POLYPHENOL ANTIOXIDANTS and LONGEVITY

Polyphenols

Polyphenols are phytochemicals with a diversity of biological activities and can be deployed either as the primary or as an adjunctive therapy. The two general classifications of polyphenols are the flavonoids and the non-flavonoids. Whereas flavonoids are often subdivided into flavanols, flavonols and anthocyanidins, the non-flavonoid classes include phenolic acid and stilbenes. Of the latter, resveratrol is the best known example.

Generally, the flavonoids are antioxidants: they neutralize or scavenge free radicals. Naturally found in berries, fruits and vegetables, they confer myriad health benefits. Among them are aiding in digestion, weight management, diabetes, neurodegenerative, and cardiovascular diseases.[1]  As micronutrients derived from plant-based diets, they have been investigated because of their role in offsetting the unfavorable effects of free-radical. Their chemical structures are important determinants in their scavenging role of RONS (ROS/RNS) [2] and the chelation of trace metals which contributes to free radical generation.

Polyphenols exert their diverse anti-inflammatory effects by interfering with the enzymes involved in the production of prostaglandins, leukotrienes, and thromboxane A2.[3]  Whereas the thromboxanes facilitate blood clotting and causes blood vessels to constrict causing hypertension, the hormone-like prostaglandins work at the local level and regulate inflammation induction, blood flow and clot formation. On the other hand, leukotrienes (especially LTD4) constricts bronchiolar smooth muscles restricting breathing (bronchospasm). They are the major cause of inflammation in asthmatic patients and the cause of rhinitis. Some leukotrienes (LTB4)[4] stimulate migration of inflammatory cells to the site of tissue injury.[5] Contingent upon their inhibitory effect on the thromboxanes, leukotrienes and prostaglandins, polyphenols are leading candidates for consideration in the treatment of hypertension, inflammation, atherosclerosis, stroke, asthma, allergic rhinitis and bacterial infections.[6]  

Oxidative stress is due to an excessive accumulation of either of the free radicals, ROS or RON. Among other adverse effects are that they accelerate aging.  Indeed, the greatest risk factor for neurodegenerative diseases is aging.  In each of the neurodegenerative disease mentioned below, neurons gradually lose function with age. It has been proposed that accumulation of DNA damage with time is the underlying link between aging and neurodegenerative disease.  About 20-40% of healthy people in the age range 60-78 years old experience cognitive decline in several realms including working, spatial perception, episodic memory and processing speed. The commonest form of neural cell death is in response to intracellular stresses.[7],[8]

Despite ROS being normal byproducts of mitochondrial respiratory activity, over-production leads to an excess buildup resulting in neurodegenerative disorders. However, intracellular ROS concentration can be reduced by enzymes such as manganese superoxide dismutase (MnSOD2).[9]  This enzyme converts the toxic free radicals like the superoxide ion into the less toxic hydrogen peroxide molecule (H2O2) which is then cleared.

There is abundant evidence to indicate that mitochondrial dysfunction and oxidative stress play causal roles in neurodegenerative disease.  Increased free radical damage of brain cell DNA is associated with Alzheimer’s disease and Parkinson’s disease. In addition to Alzheimer’s disease, faulty DNA repair has been the cause of disorders such as, amyotrophic lateral sclerosis (ALS; Lou Gherig disease), ataxia telangiectasia, Cockayne syndrome and xeroderma pigmentosum.[10] 

Neurons are particularly susceptible to free radical damage due to their strong metabolic activity, high oxygen consumption, and weak antioxidant defense. Significantly, the brain consumes up to a fifth of oxygen intake. The by-products of oxygen metabolism are ROS free radicals, the major source of DNA damage in the brain. Damage to a cell’s DNA is particularly harmful as it dictates several critical functions. The vulnerability of neurons to DNA damage and a decline in the repair mechanisms underlies neuronal damage. The end result is an accumulation of DNA damage which contributes to brain aging.

Genistein

Not all levels of cellular ROS are detrimental. Physiological levels do contribute to cell survival. Anthocyanins, the major pigments in plants, kill cancer cells by increasing intracellular ROS.  Flavonoid also improves antioxidant defenses by facilitating the elimination of unneeded or abnormal cells. Genistein has a broad pharmacological spectrum. Found in soy, it is a well-studied flavonoid. The extract has been extensively employed as an antioxidant because of its ability to scavenge RONS.  It is known to inhibit the formation of new blood vessels (angiogenesis) which supports tumor growth.[11] Besides, genistein hinders the uncontrolled proliferation of cancer cells by obstructing the ability to regulate cell division and cell survival.[12] In animal studies, dietary genistein reportedly delayed plaque formation in the arteries (atherogenesis).[13]

Researchers have demonstrated that protection against atherogenesis is due to protection of LDL by antioxidants: in other words, in the absence of the antioxidants, LDL becomes oxidized resulting in the accumulation of arterial plaques.  In general, genistein confers protection against lipoprotein oxidation and therefore protects against cell membrane damage. It also guards against oxidative DNA damage. Moreover, genistein increases the action of antioxidant enzymes in human prostate cancer cells thus providing protection against DNA damage.[14] Overactive NF-κB has been linked to inflammation, autoimmune diseases, septic shock, viral infections and cancer.[15]  Genistein is known to hinder NF-κB activity.[16]  The polyphenol esculetin is also known to disrupt tumor development and arrest cell proliferation in human liver cancer.[17]

Epigallocatechin Gallate (EGCG)

By itself, the unaffordable prices of drugs make a compelling case for the investigation into phytochemicals for the prevention and treatment of prevalent diseases.  A prime candidate for consideration is green tea extract. The health advantages of tea are due to the high polyphenol content, specifically epigallocatechin gallate (EGCG). Foremost among its anticancer properties is its ability to neutralize free radicals – reduce oxidative stress. 

Compared to other epicatechins, EGCG is most efficient at free radical scavenging. Its ability to sequester metal ions reduces the free radical content of cells.  Because of the potential of EGCG to prevent and treat cancer, neurodegenerative diseases, diabetes, obesity and cardiovascular diseases, it has been the subject of several prospective studies.  As a concentrated source of this polyphenol, green tea extract has been intensely studied because of its powerful antioxidant, anti-inflammatory, antibacterial and antiviral properties.   That EGCG inhibits cancer development is well documented. In fact, EGCG has been shown to have anti-cancer effects through its interaction with the p53 gene. This gene serves as a blueprint for the manufacture of proteins that smothers the growth of cancer cells.[18]  EGCG also induces tumor regression by inactivating NF-κB.

Although the sprouting of new blood vessels normally required to supply nutritional needs and repair tissue, the growth of  new blood vessels promotes tumor cell proliferation.  Recent studies have indicated that this process of blood vessel genesis and thus tumor growth can be inhibited by EGCG. In addition, the evidence indicates that EGCG can curb metastasis – the spread of malignant cells to distant tissues. [19]

Neurodegenerative Diseases

Neurodegenerative disease is manifested as a progressive loss of structure, function and death of neurons. Many neurodegenerative diseases – including amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, fatal familial insomnia, and Huntington’s disease are attributable to neurodegeneration.

To illustrate, Alzheimer’s disease is characterized by the loss of neurons in the cerebral cortex and adjacent areas. This results in gross atrophy of the affected regions, including degeneration in parts of the temporal lobe, parietal lobe and the frontal cortex. Comparison of brain tissue between healthy individual and Alzheimer’s disease patient, demonstrates the extent of neuronal death. According to conventional wisdom, Alzheimer’s disease is caused by accumulation of abnormally folded A-beta and tau proteins in the brain.

Next to Alzheimer’s disease, Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It manifests as slow movement, rigidity, tremors and posture instability. Whereas in western countries the prevalence of PD is estimated to be up to 328 per 100,000, the disease being less common in Asian countries. Parkinson’s disease is a degenerative disorder of the CNS.  Characteristic of this disease is the death of the dopamine producing cells, and thus the lack of dopamine. The major risk factor is age.

Huntington’s disease (HD), also Huntington’s chorea, is genetic disorder caused by the death of brain cells. The earliest symptoms are erratic movements and unsteady gait.  With time, uncoordinated random movements become more dominant. Mental abilities decline into dementia and loss of mobility. Onset is often 30 and 50 years of age.[20] Characteristic of this condition is an abnormal increase in astrocytes numbers. They become errant and destroy adjacent CNS neurons. An abnormally high density of astrocytes (astrogliosis) changes the shape, causing scar formation and inhibition of axon regeneration.[21] The frontal and temporal lobes of the brain are affected according to the structure and the types of neurons. As they cumulatively lose neural cells, the affected areas of the brain decrease in size. These star-shaped cells regulate the transmission of electrical impulses within the brain and weak signals are not transmitted normally, hence the erratic movements. Causes of this destruction are attributable to trauma, infection, stroke, autoimmune responses or neurodegenerative disease.  In healthy neural tissue, astrocytes provide energy, regulates blood flow, controls homeostasis of extracellular fluid and regulates activity within the synaptic clefts.[22],[23]

The protective properties of EGCG against neuro-degenerative disease is attributable its antioxidant, anti-inflammatory and metal chelating properties. EGCG is also capable of crossing the blood-brain barrier (BBB) and can exert its effects directly on the brain. This catechin promotes cell survival responses by inhibiting cell death.  Studies show that EGCG improves cognition and also demonstrate that EGCG induces an overall increase in the cerebral activity. It reduces the production of amyloid-β peptides which contribute to brain plaques and is implicated in Alzheimer’s disease.

Cardiovascular Diseases (CVD)

Cardiovascular diseases (CVDs) involve the heart and blood vessels. Up to 90% of CVDs are preventable through healthy diet, exercise and other lifestyle choices.  Symptoms of CVD are stroke, heart failure, hypertension, rheumatic heart disease, abnormal heart rhythms, congenital heart disease, aortic aneurysms etc. Atherosclerosis (plaque formation) in the arteries can be triggered by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, and excessive alcohol consumption.  Population-based studies show that atherosclerosis, the major precursor of cardiovascular disease, begins in childhood. However,  diets that are high in nuts, fish, fruits and vegetables but low in refined carbohydrates, red meat and saturated fats have been shown to reduce blood pressure, lower LDL, improve metabolic syndrome and decreases the risk of cardiovascular disease and death..[24] Because the cause of CVD is multifactorial prescription of a single remedy is impractical.  EGCG is known to dilate capillaries thus reducing blood pressure.  Besides, it disrupts lipid digestion by inhibiting secretory phospholipase A2 (sPLA2) and bile discharge. The net effect is a reduction of cholesterol and lipids in the circulation. This catechin can directly inhibit phospholipase A2 (PLA2; not the same as sPLA2),[25] thereby inhibiting the release of prostaglandins into the system. Prostaglandins are known to sensitize the nervous system to pain. The action of EGCG on PLA2 contributes to the anti-inflammatory property of this widely used tea catechin.

Chronic Inflammatory Disorder (RA)

Inflammation is the response to pathogens, damaged cells, or irritants. It is a protective function to eliminate the cause of injury and initiate tissue repair.  However, in chronic inflammation the response can be injurious to healthy tissue. An example of chronic inflammation is rheumatoid arthritis (RA). It is an autoimmune disorder that primarily affects joints. The symptoms are warm, swollen, and painful joints, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body such as the lungs and heart. The joint cartilage self-destructs in response to RONS and inflammatory factors such as interleukin (IL-1β) and tumor necrosis factor-α (TNF-α).[26]  Release of these factors stimulate bone reabsorption causing long-term bone erosion and bone fragility.  Among some of the symptoms of RA are inflammation of the joint membrane and joint damage. The disease progresses by forming scared tissue at the edges of the joint lining. Along with angiogenesis, the release of digestive enzymes causes extensive tissue damage. As the membranes enclosing the joint thickens, the cartilage and underlying bone disintegrate causing the entire joint to deteriorate. Although tumor necrosis factor-α (TNF-α) appears to be the dominant chemical mediator other cytokines are involved. Blocking TNF-α alone does not benefit all as one would expect if TNF-α were the primary cause of joint inflammation. However, obstructing of IL-1β, IL-15 and IL-6 has demonstrable effects in alleviating arthritic symptoms, suggesting that these elements have a contributary role.[27] Because of EGCG counteracts the effects of ROS, it decreases the inflammatory response.

Obesity

Globally, obesity one of the leading preventable causes of death. Over 600 million adults and 100 million children were obese, in 2015. Obesity is one of the most serious threats to public health.  The American Medical Association and the American Heart Association, classified obesity as a disease. When their body mass index (BMI) exceeds 30, a person is considered obese.  A BMI of range 25–30 kg/m2 is defined as overweight.

 Obesity increases the likelihood of various diseases and conditions, particularly CVDs, type 2 diabetes, sleep apnea, cancers, osteoarthritis, hypertension and depression. Most commonly, it is caused by excessive calorie intake, physical inactivity, genetic predisposition, endocrine and mental disorder.  The condition is mostly preventable through changes to diet and exercise. Dietary quality can be improved by reducing the consumption of high fats, and refined carbohydrates and substituting with plant-based high antioxidant foods.[28] As indicated prior, EGCG interferes directly with lipid digestion by blocking secretory phospholipase A2 (sPLA2) and α-amylase, a starch-digesting enzyme. Because EGCG blocks bile release, lipid and cholesterol absorption are also reduced as a consequence.

Diabetes

Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation.[29] Type 2 diabetes is characterized by frequent urination, weight loss and increased thirst and hunger. Other symptoms include blurred vision, itchiness, peripheral tingling, recurrent infections and fatigue. It is also associated with an increased risk of cognitive dysfunction and dementia. Other complications include hyperpigmentation of skin and sexual dysfunction. Among some of the causes of type 2 diabetes are lifestyle, obesity, physical inactivity and excessive sugar intake.  Diabetes is manifested because of the inability to metabolize insulin which converts glucose into glycogen and stored in the liver and muscle. Other potentially important mechanisms associated with type 2 diabetes and insulin resistance include increased breakdown of lipids within fat cells, high circulating glucagon levels and increased retention of salt and water.[30]

In 2019, there were about 463 million people with diabetes. Common to both the developed and the developing countries, the disease is rare in undeveloped places.[31] Although several prescription drugs are currently available, they are either expensive or have noxious side-effects. In this regard EGCG can be used independently or as an adjunct in diabetes therapy. EGCG has no known side effects. It improves insulin secretion and regulates glucose uptake. Its role in reducing free radical levels and inflammation are major contributory factors.  Studies have demonstrated that EGCG significantly enhances glucose tolerance in rodents with type 2 diabetes.  Cell culture studies reveal that EGCG prevents gluconeogenesis: a physiological process whereby glucose, generated from the breakdown of proteins and fats, is returned to the circulation.[32],[33]


[1]https://www.google.com/search?q=polyphenols&rlz=1C1CHBF_enCO846CO847&oq=polyphenols&aqs=chrome..69i57j0l7.6046j0j7&sourceid=chrome&ie=UTF-8

[2] RONS (RON/RNS): Reactive nitrogen species (RNS) together with reactive oxygen species (ROS) causing nitrosative/oxidative stress which damage cellular structure and tissues.  Both these species are often referred to as ROS/RNS or RONS

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055983/

[4] Leukotrienes:  A class of inflammatory factors produced by WBCs. Leukotrienes activity results in the production of histamine and prostaglandins. Leukotriene D4 (LTD4) contractions in the smooth muscles lining the bronchioles is a major cause of inflammation in asthma and allergic rhinitis.

[5]https://en.wikipedia.org/wiki/Leukotriene#:~:text=Leukotrienes%20are%20a%20family%20of,the%20enzyme%20arachidonate%205%2Dlipoxygenase.

[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055983/

[7]ROS/RON:  The initial response to stressful stimuli is to defend against the insult.  In more stressful situations the cells can induce self-destruction. 

[8] Apoptosis Mechanisms: Because apoptosis cannot stop once it has begun, it is a highly regulated process. Apoptosis can be initiated through one of two pathways. In the intrinsic pathway the cell kills itself because it senses cell stress, while in the extrinsic pathway the cell kills itself because of signals from other cells. Weak external signals may also activate the intrinsic pathway of apoptosis.[7] Both pathways induce cell death by activating caspases, which are proteases, or enzymes that degrade proteins.

[9] MnSOD: As a member of the iron/manganese superoxide dismutase family, this protein transforms toxic superoxide, hydrogen peroxide and oxygen.[4]  It therefore clears mitochondrial ROS protecting against cell death. This  enzyme preserves the life of the cell against oxidative stress, ionizing radiation, and inflammatory cytokines.[5]

[10] Ataxia telangiectasia, Cockayne syndrome, and xeroderma pigmentosum:

Ataxia: impairs areas of the brain causing difficulty with movement, a susceptibility of infections and predisposition to infection and the risk of cancer.

Cockayne syndrome: Characterized by growth failure, impaired CNS development, abnormal sensitivity to sunlight, eye disorders and premature aging.

[11] Angiogenesis: the process whereby new blood vessels are generated. It is critical for growth, development and wound healing. However, it is also an essential step in the transition of tumors from a benign to malignant.

[12] https://en.wikipedia.org/wiki/Genistein June 23 2020

[13] Atherosclerosis: a disease which causes the inside of arteries to narrow due to the buildup of plaque. In extreme cases, it can cause coronary artery disease, stroke, peripheral artery disease, or kidney problems, depending on the affected blood vessels.

[14] Antioxidant enzymes: glutathione peroxidase, catalase, and superoxide dismutase

[15] https://en.wikipedia.org/wiki/NF-%CE%BAB  June 20 2020

[16] NF-κB: Nuclear Factor kB. NF-κB is a regulator of inflammatory immune responses and is involved with regulating cytokine production. Overproduction of NF-κB is linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development.

[17] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492354/ June 24 2020

[18] p53 gene:  activate DNA repair proteins when DNA has sustained damage and may be important factor in aging. It can arrest growth by holding the cell cycle at the G1/S regulation point so that the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle. It can initiate apoptosis if DNA damage proves to be irreparable.

[19] https://www.oncologynutrition.org/erfc/eating-well-when-unwell/antioxidant-supplements-safe-during-therapy

[20] https://en.wikipedia.org/wiki/Huntington%27s_disease

[21] https://en.wikipedia.org/wiki/Astrogliosis July 012020

[22] Homeostasis:  A steady state of physico-chemical conditions in the body for optimal functioning. Among some of the conditions maintained are temperature,  pH of extracellular fluid, ion concentrations and blood blood sugar level.

[23] Synaptic cleft: Typically, a space that permits a nerve cell to pass an electrical or chemical signal to another neuron.

[24] https://en.wikipedia.org/wiki/Cardiovascular_disease

[25] sPLA2 versus PLA2: sPLA2 from the pancreas serves to digest phospholipid compounds in dietary fats.  PLA2 enzymes are commonly found in mammalian tissues as well as in snake venom.[2] Venom from snakes and insects stimulate PLA2 resulting  arachidonic acid released from the phospholipid membrane resulting in inflammation and pain at the site of injury.

[26] IL-1β: IL-1β is produced by activated macrophages and a member of the interleukin 1 family of cytokines. It is involved in a variety of cellular activities, including cell proliferation and cell death. Moreover, IL-1β stimulates the production of ROS which in turn increases the inflammation by stimulating prostaglandins via cyclooxygenase-2 (COX2) – an enzyme in prostaglandin biosynthesis – thereby indirectly contributing to inflammatory pain.

[27] https://en.wikipedia.org/wiki/Rheumatoid_arthritis#Pathophysiology

[28] https://en.wikipedia.org/wiki/Obesity

[29] https://www.who.int/news-room/fact-sheets/detail/diabetes

[30] Glucagon:  a hormone, produced by the pancreas and raises the concentration of glucose and fatty acids in the bloodstream. It is a catabolic hormone and works to neutralize the effects of insulin.

[31] https://en.wikipedia.org/wiki/Type_2_diabetes#Signs_and_symptoms

[32] https://www.statista.com/statistics/271442/number-of-diabetics-worldwide/

[33] Andreia GranjaIúri FriasAna Rute NevesMarina Pinheiro, * and Salette Reis. 2017. Biomed. Res. Int. Therapeutic Potential of Epigallocatechin Gallate Nanodelivery Systems.  5813793

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