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  • Resveratrol: The Biological Rhythm Reset Button

    April 16, 2018: by Bill Sardi

    Day / Night Cycle

    The human body and all living creatures for that matter have a biological clock entranced and synchronized by day and night (light and dark) cycles, what is called the 24-hour circadian rhythm.  As humans age their inability to maintain synchronous sleep/wake cycles shortens lifespan.  It is no surprise then to learn that with advancing age those individuals who retain uninterrupted nighttime sleep cycles tend to live longer.

    Likewise, exposure of animals to artificially short or long light/dark cycles shortens their lifespan.

    Just about everything that is taking place physiologically in the human body is staged and timed by the day/night cycle and if it gets out of sync there is a physiologic penalty to be paid.

    Researchers write that “resetting the biological clock” can restore wellbeing and prolong lifespan.

    The body’s rhythmic activity is controlled in the brain

    The loss of ability to maintain so-called circadian (24-hour) rhythms is accompanied by a reduction in the size of the suprachiasmatic nucleus (SCN), a pair of neuron clusters within the hypothalamus of the brain that directly receives light input from the retina of the human eye.  Transplantation of young for old SCN in aged animals prolongs the lifespan of laboratory animals.

    Changes with advancing age in the SCN are largely controlled by epigenetics, the modifiable dynamic aspect (protein making) of genes rather than the inherited structure of genes (order of nucleotides on the DNA ladder) called mutations.  This means aging is modifiable.

    Diet and biological rhythm

    The health and longevity of modern human populations is complicated by high-fat, high-sugar/carbohydrate diets and light pollution, which throw our biological clock out of whack.

    The diet also influences the SCN.  For example, infusion of glucose sugar alters the activity of genes in the SCN.  Caffeine affects circadian rhythms.  The red wine molecule resveratrol also alters clock gene rhythms.

    Prolonged periods of non-eating are also beneficial.  Intermittent every-other-day fasting extends the life of laboratory animals.

    Calorie restriction, circadian (24-hour day-night) rhythms and lifespan are interrelatedCalorie restriction resets the biological day/night (circadian) clock.

    Calorie restriction (food deprivation, 30-40% less calories, but not starvation) activates the sirtuin1 survival gene during the day.

    Calorie restriction (fasting) increases longevity via regulation of the day/night rhythm.  Caloric restriction in aged animals increases longevity, improves memory/thinking, and reduces markers and the onset of brain disease.  Relatively brief periods of calorie restriction are sufficient to increase sirtuin1 gene protein levels in the hippocampus.  Calorie restriction can entrain (synchronize) the SCN.

    There are two central dietary components that block the starvation signal whose removal results in lifespan extension: amino acids and glucose (sugar).

    Graph: sugar levels

    When humans produce more glucose from their liver they essentially switch off fasting (calorie restriction) signals. Of particular interest here is that as animals produce glucose in their liver they enzymatically convert it to ascorbate (vitamin C).  Humans via a gene mutation, no longer produce a required enzyme to convert glucose to vitamin C.  If this gene mutation could be corrected, a major biological signal that switches off the lifespan-prolonging calorie restriction signal would be negated.

    Cholesterol synthesis is a measure biological rhythm

    One measure of rhythmic disruption in the human body is elevated blood serum levels of cholesterol.  Normally more cholesterol is made at night, particularly in a fasted state.  In adult offspring of families that exhibit longevity, their day and night total cholesterol levels are more rhythmic.  Retention of normal cholesterol levels correlates with more nerve cells in the SCN.  (This serves as further evidence against the bogus cholesterol theory of heart disease that has been the paradigm of modern medicine for the past few decades.  Higher levels of cholesterol are associated with health and longevity.)

    Higher HDL-cholesterol levels in the offspring of longevinarians serve as a marker that longevity will be conferred to them.

    In other words, the adult children of longevinarians maintain a higher day-night rhythm of cholesterol synthesis than a comparable group with parents who don’t exhibit longevity and have lower day-night rhythms of cholesterol synthesis.

    High-fat diets and sleep/wake cycles

    High-fat diets adversely alter sleep cycles and circadian rhythms.  In laboratory mice, the provision of resveratrol to animals that consumed a high-fat diet restored blood sugar and insulin levels towards normal and decreased body weight.  Resveratrol altered clock genes (Clock, Bmal1 and Per2) that control cholesterol metabolism and rhythmic day-night cholesterol production was restored.  Researchers conclude that feeding habits (fat, sugar, calories) “provides a novel direction in anti-aging therapy.”

    Day-night rhythmic hormones

    The day-night rhythm is exemplified by vitamin d and adrenal hormone production in the day (corticosteroids, adrenaline) and pineal gland production of melatonin at night.

    Rhythmic aging correlates with mental acuity

    Chronological (calendar) age differs from biological age.

    Strikingly, age alone is not the best predictor of mental impairment.  Older hamsters with disrupted circadian rhythms were more impaired in performing a task when compared to hamsters of the same age with entrained (synchronized) circadian rhythms.

    This effect has been observed in humans, as older women with weak circadian rhythms are reportedly more likely to develop dementia than age-and health-matched women with robust circadian rhythms.  This would explain why there are vast differences in mental acuity among adults of the same age.

    Prolongation of the daily fast

    Of particular interest is that most adults consume breakfast within 2 hours of awakening in the morning and eat food (snacks) less than two hours before going to bed.  Therefore, a sizable portion of the day includes snacks between meals.  The duration of time between first feeding and last accounts for excessive calorie intake.

    Delaying feedings for 12 hours (not eating till noon) produces fasting-like health and longevity benefits.  Prolongation of fasting for 15 hours is even more ideal.  There are people who believe in skipping breakfast and not eating till noon, thus continuing the daily fasting period from 6-8 hours of sleep fasting + 4 hours of daylight fasting.  This kicks in all of the genes activated by a calorie-restricted diet.

    Importance of sleep

    Sleep is so important to maintain health, immunity, memory, mood and many other health parameters.  It is during sleep (fasting) that genes are activated that facilitate DNA repair.

    Day-night cycles affect immunity, memory and mental function.  Memory decline is a part of aging.
    Human's body biological clock

    The importance of the sirtuin1 gene

    The key gene activated during calorie restriction is the Sirtuin1 survival gene.

    Blockage of Sirtuin1 gene activity impairs day-night (circadian) control in young mice to act like what happens in aged mice.

    The sirtuin1 gene controls so-called clock genes in the central biological clock of the human body – the suprachiasmatic nucleus.

    An overlooked fact is that sleep activates the Sirtuin1 gene by virtue of the fact food is not ingested during sleep.  In laboratory animals, calorie restriction (fasting) doubles healthspan and lifespan.  So limitation of food confers longevity.

    Sirtuin1 gene activity declines with advancing age.  It behooves humans to eat less as they age in order to retard aging in the central clock (suprachiasmatic nucleus) in the brain.

    Sirtuin1 is the rheotstat for aging.  Premature decline of Sirtuin1 gene activity results in premature aging of laboratory animals.  Young mice with normal sirtuin1 gene protein levels readjust their 12-hour light/dark cycle more easily than older mice.  With advancing age comes the decline in Sirtuin1 gene activity and sleep disturbance.  A deficiency of sirtuin1 gene protein results in impaired wakefulness in brain cells.  Excessive daytime sleepiness or impaired alertness occurs with increased obesity and aging.  Eating shuts off the sirtuin1 gene.

    In brain cells of laboratory mice, the genetically engineered absence of sirtuin1 results in accumulation of cellular debris known as lipofuscin in brain cells. Lipofuscin accumulates over time leading to age-related decline in brain function.

    Lipofuscin comparison

    Accumulation of cellular debris (lipofuscin), visualized as fluorescent yellow particles in the above images, in exhibited in brain cells of mice.  In the brain cells on the right the sirtuin1 gene is absent, leading to premature aging.  Given that the sirtuin1 gene is activated by food deprivation (aka fasting, calorie restriction), reduced food intake slows aging of brain cells.  Given that humans are not likely to deprive themselves of food (continually practice fasting), molecular mimics of fasting such as resveratrol would serve to prolong lifespan.

    In one experiment the wake time over a 24-hour period was 13.4 hours for laboratory animals with intact sirtuin1 gene protein in their brain cells and just 7.5 wakeful hours among animals genetically engineered so their sirtuin1 gene was knocked out.

    It is evident that maintenance of sirtuin1 gene activity is beneficial in adjustment to changes in the day/night daily cycleLow calorie diets would accomplish this.

    Hunger hormone controlled by sirtuin1 gene

    The control of appetite (satiation) is governed by a hormone called leptin.  Leptin is primarily secreted by fat cells.  With increased obesity and advancing age, leptin resistance develops.  Humans lose control of the volume of food they consume.  Consumption of sugars and carbohydrates (bread, rice, pasta, cereal) induce leptin resistance.  Therefore, this explains why western processed food diets induce overweight populations but also prematurely aged populations from a biological standpoint.

    Leptin resistance is suppressed by the sirtuin1 gene.  In laboratory animals the red wine molecule resveratrol (rez-vair-a-trol) inhibits leptin resistance.  Two natural molecules, resveratrol + quercetin, have been shown to synergistically activate the sirtui1 gene and inhibit leptin resistance.

    Sleep hormone also preserves Sirtuin1 function

    The sleep hormone melatonin, secreted by the pineal gland at the base of the brain, when supplemented to laboratory animals preserves sirtuin1 gene protein production in the brain of sleep-deprived animals and kept their memory intact.

    Resveratrol: the reset button

    Resveratrol moleculary mimics calorie restriction.

    It is no surprise to learn that the red wine molecule resveratrol activates the sirtuin1 survival gene and plays a key role in the control of biological rhythms.

    Resveratrol has been demonstrated to control so-called biological “clock genes” that reset the human body’s day/night rhythm.  Resveratrol’s ability to favorably influence clock genes gives hope that the human body can be resynchronized to promote long lifespans.

    Essentially, resveratrol serves to reset the biological clock.

    Fasting mimicry achieved by consumption of molecules like resveratrol, would be of obvious value to those individuals who, like most people, don’t have the personal discipline to restrict food intake to one meal a day but wish to prolong life and health.

    Resveratrol, a molecular mimic of a calorie-restricted diet, would also help to maintain or restore a normal day/night (circadian) rhythm.

    In young and aged animals (primate monkeys), resveratrol has been demonstrated to improve synchronization of the light-dark cycle.  Researchers conclude: “resveratrol could be a good candidate to restore the circadian rhythms in the elderly.”

    Resveratrol shortens the time it takes for the body to return to or repeat the same biological rhythm (called free running period).

    In laboratory animals resveratrol reversed the adverse effects of a high-fat diet upon biological “clock genes” and the day/night rhythm.

    Resveratrol as a regulator of sleep/wake rhythms “could be of major interest in sleep perturbations associated with aging.”

    Of additional interest, what resveratrol does by day, melatonin does at night (activates the sirtuin1 gene).

    Daily mini-jet lag

    Mice that over-produce sirtuin1 gene proteins in their brains are protected from the effects of aging.  Sirtuin1 also facilitates adjustment to changes in the day-night (circadian) rhythm as experienced when humans experience jet lag.  Given that the length of daylight hours shifts slightly through the seasons (longer days in summer/ northern hemisphere), humans experience a slight jet lag every day.

    Essentially, because there is a slight day-night shift every day as the earth tilts to produce longer or shorter periods of light, humans experience mini jet lag every day.  Inability to adjust to shifting day-night cycles with advancing age becomes a challenge.

    Light pollution

    Except in commercial airplane pilots who are in a chronic state of jet lag, sleep disruption exaggeratedly induced by jet lag is not as commonly experienced as is light pollution from blue-spectrum light in artificial light sources.  The modern environment is of concern in this regard.  The combined exposure to nighttime artificial light emitted from personal computers, mobile phones and televisions combined with the lack of vitamin D synthesis due to indoor dwelling during daylight hours, desynchronizes the human body from its normal 24-hour day/night (circadian) rhythm.

    Blue light-filtering eyewear increases melatonin secretion at night and improves sleep quality.

    Over-doing resveratrol

    Resveratrol supplementation produces a profound mental clarity and focus that is experienced by many users of this dietary supplement.   This beneficial effect is produced by inhibition of enzymes (sulfotransferases) that normally degrade (catabolize) stress hormones produced in the adrenal glands.  These enzymes keep a lid on stress hormones (cortisol, norepinephrine) that can produce anxiety, racing heart, migraine headaches and sleeplessness.

    A modest dose of resveratrol (100-350 mg) slightly elevates adrenal hormones levels and therefore improves mental alertness.  However, excessive consumption of polyphenols – resveratrol, quercetin, curcumin, catechin) can cause adrenal stress hormones to be overactive and induce the adverse symptoms mentioned above.

    Final note

    For the more scientific astute reader, a more comprehensive scientific review of how day/night biological rhythms affect the rate of aging and lifespan can be read in the journal PHYSIOLOGY.

    It is never too late to start running a counter attack on aging.  According to some gerontologists, the 65-70 age range represents a key time to modify diets to prolong life.

    Final instruction: take your reservatrol pill in the morning to artificially extend the “fasting” period and sirtuin1 gene activation.  ©2018 Bill Sardi,

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