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It was existed in two geometric form of isomers that are cis- (Z) and trans- (E) form in the figure 2. Cis- and trans-resveratrol are bound to the glucose molecule and that is the reason they are consider as glucosides. The trans- form of resveratrol able to go through the isomerisation process to form cis when it was exposed to heat. Resveratrol exist more in the trans- form because it is the more stable compared to cis- form. Thus, trans-resveratrol was absorbed well in humans body (Shahidi & Ho, 2000).
Figure 2: Resveratrol occur in cis - (Z) and trans - (E) form
It is needed to be consumed in small doses in order to gain the maximum benefit and it is known as phytoalexin, an antibiotics substance. Resveratrol is also a defense mechanism that produced naturally from the plants to fight against the bacteria. Resveratrol's have many chemical name. It is known as (E)-5-(4-hydroxystyryl) benzene-1,3-diol. Besides that, its other chemical names are also known as trans-resveratrol; trans-3,5,4â€²-trihydroxystilbene; 3,4,5'-stilbenetriol; and (E)-5-(p-hydroxystyryl) resorcinol (Kang et al., 2008). Resveratrol is a solid white powder when at the room temperature and their melting point is at about 253ËšC to 255ËšC. Its molecular weight is 228.25 g/mol while molecular formula is C14H12O3. Resveratrol is a fat-soluble compound and slightly soluble in water at around 3 mg/100 ml. It also has an anti inflammatory effect which can help to slow down aging problem and is a polyphenol which is a type of antioxidant. Antioxidants are able to prevent or slowing down the oxidation of the cells in our body that can cause damage and stress which leads to aging problem. Due to the environmental factors like chemical, smoke and pollution, when skin was being exposed to these factors, consume of resveratrol in our body is important. Resveratrol is an antioxidant that can protect cell from damage and destruction. It will then help to prevent the free radicals to damage the cell and leads to aging processes. The oxygen and the free radicals can cause damage in our cell bodies that leads to aging (Milbury & Richer, 2008). Polyphenols can be classified into two main categories which are nonflavonoids and flavonoids. Resveratrol is a polyphenols and was classified in nonflavonoids. Non-flavonoids are the most common antioxidants, obtained from red wine. Resveratrol will activate the sirtuin genes which are a longevity gene that can help in anti aging and increase lifespan. Sirtuin genes that form in our body can reduce cell being destruction which lead to aging problem. When the cell was damaged, it has a greater energy to repair those (Klatz & Ronald, 2008). Trans-resveratrol increases a large amount of energy in our body by increasing the number of mitochondria which helps in living longer. Resveratrol also can reduce the level of superoxide, a chemical that are harmful to our body and causes the degeneration of DNA. Therefore, resveratrol are able to enhance health and helps in anti aging due to its antioxidant effect.
1.2 Sources of resveratrol
Resveratrol is naturally available on a number of plants like blueberries, cranberries and bilberries which contain less amount of resveratrol. The total concentration of resveratrol was listed in Table 1. When these fruits were heated, concentration of resveratrol will drastically decrease. Resveratrol also found in some pines such as eastern white pine and scots pine, the stalks and roots of the giant knotweed also contain resveratrol. Besides that, resveratrol can be found in over 70 species of flora which included spruce, eucalyptus, lilies and mulberries. When compared with other sources, resveratrol's mainly found in a greatest amount fromgrapes which are used to make wine. It can occur in the skin, roots, stalks and seed of the grape. The skin of the grapes contain greater amount of resveratrol (Jane Higdon, 2007). There were three types of grapes contain the most concentration of resveratrol which are Vitis rotundifolia (muscadine) grapes, Vitis vinifera (common grape vine) and Vitis labrusca (Fox grape). Vitis vinfera is a type of grape species that can commonly found in the area of central Europe, Mediterranean compound, and southwestern Asia from Spain north to southern Germany, east from northern Iran and Morocco. Vitis labrusca species can found in eastern United States. While Vitis rotundifolia is found in the southeastern United States and is cultivated for production of juice, wine, and jelly. Red wine contains the most amount of resveratrol concentration. The resveratrol content in the wine is basically determined based on the length of time of the grape skins that are present during the fermentation process. It is important to determine the resveratrol concentration. The concentration of resveratrol is higher in red wine compared to white wine (Table 2). Red wine has higher concentration of resveratrol, this is due to red wine was fermented with the skins, whereas white wine was fermented without the skins of the grapes (Watson et al., 2008). Resveratrol is vulnerable to the oxygen and light, red wines were stored away from the cool temperatures and sun light to protect the potency of resveratrol. Red and purple grape juices are the greatest sources of resveratrol (Klatz & Ronald, 2008). Red grape juice contains higher concentration of resveratrol than white grape juice (Table 1). Peanuts are the natural source that also contains resveratrol too. It is not as concentrated as red grapes but also can get a small amount of resveratrol in peanuts and peanut butter. Boiled peanuts have the highest concentration of resveratrol content in the peanut form. The total resveratrol concentration of peanuts form was listed in Table 3. Resveratrol were also found in nutritional supplement like pills and liquid form. Most of the resveratrol supplement was derived from the Japanese Knotweed. It is an herbaceous plant which can be found in Korea, China and Japan. Japanese Knotweed known as American bamboo or Japanese bamboo and grows only in summer (DeWayne McCulley, 2005).
Table 1: Total resveratrol concentration in dietary sources
Total resveratrol concentration
0.2 mg l-1
Up to approx32 ng g-1
Up to approx16 ng g-1
Red grape juices
0.50 mg l -1 (average)
White grape juices
0.05 mg l-1 (average)
(Baur & Sinclair, 2006)
Table 2: Total resveratrol content of beverages
Total resveratrol (mg/liter)
White wines (Spanish)
Rosé wines (Spanish)
Red wines (Spanish)
(Jane Higdon, 2007)
Total resveratrol (mg)
1 cup (146 g)
1 cup (258 g)
1 cup (180 g)
Table 3: Total resveratrol content of peanuts form
(Jane Higdon, 2007)
2.1 Resveratrol as an antioxidant
Resveratrol contains antioxidants that were useful in averting the clotting of blood. There are two categories of antioxidants which are flavonoids and non-flavonoids.
Flavonoids antioxidants are obtained from foods such as apples, oranges, onions, juice of grapes, tea and cocoa. Flavonoids that their antioxidant content is much smaller when compared with non flavonoids (Milbury & Richer, 2008).
The most common antioxidants are non-flavonoids. It was obtained mostly from the red wine. It contains higher antioxidant and capable in aiding the unclogging of arteries from the blockage of fatty acids. Resveratrol as an antioxidant can cancel out the cell damage effects from the free radicals. It can prevent harmful free radicals and even promotes healthier cells in our body. This means that we can live even longer life span and avoid aging processes.
Resveratrol is an antioxidant that activates a class of longevity genes form in our body which known as sirtuins. Sirtuins genes help promote the longetivity of cell (Joseph A. Baur, 2010). Sirtuins are genes that are able to reduce cellular being deteriote and cells have greater power to repair those damages. It activates the sirtuin genes which triggers a fight response in our cells. When sirtuin genes are activated, the cells have the potential to continue their processes of replication and protect our body from the damage of free radical that causing aging problem. Resveratrol is an antioxidant that able to help in anti-aging problem (Klatz & Ronald, 2008).
2.1.1 What is antioxidant?
Antioxidants can help to keep us look fit, young and healthy. Antioxidants are known as oxidation fighter. It is a substance that able to prevent and slow down the oxidation process. It protects body cells from the oxidative damage and the body from harmful free radicals that leads to aging and some diseases (Klatz & Ronald, 2008).
When the oxygen molecule undergoes oxidation, it will become a free radical. Oxidation reactions produce free radical which starts the chain reactions and damage the cells in our body. Antioxidant will help to stop chain reaction by removing the free radical and inhibit oxidation reactions being oxidized themselves. The oxygen and the free radicals can cause damage in our cell body. The damage of the skin cells in our bodies makes our skin to have wrinkles exist. Antioxidant helps to protect our body from the destruction that caused by free radicals and oxygen.Antioxidant will help to solve aging problem. Free radicals are a reactive substance. They try to steal electrons from other molecules like cellular membranes and DNA. They will continue react with other cellular molecules. These free radicals can leads to damage of body cells. Antioxidants are present into our body to stop the free radical chain by giving its own electron to the free radical to make it become stable. Antioxidant still stable even loses an electron. The free radical steals one of the electrons from the antioxidant and makes both stable. The destruction stops when both become stable (Milbury & Richer, 2008).
2.1.2 What is a Free Radical?
Free radicals are formed by cells due to exposed to variety of substances such as pollution, radiation, chemicals, alcohols, drugs, smoke, pesticides and sun exposure and other various metabolic processes. Free radicals are responsible for the aging problem. Atoms try to become stable by either receiving or giving away electrons from other atoms in order to become a stable molecule. The free radicals are an unstable substance. It will have either one electron too less or too many in order to become stable. Free radicals try to give or get electrons from other molecules, to make it stable. When a free radical attacks a molecule, it causes destruction of a cell. Free radicals caused damage to DNA in our body. Each time when a cell divides, there is a chance that some of the genes will be copied incorrectly and this is situation known as mutation. Thus, exposures to free radicals can lead to mutation in our body's genes. The body can either destroy or correct some of the mutations, but not all of them for certain. The mutated cells can accumulate copy themselves and cause problems which are related to aging processes. Free radicals can actually create and makes by our body. Body's immune system cells were purposefully created them to damage the viruses and bacteria cells that contain in our body. The digestion process also creates free radicals. If the immune system are weakened or we don't consume enough antioxidants sources, damage can occur and may leads to aging and some disease problem (Milbury & Richer, 2008).
2.2 Benefits of Resveratrol
Dr. Joseph Maroon from the University of Pittsburg Studies had done research on the benefits of resveratrol. Studies and research showed that trans-resveratrol able to help to lower cholesterol, lower blood pressure, reduced the risk of cardiovascular; protect body immune system, boost energy, helps in anti aging problem and able to increase energy levels that helps in increasing life span. Besides that, it is beneficial in acting as an anti- inflammatory and fight against viruses and fungi. Resveratrol can reduce the risk of Alzheimer's disease too (Jane Higdon, 2007).
Moreover, resveratrol can reduce the cardiovascular risk by produce an ability to reduce the platelet and monocyte which is a type of white blood cells, adhesion to the blood vessel walls. Once the monocytes and platelets stick to the vessel walls, they started to induce the blood coagulation which leads to forms a clot. The clot will break off the vessel wall and then flow to a constriction area where the clot cannot pass through. The clot can't flow through and caused the tissue death surrounding around the vessel. These types of events can lead to heart failure. Resveratrol can promote vasodilation which is a relaxed and expanded state of the artery that increased blood flow. High doses of resveratrol taken will decrease the risk of thrombosis, clot formation (Bertelli & Das, 2009).
The tests and research are carried out on plants or animals like mice and the humans to show the benefits of resveratrol that can help in reducing diseases. A study done by the Department of Science and Technology at Ohio State University in 1997 found that resveratrol was able to inhibit cancer cells from dividing at a cellular level. Resveratrol has found to inhibit grow or increase by rapid production of new cells in the human cancer cell lines, for example those from the breast, colon, thyroids, pancreatic, prostate and stomach cancers. Resveratrol can exert effect by inhibits angiogenesis is the growth of new blood vessels. In order for the tumors to grow in our body, angiogenesis must take place so that blood vessels can develop to feed the tumor. Besides that, it is by inhibiting the enzymatic activity of cyclooxygenase enzymes. Cyclooxygenase enzymes are an enzyme that is responsible for the formation of prostanoids. The three main groups of prostanoids are prostacyclins, prostaglandins, and thromboxanes where they involved in the inflammatory response. Resveratrol helps in inhibition of cyclooxygenase enzymes that can reduce the risk of many cancers diseases (Gene Bruno, 2006). The Department of Microbiology Immunology NE Ohio University, College of Medicine in 1997 was also discovered that resveratrol can help reduced skin cancer by as much as 98%.
Doctors Philippe Marambaud, Peter Davies and Haitian Zhao from the Litwin-Zucker Research Center, study for Alzheimer's disease and Memory Disorders at the North Shore-Long Island Jewish Institute for Medical Research in Manhasset, New York doing a study in 2005 found that resveratrol can lower the levels of an Alzheimer's disease. Moderate red wine consumption will lower the risk of Alzheimer's disease. Antioxidants compounds have potential in protect nerve characteristics. In this study, resveratrol lower the levels of a protein known as beta amyloid which can lead to memory loss, features of Alzheimer's disease that clumps in the brain as a result of a gene variation (Milbury & Richer, 2008).
Consume resveratrol everyday can reduce and reverse DNA mishaps; this is the reason of resveratrol help in aging problem. Destruction of cell can cause aging. Aging problem occur when cells can no longer replicate cell DNA thus begins the gradual decline of the body. Resveratrol stimulates the longevity gene which called sirtuin 1 and also known as NAD-dependent deacetylase sirtuin-1 or SIRT1 in body and succesfully showed resveratrol reduces DNA mishaps and help in aging problem. Resveratrol protects our cells from oxidative damage that caused by free radical. It also prevents the signs of aging so that we can look younger (Richard A. Passwater, 2008).
It is not correct to say that supplements that rich in resveratrol are enough for our health. Besides uptake of resveratrol supplement, correct intake of foods which are rich in minerals, fruits and vegetables that contain antioxidant are important for our health too.
Even though wines are good for our health and contain resveratrol content but it also contains unwanted amounts of alcohol and calories that can make people dizzy. Nowadays people able to get the resveratrol content through supplement and achieve the best results. Consumers can achieve the health benefits without worry the consequences of alcohol consumption.
2.2.1 Effect of resveratrol on anti aging
Before getting to know how the effect of resveratrol on anti-aging is, we need to know what the cause of aging problem is. Aging is the process where bodies start to degenerate which means the metabolic processes start to slow down. There are four reason causes aging to occur on the cellular level. DNA carries genetic information for our physical characteristics and helps define each cell's function. Outside the nucleus in the cellular fluid are mitochondria where the organelles in the body cells that can generate energy to work on the cell's daily activities. If everything works well, the DNA in each cell will well protected and can be copied correctly when the cell divides. The cell will well repair too. Mitochondria generate energy effectively thus all the systems in our body operate efficiently (Miranda A. Farage, 2010).
The aging is considering a very complex process. Aging was caused by genetic factors and also external influences like smoking, environmental conditions and other. Biological action of free radicals, especially to oxygen species like OH, ozone, peroxyl and other oxidizing species that cause oxidative stress leads to aging problem. The oxidative stress can lead to skin aging (Nikola Getoff, 2007). One of the reasons that caused aging is DNA damaging assaults. Cells lose their ability to replicate DNA in every new cell. DNA "mistakes" accumulate and allow the small pieces of DNA to become active and get them out to create a type of "DNA debris" that eventually stops a cell from functioning. This build up of "debris" is connected to aging, and death of individual cells. Besides that, aging occurs through the deterioration of cells body that initiates the free radicals. Free radicals become common invaders in our bodies due to concentration increased in the atmosphere through the emissions from vehicle and aircraft, seas and rivers through the problems of industrial pollution. Excessive radiation like the harmful UV radiation content of sunlight that is not effectively filter by an adequate ozone layer created the free radicals. Every cell in our body also gets bombarded by things like an unhealthy diet and smoking that caused DNA damage. This DNA damage is the first mechanism of cellular aging to occur (Starr & McMillan, 2010).
While the second reason causes aging is a class of compounds that known as genetic regulators. It can contribute to age-related cellular deterioration and control the dynamic balance between damage and repair, whether a cell lives or dies. When we aged these genetic regulators promoting cell renewal and production of energy declines throughout the activities, the genetic regulators promoting cell death become even more active. When the natural defenses decreases, the function of the self-repair also decreases, the cell damage increases and able to lead to age-related cellular deterioration.
The third cause of cellular aging is due to the decline of cellular energy produce. Mitochondria were responsible in all the cellular functions. As time passed, mitochondrial efficiency decreases, leading to a decline in energy production which then affects cell function. This one of the reason leads to age-related cellular deterioration (Miranda A. Farage,2010).
The fourth causes of cellular aging are known as Advanced Glycation End Products, or also known as AGE proteins. The AGEs are a sugar molecule that bonds to either a lipid or protein molecule without an enzyme to control the reaction and end-products of glycation reactions are AGEs. Another similar reaction that known as glycosylation was used an enzyme to control the reaction, targeting the specific receptor sites on the cells. Advanced glycation end products increase the blood and tissue levels and increases nerve damage. It will then cause aging problem (John O'Brien, 1998).
Resveratrol help activates a cell's on defense survival enzyme, which can help to repair the damage DNA. Resveratrol can enhance the blood flow well and reduces the damage that caused by UV radiation, thus making the skin wrinkle free and living younger. Resveratrol able to help in anti- aging since the antioxidants in resveratrol boost the body's metabolism result of the muscles using up oxygen more efficiently, this is able to increase our energy and stamina. Resveratrol has an effect that mimics those of caloric restriction, the best way of anti-aging strategy. It helps us to limit our caloric intake to our body. Caloric restriction (CR) is define as restricting large amount calorie intake in our body and meanwhile maintaining good nutritional way and increase longevity and living in healthy life. In humans, consuming a low-calorie diet provides greater longevity like reduced body temperatures, lower insulin levels, and with less chromosomal damage that typically caused aging problem. Caloric restriction can produce changes in gene expression which those are associated with longer lifespan and a slow down the aging process. Meanwhile, reduced caloric intake means reduced rate of energy metabolism and reduced the production of free radicals. Resveratrol also can reduce the formation of the AGE proteins that can eventually clog up our cells (Ronald R. Watson, 2009).
Resveratrol worked as a powerful antioxidant and help to extinguish the free radical damage in the cell body, but it also has a special action of mechanism that might prove to have extended life span. Antioxidants can slow down cell damages. Resveratrol can activate a gene that known as sirtuin 1, SIRT1. SIRT-1 can suppress the p53 enzyme systemin our body that will help to inhibit the tumor growth and trigger cell death which is apoptosis. When cellular DNA is stressed or damaged, the p53 activity was suppressed, SIRT-1 will prevent those premature aging and apoptosis was induced. This giving cells an opportunity to repair the damage cell. Thus, SIRT1 is also known as the rescue gene and rescue the damage gene in our body. Resveratrol and caloric restriction are proved to be the two primary methods of activates the gene and unleash its anti-aging properties. SIRT1 is known as NAD+-dependent deacetylase that can modulate the proteins activities that are in pathways toward of the beneficial effects of restriction of calorie. SIRT1 can catalyse a reaction where the NAD+ hydrolysis is coupled to the deacetylation of the acetylated lysines in the target proteins. These target proteins were included transcription factors, transcription factor co-regulators and histone. When the sirtuin 1 gene is activated, it will produce proteins that can protect cells from DNA damage which caused by aging. The gene has a defense mechanism, activated by low amount of calorie consumption that protects the cells during the periods of time when they need it. If without the sirtuin, the cell would have died and leading to aging problem. High SIRT1 levels appear to have effect on slowing the aging process and living a healthier life, calorie restriction and resveratrol are the two primaries of SIRT1 activators (Knutson & Leeuwenburgh, 2008).
2.3 Mechanism by which resveratrol help in anti-aging
Resveratrol or trans-3,4',5-trihydroxystilbene is a natural polyphenolic, is a phytoalexin and also a non-flavonoid antioxidant. Scientists around the world are studying and doing research on resveratrol to determine how it is able to fight against aging. Antioxidants properties can help prevent damage that caused by free radicals. Aging is caused by the degeneration of body cells that free radicals attack and initiate. This is important in anti-aging because free-radicals can damage cells and leads to the process of causing the formation of wrinkle. Evidence showed that resveratrol has antioxidant effects, able to increase energy production, and alters patterns of gene expression. The anti-aging properties of resveratrol help to prevent these effects. Oxidative stress can cause aging problem. Oxidative or nitrosative stress is an increased production of O2Â·, H2O2 and ONOOâˆ’ eventually lead to age-related cardiovascular dysfunction. Free radical can cause damage at the cellular level and leads to aging. Resveratrol anti-aging benefits can activate a class of genes in the body that known as sirtuins. Sirtuins reduce cellular decay and have a greater energy to repair it. Resveratrol will slow down cellular decay, reduces cell death, and gives the cells more capacity to repair themselves (Baur et al., 2006).
2.3.1 Mechanism of resveratrol on low-density lipoprotein (LDL)
Resveratrol inhibits the harmful free radicals and oxidation of dangerous low-density lipoprotein (LDL) which is a molecule, combination of lipid and protein. Lipoproteins are the form where lipids are transported in the blood. Low density lipoprotein (LDL) was oxidatively modified. LDL contains some amount of endogenous antioxidants. The harmful free radicals and oxidation of dangerous low-density lipoprotein (LDL) can cause aging. In the beverages of red wine that contains resveratrol concentration can reduce low-density lipoprotein but white wines do not have such effect. This is due to red wine is a flavonoids and have polyphenols. It has antioxidant properties that can reduce the atherosclerosis metabolism. When consume red wine, it able to reduce the aging problem. There are several compound that can found in red wine were sugars, ethanol, phenols, glycerol, fats, amino acids, vitamins, and other volatile. Resveratrol has found to exert a great inhibitory effect on hydrogen peroxide and superoxide anion production by the macrophages, stimulate by the lipopolysaccharides.
The resveratrol showed a great cardioprotective effects in ischemia reperfusion (I/R) injury. Antioxidants including polyphenolics showed to protect renal cells from the cellular injury which caused by ischemia reperfusion. Resveratrol is a stilbene polyphenol that can be found in red wine and grapes able to protect isolated rat heart from ischemia reperfusion injury (Giovannin et al., 2001). This showed that resveratrol can inhibit the oxidation of low density lipoprotein. Resveratrol can protect the cardiovascular system by protecting against ischemia-reperfusion injury. Ischemia-reperfusion injury refers to the damage of tissues when blood flow is restored following a temporary loss of circulation. This situation occurs when temporary blockage of blood flow by blood clot. Hydroxyl radical (OH-) can cause effect on the (I/R) injury. They exert damage to tissues in biological systems. Hydroxyl radicals are formed in the lipoproteins and membranes as an intermediate product of lipid peroxidation, which associated with the ischemia reperfusion injury. Resveratrol will inhibit OH formation that caused aging problem. Resveratrol protected DNA from damage by acting as a radical-scavenging antioxidant. Resveratrol stimulates energy production in the mitochondria. While diminished energy production from mitochondrial is associated with decreased longevity. Resveratrol can protect the myocardium from the damaging effects of I/R injury. The species of male Wistar rats were treated with control and the resveratrol plus L-Nitro-Arginine Methyl Ester or known as L-NAME. L-NAME is a bloker of nitric oxide. Results showed that resveratrol can reduce the ischemic rats of mortality from 10% to 50% and renal damage was reduced. The resveratrol can inhibit renal lipid peroxidation that induced by ischemia and reperfusion both in medulla and in cortex (Giovannin et al., 2001). Resveratrol can reduce oxidative stress and inhibit platelet aggregation. Resveratrol reduces ischemia/reperfusion (I/R) injury of heart by antioxidant. Through enhancing the production of life-sustaining energy, resveratrol protect the body against metabolic disease and obesity, this will improve health and slow down aging (Lastra & Villegas, 2007).
2.3.2 Mechanism of resveratrol on caloric restriction
Many genetic pathways were influence by resveratrol. Some of the genetic pathways were influenced by resveratrol and affected by caloric restriction too. Resveratrol is a polyphenols exert some of the health benefits by activates the intracellular pathways; many of it are the same with those were activated by calorie restriction that improve health and prolong lifespan (Wood et al., 2004). Caloric restriction is the greater way to delay age related diseases. Resveratrol and caloric restriction also cause metabolic changes like increased mitochondrial biogenesis and decreased insulin signaling. Insulin signaling and mitochondrial activity result from activation of AMP-activated kinase (AMPK), a sensor of energy cellular levels which an enzyme is promoting fatty-acid oxidation and insulin sensitivity. When the AMPK activation occurs on a caloric restriction diet and has been proposed as a longevity method for mammals. Resveratrol showed a greater tendency towards induced the phosphorylation of AMPK (Lastra &Villegas, 2007). Caloric restriction increases life span caused by the sirtuin genes as shown in figure 3. Low-calorie diet is associated with lower insulin levels and reduced body temperatures, along with less of the chromosomal damage that typically accompanies aging. Sirtuin genes are associated with aging and longevity. The genes and pathways affected by resveratrol are related to the activation of sirtuins gene. Resveratrol and caloric restriction also cause metabolic changes like decreased insulin signaling and increased mitochondrial biogenesis. Sirtuin gene helps in aging problem because possess unique biochemical activity which is NAD dependent protein deacetylase (Hyon Jeen Kim et al., 2002).
Figure 3: Effects of caloric restriction when aging occured (Tahira & Akhlaq, 2008).
In the November of 2006, Dr Sinclair and Rafael De Cabo were did a research on middle aged mice and found a great discovery. The experiment was done on 3 groups of mice. The first group was given them standard diet, the second group was feed them with high calorie diet plus resveratrol, while the third group was feed them with high fat, high calorie diet. The third groups of mice got symptoms like heart disease and diabetes and shorter lifespan. While the second group with high fat, high calories with resveratrol had no symptoms like heart disease or diabetes and they were living longer than the third group. The experiment was done and showed that the mice without resveratrol in the high caloric diet will have lowest proportion of mice surviving with aging problem. While mice with resveratrol in the high caloric diet will have the highest proportion of mice surviving with lower aging problem compare to the mice without resveratrol treated group (Figure 4). High-calorie diets can cause many pathological conditions including increased glucose and insulin levels leading to diabetes and cardiovascular diseases. This will lead to aging problem. Dr Sinclair found that in resveratrol-treated mice, insulin sensitivity and motor function were improved, and so as the mitochondrial activity was increased too. They found that resveratrol-treated mice acetylation status of peroxisome proliferator-activated receptor-Î³ co-activator 1Î± (PGC-1Î±) was decreased, thus its activity was increased greatly. The result is important because mitochondrial biogenesis in liver and muscle is controlled by PGC-1Î±, deacetylation of which is positively regulated by SIRT1. Stimulation of the SIRT1-mediated deacetylation of PGC-1, improves mitochondrial function and energy balance in mice (Baur et al., 2006). The SIRT1 enzyme increases the activity of the mitochondria. Mice that fed with resveratrol showed more energetic mode. The reason is due to the muscle tissue increased. This helps in aging because the aging process coincides with the efficiency of the mitochondria within the cells. Resveratrol helps to limit the caloric intake in the diet. When the metabolism increase and mitochondria activity increase showed an uptake of higher calorie, this caused free calories reduction available in the body. So, keeping mice on a restriting calorie on diet showed a delaying in the age-related diseases, and slower decrease in function. Therefore, consume resveratrol regularly may prevent age related illnesses and extend lifespan (Garrett Peck, 2009).
Figure 4: The proportion of mice surviving over age (Garrett Peck, 2009).
A number of intracellular pathways were activated by sirtuin 1 gene, also known as SIRT-1 (Figure 6). SIRT1 participates in many important functions, including protection from aging, stress, insulin production, fat metabolism and cell cycle regulation that have effects on caloric restriction (Baur et al., 2006). Sirtuin 1 is a rescue gene and protector cell and helps cells to self repair when the cell is damaged. Sirtuin will persuade the cell to keep on fight and to repair the damage cell. If without the sirtuin, the cell will die and caused aging. Sirtuins will activate the forkhead box O (FOXO) which is a group of transcription factors. Then FOXOs activate specific genes, lead to decrease in apoptosis, and increase in antioxidant activities, DNA protection, anti-inflammatory effects that can reduce aging problem (Guarente & Picard, 2005). SIRT1 will deacetylate some of the metabolic regulator and transcriptional coactivator, peroxisome proliferator-activated receptor-Î³ co-activator 1Î± (PGC-1Î±). This can help improve mitochondrial function, increases mitochondrial membrane potential and induces genes for fatty acid and mitochondrial oxidation (Lagouge et al., 2006). When we aged, our mitochondria start to deteriorate and the metabolism begins to slow down. Mitochondria also play n important role in mediating apoptosis in able to response to DNA damage or oxidative stress. Dysfunction of mitochondrial is associated with aging. Resveratrol helps to improved mitochondrial function by activates the sirtuin gene (Wallace, 2005). Besides that, a second sirtuin, SIR2, increases the DNA stability and speeds up cell to repair the damaging, at the same time increasing the cell lifespan. Sir2 is associated with increasing life span in a different of species, whereas delete the Sir2 gene results in decreased of longevity. The members of Sir2 family of NAD-dependent protein deacetylases regulate diverse cellular processes including aging. Resveratrol was effective in triggered the production of sirtuin. Small amount of resveratrol helped yeast cells to live as much as 60 to 80 percent longer as shown in the figure 5 (Knutson & Leeuwenburgh, 2008). SIRT1 can produce different outputs resulting in different stimuli. SIRT 1 was activated in the brain causes an increase in the of the transcription factor, FOXO 3A with the antiaging properties. When NF transcription factor increased, this may explain as the properties of neuroprotective of SIRT1. SIRT1 can protect the muscle sells and pancreatic cells against the induced stress of apoptosis by increasing activity of the forkhead protein FOXO1. In the liver, SIRT1 will deacetylase the coactivator PGC-1Î±, thus increasing the expression of genes for gluconeogenesis. In the muscles, the effect of SIRT1 on FOXO1 increases the mitochondrial biogenesis and insulin secretion (Figure 7) (Camins et al., 2010).
Figure 5: The graph showed that the percentage of survivors between resveratrol treated groups and untreated group (Tahira & Akhlaq, 2008).
Figure 6: SIRT1 activation pathways. Resveratrol and calorie restriction activate the SIRT1 mediated pathways that can prevent the age-related diseases (Markus &Morris, 2008).
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Figure.7: SIRT1 can produce different outputs resulting in different stimuli (Camins et al., 2010).
2.3.3 Mechanism action of resveratrol on reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation
Aging disturbs the balance of cellular redox, produce higher levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The oxidative damage from the reactive oxygen species (ROS) and reactive nitrogen species (RNS) where the main contributor on to the cellular damage. Resveratrol has antioxidant properties are important role that oxidant damage act in different conditions. Reactive oxygen species or ROS include free oxygen ions, free radicals, and both inorganic like organic peroxides. Free radicals can interact with lipids, proteins, and DNA which lead to cause oxidative damage. RNS include peroxynitrite (ONOO-) and nitric oxide (NO.). There are many important biological functions for ROS and RNS. Due to the presence of free electrons and the molecules size are very small, they are highly reactive. ROS and RNS are formed during natural metabolism as a byproduct. It has important roles in cell signaling. ROS and RNS levels were increased during the inflammation by macropahages, eosinophils and neutrophils. Through the process, nitric oxide (NO.) is produced and was reacted with ROS to form the RNS peroxynitrite (ONOO-), a highly oxidizing and nitrating substance (Gatz & Wiesmuller, 2008). Due to cause of environmental stress ROS levels increased, which result damaging to cell structures. This is a situation that known as oxidative stress. DNA damaged by ROS was resulting in mutagenesis and aging. Cells were defending themselves against ROS damages through enzymes like superoxide dismutases (SOD) catalases. Resveratrol can maintain the concentration of the antioxidants that were found in the biological systems. Resveratrol increases in the levels of glutathione in a concentration dependent in human lymphocytes were activated with H2O2. Resveratrol was increased the amounts of several antioxidant enzymes like glutathione peroxidase, glutathione S-transferase and glutathione reductase (Lastra1 &Villegas, 2007). SOD is a metalloenzyme which plays an important role in protect all the aerobic life-systems against oxygen toxicity like free radicals derived from oxygen. Most of the organisms are exposed to oxygen. However oxygen can be converted to reactive radicals that bind to DNA, proteins and lipids that caused damage to our cell. Superoxide dismutase and catalase enzymes can protect from this damage.SOD has value as an antioxidant that can help to protect against cell destruction. It has ability to neutralize superoxide that is one of the most damaging free radical substances. During aging, astrocytes will generate a large amount of nitric oxide (NO). The reaction between superoxide and NO will generates peroxynitrite (ONOOâˆ’). Then, ONOOâˆ’ reduces the respiration of mitochondrial, inhibits membrane pumps, cellular glutathione depleting, and damages DNA, thus poly-(ADP-ribose) synthase was activated which is an enzyme that leads to depletion of cellular energy. According to all these processes, it may contribute to deficiency of neuronal energy and the oxidation of protein sulfhydryls caused by aging-associated changes same as neurotraumatic situations (Figure 9) (Thomas & Mallis, 2001). At low levels, ROS such as hydrogen peroxide, superoxide and hydroxyl radical may function in the cell signaling processes for the modulation of important cell activities like includes growth and adaptation responses (Tahira & Akhlaq, 2008). When at the higher levels, ROS may cause cellular damage on macromolecules like nucleic acids and lead to apoptosis which was cell death. Mitochondria are the major energy producer of ROS that shown in figure 8. Another source of ROS generation is polyunsaturated fatty acids, components of neural membrane glycerophospholipids. These glycerophospholipids are enriched in arachidonic acid (AA) and docosahexaenoic acid (DHA).ROS are produced by NADPH oxidase 4 (Nox 4). NADPH oxidase in astrocytes and microglial cells is regarded as a major source of ROS for mediating oxidative stress and neuroinflammation (Zekry et al., 2003). Resveratrol helps in ROS damage. Resveratrol able to maintain the intracellular concentration of antioxidants found in biological systems. Resveratrol increased the level of several antioxidant enzymes, including glutathione peroxidase, glutathione S-transferase and glutathione reductase (Shankar et al., 2007).
Figure 8: Generation of reactive oxygen species (ROS) in normal aging. Low levels generation of ROS during normal aging is countered by the antioxidant enzymes. High levels of ROS can cause downregulation of antioxidant mechanisms results in neural cell death in neurodegenerative diseases (Tahira & Akhlaq, 2008).
Figure 9: The production of ROS and RNS and synthesized peroxynitrite through interactions of nitric oxide and superoxide radical in non-neural and neural cells during aging (Tahira & Akhlaq, 2008).
Dr. David Sinclair's laboratory has proven that resveratrol is a activator of sirtuin and this resveratrol has anti-aging effects. Sirtuins are NAD+-dependent histone deacetylases which acts to increase life span. Resveratrol can inhibit the respiratory chain of mitochondrial, which may affect NAD+or NADH ratios. Effect of resveratrol helps in age-related decreased in cardiovascular function.
When the DNA damage occurs, PARP-1 can cleave the nicotinamide adenine dinucleotide (NAD+) to become nicotinamide and ADP-ribose and to form a long branch of ADP-ribose polymers on the glutamic acid residues of a number of target proteins including also the histones. Poly (ADP-ribosylation) was involved in the regulation of many cellular processes like gene transcription; DNA repair, cell cycle progression, cell death and genomic stability were showed in figure 10.The activation of moderate PARP-1 helps in repair the damage of DNA resulting from reactive nitrogen and oxygen species such as H2O2 and ONOO-. NADH was functions as electron carrier in the respiratory chain of mitochondrial, depletion of NAD+ rapidly leads to decrease of intracellular ATP levels, thus leading to dysfunction and death of cellular (José Marín-García et al., 2008).
PARP inhibitors and deletion genetic of the PARP-1 enzyme were increased cardiovascular oxidative stress and leads to aging problem occured. When inhibition PARP decreases NAD+ consumption and thus increased levels of nuclear NAD+, which in turn is to activate the sirtuins gene (Hyon Jeen Kim et al., 2002).
The mechanisms were showed by which aging promoting dysfunction of endothelial, oxidative stress, and pro-inflammatory phenotypic alterations in blood vessels. The model showed that aging was associated with ROS generation increased by NADPH oxidase or mitochondrial sources that activates the redox-sensitive transcription factors (NF-ÎºB) and causing aging upregulating inflammatory gene expression. While the pro-inflammatory phenotype of arteries will promote atherogenesis, like if other risk factors such as the present of hypertension. Resveratrol may inhibit the ROS - NF-ÎºB axis, inhibits the activation of platelet, increases NO bioavailability or sirtuins activation thereby helps to maintain a youthful and younger phenotype. It is likely when the PARP-1 inhibition will increase NAD+ levels, and served as a co-factor for activation of sirtuin. Thus, it was predicted that resveratrol and PARP inhibitors can exert anti-aging properties and action (Figure 10) (Nazar Labinskyy et al., 2006).