Lifespan
Project Launched
by Richard Weindruch and Stephen R. Spindler
Page 3 of 4
Coenzyme
Q10
Coenzyme Q10 (CoQ10) is a small, vitamin like molecule
which is an essential component of the electron transport
chain in mitochondria, the power plants in our cells. ATP
(adenosine-tri-phosphate) is the energy molecule used inside
cells to do work. ATP is fabricated in mitochondria. The
electron transport chain is the biochemical pathway by which
electrons extracted from food are used to fabricate ATP. In
the process, the electrons convert the oxygen in air to water.
CoQ10 is an electron acceptor and donor. It shuttles electrons
back and forth between several of the enzymes which carry out
ATP fabrication.
In addition to its function as an electron shuttle, CoQ10
is an antioxidant (Beyer, 1992; Kanter, 1994), which may be
especially important inside mitochondria. The electron
transport chain generates about 1 trillion oxygen radicals per
cell every day. About 2 percent of them get free of the
enzymes that try to hold on to them until they can be used to
generate energy. These free oxygen radicals are very dangerous
to the mitochondria, but also to the rest of the cell. In
fact, the reason electron transport takes place in
membrane-bound sacks such as mitochondria is, in part, to keep
these free radicals trapped inside the mitochondria. This is
why having a strong antioxidant like CoQ10 in mitochondrial
membranes is important.
Supplementation with CoQ10 raises the levels of this
antioxidant in our cells and tissues. Furthermore, CoQ10
increases the activity of the electron transport chain,
improving energy generation by mitochondria. We gradually lose
some of our ability to produce energy from the food we eat as
we age. Supplementation with CoQ10 partially reverses this
loss, especially in the heart muscle. In animal experiments,
CoQ10 protected the heart against oxidative damage caused by
the blockage and restoration of blood flow (Mortensen, 1993).
In animal studies, CoQ10 protected the brain from oxidative
damage (Beal et al., 1994) and protected the liver from
free-radical-generating toxins.
Acetyl-L-Carnitine
Many tissues use a metabolic strategy termed beta oxidation
to "burn" fatty acids to obtain energy. This activity takes
place in the mitochondria. Carnitine is a small molecule
resembling an amino acid. It serves as a sort of ticket or tag
for entry into the mitochondria. Carnitine is chemically
attached to the fatty acids in the cell cytoplasm outside the
mitochondria. A transport system in the mitochondrial membrane
recognizes the attached carnitine ticket, grabs it along with
the fatty acid, and moves them both into the mitochondria.
Once inside, carnitine is removed from the fatty acid and
transported back outside the mitochondria so it can be used
again.
In heart mitochondria, this transport process decreases
with age, as does mitochondrial function. A decrease with age
also has been found in the body's pool of carnitine. This
decrease may be responsible for some of the age-related loss
in mitochondrial function. There is a growing body of
scientific evidence indicating that the accumulation of
mitochondrial defects with age can be slowed or reversed by
supplementation with acetyl-L-carnitine (ALC) (reviewed in
Shigenaga et al., 1994). ALC is the natural precursor to both
carnitine and acetylcholine (a "neural transmitter").
Acetyl-L-carnitine improves mitochondrial function in
several ways (Shigenaga et al., 1994). For example, ALC fed to
old rats increases mitochondrial cardiolipin levels to those
of young rats. Cardiolipin is a natural component of
mitochondrial membranes, that is important for membrane
structure and function. It also is important for the
functioning of the enzymes responsible for energy generation
within the mitochondria. Aging decreases the cardiolipin
content of mitochondria in heart, liver and brain, which
generates extra oxygen radicals.
ALC helps to reduce oxidative damage with age, and protects
the brains of experimental animals from age- and
stroke-related neural degeneration. In humans, one controlled
clinical trial showed that the progression of Alzheimer's
disease was significantly reduced in patients receiving 2
grams per day of ALC for a year (Bowman, 1992). We will
conduct the first test of the effect of ALC supplementation on
lifespan.
Procysteine
Cysteine is a non-essential amino acid used for protein
synthesis. Although we make some cysteine in our cells, it is
also the rate-limiting amino acid for the synthesis of
glutathione, a small molecule that plays many essential roles
in cells. Cysteine is unstable, somewhat toxic, and weakly
mutagenic when taken orally or by injection. But procysteine,
a modified form of cysteine, is somewhat less toxic, and much
more stable "on the shelf" than cysteine (White et al., 1993).
It is rapidly converted into cysteine and carbon dioxide
inside cells. This conversion makes it good for raising
intracellular concentrations of cysteine, which, in turn,
raises intracellular levels of glutathione.
Glutathione is made up of three amino acids, linked
together like the amino acids in normal proteins. But,
glutathione is a small molecule. It is important in many
cellular functions including the folding of proteins into
their correct structures. It also is an antioxidant (Kehrer
and Lund, 1994) that detoxifies free radicals directly by
interacting with them. And, it also is an important
contributor to the detoxification of many free radicals and
foreign chemicals by enzymes (Hayes and Pulford, 1995; Talalay
et al., 1995). For example, it aids in the enzymatic
detoxification of lipid peroxides and hydrogen peroxide.
The synthesis of glutathione is often limited by the supply
of free cysteine. The concentration of free cysteine is very
low in plasma. Low levels of glutathione lead to a decrease in
intracellular antioxidant activities, and a decrease in the
activities of the enzymes which depend on correct
intracellular oxidation-reduction potential for their
structure and activity.
There are no large clinical trials that demonstrate health
benefits from glutathione or NADH supplementation. But a
decrease in glutathione levels has been found in aging animals
and humans, and in various disease states (Meydani et al.,
1995). Glutathione levels decrease in the lens of the eye as
we age. Lower glutathione levels have been found in the lens,
spleen, liver, kidney and heart of old mice compared to young
mice. In one study, half of elderly subjects had lower blood
glutathione concentrations than younger subjects. There is a
positive correlation between tissue glutathione levels and
lifespan in mice. Glutathione inhibits liver cancer growth in
humans and oral cancer in hamsters. Thus, the decline in
glutathione levels with age may be related to the increase in
cancer.
The decrease in glutathione levels with age also may partly
explain the age-related decrease in immunity. And, decreased
glutathione may partly be responsible for the liver's loss of
detoxification ability. This loss is found in most mammals,
including humans. Low glutathione levels are associated with
arthritis, diabetes, heart disease and cataracts.
In clinical studies in the elderly, higher glutathione
levels are associated with fewer illnesses and the perception
of improved health. Finally, dietary supplementation with
glutathione, or with supplements that raise glutathione
levels, appears to improve the immune response in humans and
experimental animals.
NADH
NADH (a form of nicotinamide adenine dinucleotide) is a
coenzyme that assists enzymes involved in energy production
within mitochondria. NADH plays an important role in the
generation of ATP, the body's energy currency, and has been
found to be deficient in several age-related degenerative
diseases. Uncontrolled studies in Europe have found NADH
beneficial for patients suffering from Parkinson's disease,
Alzheimer's disease, and depression (Birkmayer, et al,
1990).
NADH also is needed for the regeneration of glutathione
after it becomes oxidized (Sies and Stahl, 1995; Kehrer and
Lund, 1994). If NADH levels are depleted, glutathione levels
also may fall. Thus, supplementation with NADH also may help
restore glutathione to its active form.
Melatonin
Melatonin is a mammalian hormone, secreted at night during
sleep by the pineal gland. Although melatonin's role as a
hormone is subtle, it is clearly a potent antioxidant (Reiter
et al., 1996). It is both water- and membrane-soluble, and
acts as an antioxidant in both lipid and aqueous environments.
Dosages that raise blood levels of melatonin to
higher-than-normal levels protect against agents that damage
cells by generating oxygen radicals.
These include ionizing radiation, the chemical carcinogen
safrole, the diabetes-inducing toxin alloxan, the herbicide
paraquat, bacterial lipopolysaccharide, and the liver toxin
carbon tetrachloride. Melatonin also protects against
cataracts caused by buthionine sulfoxamine, a drug that blocks
the production of glutathione.
Melatonin is absorbed readily when taken orally, and has
very low toxicity. In fact, few if any negative side effects
have ever been reported for melatonin. In addition to its
antioxidant effects, melatonin has been proposed as a
regulating agent for the biologic aging clock. A previous
study suggested that melatonin may be able to extend lifespan
in rodents. Our study will seek to determine if this is
possible.
The Mystery of
Aging
Two additional theories of aging also will be examined
during The Lifespan Project.
The questions? How does glycation and hormone depletion
influence longevity?
Why do we age? In addition to the free radical and
energy-depletion theories of aging, there also are the
glycation and hormonal theories. Each theory proposes
different biochemical mechanisms for aging. It's possible that
all four are right, that their concerted action produces the
symptoms of aging.
Anthony Cerami and colleagues proposed the glycation theory
of aging. This theory postulates that cellular damage from
glucose (blood sugar) is a factor in aging. Diabetes, which is
characterized by abnormally high levels of blood glucose, is
probably a form of accelerated aging.
High blood glucose levels are associated with long-term
neurologic problems, kidney damage, atherosclerosis, loss of
vision, cataracts and impaired cellular immunity (Ziyadeh.
& Cohen, 1993; Anonymous, 1993; Rossetti et al.,
1990).
High insulin levels often are found in people with heart
disease, atherosclerosis and high blood pressure (Ferrari
& Weidmann, 1990; Stout, 1990; Ducimetiere et al., 1980).
These are many of the diseases and complications that occur in
old age.
In fact, one of the characteristics of human aging is a
progressive rise in blood glucose levels. Blood glucose rises
because insulin becomes less effective in causing glucose
uptake by muscle and fat cells.
Glucose reacts slowly with proteins, fats, lipids and even
with the genetic material of our cells (Lee & Cerami,
1992). With the passage of time, it forms toxic chemicals that
have been given the name "advanced glycation end products," or
AGEs (Baynes, 1991). This same process takes place much faster
through the heat of frying or broiling, which is what gives
cooked meat its brown color. During this process, reactive
glucose forms free radicals which continue and amplify the
reaction, enlarging the damaged area. Over a lifetime, this
kind of damage accumulates, even in people without diabetes.
The damage may even be involved in the loss of neurologic
functions during aging.
Recent research has shown that the effects of many small
strokes in older people accumulate over the years to finally
rob us of short-term memory. The neurofibrillary tangles and
senile plaques in the brains of patients with Alzheimer's
disease contain AGE, while little if any of these products are
detected in healthy brain regions, even within the same brains
as the afflicted persons (Smith et al., 1994).
Continued on Page 4 of 4
|