would
raise. The solution rather lies in digging into molecular and physiological
mechanisms of aging in the hope of mimicking the beneficial effects of
artificial selection. Thanks to research, a few clues about the human ageing
process have emerged over the years.
Immunity as a key to aging
The immunological theory of aging arose from the fact that immune functions decline with age.
Foreign antigens are progressively less well recognized while, on the opposite, increased reactivity
toward auto-antigens is generally observed. Thymus involution, largely due to degradation of its
microenvironment, is believed to play a major role in immune senescence (Manley et al., 2011). The
thymus is a gland located in the upper part of the mediastinum, behind the sternum and above the
heart. The thymus produces peptide factors that contribute to the maturation of T-lymphocytes first
produced in the bone marrow. T-cells are responsible for identifying foreign antigens, boosting B
cells to produce appropriate antibodies, stimulating phagocytosis and eliminating cancer cells as
they appear. Moreover T-cells should do all these tasks while preserving the organism's healthy
cells. A good healthy thymus is vital for the development of T-cells to their full bloom and
particularly to get rid of the auto-reactive lymphocytes that form every now and then.
Unfortunately, starting at puberty, as we grow older the thymus goes smaller. By age 30, the
thymus gland has typically decreased its mass by two-thirds and its T-lymphocytes content by 90%.
By age 60, functional thymic tissue has almost completely disappeared. Concomitantly, the level of
thymic hormones declines in blood as we get older (Iwata et al., 1981). The gradual loss of thymic
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functions leads to an increased susceptibility to infections, cancer and autoimmune diseases as we
age (Goya et al, 2002).
Concomitantly with thymus involution, the nature of the T-lymphocyte response in the aging body
progressively derives from a cellular-prone (Th1) to a humoral-prone (Th2) type (Ginaldi et al.,
1999). Upon activation and under the influence of specific factors called cytokines, T-helper cells
differentiate into either Th1 or Th2 cells. Th1 cells provide cellular protection against invading
pathogens such as bacteria or virus. They also activate other immune cells responsible for tracing
and eliminating cancer cells as they form. An excessive Th1 response may lead to autoimmune
diseases such as type I diabetes, multiple sclerosis or rheumatoid arthritis (among others). For their
part, Th2 cells fight larger parasites by promoting the production of neutralizing antibodies.
Overactive Th2 cells may cause allergic responses in predisposed individuals. Th1 and Th2 cells
influence each other through the production of cytokines. An overactive Th1 response blunts the
Th2 arm of immunity, and vice-versa.
A balanced Th1-Th2 immune responsiveness is a guarantee of good health. Unfortunately
throughout life a number of events can affect the system. As an example, stress stimulates the
production of cortisol, a hormone that favors Th2 response, making affected people more susceptible
to viral infections.
As mentioned
above, age also impacts on the Th1-Th2
balance. In small children, as their
immune system builds up, a Th2 type
predominates.
Middle-aged people
tend to have a Th1 bias that switches
again to a Th2 type in the elderly. As a
consequence of this imbalance, aging
people are more susceptible to
infections such as influenza and
pneumonia, old infections can be
reactivated causing problems such as
shingles or tuberculosis and cancer
cells
tend
to
escape
immune
surveillance more easily.
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To thwart immune imbalance, dietary supplements containing thymus extract can be used. Thymus
extract contains small peptides and other thymus-derived factors which help to restore and support
an optimal immune balance (Hannappel and Huff, 2003). Thymic peptides and factors include
thymopoietin, several thymosins, thymulin, thymostimulin, and thymic humoral factors. In vitro,
thymus extract has the ability to stimulate maturation and differentiation of peripheral blood
mononuclear cells (PBMC) in order to mount a full immune response and, in this aspect, is more
powerful than Echinacea, a popular herb often used as an immunostimulant.
Clinically, thymus extract supplementation has
been shown to be extremely effective in treating a
wide variety of illnesses (including cancer) with
impaired immunological functions as a common
denominator (Ioannou et al., 2012; Ben-Efraim et
al., 1999; Walker, 1994 & 1998). The pertinence of
thymus extract supplementation in restoring
immunocompetence in the elderly is supported by
studies that examined different uses of thymic
peptides.
In a double-blind placebo-controlled
clinical study, the deemed antibody response in
older men was shown to be enhanced by
augmentation with thymosin (Gravenstein et al.,
1989). Similarly, thymopoietin, which is yet another
thymic peptide, was shown to enhance the impaired
lymphocyte stimulation in older people (Verhaegen
et al., 1981). In another study, herpes zoster
(shingles) was used as a clinical model to study the
effects of thymus extract in 28 otherwise non
immunocompromised patients.
Results of this
double blind study reported an accelerated rate of wound healing, shorter duration of vesicles,
shorter time to first and crusting lesions, and a greater reduction of pain during the acute phase
(Skotnicki 1989).
Hormones as a key to aging
Other experiments have look at the way hormones may affect the aging clock. Menopause and
andropause are the direct results of the fall in sexual hormones that takes place as we age. Other
hormones such as dehydroepiandrosterone (DHEA), melatonin, thyroid and various growth
hormones also decline with age, affecting among others muscle functions.
Levels of
neurotransmitters (dopamine, GABA, norepinephrine, acetylcholine and serotonin) also diminish in
the aging brain and are at the root of some of the pathologies seen in aging such as Parkinson’s
disease. On the other hand, levels of cortisol, a glucocorticoid steroid hormone, tend to rise with age.
Cortisol strongly impacts on brain functions and also modulates the immune system. Sustained high
cortisol levels are known to contribute to the deterioration of brain functions and immunological
perturbations that are commonly seen in the elderly (Bauer et al., 2009). So, although it is not
always clear if changes in hormone levels are a cause or a consequence of aging, their fluctuation
obviously is responsible for some of the undesirable signs of aging.
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Age-related changes in the HPA axis reactivity have been reported (Aguilera, 2011). The HPA axis
is a major component of the body’s response to stress and refers to the hypothalamus (H), pituitary
(P), and adrenal glands. The stress response begins in the brain, through the release of the
corticotropin releasing hormone (CRH) by the hypothalamus. CRH stimulates the anterior pituitary
gland which releases the adrenocorticotrophic hormone (ACTH). ACTH is detected by the adrenal
cortex where it induces secretion of glucocorticoids such as cortisol. A feedback loop exists through
which cortisol prevents excessive secretion of CRH, ACTH and so, refrains its own production. There
is evidence that an impairment of this feedback loop in the elderly is most probably caused by a
diminished sensitivity of the brain corticosteroid receptors (Aguilera, 2011). At the same time,
DHEA levels (which normally buffer excess cortisol) fall, leaving the high cortisol levels unchecked
(Goncharova and Lapin, 2002). The ratio of cortisol/DHEA increases with age, and is even higher in
instances of dementia (de Bruin et al., 2002). Age-related changes in the HPA axis reactivity affect
immune functions, are a source of psychological stress, precipitate memory impairment, and
contribute to chronic
fatigue and pain as often
seen in the elderly
(Buford and Willoughby,
2008;
Ferrari
and
Magri, 2008)
Synthetic corticosteroids
and growth hormones
have been tentatively
used as replacement
therapy in the hope of
rejuvenating
aging
bodies. Some beneficial effects have indeed been seen with such therapies but hormone substitution
is a tricky business given that many hormones have the potential of promoting cancer.
Supplementation with adrenal extracts appears much safer. Adrenal extracts provide natural
signalling factors that may help restore and preserve HPA axis functions, improve adrenal functions,
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and maintain a proper corticosteroid balance (Wilson, 2000). Adrenal extract could benefit people
experiencing age-related symptoms such as fatigue and cognitive impairment.
Free radicals as a key to aging
The free radical hypothesis of aging has gained in
popularity among scientists, over the years (Gilca
et al., 2007; Viña et al., 2007). Free radicals are
molecules that have lost an electron due to the
splitting of a molecular bond. Free radicals such
as superoxide (.O2-) and hydroxyl radical (.OH-)
are short-lived but highly reactive molecules that,
in a desperate attempt to restore their integrity,
will steal electrons from surrounding molecules.
This ignites a chain reaction where molecules are
stealing electrons from each other. Under normal conditions, the antioxidant defence system within
the body, comprising superoxide dismutase (SOD), catalase and glutathione peroxidase, can handle
free radicals as they are produced. But as we age, this natural defence mechanism loses its strength
and free radicals are left unchecked, generating important oxidative damages to DNA, lipids and
proteins in our cells that cumulate to impair bodily functions.
Within cells, mitochondria are the organelles
most susceptible to free radical action (GomezCabrera et al., 2012). Mitochondria, little
bean-shaped organelles delimited by a double
membrane, are found inside every cell and are
responsible for energy production through the
respiratory chain.
The respiratory chain
refers to an assembly of enzymes embedded
within the mitochondrial membranes that
work in concert to transport electrons
(extracted from food) through a series of
complex oxydoreduction reactions. The rate of
respiration is determined by the electron flux
through the respiratory chain.
Electron
transport is coupled to the pumping of protons
that build up within the mitochondrial
intermembrane space to create a pH gradient.
This gradient serves as a potential energy
store that is used by ATP synthase to drive
the synthesis of ATP, the major source of
energy for the body. In the process of energy
production,
mitochondria
generate
an
important part of the free radicals susceptible
of causing cellular damage. For their own
protection, mitochondria have evolved specific antioxidant defences that unfortunately may become
less efficient with age, resulting in the accumulation of mitochondrial damages. Old mitochondria
consume less oxygen, have stiffer membranes, transport electrons much less efficiently then younger
ones, generate more radicals and produce less ATP (Lee and Wei, 2012; Shigenaga et al., 1994).
Mitochondrial decay has been associated with age-related conditions resulting from neuronal
degeneration and decreased cell-mediated immunity (Bertoni-Freddari et al., 2004; Liu et al., 2002).
Halting age-related oxidative damage to mitochondria and optimizing mitochondrial functions
therefore appear as a highly desirable target in the elderly (Liu and Ames, 2005).
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Apparently, caloric restriction (CR) can do just that (Speakman and Mitchell, 2011). Somehow,
limiting the amount of calories available from feeding seems to force mitochondria to work more
efficiently by optimizing mitochondrial respiration rate (Merry, 2002). In the process, CR limits the
rate of free radical production in mitochondria, alleviating the burden of oxidative stress to cells (Liu
and Ames, 2005; Lopez et al., 2002). Moreover, CR generally up-regulates the expression of genes
involved in free radical scavenging, energy metabolism and genomic stability, although with some
variability among tissues and species (Lee et al., 1999). This translates into direct general health
benefits. In animals, CR can prevent or reduce the occurrence of age-related conditions such as
heart disease, diabetes, cancer, cataracts, Parkinson’s and Alzheimer (Liu and Ames, 2005).
CR can extend both the average and maximum lifespan of all animals tested ((Speakman and
Mitchell, 2011; Weindruch and Walford, 1988). When applied to mice from one month of age, CR had
a dramatic effect on life extension and this effect was increasing with the degree of CR, prolonging
life up to 40-50%. Life extension is more modest when CR is onset later in the animal life and
requires an extended gradual phase-in. Still a 10-20% increase was observed when CR was applied
to animals of age equivalent to 30-40 years of human life.
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CR is, in fact, the only one intervention that has ever been proven to extend the lifespan of all
animal species tested. Sounds appealing? Think twice, because caloric restriction is more than just
dieting. Under caloric restriction, laboratory animals are fed at least 30%
fewer calories than they would normally consume to satisfy their hunger.
Beyond the obvious mental distress that may result from perpetual hunger,
there are other major drawbacks to CR. Rodents fed on a restricted diet
are less fertile, develop a reduced muscular mass, are more susceptible to
bacterial infection, heal their wounds more slowly, and suffer/shiver
constantly from cold.
And what about CR in humans? Short term CR experiments with humans within the Biosphere 2
project, the self-sustaining greenhouse in Arizona, resulted in substantial weight loss, remarkable
fall in blood cholesterol, blood pressure, fasting blood sugar, and low white blood cell counts--exactly
as seen in rodents on such a regimen (Walford et al., 1995). Potential risks with CR in humans are a
decrease of stress responses and other defence mechanisms, and possibly an increased risk of
osteoporosis, since lower bone densities were reported in other primates such as monkeys (Black et
al., 2001). Humans on long term restriction report similar negative side effects to those observed in
animals – perpetual hunger, reduced body temperature leading to a feeling of being cold, and
diminished libido (Speakman and Mitchell 2011).
It should be emphasized that, when transposed to a human scale, CR represents a restricted daily
intake of about 600 and 800 calories for a middle-aged healthy woman and man respectively (when
the recommended daily intake is normally of 1900 and 2700 calories). Strict balanced proportions
between fat, proteins and carbohydrates in the diet must be respected and minerals and vitamins
have to be supplemented. Clearly, this is not the kind of regimen that can be improvised and a
professional follow-up with a nutritionist would be mandatory. Moreover the regimen would have to
be maintained life-long for lasting benefits. Keeping up with such a Spartan regimen is not given to
everybody. Could there be an easier choice? Supplementation with mesenchymal extract might be
the answer.
Proliferation
(Hoescht DNA count)
Mesenchymal extract is prepared from mammal extra-embryonic connective tissue. Mesenchymal
cells are undifferentiated cells (or stem cells) that, when triggered under appropriate conditions, can
become almost any type of cells to help restore damaged or aging tissues (Jamnig and Lepperdinger
2012; Caplan, 1994). Mesenchymal extract is obtained by breaking down mesenchymal stem cells to
liberate active molecules. These active molecules
are then selectively picked up to obtain a
250%
mesenchymal liquid extract that provides a
natural rich source of cell factors and signalling
200%
molecules. Mesenchymal extract is known for
enhancing the healing and repair of damaged or
150%
slow-to-heal tissues. Moreover, and of major
interest for anti-aging applications, addition of
100%
mesenchymal extract to fibroblasts in culture
triggered an increase in the aerobic metabolic
50%
activity (respiration) of the cells, while negligibly
affecting their proliferation rate.
0%
FBS Serum
FBS Serum +
This biological profile suggests that mesenchyme
Mesenchym e
extract can increase mitochondrial respiration
efficiency and possibly stimulate ATP production.
Who would not welcome more energy? Moreover, as seen with caloric restriction, improved
mitochondrial functions are associated with a slowdown of the aging process and a better recovery of
oxidative insults (Broderick et al., 2002). Thus, the biological activity profile of mesenchymal extract
supports its use as a nutritional supplement to regenerate functional tissues and boost energy level.
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Proteolytic activity as a key to aging
Proteins such as collagen, elastin and others are linked with surrounding macromolecules such as
glycosaminoglycans to form the extracellular matrix (ECM) components of all solid body tissues.
Examples include cartilage, the fibrous sheaths of muscles, tendons and ligaments, and the dermal
layer of the skin. ECM components are in constant renewal, or turnover, a process based on
equilibrium between synthesis and degradation.
Collagen fibbers are synthesized by cells such as
articular cartilage chondrocytes or skin fibroblasts.
In addition to their anabolic activity, chondrocytes
and fibroblasts also produce and secrete enzymes
known
as
collagenases
or
matrix
metalloproteinases (MMPs). MMPs represent a
special class of enzymes that target and cleave the
fibrous proteins of the ECM.
Almost
paradoxically, chondrocytes and fibroblasts also
produce MMP inhibitors. These inhibitors are
important in restraining the proteolytic action of
MMPs. A balance must therefore exist between
these two opposing cellular activities in order to
maintain cartilage and tissue matrix integrity (Ra
and Parks 2007).
With aging and in various conditions, the metabolic activity of cells such as chondrocytes and
fibroblasts may become disturbed. Such a disturbance may affect the equilibrium between
production and breakdown of extracellular matrix (ECM) components. In these conditions, the
balance between MMPs and MMP inhibitors is no longer respected so that, in most cases, the
enzymatic activity of MMPs predominates. Aging, long-term sunlight exposure and mechanical
stressing of joints are all factors associated with an increased enzymatic activity of MMPs
(Hernández-Pérez and Mahalingam, 2012; Quan et al., 2009; Tanaka et al., 1998). This activity
eventually leads to the degradation of the collagen fibre meshwork. The phenomenon is well
exemplified by the fate of skin with aging. Loss of skin elasticity, wrinkling, sagging, atrophy, and
changes in tone and moisture levels are hallmarks of time that have been related to excessive MMP
activity (Sárdy, 2009; Quan et al., 2009).
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But MMP action is more than skin deep. MMPs also influence important cellular processes and
immune cell functions through proteolytic processing and shedding of bioactive molecules such as
cytokines and growth factors (Vargová et al., 2012). MMPs are overactive in numerous models of
inflammatory diseases and degenerative processes, including Alzheimer, Parkinson’s disease,
macular degeneration, colitis, rheumatoid arthritis, osteoarthritis, periodontitis, psoriasis, asthma,
chronic obstructive pulmonary disease, emphysema, multiple sclerosis, amyotrophic lateral sclerosis,
atherosclerosis, arterial restenosis after angioplasty
and, aneurysm development ((Hernández-Pérez and
Mahalingam, 2012; Vargová et al, 2012; Tayebjee et
al., 2005; Dove, 2002).
How can we control MMPs? Liquid cartilage extract
(LCE), contains natural molecules that can stop the
proteolytic activity of MMPs. Although the exact
molecular mechanism by which cartilage extract
performs this inhibitory action remains elusive, it has
found applications in various conditions involving
MMP over activity that tend to develop with age such
as cancer, psoriasis, arthritis and macular
degeneration (Brown, 2000; Gingras et al., 2003;
Sauder et al., 2002; Thibodeau and Behr, 2002).
LCE causes anti-inflammatory action. This has been demonstrated by the effects that the extract
displayed in a murine model of contact hypersensitivity in which it decreased production of several
inflammatory cytokines, including interferon-gamma (INF-gamma), and stimulated production of
the anti-inflammatory cytokine IL-10 (Dupont et al., 2003). Anti-inflammatory action and analgesic
effects of LCE have also been demonstrated in the paw edema model in rats (Fontenele et al., 1996).
Since inflammation is an important component of many age-related diseases, taming the process
might be beneficial for successful aging. In addition, LCE is already widely used in cosmetic
preparations as an anti-aging agent to help prevent formation of wrinkles. Maintaining a proper
balance between collagen formation and degradation with LCE supplementation may help fighting
the signs of age arising both internally and externally.
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Conclusion
Advances in knowledge and technology have generated a dramatic bound in life expectancy, which,
in the United States, went from roughly 47 years in 1900 to 76.9 years in 2000. Since more people
are now reaching old age, aging manifestations and limitations have become much more of a concern.
Not only do we want and can live longer but we also wish to do it gracefully. A better understanding
of the aging process has given us some clues on how to age well. A proper diet combined with
exercise is mandatory. Supplementation with glandular extracts may be helpful in restoring and
maintaining the homeostasis of the body. Glandular extracts contain concentrated active cell factors
and signalling molecules derived from their tissue of origin. Thymus gland extract may help balance
and boost a weakening immune system. Adrenal extract may normalize the HPA axis that is often
compromised in the elderly. Mesenchymal extract provides rejuvenating molecules and can boost
the energy level of cells. Cartilage extract with its anti-MMP action preserves the integrity of the
extra-cellular matrix in cartilage, tendons, skin and other tissues. These extracts have been
conveniently combined in a special formulation aimed at sustaining the body functions of an aging
population.
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