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Fasting and Calorie Restriction
Benjamin Franklin not only had an understanding of the needs
of his generation, but also a vision for the future when he asserted that
the best of all medicines are not potions or drugs, but rather rest and
fasting. Fasting often addresses the cause of the illness, whereas drugs
are often directed toward the symptoms that accompany the condition.
The early church recognized fasting as a means of obtaining
spiritual peace, while at the same time enhancing physical health (Wallis
1993). Throughout history, reports of the merits of fasting have inspired
a subset of the population to engage in the ritual. However, the United
States still lags behind in exploiting the benefits of fasting. European
clinics have successfully used fasting for detoxification and healing
purposes for many decades.
Various forms of food withdrawal may be described as a fast. A faster
can abstain from specific foods such as meat or sugar; fast from dawn
to dusk; fast one meal per day; fast one day per week; totally withdraw
from all foods; or fast only on juices and broths. Juice fasting, which
is considered much safer than total food abstinence, requires instruction
to be successful. This is the primary focus of this protocol.
A 2003 report showed that the health benefits of sharply cutting calories
(as occurs with periodic fasting) accrue even if the fast does not result
in eating less overall (Anson et al. 2003). Benefits ranging from longer
life, to less stress, and to greater sensitivity to insulin have been
reported. Mice fed every other day, but allowed to gorge themselves on
the days they were permitted food, had similar health benefits to mice
on a diet reduced to 60% of normal food intake (Associated Press , 2003).
Some researchers believe that skipping meals will not result in injurious
effects to fasters. Fasting aficionados believe that by fasting three
days a month, people will heal faster and extend their lives by several
years (a 3-day fast helps rid the body of toxins; a 5-day fast is thought
to start the healing process) (Healing Celebrations, 2002; The Associated
Press, 2003).
Although fasting is touted as one of the oldest and surest ways to establish
good health by promoting internal cleansing and healing, normalizing blood
pressure and cholesterol, rebuilding the immune system, and reversing
the aging process, it is not without its critics. Because the Life Extension
Foundation is committed to improving the health of the public and increasing
life span, both sides of the fasting issue will be presented.
Health Begins at the Cellular Level
There are more than 200 different cell types and a debatable number of
cells in the entire body (some sources estimate about 50 trillion cells
are contained in the human body, but others calculate the number may be
nearer 100 trillion). The number of cells is not constant. As cells die
or are destroyed, new ones are formed, so the numbers are constantly changing.
It is estimated that half of all body cells are at the peak of development
and working condition; one-fourth are in the process of growth; and one
fourth are in the process of dying and replacement.
Natural hygienists believe that one cause of disease is toxin saturation
at the cellular level. Every function the cell performs produces waste
products (toxic materials that are incompatible with cellular health).
Cells have capacities for ridding toxins, but these pathways can become
saturated and overwhelmed. If the body becomes overwhelmed, it will try
to rid its toxins through other mechanisms that manifest as colds, inflammation,
and skin eruptions. Toxemia has been described as nature's way of eliminating
toxins.
The body is fully capable of healing itself if these toxic accumulations
are stopped and proper nutrients provided. Conversely, there is a clear
connection between systemic toxicity and development of many debilitating
health conditions. Biochemical suffocation (or the interference with normal
cell metabolism) is the principal cause of disease and aging. Some believe
that life is only as strong as the weakest vital link, the cell.
Because toxic waste products interfere with the functioning of the cell,
it is important that toxins and dying cells are eliminated from the system
as efficiently as possible. This elimination stimulates growth of more
functional cells. As your cells go, so goes your health. Cleanse and nourish
your cells, and you're on the road to better health (Airola 1977; FCI
2002; Nison 2003).
Autotoxicity (Self-Poisoning)
Cellular decline may be caused by the accumulation of waste products in
various tissues, which interferes with nourishment, and oxygenation of
the cell. When dietary deficiencies, sluggish metabolism, sedentary lifestyle,
lack of fresh air and water, overeating, and poor digestion deprive the
cells of key nutrients, they start a process of degeneration and decay
(Airola 1977). The body ages from the inside out and becomes vulnerable
to disease and senescence. Proponents of fasting declare that aging is
not commensurate with calendar years, but rather with the health of the
cells. As toxins build up in tissues, a toxic environment is created.
It is not uncommon for the symptoms of headache, diarrhea, or depression
to occur as the body deals with autotoxicity (self-poisoning). During
fasting, the concentration of toxins removed from the body and appearing
in the urine can increase ten-fold.
Fasting and Cellular Toxicity
Fasting triggers a cleansing process that affects every cell and tissue
in the body; elimination of dead and dying cells while stimulating generation
of new cells (Shirley's Wellness Cafe 2003). During a fast, toxic waste
products impair nourishment of cells are eliminated with restoration of
normal metabolic rates and oxygenation. A fast offers respite from energy-demanding
digestion (10% of caloric intake is used for mastication, digestion, assimilation,
and elimination). Instead, energy can be redirected toward improved immune
function, elimination and cell growth.
Within 24 hours of food restriction, digestive enzymes stop entering
the stomach and instead other enzymes are released into the intestines
and bloodstream, where they circulate and digest waste materials of daily
living. Advocates of fasting believe that the body will first decompose
and burn those cells and tissues which are diseased, damaged, or aged,
e.g., dead cells and morbid accumulations (tumors, abscesses, and fatty
deposits). Renowned advocates of fasting refer to fasting as a means of
burning the rubbish' (Saxion, 2002). Essential and vital organs, such
as nervous tissue and brain, are not damaged during a well-planned fast.
Starvation can have pronounced effects on major body systems and organs.
The basic metabolic response to starvation is to preserve vital tissues
and create energy. Eventually, following prolonged starvation, the body
is must survival by use of essential tissues for energy, including muscles
and organs. Liver and intestines typically lose higher percentages of
their weight during starvation, followed by the heart and kidneys. Reduction
in heart size may lower blood pressure and pulse rate. Total starvation
is usually fatal in 8-12 weeks, depending on body size. Long-term dehydration
ultimately leads to kidney failure (Pale Reflections 1998; Merck 1999).
Fasting to Lose Weight
The reason for a fast should be to regain lost energy, heighten clarity
of consciousness, enhance innate spirituality, cleanse, rest, regenerate,
and rejuvenate the body along with the weight loss. A prolonged fast should
result in the loss of about 5-7 pounds of fecal material from the colon,
but this amount is quickly regained upon feeding. It is also common to
detoxify 5-10 pounds of toxic substances (FCI 2003). Although a short
fast of 3-5 days may not accomplish a lot, it is the safest recommendation.
It has taken years to wear the body down, and will take time to restore
it to peak condition. Recall that a short fast can be repeated several
times per year to optimize benefits. Consult with your physician to determine
if your health precludes a fast. If under the care of an experienced health
provider, a longer fast may be considered.
Preventive and Therapeutic Objectives
Preventive fasting reduces the effects of dangerous risk factors (hypertension,
smoking, obesity, elevated uric acid and blood lipids, and sedentary lifestyles).
Therapeutically, a fast has proven effective against the following conditions
(Fuhrman 1998; AFL 2000; FCI 2002):
- Cardiovascular diseases, including dysfunctional circulation, future
myocardial infarction (heart attack), and recovery
- Migraines and glaucoma
- Disorders of the stomach and intestines, bulimia, and chronic constipation
- Diseases of the liver and biliary tract
- Crohn' s disease and ulcerative colitis
- Diseases affecting locomotion; rheumatism, joint and vertebral degeneration,
and disorders of muscle and connective tissue
- Skin diseases; allergies, psoriasis, and eczema
- Diseases of the upper respiratory tract; nose, nasal cavity, ethmoidal
air cells, sinuses, larynx, and trachea
- Fibroid tumors, nasal polyps, lipomas, benign ovarian and breast
tumors
- Lagging libido
- Post-treatment for malignant disease [The residue of a necrotic (dead)
mass can be highly toxic. A fast does more than detoxify noxious by-products
of malignancy; it degrades abnormal cells and tumors, releasing cellular
toxins and by-products into the circulation for elimination.]
Mice fed every other day were more protected from diabetes and Alzheimer's
disease than mice on low-calorie or unrestricted diets (Anson et al. 2003).
The mice consumed the same amount of calories in the long term. A third
group of mice were fed a low-calorie diet with 40% fewer calories. When
given a neurotoxin that damages nerve cells similarly to Alzheimer's disease,
fasted mice had fewer damaged nerve cells than mice on unrestricted or
low-calorie diets. Fasted mice had lower insulin levels, implying a lower
risk of developing diabetes (Mercola 2003a).
Studies showed that 70% of the patients with psychiatric disorders improved
with fasting (FCI 2002). Other researchers have observed that fasting
patients with psychosomatic disease had an 87% success rate (Christian
Century 1977; AFL 2000).
The Best Way to Fast
A uthorities agree that juice fasting is the best, safest, and most effective
method of fasting. The classic form of fasting extended, pure water fast)
introduces considerable toxins into the bloodstream and has been discredited
as the best form of fasting. A water fast is often too debilitating. When
fresh fruit and vegetable juices, alkalizing vegetable broths, and herbal
teas are used, electrolytes are maintained. The faster receives a daily
infusion of vitamins, minerals, and enzymes. Freshly prepared juices require
no digestion and are easily assimilated. Juices do not disrupt the healing
and rejuvenating effects of autolysis (self-digestion). By providing about
400 calories per day, the release of toxins from fat cells is more gradual
than a strict water fast.
Do not chew gum while fasting; it promotes release of digestive enzymes.
During a fast, the stomach is void of solid foods so enzymes can injure
the stomach lining. Avoid mints and hard candies. Following the fast,
there is a loss of appetite for caffeine, nicotine, alcohol, sugar, and
junk foods.
Typically, a well-planned fast allows normal workload, exercise, and
study habits. During a fast, walking and deep-breathing exercises provide
fresh air to cleanse the blood, effectively regenerating and revitalizing
body functions. It is important to get rest, especially when fatigued.
Some fasters prefer a weekend fast with less demanding schedules.
Adjuvants to a Successful Cleanse
A fast does not always help eliminate impacted waste materials from the
colon, so plan a colon-cleansing regimen. Fasters use colonics and herbal
laxatives (like senna). Others use psyllium powder as a bulking agent.
Enemas (containing 1-4 pints of water) can cleanse when taken once, but
preferably twice a day (Horowitz 2001). Fasting without the aid of enemas
allows toxins in the colon to be reabsorbed. This can poison the body.
The organs of elimination (particularly the kidneys) may become over-burdened
and damaged (Airola 1977).
Dry brush massage (morning and evening) is a helpful adjunct to detoxification
(over a pound of waste products is discharged through the skin every day).
Use a natural bristle brush (the size of your hand) with a long handle.
Avoid nylon or synthetic fiber brushes because the sharp, unnatural bristles
can damage skin. Brush the entire body except the face. First brush the
feet and legs, then the hands and arms, and lastly the back, abdomen,
chest, and neck (Airola 1977). Brush for at least 3 minutes, producing
a warm, glowing hue. Avoid aggressive brushing that may damage the skin.
Remember to always brush toward the heart. All lymph vessels have one-way
valves, which drain towards the heart, emptying into the large blood veins
leading to the heart. After brushing, take a hot shower (3 minutes in
duration), followed by a 10-20 second cold rinse. Repeat this procedure
three times. If the hot/cold showers are too extreme, a warm shower can
be used. Follow the shower with a rubdown with either a sponge or towel
to remove dead skin.
The cleansing process is performed by a number of organs, glands, and
transportation systems, including the alimentary canal, kidneys, liver,
lungs, lymphatic system, and mucous membranes. The skin is regarded as
the largest eliminative organ. It is estimated that one-third of all body
impurities are removed through the skin's tiny sweat glands, the so-called
third kidney. Sweating is an effective means of purification. One-third
of all diseases could be cured by sweating according to 17 th century
physicians.
Recommended Liquid Intake while
Fasting
Opinions vary on the amount of liquid to consume while juice fasting.
Some recommend at least eight, 8-ounce glasses of distilled water per
day, two cups of herbal tea, along with diluted juices (Balch et al. 19
7 97). Regardless of your fitness goal, make sure you drink enough water
daily. Many diseases respond to adequate hydration, flushing out disease-provoking
toxins. An easy formula for calculating your daily water requirements
is to take your weight, divide it in half, then consume that amount of
water (or juice), generally 9 to 10 glasses daily. Caffeinated and alcoholic
beverages will dehydrate, so for every glass of these beverages you drink,
you need to add an extra glass of water (Airola 1977; Balch et al.1997;
Woman's World 2001; Horowitz 2002).
Drink freshly prepared juice made from a combination of any of the following
(ideally organic) fruits and vegetables: spinach, dandelion, parsley,
kale, celery, apples (with seeds and skin), and carrots. Raw fruits and
vegetables are perfectly compatible when eaten together. Melons are the
exception. Making the entire meal melon is an option. If refined sugar
or flour is eaten during the same meal with fruits (except bananas, dates,
figs, or raisins), within an hour or two, the sugars and starches will
ferment in the digestive tract and cause acidosis (Walker 1986). Another
juice combination may be prepared from three carrots, two stalks of celery,
one turnip, two beets, one-half head of cabbage, a quarter bunch of parsley,
and a clove of garlic (Healing Celebrations 2002). Other juice detoxifiers
include fresh lemon, grape, and green drinks (prepared from leafy green
vegetables). Dilute all juice with water (1:3 parts) and drink throughout
the day. Avoid orange or tomato juice (because of their high acidity)
and avoid using sweetened juices.
There are a number of juicers that are ideal for home application, but
Champion Juicers (Albion Enterprises, 800-248 - 1475) is an excellent
choice. During the fast, select juicing materials and teas that are specific
to your health conditions (Balch et al. 1997; Horowitz 2001). For example:
- Freshly prepared cabbage juice is excellent for ulcers, cancer, and
colon problems. Do not store cabbage juice because its vitamin U content
can be quickly lost. (Vitamin U, named for its ulcer applications, is
found in cabbage juice and responsible for healing ulcers in the digestive
tract.)
- Alfalfa, burdock, chamomile, dandelion, milk thistle, red clover,
and rose hips tea may be used to rejuvenate the liver and cleanse the
bloodstream.
- Two parts pau d'arco and echinacea tea mixed with one part unsweetened
cranberry juice assists in rebuilding the immune system, improving bladder
function, and ridding the colon of unwanted bacteria.
- Peppermint tea has a calming, yet strengthening effect upon the nerves.
It is excellent for nausea, indigestion, and flatulence.
- Slippery elm reduces inflammation in the colon. The tea is also beneficial
when used as an enema.
- Pure vegetable broths (with no seasonings added) are excellent additions
to a fast. Prepare them by gently simmering the vegetables in water
until tender (garlic and onion may be added for taste and healing properties).
The blended or strained broths may be consumed 2-3 times per day. If
you must eat, select a slice of watermelon (eaten alone). Fresh applesauce
(blended with skins) is satisfying and will not disrupt the fast (Healing
Celebrations 2002).
Food Transitioning On and Off a
Fast
Two days prior to initiating the fast, a short cleansing diet (of only
raw fruits and vegetables) is recommended. Caution must be exercised when
breaking a fast. The benefits of a fast are lost by bingeing on unhealthy
fast and processed foods. The main rule in breaking a fast is not to overeat.
Take several days to transition to a normal diet. Initially, rely upon
a small apple, a piece of melon, nectarine, or pineapple for breakfast
and a small bowl of fresh vegetable soup (from raw vegetables) for lunch.
Continue with fresh juices and broths for dinner or eight ounces of any
fruit. The second day, add soaked prunes or figs, additional apples, and
a fresh garden salad. The third day, include a cup of yogurt and a few
finely ground nuts. Increase the size of salad servings and include a
boiled or baked potato. A slice of whole grain bread and a serving of
cheese with soup is appropriate for the evening meal. Eat slowly and chew
your food well. The fourth day, return to normal eating, but try to incorporate
as many healthy foods as possible into your diet (Airola 1977; Murray,
1991).
Taking Medications and Nutritional
Supplements
Medications are usually withdrawn during a fast, but exceptions occur
as in medications for a heart condition. A physician should make the decision
regarding the use of medications during a fast. Typically, supplements
are not used, but again exceptions arise. Certain health conditions may
require support with appropriate supplementation. Even though juices provide
a numerous nutrients, some physicians recommend use of an abbreviated
list of vitamins and minerals for elderly fasters (Airola 1977; Balch
et al. 1997).
Is Fasting Safe?
Professionals who supervise fasts unequivocally state that a juice fast
is not only the most effective healing method available, but also the
safest. There are certain people who should not fast and others who should
only fast under the close supervision of a physician. Children, still
forming bone and teeth, are not candidates for fasts nor are pregnant
and lactating women. According to the Fasting Center International, if
the patient has advanced cancer, diabetes, tuberculosis, or cardiovascular
disease, a fast should be undertaken only on the advice and direction
of a competent medical doctor (FCI, 2003). Individuals with hypoglycemia
should never fast without using a protein supplement. Spirulina (a microalgae
that produces 20 times as much protein as soybeans is a popular choice
(Balch et al. 1997).
Most fasters report darker urine and a catarrhal elimination of excess
mucus (the condition is referred to as rhinorrhea or a free discharge
of thin, watery nasal fluid). This occurs during the days of solid food
abstinence. Others report a coated tongue, nausea, insomnia, or feelings
of anxiety.
If detoxification occurs too rapidly, allowing toxins to enter the bloodstream
quicker than they can be eliminated, a healing crisis can occur (Herxheimer's
reaction). The released toxins can either exacerbate the symptoms being
treated or create their own symptoms such as headaches, body ache, joint
pain, dizziness, sweating, general malaise, sore throat, nausea, and/or
flu-like symptoms. Although the experience is not pleasant, Herxheimer's
reaction is actually a sign of healing. The approach to Herxheimer's reaction
is to go slowly. If a healing crisis occurs, reduce the cleansing regimen,
allowing the body to detoxify. Unpleasant symptoms subside rather quickly,
allowing the individual to continue with normal activities. The classic
response to a fast is a feeling of euphoria (high energy, clarity of thought,
and an exuberant spirit).
The Swedish Fast Marches were a great scientific success. All of the
participants in the marches (1954, 1964) walked 325 miles over 10 days
without solid food. The marches clearly showed humans can live for an
extended period without food, and participate in strenuous physical activity
while fasting. It was observed that serum albumin levels remained constant,
as did blood sugar levels, even though no protein was consumed over the
course of the 10-day march. Body protein is in a dynamic state of catabolism
and anabolism. When old or diseased cells are decomposed, the amino acids
are simply recycled to build young, healthy cells (Airola 1977).
The human body has an incredible capacity for healing and longevity;
an innate intelligence more powerful than any drug or surgeon's knife.
All the body needs is the latitude to accomplish this and fasting grants
that freedom (Meyerowitz 1999).
Seldom Are Scientific Opinions
are Seldom Undisputed
Opponents challenge that fasting is starvation. Some researchers assert
that a fast will not cleanse your body of toxins, that there is no evidence
the body needs internal cleansing, nor the digestive system needs to rest.
The digestive system is quite efficient at cleansing itself and ridding
the body of waste materials. The notion that stagnation and decay in the
colon produce toxins that poison the body is an ancient concept that has
been long ago discredited (UCB, 2002). Total fasting does result in a
rapid initial weight loss, but most of the loss is fluid, rather than
fat. As the fast continues, you lose body fat, but also considerable muscle
(including heart muscle) and minerals. Depending upon the duration of
the fast, the muscle and mineral loss can reach dangerous proportions.
Few people who actually lose weight via a fast maintain their loss once
they renew eating habits. An individual in good health can undergo a 24-hour
fast without danger. Beyond a day or two, fasting can cause fatigue, headaches,
irritability, nausea, low blood pressure, and problems with heart rhythms.
It is especially hazardous for anyone with a chronic illness such as diabetes,
liver or kidney disease, to undergo a fast.
CRON (Caloric Restriction
with Optimal Nutrition) With Dietary and Supplemental Suggestions to Increase
Life Span
Note: Because
of the parallel between the two models, fasting and calorie restriction
are presented in the same protocol.
Claims that various nutritional interventions can extend life span are
manifold, but some have greater credibility than others. Gerontologists
agree that Caloric Restriction with Optimal Nutrition (CRON) offers the
greatest likelihood of succeeding.
The concept of restricting calories to improve health was first introduced
in the early 1900s, but the theory was advanced (1930s) when it was found
that calorie-restricted rats lived longer than those allowed to eat ad
libitum. Although decades have passed since these initial findings,
the mechanisms whereby dietary restriction retards aging and extends life
span are not fully understood. Data suggest s that calorie-restricted
rodents lived longer and aged more slowly because they were more resistant
to stress and their cells were protected against damaging agents (Van
Remmen et al. 2001).
Some substantiation of CRON was demonstrated by the BioSphere II experiment
which imposed a calorie-restricted diet for two years. The eight people
averaged 1800 calories per day during the first 6 months, 2200 calories
per day at the end of 2 years. Body weight dropped 15%, blood sugar dropped
20%, blood cholesterol dropped 38%, blood pressure dropped 30/27% (systolic/diastolic);
and white blood cell count dropped 24% (Walford 1988, 1994; Best 1995).
The results were consistent with animal studies.
Calorie-restricted monkeys weighed less, had less body fat, exhibited
lower temperatures, lower fasting blood glucose and insulin levels, and
increased insulin sensitivity. The monkeys had lower blood pressure, reduced
triglyceride and cholesterol levels, and increased levels of HDL-2B (low
of HDL-2B is associated with cardiovascular disease in humans) (Lane et
al. 1999).
From an evolutionary point of view, many of the observed effects of
CRON make sense. When food is abundant, an animal grows large, matures
quickly, and reproduces. When food is scarce, less energy is devoted to
growth, basal metabolism, or reproductive capacity. Energy is maintained
for muscular action, which is most important for survival. Adult male
rats with 50% caloric restriction show a 42% drop in serum testosterone
and a 29% drop in luteinizing hormone (LH). Female adult rats also show
a drop in LH, but follicle-stimulating hormone (FSH) increases. Puberty
is delayed in males and females, and fertility is reduced after puberty.
However, irregularities in estrus cycles were correctable by increased
feeding (Best 1995).
Prior attempts to apply CRON to adult animals often did not succeed,
and resulted in a shorter life span, if the restrictions were applied
too rapidly. CRON produces the greatest extension of life span when started
just before puberty, but the result is a smaller sized animal. Applying
CRON just after maturity, it was possible to achieve 90% of the extension
of life span without stunted growth. If applicable to humans, a 60% calorie
restriction could produce a 50% increase in life expectancy from whatever
age the program is begun. A 10% caloric restriction could produce approximately
a 25% increase in life expectancy. Dr. Walford believes that even a person
between the ages of 50 and 60 could experience a 10- to 15-year life extension
with CRON (Walford 1988, 1994; Best 1995; Bozhkov 2001).
Animal Studies Yield Valuable Data
The CRON theory has been studied mostly in lower species, but the underlying
principle has been extended to include long-lived primates. A 30% caloric
reduction in rhesus monkeys living in captivity began in 1987; the species
can live to about 40 years old. Rhesus monkeys and humans are very similar
genetically, sharing a genome that is more than 90% identical (Divett
1998). The study demonstrated that calorie restriction decreased body
weight and fat mass, improved glucoregulatory function, and decreased
blood pressure, blood lipids, and body temperature. Juvenile males exhibited
delayed skeletal and sexual maturation and were able to overcome an age-associated
decline in dehydroepiandrosterone (DHEA) and melatonin normally seen with
aging. Bone mass was unaffected. Because 81% of the monkeys are still
alive, it is possible that calorie restriction had beneficial effects
on morbidity and mortality (Mattison et al. 2003).
Mice studies are valuable in assessing therapies to increase life span.
Different strains of mice live longer than others, but murine life spans
are measured in months rather than years. The SAMP8 mouse (genetically
prone to undergo accelerated aging) has a life span of 12 months. Few
people will derive useful information that might extend their life spans
while awaiting data from decades of primate studies. Researchers have
been able to extend the life span of some strains of mice to 45 months
from 32 months. Calorie restriction has been shown in other studies to
increase maximum life span to 53 months from 40 months.
The overall incidence of tumor formation was 78% in the control group
vs. 38% in the calorie-restricted group. Mice consuming fewer calories
stayed younger longer as judged by many age-sensitive biologic parameters
of immune system aging, eye & and lens proteins, liver enzyme activities,
and learning/behavioral patterns. Because calorie restriction can restrain
the diseases of aging, maintain health and youthfulness in animals at
advanced ages, and extend maximum life span (to the equivalent of 160
human years), calorie restriction is acknowledged as a valid way of slowing
aging in mammals (Weindruch et al. 1986; Kent 2003; UW-Madison Institute
on Aging 2003).
Scientists are searching for quicker methods (or surrogate, biomarkers
of aging) for measuring the rate of aging in humans. Because genes control
every aspect of biological life (including health, senescence, and longevity)
and caloric restriction extends healthy life spans, a rational approach
to finding biomarkers of aging is to compare gene expression in normal
aging animals with gene expression in calorie-restricted animals. The
use of high-density DNA microarrays (gene chips) to rapidly detect the
expression in up to 6347 genes at once, revealed that genetic changes
associated with aging were reversible by calorie-restriction (Lee et al.
1999).
Scientists at BioMarker Pharmaceuticals, a company funded by The Life
Extension Foundation,determined that the positive responses
of animals on calorie restriction are much quicker than first theorized
(after studying over 12,000 genes). It was previously thought that calorie
restriction would have to be applied over the lifetime of the animal to
be of significant advantage. Instead, it was determined that 70% of the
changes in gene expression caused by two years of calorie-restriction
occurred in only 2-4 weeks after placing mice on a calorie-restricted
diet.
Biomarker scientists established that senior rodents realized a 40%
extension of life span on a calorie-restricted diet; accordingly, rodents
of all ages are candidates for extension of life through caloric restriction.
BioMarker scientists found that some genes showed increased expression
(including genes associated with inflammation and stress), while others
revealed decreased activity as the animals aged. A single gene can control
life span affecting the timing of systemic and cellular aging processes
in mammals, indicating that only a few pivotal genes may be intricately
involved in longevity.
For example, unlike calorie-restricted mice, long-lived Snell dwarf
mice can eat all they want, became obese, and exhibit higher levels of
a fat-tissue-derived hormone: leptin. The Pit1 gene produces dwarfism
in Snell dwarf mice secondary to pituitary deficiencies of thyroid hormone,
growth hormone (GH), and prolactin. It is possible life extension may
relate to deficiencies of one or more of these hormones. A deficiency
in growth hormone may account for most of the longevity [recall that insulin-like
growth factor-1 (IGF-1) is produced in response to GH] (Premo 2001; Kent
2003). To read more about IGF-1, consult the section entitled The
Effects of Calorie Restriction, IGF-1, and Leptin in this protocol.
When the exact genes that govern aging are pinpointed, scientists will
be able to target those genes, the proteins they produce, and the biologic
mechanisms they affect in order to develop new drugs and therapies to
slow aging, prevent disease, and extend a healthy life span. (The screening
techniques used at BioMarker to assay anti-aging drugs are 25 times faster
than any other methods presently used.) The current best estimate of the
number of genes in the human body is 24,847. Many scientists think the
estimated gene tally will eventually rise, perhaps to above 30,000 (Pearson
2003).
Calorie Restriction and Oxidative
Stress
Accumulating evidence strongly suggests that oxidative stress underlies
the aging process. Senescence can be forestalled by calorie restriction
that may work through an anti-oxidative mechanism. An imbalance in reduction-oxidation
reactions (redox) occurring during the aging process may be minimized
through the anti-oxidative action of calorie restriction (Cho et al. 2003).
Animals chronically calorie-restricted had limited oxidative stress as
evidenced by the rapid recovery in glutathione levels in previously hypoxic
heart muscle. The kappa-B-responsive cytokines (interleukin-1-B and tumor
necrosis factor-a) were transiently expressed in the calorie-restricted
group, but persisted in the control group. The expression of manganese
superoxide dismutase, a key antioxidant enzyme, was delayed in the group
receiving unlimited calories. These data indicate that calorie restriction
significantly reduces myocardial oxidative stress and the post-ischemic
inflammatory responses (Chandrasekar et al. 2001; Sreekumar et al. 2002).
Calorie Restriction and Dementia
Researchers evaluated the effect of dietary restriction on oxidative stress
in mice allowed to eat normally or only 60% of normal caloric intake.
Basal metabolic rates were lowered by 15-22% and lipofuscin, a product
of free radical damage, was reduced by 16% in calorie-restricted mice.
The amount of superoxide radical was lowered 45%. There was a marked improvement
in graded scores of senescence. Neurotransmitters (acetylcholine, dopamine,
norepinephrine, and serotonin) levels were increased following dietary
restriction. The generation of reactive oxygen species (ROS) in the brain
decreased by 20%. Monoamine oxidase-B (MAO-B), an enzyme that increases
oxidative deamination (catabolism) of neurotransmitters in the brain,
was suppressed 7-10%. These results suggest that dietary restriction inhibited
oxidative stress and plays a role in reducing the age-related changes
observed in dementia (Choi et al. 2000; Kim et al. 2000).
Monoamine oxidase is a source of H2O2
(hydrogen peroxide). Free h ydroxyl radicals, one of the most potent of
all radicals, are produced from H2O2 and oxygen
reactions along with gamma rays from low-wavelength electromagnetic radiation.
These reactions contribute significantly to the
aging process and underscore the ‘free radical theory of aging'.
It has been determined that certain proteins, linked to brain cell death,
naturally increase with age, but were reduced in calorie-restricted rats.
Levels of a protein that protects against neuronal death doubled in old
rats whose calories were restricted by 40% (UF 2002). Individuals with
the APOE epsilon 4 gene (associated with Alzheimer's disease), whose calorie
consumption was the highest, had 2.3 times the risk of developing Alzheimer's
disease than did those with the gene who consumed the least calories (Luchsinger
et al. 2002). These findings have significant implications for approximately
four million people in the United States afflicted with Alzheimer's and
Parkinson's diseases.
Calorie Restriction Benefits Diabetics
Rats on a CRON diet showed a 15% reduction in blood glucose, which could
also mean less non-enzymatic glycosylation. This glycosylation contributes
to aging, perhaps cancer, and the complications arising from diabetes.
Reduction of blood levels of glycated hemoglobin has been observed in
human studies when hyperglycemia was treated with a CRON diet. Glycation
of collagen in the kidney could be a factor in diabetic kidney failure
and glycation of capillary membranes could contribute to age-related insulin
resistance (Best 1995). Rhesus monkeys (fed ad libitum, 6-8
hours per day) had higher basal glucose, basal insulin, insulin responses
to glucose, and decreased insulin sensitivity. Conversely, monkeys fed
a dietary-restricted diet (30% less than controls) showed decreases in
glucose/insulin parameters, and increased insulin sensitivity. Insulin
changes were significantly related to changes in obesity measured by weight
and abdominal circumference (Kemnitz et al. 1994).
A lean body may be more significant in determining life span in mice
than a calorie-restricted diet (Bluher et al. 2003). The mice ate whatever
they wanted and stayed slim because their fat tissue had been altered
and could not respond to insulin. Insulin is the primary hormone that
transports sugar into the cells and facilitates storage of fat in adipose
cells. Altered mice ate 55% more food per their body weight than normal
mice, yet they had 70% less body fat at three months of age. Essentially
, these mice were protected against obesity. These mice increased mean
life span (134 days or 18%), median and maximum life spans. A reduction
of fat mass (even without caloric restriction) was associated with increased
longevity, possibly through effects mediated by insulin. These findings
raise the possibility that a new drug for obesity and diabetes mellitus
Type-2 (DM-2) might act by blocking insulin receptors in fat tissue. The
drug would need to target fat tissue only because a loss of insulin sensitivity
throughout the body would mimic DM-2 (Bluher et al. 2003; Mercola 2003b).
The dangers of hyperinsulinemia (high blood insulin)
are well-established (many degenerative diseases develop secondary to
an excess of insulin). A detailed explanation of hyperinsulinemia is available
online, please refer to Diabetes
Type II and the Syndrome X Connection elsewhere in this volume.
How the Immune System Responds
to Calorie Restriction
Moderate caloric restriction in humans has a beneficial effect on cell-mediated
immunity (Santos et al. 2003). Cell-mediated immune reactions are triggered
by bacterial, fungal, and viral pathogens, malignant cells, foreign proteins
or tissues. Allergic dermatitis is a cell-mediated immune response. Tumor
necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) are generally increased
in the serum of aged humans and mice. The abnormal regulation of these
cytokines is common in immune dysfunction. Old mice subjected to long-term
calorie restriction had serum levels of TNF-a and IL-6 comparable to young
mice (Spaulding et al. 1997; Kim et al. 2002).Production
of TNF- a can activate nuclear factor-kappa-B (NF-kB), a transcription
factor. Once activated, NF-kB becomes a potent stimulus to cytokine production.
Excesses of IL-6 (a pro-inflammatory cytokine) have been demonstrated
in irregularities in immune function, heart disease, arthritis, and cancer.
Calorie Restriction and Malignancies
Tumors transplanted into underfed mice did not grow as well as those transplanted
into mice fed ad libitum. Caloric restriction affects the growth
of spontaneous tumors. Researchers have shown that caloric restriction
is beneficial despite the source of calories. Energy restriction enhances
DNA repair, moderates oxidative damage to DNA, and reduces the expression
of oncogenes (cancer-causing genes). Reduced caloric intake influences
insulin metabolism and may link overconsumption (elevated release of insulin)
with the establishment and proliferation of tumors (Moreschi 1909; Kritchevsky
1995, 2001). There was a delay in the onset of spontaneous hepatomas (malignant
liver tumors) and a reduction in their frequency following calorie-restriction.
The incidence of hepatoma in calorie-restricted mice was reduced (Yoshida
et al. 1999).
Even moderate dietary restriction is an effective antiangiogenic (anti-cancer)
therapy against recurrent brain cancers. Dietary restriction shifted the
tumor vascular environment from pro-angiogenic (favoring a well-developed
vascular system to nurture the growing tumor) to an anti-angiogenic state
through multiple effects on tumor cells and tumor-associated host cells
(Mukherjee et al. 2002).
Calorie restriction favors apoptosis (programmed cell death) of damaged
cells. Damaged cells either undergo repair or trigger apotosis. Chaperones
are stress proteins that enable polypeptides to assume their proper shape
(quaternary structure) and participate in mechanisms of apo ptosis by
secretion of proteins that inhibit apoptosis. High levels of chaperone
occur with aging and prevents the useful induction of apotosis. Calorie
restriction lowers chaperone levels, favoring apotosis of damaged and
pre-cancerous cells.A balance must exist in the need
to maintain sufficient cell numbers for a particular tissue function and
the need to eliminate damaged, potentially toxic cells. Non-dividing cells,
such as neurons, cannot be replaced. Calorie restriction induces chaperone
expression in neuronal cells and may delay the onset of neurologic disorders
of aging, including Alzheimer's disease, Parkinson's disease and stroke.
Rapidly dividing cells, such as liver cells, has shown that calorie restriction
reduces chaperones, encouraging the death of aged and precancerous cells
(Wickner et al. 1999;Spindler, 2001a; Suh et al. 2002;
Ken t, 2003).
Although the anti-cancer effects of calorie restriction are well-established,
Spindler (BioMarker Pharmaceuticals) does not recommend calorie restriction
for individuals with cancer. There is no question that calorie-restriction
improves health, but it is impractical to try to improve the health of
very sick people by under-feeding them.
The Effects of Calorie Restriction
on p53, IGF- 1 , and Leptin
Heterozygous p53-deficient mice are prone to spontaneous neoplasms, most
commonly sarcoma and lymphoma. The median time to death is 18 months.
Juvenile mice (eating 60% of an ad libitum diet) delayed tumor
development by mechanisms dependent of insulin-like growth factor-1 (IGF-1).
Calorie restriction or a fast limited to one-day per week suppressed carcinogenesis,
even when this restriction started late in life, in mice prone to develop
tumors because of this deficient p53 gene (Poetschke et al. 2000; Berrigan
et al. 2002). Plasma IGF-1 levels in calorie-restricted mice were reduced
by 20% after 4 weeks treatment. Leptin levels were reduced by 71% (Berrigan
et al. 2002).
The following technical comments explain how caloric restriction
(acting upon p53, IGF-1, and leptin) might influence life span.
p-53 (The Guardian
of the Genome)
p -53 prevents replication of damaged DNA in normal cells and promotes
apoptosis of cells with abnormal DNA. Faulty p53 molecules allow cells
with damaged DNA to survive and to replicate. A lack of p53 regulation
promotes the continued growth of spontaneous emergent mutant cells, precursors
to cancer (Greenblatt et al. 1994; Oliff et al. 1996).
Most natural systems function best when in balance, neither
showing hyper- nor hypo-responsiveness to any natural stimulus. High activity
of the tumor-suppressing p53 genes lowers cancer rates, but causes premature
aging. This finding suggests that aging might relate to the body's innate
vigilance against cancer. Mutant mice with over-active p53 genes were
more resistant to cancer than normal mice, but had a 20% shorter life
span. Instead of cancer, these animals showed bone thinning, organ breakdown,
vulnerability to physical stress, sagging skin, and balding. Hyperactivity
of the p53 gene may prematurely compromise the body's reserve of stem
cells. This might prevent undifferentiated stem cells from replenishing
necessary tissues and lead to premature tissue degeneration (Ferbeyre
et al. 2002; infoaging.org 2003).
Insulin-like Growth
Factor-1 (IGF-1)
A reduction in caloric intake dramatically slowed cancer progression in
rodents, suggesting a prophylactic and a therapeutic advantage (Dunn et
al. 1997). Part of the mechanism may relate to the fact that dietary restriction
lowers IGF-1, a growth factor involved in cell proliferation, apoptosis,
and tumorigenesis, by about 24. Mice dosed with a carcinogen, while consuming
20% fewer calories, developed fewer tumors. A cancer shows uncontrolled
development and malignant properties when stimulated by IGF-1. Calorie
restriction reduces this multifaceted growth factor. As IGF-1 levels are
reduced, the stage and virulence of existing cancerous tumors are also
reduced. When IGF-1 levels are restored, the protective effect of caloric
restriction disappears and the cancer advances. Rates of apoptosis were
ten times higher among calorie-restricted mice compared to ad libitum-fed
or calorie-restricted mice undergoing IGF-1 restoration. Administration
of IGF-1 to dietary-restricted mice increased cell proliferation six-fold.
IGF-1 may modulate pivotal stages in cancer development in general (Dunn
et al. 1997; Hansen 2002).
Leptin
Measuring of a woman's leptin levels could be an indicator of risk of
developing breast cancer. A woman's production of leptin might reveal
her history of fat consumption (Anson et al. 2003). Leptin levels may
offer prognostic data beyond the measurement of body mass index and fat
consumption (ANI 2003). Hyperleptinemia (or excess leptin in blood) increases
proliferation of breast cancer cell through acceleration of the progression
of the cell cycle (Okumura et al. 2002). Leptin influences cellular differentiation
and progression of prostate cancer. Leptin has a role in the development
of prostate cancer mediated by testosterone and other factors related
to obesity (Saglam et al. 2003).
Hyperleptinemia is linked with cardiovascular disease.
Moderate increases in the level of leptin enhance the relative risk of
a cardiovascular event by 25%. Leptin is a novel, independent risk factor
for coronary heart disease (Wallace et al. 2001). Levels of leptin are
increased in obesity. This hormone may play a role in the development
of insulin resistance and non-insulin dependent diabetes mellitus (Haque
et al. 2003).
Calorie Restriction
and the Heart
If people reduce their current caloric intake from 20-40%, even starting
in middle age, they may prevent or delay the development of heart disease.
Animals whose food intake was reduced by one-third showed less heart disease.
The hearts of mice on a low-calorie diet showed 20% fewer age-related
genetic changes and had less DNA damage (Parker, 2002). Recall the persuasive
cardiovascular results obtained from the Biosphere II experiment: In the
first 6 months body weight dropped 15%, blood sugar 20%, blood cholesterol
38%, and systolic/diastolic blood pressure dropped 30%/27% on a calorie-restricted
diet (Walford , 1994; Best, 1995). A 30% reduction in caloric intake in
30 rhesus monkeys led to a 25-point elevation in HDL-2B and a 20-point
decrease in triglycerides. Increases in HDL-2B and decreases in triglycerides
of this magnitude in humans would be a great health benefit, especially
for those at risk for stroke or heart disease (Verdery et al. 1997; Lane
et al. 1999). Multiple studies have shown increased insulin sensitivity
(four-fold) and decreased levels of insulin on calorie-restricted diets
(Spindler 2001b), suggesting that hyperinsulinemia may be a risk factor
associated with heart disease.
Convincing Summation
Calorie restriction has been shown to increase longevity in organisms
ranging from yeast to mammals (Bluher et al. 2003). These remarkable effects
that result from restricting food intake 50% to 70% of normal may occur
through three mechanisms: (1) reduction in oxidative damage; (2) modulation
of glycemia and insulinemia; and (3) hormesis (a beneficial biological
action from a small dose of an agent generally toxic a t y higher doses.
Extension of life span by dietary restriction (small doses of food) is
an example of hormesis (Masoro 1998, 2000).
At least a 30% reduction in calories is necessary to realize
significant health advantages. Such
austerity requires a psychological profile that only 1 person in 1000
possesses. Thus, t he best objective may not be to develop another diet
that people will not follow, but rather to develop a medicine that mimics
the beneficial effects of calorie restriction (Taubes, 2000). An agent
that mimics the function of a compound called PPAR-delta seems to provide
similar benefits to calorie restriction (at least in monkeys).
Middle-aged, insulin-resistant, male monkeys (with imbalances in blood
lipids) were administered an agent that mimics PPAR. PPAR-delta activates
genes that regulate fat transport and insulin sensitivity. After four
weeks of treatment with this PPAR imitator, monkeys showed higher HDL
cholesterol levels (79%), lower triglycerides (56%), and increased insulin
sensitivity. It is unknown whether the drug mimicking PPAR-delta would
lengthen life span in humans through actions on insulin sensitivity and
cholesterol levels, particularly in people that are not at risk for developing
diabetes or heart disease (Christensen 2001).
Many longevity medicines have yielded disappointing results. For example,
2-deoxy-D-glucose (2-DG), a compound that inhibits glucose metabolism,
was toxic for some animals even at low levels or when given over long
periods. The narrowness of this range of safety (low therapeutic index)
precludes it from human use, although studies provide some clues that
inhibition of glucose metabolism can mimic some effects of caloric restriction
(Lane et al. 2002).
BioMarker Pharmaceuticals has discovered that metformin (Glucophage®),
a drug used to treat diabetes, can mimic many of the changes in gene expression
found in calorie-restricted mice (Kent 2003). Metformin has a unique mechanism
of action compared to many antidiabetic agents; it does not increase insulin
production; rather it lowers blood sugar by decreasing sugar production,
absorption, while increasing insulin sensitivity. Metformin was more effective
in mimicking the genetic responses to caloric-restriction than glucotrol
(Glipizide®), which stimulates the pancreas to secrete more insulin,
or rosiglitazone, which reduces resistance to insulin. A number of studies
have linked aging to poor glucose control, lack of insulin sensitivity,
and hyperinsulinemia. Metformin impacts genes involved in (drug) metabolism
and detoxification, energy metabolism, protein biosynthesis and degradation,
cell growth and proliferation, and in the formation of the cytoskeleton.
The cytoskeleton is an internal reinforcement of the cytoplasm of a
cell. Microtubules contained in the cytoskeleton of most cells, provide
structure to the cell and a conduit for intracellular transport. It is
speculated that microtubules act as processors of electrical information.
When a cell divides, it may pass on genetic information, not just in the
form of DNA, but also in the form of microtubules, integral to the mechanics
of cell division.
Metformin has been shown to increase the life span of mice
by 20%. BioMarker Pharmaceuticals is conducting a life span study using
metformin to see if they can replicate this study. The results of multiple
studies suggest that metformin needs to be evaluated as a longevity medicine.
(Visit www.lef.org to read The
Multiple Benefits of Metformin, September 2001 Life Extension
magazine for dosing instructions and caveats. For additional information
about BioMarker Pharmaceuticals, contact www.biomarkerinc.com.)
Interventions to Support
Longevity
Until potent and practical medicines are found to enhance longevity, many
useful natural options still offer significant benefits ( alternatives
that The Life Extension Foundation has recommended to members for decades).
The Journal of the American Medical Association (JAMA)
reported that underfed animals (consuming 50% less food) live up to 50%
longer, perhaps because of higher levels of dehydroepiandrosterone (DHEA),
lower body temperature, and lower insulin levels (JAMA 2002).
The following sections will address the findings reported in JAMA.
The Glycemic Index and Glycemic
Load
Consideration of a food's glycemic index, and its glycemic load, may be
valuable in keeping blood glucose and insulin levels within healthy ranges.
The glycemic index is a numerical representation of how quickly 50 grams
of the food's carbohydrate content will raise blood sugar levels, compared
to 50 grams of a reference food (such as glucose or white bread). The
reference food is given an arbitrary value of 100, and the glycemic index
of a food is expressed as a percentage of that value. Many factors contribute
to the glycemic index, including its fat and fiber content, and how much
it has been processed.
The glycemic index does not indicate the level of carbohydrate
contained in food. While the carbohydrates in carrots have a high glycemic
index, carrots contain relatively fewer carbohydrates than corn chips.
The unfavorably high glycemic index of carrots (131%) is based on the
blood-sugar response to eating 50 grams of carbohydrate (or a pound and
a half of carrots), which few people would consume. The net effect of
carrots on blood sugar levels is considerably less than corn chips, even
though the glycemic indices are similar.
The glycemic load is calculated by taking the amount of
carbohydrate in a serving of food multiplied by that food's glycemic index.
A half-cup serving of carrots (which has 8 grams of carbohydrate) has
a glycemic load of about 10 (8 × 131% or 1.31 = 10.48). Many advocate
assessing the overall glycemic load of a diet, rather than focusing too
much on any one food. Increased risk for cardiovascular disease begins
at a daily glycemic load of 161 (Faloon, 2002; Harvard Women's Health
Watch, 2002). (Glycemic indices of 100 foods can be found at
http://www.health.harvard.edu/article.cfm?id=48.)
It is obvious that living to the maximum (well beyond 100 years) is
no longer just a whim, but rather a cooperative effort, one pursued by
committed individuals and scientists. It is reassuring to know that one
can influence the odds of living long and living well (through mind-set,
diet, supplements, and exercise), and that the scientific community is
passionate about helping achieve this objective. The Life Extension Foundation
certainly does its part. It is the Number One source for information about
staying alive and healthy. The Life Extension Foundation is totally committed
to extending the lives of every member by offering useful products before
they are widely accepted by conservative medical establishments and by
continuing to fund revolutionary research.
For More Information
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