THE SCIENCE OF SIRTUINS: REPROGRAMMING
THE FUTURE OF SKIN
8.29.12
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INTRODUCTION
Resveratrol isn’t new in skincare circles. In fact, resveratrol—
a key ingredient in red wine—is singled out in The French
Paradox as one possible explanation for why, despite their
high-fat diets, the French have low rates of heart disease:
moderate amounts of red wine, France’s beverage of choice,
appear to be beneficial to the heart.
Beyond its primary function as an antioxidant, resveratrol
has recently led scientists to a potentially powerful new
pathway in helping to maintain the health and vitality of the
skin. Resveratrol is believed to help promote a group of
proteins in the skin known as the sirtuins, which have been
dubbed “longevity proteins.” Research is now uncovering the
specific roles of sirtuins in the cellular aging process. And
lately in laboratory testing, scientists continue to discover
ways sirtuins are activated, and in doing so, identify ways to
encourage skin cells to help hold onto their youthful
appearance longer than if left to chance.
The latest game-changer in skincare involves targeting these
sirtuins at just the right time—before the visible signs of
aging manifest—to prolong the look of youth.
This guide will explore the vital role that cells play in the skin,
the process by which skin starts to appear aged, and how
sirtuin research suggests a natural way to help delay that
process.
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CELLS AND HEALTHY SKIN
BASICS OF THE SKIN
Every square centimeter of skin contains millions of cells, as
well as hundreds of sweat glands, oil glands, nerve endings
and blood vessels. This complicated pattern can be divided
into three distinct compartments (Figure 1): the epidermis,
the dermis, and the subcutaneous tissue (also known as the
hypodermis).
The skin is the largest organ in the human body, accounting
for approximately 16 percent of total body weight (Martini
and Nath, 2009). It is a constant and dynamic interface
between the body and its environment.
The epidermis forms the skin’s protective outer layer. About
as thick as a sheet of paper (~0.1 mm) (Starr and McMillan,
2008), the epidermis has several layers of cells that are
constantly flaking off and being renewed.
On a cosmetic level, the appearance of the skin is a
reflection of health and a measure of age and beauty. The
skin is the only organ continually exposed to the environment
and on display for all to see (Fisher et al., 2008). Not
surprisingly, skin changes are among the most visible signs
of aging.
The main cells of the epidermis are keratinocytes, which
produce keratin, a tough protein that is a basic component of
hair, skin and nails and that helps create an intact,
waterproof barrier.
THE UNDERLYING CAUSE OF THE APPEARANCE OF
AGE-RELATED CHANGES LIES IN THE HEALTH OF
THE CELLS THAT COMPRISE THE SKIN.
Below the epidermis is the skin layer most critical to the
physiology of aging, the dermis. Up to 20 times thicker than
the epidermis, the dermis regulates body temperature and
nourishes the epidermis. The dermis is made up of blood
vessels, nerve endings, hair follicles, oil glands and
connective tissue – where changes are critical to the
formation of wrinkles.
The dermis is primarily composed of the extracellular matrix,
a scaffolding network of fibers. These fibers, including
collagen and elastin, are produced by cells in the dermis
called fibroblasts and secreted into the tissue environment
(Fisher et al., 2008).
The fatty bottom layer of the skin, the subcutaneous tissue,
is made up of connective tissue, blood vessels, and cells that
store fat. This layer helps protect the body from injury and
helps hold in body heat.
Figure 1. Compartments of the skin.
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THE ROLE OF CELLS AND
PROTEINS IN SKIN AND AGING
The healthy appearance of skin depends on the fitness of its
components—especially its cells, along with the proteins and
extracellular matrix components these cells produce.
Fibroblasts in the dermis, for instance, produce important
matrix fibers such as collagen, which is strong and hard to
stretch (Figure 2), and the stretchy fibers of elastin. These
fibers give the skin its strength and flexibility and are part of
the reason young skin looks plump and healthy.
Bundles of collagen lend strength and support to the skin. In
the dermis, the collagen network is organized and
maintained through tension provided by the fibroblasts that
produce it. Age-related reduction in this tension (Figure 3) is
believed to be a driving force behind many of the changes in
the appearance of aged skin (Fisher et al., 2008).
Beyond collagen and elastin, fibroblast cells in the dermis
produce other matrix components, such as long
carbohydrate chains known as glycosaminoglycans (GAGs)—
in particular, hyaluronic acid. Because water tends to latch
onto GAGs, these chains are another element that helps
keep skin looking plump and fresh.
Figure 2. Collagen fibers in the dermis. Modified from Lim et al.
2008.
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Figure 3. Young skin fibroblasts (left) are stretched tight by attachments to the extracellular matrix. Old fibroblasts (right) lose
their connections and collapse, leading to a loss of skin plumpness. Modified from Fisher et al. 2008.
In the epidermis, the rapid renewal of keratinocytes helps
maintain the healthy status of this skin layer (Hwang et al.,
2011) and is critical for the youthful radiance of skin.
One main driving force of visible aging is a change in the
lifecycle of critical skin cells such as epidermal keratinocytes
and dermal fibroblasts. As we age, critical cells die or
become inactive in a process known as cellular senescence,
which deprives us of the resources to renew young-looking
skin. Cell death and senescence can greatly reduce cells’
capacity to synthesize important elements of the skin such
as GAGs, collagen, elastin and other matrix proteins. Some of
the cellular effects of aging are listed below:
— The proliferation of keratinocytes begins to wane,
leading to duller, less radiant skin
— Fibroblasts in the dermis begin to senesce and die off,
leading to a decline in collagen and elastin production,
and consequently a loss in skin firmness and elasticity
— The aging of the extracellular matrix causes many of
the remaining fibroblasts to lose their taut shape and
connectivity to the dermal matrix, which is necessary
for their healthy function (Figure 3)
Adding to these problems, aging is also associated with the
active destruction of the existing collagen and elastin
networks.
SIGNS OF AGING
The first signs of aging include the appearance of fine lines
and wrinkles, the loss of skin vibrancy and elasticity, and an
increase in dullness, dryness and flakiness. Dark circles and
puffiness around the eyes also begin to appear. These
symptoms are caused by a combination of internal and
external factors – namely genetics and lifestyle choices as
well as environmental factors. While physical and
psychological stress, smoking, alcohol, poor nutrition and
pollution all age the skin, the extrinsic factor that contributes
the most (up to 80 percent) is ultraviolet (UV) irradiation from
the sun.
At early stages, the signs of aging may not be visible, since
the cellular changes happen beneath the surface of the skin.
But if not addressed at the proper time, these early signs can
rapidly develop into more visible problems (Figure 4).
SCIENTISTS ARE NOW DEVELOPING METHODS AND
MATERIALS TO ADDRESS THE EARLY AGE-RELATED
CHANGES IN SKIN CELLS AND PROTEINS, IN
ORDER TO HELP DELAY CHANGES IN MIDDLE-AGED
SKIN THAT CAN LATER LEAD TO THE AGED
APPEARANCE OF OLDER SKIN. THE GOAL IS TO
HELP REPROGRAM THE FUTURE OF SKIN.
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EARLY SIGNS OF AGING
Figure 4. The damage of aging occurs before physical signs appear. Graph based on Amway R&D research.
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AGING AND THE SIRTUIN
CONNECTION
For those interested in slowing the march of time, research
into wine and its highly touted ingredient, resveratrol, has
provided an unexpected windfall. Perhaps the most exciting
effect of resveratrol for skin care lies in its ability to affect
these cellular proteins (sirtuins), which regulate cellular
longevity by delaying senescence (Catalgol et al., 2012;
Bastianetto et al., 2010).
It has been a decade since the first demonstration that a
sirtuin extended the lifespan of yeast cells (Haigis and
Sinclair, 2010) (Figure 5). For yeast, sirtuins increase the
number of times that a mother yeast cell can produce
daughter cells before the mother dies—thereby delaying the
yeast version of senescence. More sirtuins delayed
senescence, while less hastened it (Sinclair and Guarente,
1997; Kaeberlein et al., 1999).
Since that time, every organism analyzed, including bacteria,
insects, plants, and humans, has been found to contain at
least one of its own versions of these life-extenders (North
and Verdin, 2004). In some cases, including in worms and
flies, scientists found that ramping up sirtuin activity by
pharmacological means increased that organism’s lifespan
and improved its health (Haigis and Sinclair, 2010; Blander
and Guarente, 2004). Further investigation is required to
better understand how and to what extent sirtuins can
extend an organism’s lifespan (Burnett et al, 2011), but the
majority of results to date suggest that sirtuin activation at a
minimum leads to healthier functioning cells that mimic their
youthful state. Altogether, these findings have led to great
interest in developing sirtuins as a means to treat human
diseases related to aging.
Research leveraging the power of sirtuins in skin, however,
has not been as thoroughly investigated and is not as well
understood – until now. In skin, while much science around
the world has focused on reversering and reparing the signs
of aging that have already emerged in older skin.
THE GREATER TECHNICAL OPPORTUNITY MAY
LIE IN ALTERING SIRTUIN ACTIVATION TO DELAY
THE DEVELOPMENT OF THESE SIGNS IN THE
FIRST PLACE
Studies have shown that humans have several different
sirtuins, named SIRT1 (silent mating type information
regulation 2 homolog 1) through SIRT7 (Michan and Sinclair,
2009). SIRT1 in particular has many of the properties of its
yeast counterpart that helps control longevity (Michan and
Sinclair, 2009). In skin cells, sirtuins act as a “youth switch;”
when the switch is on SIRT1 helps skin cells repair the
appearance of damage and boosts the production of
important proteins for maintaining a youthful-looking state.
When the switch is off and SIRT1 activity is low, skin cells
cannot combat environmental stress to repair damage, and
the production of those important proteins is reduced.
Figure 5. Structure of human SIRT1. Modified from Autiero et
al. 2008.
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FINE-TUNING SIRTUINS TO
IMPACT SKIN CELLS
Approximately four years ago, ARTISTRY™ scientists became
excited by the idea that certain ingredients might help delay
skin cell senescence and death by impacting SIRT1
activation. While the idea worked in theory, there were
problems with the most popular ingredient - resveratrol itself.
First, it is not a particularly stable compound. Second, skin
cells don’t seem to absorb it readily. And third, resveratrol is
difficult to add to skin care formuations. This led the
researchers to search out other, more stable, “longevity
boosters,” that would activate SIRT1 in skin cells.
The scientists analyzed many ingredients in their pursuit, but
the most effective, stable and safe ingredient they found
came from an extract of the leaves of a Mediterranean plant
called myrtle, a flowering shrub native to southern Europe
and northern Africa (Figure 6). In ancient Greece and Rome,
myrtle essential oil was used to prepare "angel water," which
was said to restore freshness and youth to the skin.
Scientific experiments by ARTISTRY scientists support the
notion that this hydrolyzed myrtle extract, dubbed LifeSirt,
helps to delay the signs of aging in skin.
First, LifeSirt enhanced the longevity of fibroblasts—the skin
cells that make collagen and elastin—under in vitro
conditions that mimicked the oxidative damage of aging
(Figure 7). This experiment revealed that LifeSirt helped
cells resist environmental damage by boosting their internal
repair mechanisms.
Second, in vitro experiments showed that LifeSirt increased
the activity of genes that code for certain youth proteins in
skin cells by 280 percent* (Figure 8). As a group, youth
proteins are those that help maintain the elasticity and
plumpness of young-looking skin. Although youth proteins
normally decline with age, this finding suggested that LifeSirt
can boost some of these proteins, even in aging skin.
With these experiments, ARTISTRY scientists have found that
the combined impact of LifeSirt on skin cells may be more
effective than that of resveratrol. The benefit of SIRT1
activation with LifeSirt is seen both in cells of the epidermis,
through increased cell turnover/cell rejuvenation, and in
cells of the dermis, through increased production of matrix
components. All together, the evidence supports the idea
that the inclusion of LifeSirt in skin care products will help
extend the youthful look of skin and delay the signs of aging†.
*
Figure 6. Mediterranean myrtle.
Based on in vitro gene expression assays
† Based on in vitro oxidative stress assays
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Figure 7. LifeSirt increases the longevity of skin cells under
oxidative stress†.
Figure 8. Youth proteins (green) are abundant in young skin
cells (top left) but lacking in aged skin cells (top right). Cells
that have been aged in vitro (bottom) produce more youth
proteins after treatment with LifeSirt.
In discussions with the Artistry Scientific Advisory Board,
representing academics, scientists, dermatologists, and
other key leaders in the field of anti-aging skin care, the
board agreed that sirtuin research has great potential to
positively impact skin cells, and thus delay the signs of aging.
They recommended that younger women—those in their
upper 20s to 45—could best use this technology to maintain
their youthful appearance and keep it looking that way
longer. By leveraging LifeSirt to positively impact their skin
cells, their skin could remain in a younger state (Figure 9)
and delay the appearance of the signs of aging†.
† Based on in vitro oxidative stress assays
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Figure 9. SIRT1 helps middle-aged skin remain in a youthful state.
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GLOSSARY
Collagen – The structural proteins of the skin that give it
strength, elasticity, and firmness.
Dermis – The layer of the skin that forms the cushion of the
skin and comprises collagen, elastin and other extracellular
matrix proteins.
Elastin – Protein that accounts for the elasticity of structures
such as the skin, blood vessels, heart, lungs, intestines,
tendons and ligaments.
Epidermis – The protective outer layer of cells that make up
the barrier of the skin.
Hypodermis – See subcutaneous layer.
In vitro – A method to perform experiments such as testing
efficacy of a product or ingredient using cells or tissues
outside the body in an artificial environment.
Keratinocyte – The main epidermal cell type, which produces
keratin.
Procollagen – A helical protein that is the precursor of
collagen.
Sirtuins – Natural youth proteins shown to strengthen and
extend the lifespan of skin cells.
Extracellular matrix – The layer consisting mainly of proteins
and chains of sugars (polysaccharides) that form a sheet
underlying cells. Substances within are produced by cells in
the vicinity, especially fibroblasts.
Subcutaneous tissue – The deepest layer of the skin,
containing connective tissue, sweat glands, blood vessels,
and cells that store fat.
Fibroblast – A common cell type found in the dermis that
secretes collagen and other matrix molecules.
Youth Proteins – Proteins that encourage youthfulness in
skin cells, for instance by boosting collagen levels.
Glycosaminoglycans – A class of various conformations of
long-chain carbohydrates that are important to the make-up
of the extracellular matrix in the dermis.
Hyaluronic acid – A particular type of glycosaminoglycan
(GAG) found in the extracellular matrix and other parts of the
body. Due to its strong ability to bind water, it helps lubricate
tissues such as the skin.
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BIBLIOGRAPHY
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