An estimated 30 million Americans over age 201,2 face lethal risks from excess caloric intake, but have no idea they are jeopardizing their health and longevity.
The reason why may surprise you: these individuals appear thin and healthy. Many adhere to a decent dietary and exercise regimen.1,2 But according to a comprehensive analysis conducted by heart researchers at the Mayo Clinic, they are still ingesting more calories than their bodies are able to utilize. The deadly consequences, published earlier this year, include:
- Four-fold higher rates of metabolic syndrome in later life
- Increased cardiovascular disease risk
- Blood lipid abnormalities in men and women
- Hypertension in men
- Double the risk of cardiac death in women.1,2
This modern scourge of overconsumption happens to be an independent risk factor for virtually all age-related diseases—from cancer and atherosclerosis to arthritis and dementia.3-8
It is also the principal challenge confronting aging individuals who wish to reap the extraordinary benefits of caloric restriction or CR. Reducing the number of calories you consume while maintaining optimal nutritional status initiates a system-wide anti-aging cascade. By “switching on” genes that favor youthful physiological function, caloric restriction dramatically slows the pathological aging process.
CR also improves biomarkers of health across the board, from cognitive function and cancer risk to glucose control and cardiac health.9-14 Yet most people cannot submit to a sufficiently restrictive dietary regimen to obtain the benefits.
The good news is that avant-garde researchers have brought to light a novel class of nutrients called calorie restriction mimetics. This handful of natural compounds has been shown to safely simulate some of the beneficial effects of calorie restriction without the need for stringent dietary measures.
Earlier this year, Life Extension® provided you with the first comprehensive review of five known CR mimetics, some that Foundation members have been taking for many years.
In this article, you will learn of the latest research on these cutting-edge compounds. You will also discover the sixth CR mimetic to emerge in the scientific literature. This little-known but potent flavonoid called fisetin is difficult to obtain in sufficient amounts through diet alone.15 The most recent scientific evidence indicates it affords particular protection to the aging brain—and enhances the action of resveratrol!16-20
Caloric Restriction: The Longevity Gene Activator
A wealth of scientific data spanning more than seven decades confirms caloric restriction’s unmatched power to boost longevity in nearly all forms of life, as much as 100% in some species.21,22
One of the primary means by which calorie restriction induces its profound anti-aging effects is through favorable gene expression. CR has been shown to activate a class of powerful signaling molecules known as silent information regulators (Sir), or sirtuins. These operate across multiple cellular pathways, regulating gene expression, aging, metabolism, DNA repair, and apoptosis (programmed cell death).23-25
Sirtuins are ubiquitous in nature; one or more sirtuins are present in most species, from bacteria to mammals.23 This may explain why calorie restriction so radically increases life span across the full range of living organisms.
In response to a reduction in caloric intake—sirtuins initiate a sequence of profoundly beneficial age-delaying processes. The sirtuin-mediated effects of calorie restriction have been successfully replicated in species ranging from yeast to higher primates.9,26 Sirtuins have been shown to:
- Enhance protection against oxidative stress
- Minimize protein damage by glucose (glycation)
- Prevent accumulated DNA damage
- Inhibit inflammation
- Improve mitochondrial function
- Promote the function of organelles (cellular sub-structures) responsible for maintaining structural and functional integrity 27-40
Through these and other mechanisms of action, caloric restriction improves virtually all biomarkers of health. In a landmark 20-year controlled study of CR in primates published last year, a moderately restricted diet produced a three-fold reduction in the risk of age-related disease. Cardiovascular disease and cancer incidence were less than half in the calorie restricted group, and none of the monkeys developed impaired glucose control or diabetes.9
Fisetin: A New Multimodal CR Mimetic
Although present in strawberries, the flavonoid fisetin is a relatively rare nutrient found only in minute quantities in the plant kingdom. It has been shown to maintain levels of glutathione (the primary antioxidant internal to most cells in the body) in the presence of oxidative stress.17 Its exceptional capacity to ward off age-related cognitive decline through the modulation of multiple neuronal (nerve cell-related) pathways has drawn the most intense scientific interest.17 Fisetin also exerts multimodal effects common to known caloric restriction mimetics.
Among the many recent findings on fisetin, one in particular stands out: it may act to stabilize resveratrol by shielding it from metabolic breakdown in the liver.20 Scientists believe fisetin may thus increase the amount of resveratrol staying in the blood, enhancing its effects. This is important because one of resveratrol’s possible limitations is a relatively short half-life in the body.
Fisetin’s antioxidant potency is comparable to quercetin.41 Alone among the polyphenols, fisetin induces genetic expression of a powerful cellular antioxidant system called quinone reductase or QR, which is vital in preventing oxidant-induced carcinogenesis.42 The antioxidant action of fisetin has been shown to significantly extend the life span of C. elegans—a benchmark indicator of CR mimesis (simulation).43,44 Its proven ability to inhibit oxidation of harmful LDL cholesterol also indicates fisetin’s potential in preventing cardiovascular disease.45,46
Laboratory studies show that fisetin inhibits glycation (destructive binding of sugar molecules to functional proteins) in human hemoglobin, protecting red blood cells from long-term damage.47 It interacts beneficially with other human proteins and with DNA.48 These effects likely account for its specific ability to protect brain and nerve tissues. Studies show that advanced glycation end-products (AGEs) and their receptors are closely linked to conditions such as Alzheimer’s disease and other forms of cognitive decline.49-51
Fisetin ranks very high among flavonoids at preventing DNA damage.52 Low doses of fisetin offer superior protection against DNA strand rupture induced by hydrogen peroxide, a potent free radical.53 These effects also place fisetin high on the list of potentially effective cancer-preventing agents.
Fisetin suppresses inflammatory cytokine production by diverse mechanisms.54 It downregulates the master inflammatory modulator NF-kB,55 which may reduce inflammatory responses, cancer-related cell proliferation, and metastatic alterations through a unique set of cellular mechanisms.56,57
Fisetin has been shown to protect mitochondria against repeated oxidative stress.17 Cells treated with fisetin are able to maintain mitochondrial-dependent levels of adenosine triphosphate or ATP—the body’s primary “energy currency”—in the presence of powerful mitochondrial toxins.17 In live animal studies, researchers found that fisetin could significantly improve behavioral outcomes when administered five minutes after the initiation of an embolic stroke.17 Strokes impose a huge metabolic burden on brain tissue, and destruction of mitochondria is one reason for the neurological deficits observed after such events. Fisetin was shown to reduce the amount and volume of brain damage following induction of stroke in animal models.17
Protection of Vital Cellular Components
Fisetin consistently increases activity of a vital cellular waste excretion unit called the proteasome, to such an extent that it promotes nerve cell survival following withdrawal of otherwise vital growth factors.58 Proteasome activity is decreased in a variety of age-associated neurological disorders including Alzheimer’s and Parkinson’s diseases.17 Researchers in the laboratory of Dr. Pamela Maher of the Salk Institute for Biological Studies found that fisetin was able to modestly increase proteasome activity in primary cultures of brain cells, promoting their survival and preserving their optimal functioning.17
Maher and her colleagues found that fisetin promotes long-term potentiation of brain neurons, thereby enhancing memory in two pre-clinical models of aging.17,18