Life Extension Magazine®
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:
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 ActivatorA 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:
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 MimeticAlthough 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. Antioxidant ProtectionFisetin’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 Glycation BlockadeLaboratory 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 DNA ProtectionFisetin 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. Inflammation ControlFisetin 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 Mitochondrial SupportFisetin 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 ComponentsFisetin 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 | |||||
Compelling New Evidence for Established CR MimeticsResveratrolResveratrol, the most widely known of the CR mimetics, is a polyphenol found most abundantly in red wine grape skins, as well as in many other darkly colored fruits, accounting in part for their known health-promoting effects.59 Its ability to activate sirtuins has been thoroughly documented in the scientific literature.26,59-64
While a potent sirtuin activator and antioxidant in its own right, resveratrol also mobilizes a number of antioxidant processes internal to cells.59,65-69 These combined effects are responsible for resveratrol’s ability to prevent oxidative damage following heart attack or stroke, heading off many of its deadly consequences.70 Similarly, resveratrol’s antioxidant function is credited with prevention of the neuronal damage observed in Alzheimer’s and other neurodegenerative diseases.63,68,71,72 Resveratrol also inhibits advanced glycation end products (AGEs) that arise from lifelong exposure to glucose in blood—both effects and causes of type 2 diabetes. Resveratrol inhibits AGE-induced smooth muscle cell overgrowth in blood vessel walls.73 It protects laboratory animals from kidney damage in early-stage diabetes by switching on a protective enzyme system called adenosine monophosphate-activated serine/threonine kinase (AMPK).74 Resveratrol improves insulin sensitivity and regulates genetic expression of dangerous adipokines, cytokines produced by fat tissue, which are associated with development of diabetes and the consequences of the metabolic syndrome.75 In early 2010 it was discovered that resveratrol reduces body weight and fat content in obese animals through its effects on gene expression and enzyme activities.76 PterostilbenePterostilbene is a polyphenol closely related to resveratrol, but with unique attributes, including potent cancer-preventing and lipid-lowering capabilities.77,78 It has powerful antioxidant capabilities, scavenging destructive free radicals and inhibiting oxidant-induced electrolyte loss from cells.79 Diabetic animals supplemented with pterostilbene demonstrate marked improvements in their damaged cellular antioxidant systems.80 Supplemented rats experience remarkable reversal of age-related cognitive deficits.81 Astonishingly, pterostilbene switches on genes governing the production of intracellular antioxidant enzymes such as superoxide dismutase (SOD).82 Pterostilbene has been shown to directly lower blood glucose, which may help prevent the formation of AGEs. Remarkably, pterostilbene’s ability to lower glucose was comparable to that of metformin, a pharmaceutical used in the management of diabetes.83
Pterostilbene displays potent cancer-preventing effects related to its ability to prevent or repair DNA damage, one of the first steps in cancer initiation. It inhibits development of pre-cancerous lesions in mouse models of breast cancer, similarly to resveratrol.79 And pterostilbene can prevent expression of genes that otherwise promote cancer metastasis; it has also been shown to inhibit metastatic malignant melanoma growth and extend host survival.84 Like its close relative resveratrol, pterostilbene is perhaps best known for its potent inflammation-quenching effects, which it achieves, as usual, by several complementary mechanisms. Pterostilbene inhibits the ubiquitous COX-2 enzyme responsible for producing inflammatory prostaglandins, which are also involved in creating the pain sensation.85 Pterostilbene also targets inflammatory cells called macrophages, reducing their ability to multiply; this has enormous application to atherosclerosis, which requires activated macrophages to initiate deadly inflammatory plaques.86,87 Grape Seed ExtractGrape seed extracts (GSE) favorably influence expression of genes involved in cellular aging, giving them a broad array of multitargeted benefits.88,89 GSE has been shown to enhance antioxidant status and decrease free radical-induced protein oxidation in aging rats’ brains.90 A 2009 study of type 2 diabetics at high risk of cardiovascular disease showed that GSE significantly improved markers of inflammation, oxidative stress, and blood sugar over a 4-week period.91 GSE’s remarkable cardiovascular health benefits also derive from their ability to fight advanced glycation end products (AGEs) in endothelial tissue.92,93 GSE effectively combats inflammatory responses throughout the body by modifying gene expression. One early study found beneficial alterations in expression of 13 proteins in brain tissue alone.88 GSE inhibited platelet inflammatory responses at doses easily attainable in humans, demonstrating an additional vascular protective effect.94 And GSE switched off the inflammatory “master molecule” NF-kB in mice exposed to UV radiation, helping to mitigate oxidant-induced inflammation.95 Quercetin
The polyphenol quercetin protects endothelial tissue against oxidative damage by preventing oxidation of LDL cholesterol, one of the chief offenders in the atherosclerosis cascade.96,97 It also reduces the new production of fats by liver cells.98 Quercetin’s antioxidant capacity prevents heart enlargement caused by blood pressure overload in laboratory animals.99 By a different mechanism, quercetin prevents migration and proliferation of vessel wall muscle cells in response to oxidative stress and activated platelets.100 Quercetin sharply reduces genetic expression of major inflammatory cytokines, suggesting its use for treatment of allergic and other inflammatory conditions.101,102 Inflammation plays a vital role in cancer development and cardiovascular disease as well, and quercetin’s anti-inflammatory effects lead to reduced invasiveness of certain breast cancers and reduced production of adhesion molecules in vascular endothelia.103,104 Black TeaConsumption of black tea is widely known to improve circulating antioxidant status in humans.105,106 Black tea’s polyphenols and other constituents are particularly notable for their cardiovascular protective effects.107 These arise through a host of interlocking antioxidant-mediated mechanisms including reduced platelet aggregation, improved endothelial function, and reduced vascular inflammation.108-110 Components of black tea are powerful inhibitors of glycation and can prevent diabetic cataracts, further proving their calorie restriction mimetic credentials.111 Unlike most of the other nutrients we’ve discussed, the black tea polyphenols don’t directly reduce production of advanced glycation end products (AGEs); rather, they trap them as they are produced, reducing their concentrations in tissues.112,113 Activate Your Longevity Genes without HungerScientists estimate that 30 million Americans face the lethal risks of excessive energy intake, even though they appear thin and healthy.
These alarming findings underscore the enormous challenge of avoiding excess energy intake and the obstacles of undertaking a caloric restriction regimen. Fortunately, avant-garde research has brought to light a handful of nutrients that can safely simulate many of the effects of caloric restriction. Each operates in a multitargeted and complementary fashion. These nutrients have been shown to limit oxidation, reduce glycation, restrict or even repair DNA damage, quell inflammation, support mitochondrial health, and enhance the function of the cellular sub-units called proteasomes and lysosomes. In addition to the five natural CR mimetics Life Extension reviewed earlier this year, a sixth has been identified called fisetin. It optimizes levels of the endogenous antioxidant glutathione in cells, targets factors implicated in brain aging, and may even enhance the action of resveratrol. To read an in-depth scientific report that describes all of the documented benefits of calorie restriction mimetic nutrients, log on to www.LifeExtension.com/Calorie-Restriction If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027. Editor's NoteScience continues to evolve, and new research is published daily. As such, we have a more recent article on this topic: Nutrients that Provide Benefits of Caloric Restriction | ||||
| References | ||||
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