In this episode, Rhonda gives a summary of the science of resveratrol including its effects in animals and humans, the mechanisms behind how it works, and the bottom line on resveratrol supplementation and safety.
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Initial study at Cornell that suggested resveratrol was responsible for cardiovascular benefits of drinking red wine. Study.
Overview of what resveratrol is and where it is found.
Clinical effects of resveratrol in humans.
How 150 mg/day resveratrol supplementation promoted caloric restriction-like effects in obese individuals. Participants had a significant decrease in blood pressure, blood glucose, and triglyceride levels. Study.
How 10 mg/day of resveratrol in patients with a history of heart attack decreased LDL, and improved left ventricular diastolic function and endothelial function. Study.
How 40 mg/day of resveratrol lowered reactive oxygen species, TNF-alpha and IL-6. Study.
How 480 mg/day of resveratrol completely reversed arterial stiffness in monkeys fed an obesogenic diet. Study.
How 200 mg/day of resveratrol improved memory in healthy individuals. Study.
How 500-2000 mg/day of resveratrol improved mental status exam, spinal fluid amyloid beta levels, and spinal fluid levels of matrix metalloproteinase 9 in patients with Alzheimer’s disease. Study.
The mechanism by which resveratrol is able to extend lifespan is through sirtuin activation, similar to caloric restriction.
Resveratrol negated the negative effects of an obesogenic diet in mice by mimicking caloric restriction. Study.
Resveratrol increased genes that are also activated by caloric restriction and reduced osteoporosis, cataracts incidence, vascular dysfunction and declines in motor skills in mice fed a normal diet. Study.
Resveratrol induces autophagy- the adaptive response mechanism to remove unnecessary or dysfunctional cellular debris. Study.
Resveratrol also induces longevity genes also known as stress response genes via xenohormesis.
An evolutionary explanation of why our body responds to resveratrol the way it does. Hypothesis on origins of xenohormesis.
How 250 mg/day of resveratrol blunted the positive effects of exercise in elderly men who exercised by engaging in cycling and crossfit 3 times a week. Study.
How 150 mg/day of resveratrol blunted the positive effects of exercise in young men who performed high-intensity interval training 3 times a week. Study.
How 500 mg/day of resveratrol increased mitochondrial density, muscle fiber and maximal oxygen consumption in elderly men and women who did resistance and aerobic exercises 3 times a week. Study.
How resveratrol can be a mild direct antioxidant and what the difference between direct and indirect antioxidants are.
Resveratrol bioavailability is increased with a moderate fat breakfast compared to a high fat breakfast. Study.
Resveratrol is insoluble in water, but studies have shown that if it is enclosed in a nanocapsule – a shell that encapsulates an inner core – its stability and bioavailability are increased. Study.
When consumed with black pepper derived piperine, the bioavailability of resveratrol increases over 14-fold in mice. Study.
In humans, piperine consumption did not improve the bioavailability of resveratrol but it did improve cerebral blood flow. Study.
How a glass of wine only contains a very small (arguably clinically irrelevant) amount of resveratrol.
How 2 grams/day of resveratrol supplementation was shown to be safe in obese elderly individuals. Study.
A word of caution about resveratrols effects on drug metabolism.
Resveratrol causes 33% inhibition in CYP3A4 and 171% inhibition CYP2C9- two enzymes responsible for the metabolism of many commonly taken drugs. Study.
Men with prostate cancer given 1 gram/day of resveratrol for 4 months had lower levels of androgen precursors but no effect on testosterone itself. Study.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
An enzyme that plays multiple roles in cellular energy homeostasis. AMP kinase activation stimulates hepatic fatty acid oxidation, ketogenesis, skeletal muscle fatty acid oxidation, and glucose uptake; inhibits cholesterol synthesis, lipogenesis, triglyceride synthesis, adipocyte lipolysis, and lipogenesis; and modulates insulin secretion by pancreatic beta-cells.
A toxic 42 amino acid peptide that aggregates and forms plaques in the brain with age. Amyloid-beta is associated with Alzheimer's disease, a progressive neurodegenerative disease that can occur in middle or old age and is the most common cause of dementia. Heat shock proteins have been shown to inhibit the early aggregation of amyloid beta 42 and reduce amyloid beta plaque toxicity .
A molecule that inhibits oxidative damage to DNA, proteins, and lipids in cells. Oxidative damage plays a role in the aging process, cancer, and neurodegeneration. Many vitamins and plant-based compounds are antioxidants.
An intracellular degradation system involved in the disassembly and recycling of unnecessary or dysfunctional cellular components. Autophagy participates in cell death, a process known as autophagic dell death. Prolonged fasting is a robust initiator of autophagy and may help protect against cancer and even aging by reducing the burden of abnormal cells.
The relationship between autophagy and cancer is complex, however. Autophagy may prevent the survival of pre-malignant cells, but can also be hijacked as a malignant adaptation by cancer, providing a useful means to scavenge resources needed for further growth.
The extent and rate at which drugs or other substances, such as plant-based dietary compounds, enter the body’s circulation. Bioavailability is influenced by a variety of factors, including dose, the presence of other foods or substances, and interindividual differences in metabolism due to gut absorptive surface and commensal microbial populations.
The practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels. Caloric restriction has been shown to extend lifespan and delay the onset of age-related chronic diseases in a variety of species, including rats, mice, fish, flies, worms, and yeast.
Compounds that induce a similar biochemical milieu in the cell as starvation or nutrient deprivation, including the reductions in cytosolic acetyl CoA and increases in protein deacetylation that serve as a trigger for the cellular autophagic machinery. Popular examples of compounds that exhibit this type of effect include: hydroxycitrate (inhibits ATP citrate lyase), spermidine (inhibits Ep300, a protein acetyltransferase), and resveratrol (activates deacetylases called sirtuins).
The body’s 24-hour cycles of biological, hormonal, and behavioral patterns. Circadian rhythms modulate a wide array of physiological processes, including the body’s production of hormones that regulate sleep, hunger, metabolism, and others, ultimately influencing body weight, performance, and susceptibility to disease. As much as 80 percent of gene expression in mammals is under circadian control, including genes in the brain, liver, and muscle. Consequently, circadian rhythmicity may have profound implications for human healthspan.
A broad category of small proteins (~5-20 kDa) that are important in cell signaling. Cytokines are short-lived proteins that are released by cells to regulate the function of other cells. Sources of cytokines include macrophages, B lymphocytes, mast cells, endothelial cells, fibroblasts, and various stromal cells. Types of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
The single layer of cells that lines the interior of the blood and lymphatic vessels. The endothelium participates in blood flow, platelet aggregation, and vascular tone. It also regulates inflammation, immune function, and angiogenesis. Endothelial dysfunction is a systemic pathological condition broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium. It is a robust predictor of heart attack and stroke risk.
Flavonoid are widely distributed in plants, fulfilling many functions. Flavonoids have been shown to have a wide range of biological and pharmacological activities in animal, human, and in-vitro studies. Examples include anti-allergic, anti-inflammatory, antioxidant, antimicrobial, anti-cancer, and anti-diarrheal activities.
An antioxidant compound produced by the body’s cells. Glutathione helps prevent damage from oxidative stress caused by the production of reactive oxygen species.
The years of a person’s life spent free of disease.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
One of the most potent natural activators of the AKT signaling pathway. IGF-1 stimulates cell growth and proliferation, inhibits programmed cell death, mediates the effects of growth hormone, and may contribute to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role in growth during childhood and continues later in life to have anabolic, as well as neurotrophic effects. Protein intake increases IGF-1 levels in humans, independent of total caloric consumption.
A pro-inflammatory cytokine that plays an important role as a mediator of fever and the acute-phase response. IL-6 is rapidly induced in the context of infection, autoimmunity, or cancer and is produced by almost all stromal and immune cells. Many central homeostatic processes and immunological processes are influenced by IL-6, including the acute-phase response, glucose metabolism, hematopoiesis, regulation of the neuroendocrine system, hyperthermia, fatigue, and loss of appetite. IL-6 also plays a role as an anti-inflammatory cytokine through inhibition of TNF-alpha and IL-1 and activation of IL-1ra and IL-10.
An enzyme that participates in genetic pathways that sense amino acid concentrations and regulate cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. It plays key roles in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are the subject of many studies), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.
The process by which new mitochondria are made inside cells. Many factors can activate mitochondrial biogenesis including exercise, cold shock, heat shock, fasting, and ketones. Mitochondrial biogenesis is regulated by the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha, or PGC-1α.
A coenzyme that is required for the production of energy in cells. NAD+ is synthesized from three major precursors: tryptophan, nicotinic acid (vitamin B3), and nicotinamide. It regulates the activity of several key enzymes including those involved in metabolism and repairing DNA damage. NAD+ levels rise during a fasted state. A group of enzymes called sirtuins, which are a type of histone deacetylase, use NAD+ to remove acetyl groups from proteins and are important mediators for the effects of fasting, caloric restriction, and the effects of the plant compound resveratrol, a so-called caloric restriction mimetic.
Fat is deposited in the liver due to causes other than excessive alcohol use such as diet, genetics, and long-term medication use. NAFLD is related to insulin resistance and the metabolic syndrome and may respond to treatments originally developed for other insulin-resistant states.
A protein typically present in the cytoplasm of mammalian cells. Nrf2 can relocate to the nucleus where it regulates the expression of hundreds of antioxidant and stress response proteins that protect against oxidative damage triggered by injury and inflammation. One of the most well-known naturally-occurring inducers of Nrf2 is sulforaphane, a compound derived from cruciferous vegetables such as broccoli.
A class of chemical compounds produced in plants in response to stressors. Polyphenols contribute to the bitterness, astringency, color, flavor, and fragrance of many fruits and vegetables. They often serve as deterrents to insect or herbivore consumption. When consumed in the human diet, polyphenols exert many health benefits and may offer protection against development of cancers, cardiovascular diseases, diabetes, osteoporosis, and neurodegenerative diseases. Dietary sources of polyphenols include grapes, apples, pears, cherries, and berries, which provide as much as 200 to 300 mg polyphenols per 100 grams fresh weight.
Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
A polyphenolic compound produced in plants in response to injury or pathogenic attack from bacteria or fungi. Resveratrol exerts a diverse array of biological effects, including antitumor, antioxidant, antiviral, and hormonal activities. It activates sirtuin 1 (SIRT1), an enzyme that deacetylates proteins and contributes to cellular regulation (including autophagy). Dietary sources of resveratrol include grapes, blueberries, raspberries, and mulberries.
Resveratrol Autophagy ↑ Deacetylases (especially SIRT1) → ↓ Protein Acetylation → Autophagy
Environmental factors which may reduce reproductive success in a population and thus contribute to evolutionary change or extinction through the process of natural selection.
A member of the sirtuin protein family. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity). It is activated by the phytochemical resveratrol as well as fasting.
A class of enzymes that influence that influence aging and longevity through multiple molecular pathways. Sirtuins regulate a variety of metabolic processes, including release of insulin, mobilization of lipids, response to stress, and modulation of lifespan. They also influence circadian clocks and mitochondrial biogenesis. Sirtuins are activated when NAD+ levels rise. The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or nicotinamide or a combination of these variables. There are seven known sirtuins, designated as Sirt1 to Sirt7.
A class of drugs that lower blood cholesterol levels by blocking the production of an enzyme in the liver called hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). Taking statins may reduce the risk of cardiovascular disease in some people. Although statins are generally well tolerated, as many as 10 – 20 percent of people taking the drugs experience complications, including myopathy (muscle damage), liver damage, and cognitive problems, including issues with forgetfulness, memory loss, and confusion.
An isothiocyanate compound derived from cruciferous vegetables such as broccoli, cauliflower, and mustard. Sulforaphane is produced when the plant is damaged when attacked by insects or eaten by humans. It activates cytoprotective mechanisms within cells in a hormetic-type response. Sulforaphane has demonstrated beneficial effects against several chronic health conditions, including autism, cancer, cardiovascular disease, diabetes, and others.
The primary male sex hormone. Testosterone is critical to the maintenance of fertility and secondary sexual characteristics in males. Low testosterone levels may increase risk of developing Alzheimer’s disease.
A molecule composed of a glycerol molecule bound to three fatty acids. Triglycerides are the primary component of very-low-density lipoproteins (VLDL). They serve as a source of energy. Triglycerides are metabolized in the intestine, absorbed by intestinal cells, and combined with cholesterol and proteins to form chylomicrons, which are transported in lymph to the bloodstream.
A proinflammatory cytokine. TNF-alpha is produced by a wide range of cells, including macrophages, lymphocytes, glial cells, and others. TNF-alpha signaling inhibits tumorigenesis, prevents viral replication, and induces fever and apoptosis. Dysregulation of the TNF-alpha signaling pathway has been implicated in a variety of disorders including cancer, autoimmune diseases, Alzheimer’s disease, and depression.
A metabolic disorder characterized by high blood sugar and insulin resistance. Type 2 diabetes is a progressive condition and is typically associated with overweight and low physical activity. Common symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, fatigue, and impaired healing. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow which may lead to amputations.
An excess of visceral fat, also known as central obesity or abdominal obesity. Visceral fat, in contrast to subcutaneous fat, plays a special role involved in the interrelationship between obesity and systemic inflammation through its secretion of adipokines, which are cytokines (including inflammatory cytokines) that are secreted by adipose tissue. The accumulation of visceral fat is linked to type 2 diabetes, insulin resistance, inflammatory diseases, certain types of cancer, cardiovascular disease, and other obesity-related diseases.
A potent water-soluble antioxidant found in citrus fruits. Vitamin C is an essential nutrient involved in tissue repair, neurotransmission, and immune system function. Also known as ascorbic acid.
A fat-soluble vitamin. Vitamin E is the collective name for a group of eight fat-soluble compounds (alpha-, beta-, gamma-, & delta-tocopherol and alpha-, beta-, gamma-, & delta-tocotrienol) with distinctive antioxidant activities. Of these eight, only alpha- (α-) tocopherol meets human requirements. Vitamin E serves as an antioxidant that breaks the chain reaction formation of reactive free radicals. In doing so it becomes oxidized and loses its antioxidant capacity. Vitamin E also protects LDL from oxidation and maintains the integrity of cell membranes throughout the body. Dietary sources of vitamin E include nuts, seeds, eggs, and fatty fish, such as salmon.
An adaptive physiological response in which bioactive compounds, produced by environmentally stressed plants, induce beneficial stress response pathways in animals, including humans. Xenohormetic responses ultimately confer stress resistance and longevity and may explain some of the beneficial effects of plant-based foods. The term xenohormesis stems from two terms: xeno (stranger) and hormesis (a protective physiological response induced by mild stressors). Polyphenols, isothiocyanates, and other plant compounds are thought to exhibit some of their beneficial properties by inducing a type of xenohormesis.
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