The science behind the current wave of anti-aging diets and supplements, although demonstrating some promise, is nonetheless frought with set-backs, limitations, and false hope. Nonetheless, people are desperate to find ways to delay the inevitable processes of aging such that the anti-aging dietary supplement industry is approching sales of 50 billion dollars annually in the US alone.
There are several clearly identified means by which one can reduce their likelihood for debilitating disease and to extend not only the quality of their life but also the length of their life. Unfortunately most individuals are loathe to set out on the obvious path, that being a healthy diet and a healthy lifestyle. With these two alone nearly all individuals can have the expectation of a more disease free existence and the potential for 2-5 (or more) extra years of life.
The vast majority of anti-aging research in humans has focused on the composition of the diet and on the addition of various types of supplements. However, little work in the area of diet composition and supplement addition has been founded in concrete and verifiable research not to mention providing reproducibility. Many so-called clinical trials are not carried out in large populations nor in the correct double-blinded design.
One potentially promising dietary regimen that has shown some, albeit limited, promise in life extension in humans studies is the calorie restriction diet. The idea behind calorie restriction and life extension (anti-aging) evolved from studies in fruit flies and the roundworm (Caenorhabtidis elegans) where there is a definitive correlation between reduced calories and life span extension. The gene that was identified in these organisms as playing a role in the life extension in response to calorie restriction is called Sir2. The Sir2 gene in these organisms is related to a gene first identified in yeast called silent mating-type information regulator 2. In humans there a seven genes that are related to the Sir2 gene and these genes are called the sirtuins (SIRT1-SIRT7) which are discussed in more detail in the next section.
Another protein that plays an important role in response to nutrient deprivation is the protein kinase (a type of enzyme that transfers the phosphate ion to its substrate) known as AMP-dependent protein kinase, AMPK. The details of AMPK function and its role in anti-aging processes is discussed below. Briefly, the primary function of AMPK is to phosphorylate and, thereby regulate the activity of numerous metabolic enzymes in response to energy and/or nutrient deprivation. However, if ATP depletion remains protracted AMPK will phosphorylate a number of transcription factors and transcription co-regulators in order to change the prograam of genes that are active. It turns out that these same AMPK targets are also targets for regulation by SIRT1. Like SIRT1, AMPK has been proposed to be one of several molecules involved in the regulation of mammalian longevity. Increasing the activity of AMPK has been shown to increase the life span of the roundworm (C. elegans) and in aging rats the level of AMPK-mediated phosphorylation is decreased relative to younger rats. Caloric restriction research in humans has provided evidence that caloric restriction may have potent protective effect against secondary aging such as is typical in type 2 diabetes and coronary artery disease. Numerous plant-derived supplements (as described in greater detail in the subsequent sections of this page) have been purported to enhance the activity of the SIRT proteins and of AMPK, and therefore, have been suggested to be viable dietary supplements for life extension.
Significant numbers of studies have suggested that the aging process involves the progressive accumulation of cellular damage due to increasing levels of reactive oxygen species (free radicals). Therefore, it is not surpising that the use of antioxidant supplements, such as vitamin C, vitamin E, coenzyme Q (CoQ10), and plant-derived phytochemicals have been purported to be beneficial as anti-aging supplements. However, caution must be taken because in many cases (for example with vitamin E) high doses of these compounds have been shown to be associated with increased mortality.
Hormone treatments have also been touted as effective anti-aging agents. However, the evidence is, in most cases, unverifiable. In addition there are significant health dangers to the use of hormone therapies as anti-aging regimens. Some studies have shown that low-dose growth hormone treatment in adults with deficiencies in the hormone does result in increased muscle mass and increased bone density, decreased fat mass, improved cardiovascular function parameters, and enhances the quality of life without significant side effects. However, evidence for the use of growth hormone as an anti-aging medication in humans is lacking.
One of the easiest and most proven methods to extend, not only the quality of life, but the length of life, is physical exercise. Individuals who participate in moderate to high levels of physical exercise have a lower mortality rates when compared to individuals who are not physically active. Moderate levels of exercise are not difficult to attain even for the most physically challenged individual. For example, walking up stairs for 10 minutes, vacuuming for 15 minutes, or gardening for 20 minutes on a daily basis constitutes the moderate level of activity required to attain the longevity and health benefits of exercise.back to the top
The human sirtuin proteins are encoded by one of seven related genes identified as SIRT1-SIRT7. Thes proteins are enzymes that catalyze the removal of acetyl groups from numerous substrate proteins. An acetyl group is composed of two carbon atoms where one has three hydrogens bonded to it and the other has an oxygen attached by a double bond. The addition and removal of acetyl groups is an importnat means for the regulation of the activity of transcription factors (proteins that turn genes on and off) and for the regulation of the structure of DNA altering its ability to be transcribed into RNA and thus subsequently into protein. The sirtuins are a unique class of deacetylating enzymes in that they utilize the vitamin-derived cofactor NAD+ (produced from niacin, vitamin B3) to carry out the deacetylation reaction. Accumulating evidence strongly indicates that due to their activities the sirtuins are important regulators of life span, i.e. they may be critical modulators of the processes of cellular aging. In addition, and importantly, the sirtuins are critical regulators of fat mobilization, insulin secretion, the cellular responses to stress, nerve cell degeneration, and apoptosis (programmed cell death), to mention just a few of the activities of these important genes.
The seven human sirtuin proteins have very diverse substrates whose functions can be classified into three major overlapping classes: transcription, regulation of apoptosis, and regulation of metabolism. In general, the transcriptional control exerted through the activity of the sirtuins is downregulation due to the deacetylation of histone proteins which are the proteins that confer the overall organizational structure of DNA within the nucleus. However, the deacetylation activity of the sirtuins is not solely associated with transcription silencing since in some cases the deacetylation of transcription factor proteins leads to transcriptional activation. In these latter cases the transcription factors are involved in the control of cellular growth, the cell cycle (the process of cell division), and/or the control of apoptosis. With respect to cell survival and inhibition of apoptosis, the human SIRT1 encoded protein is the predominant player.
Given that the activity of the sirtuins is absolutely dependent upon the presence of their required cofactor, NAD+, it should not be a leap to appreciate the need for an adequate supply of vitamin B3 (niacin) in the diet. Within cells the abundance of free NAD+ is determined by its synthesis and its salvage. In humans NAD+ can be synthesized from the amino acid tryptophan, although the amount produced in this pathway is not sufficient for all of the enzymes in the cell that require NAD+ as a cofactor which is why we require a dietary source. Some of the required NAD+ comes from a salvage pathway that utilizes nicotinamide which is the product of the sirtuin reactions as well as those carried out by ADP-ribosyltransferases, polymerases, or exogenous nicotinic acid. In humans nicotinamide is converted directly to an intermediate in NAD+ synthesis, nicotinamide mononucleotide (NMN). This salvage is catalyzed by an enzyme called nicotinamide phosphoribosyltransferase (NAMPT). Of significance is the fact that expression of NAMPT increases in response to various forms of cellular stress resulting in increased NAD+ levels, which in turn increases the activity of the sirtuins.
Accumulating scientific evidence suggests that the activation of the SIRT genes can promote life extension, in particularly that associated with calorie restricted dietary regimens. Although there is a more definitive correlation between calorie restriction and life span in microorganisms, fruit flies, and the roundworm, the evidence is not as clear cut in humans. For example the plant-derived polyphenolic compound resveratrol (as an example it is present in red wine) has been shown to activate yeast Sir2 and promote its life span. However, it is important to be mindful of the fact that there is still much controversy in the scientific literature reagarding the direct link between polyphenolic compounds, and other types of dietary supplements, and activation of sirtuin function for the purposes of life extension. Of significance is fact that there is a direct coupling between activation of sirtuin function and the subsequent activation of the potent regulatory enzyme identified as AMPK (discussed in the next section).back to the top
AMP-activated protein kinase (AMPK) is an enzyme that modifies its substrates through the additoin of phosphate (PO43–). AMPK was first discovered as an activity that inhibited fatty acid and cholesterol synthesis. Subsequent research has demonstrated that AMPK induces a cascade of events within cells in response to the ever changing energy state of the cell. The role of AMPK in regulating cellular energy status places this enzyme at a central control point in maintaining energy homeostasis. More recent evidence has shown that AMPK activity can also be regulated by physiological stimuli, independent of the energy charge of the cell, including hormones and nutrients. As indicated above, AMPK is now known to be a critical enzyme involved in the control of cell survival and the prevention of cellular aging.
Once activated, AMPK-mediated phosphorylation events switch cells from active ATP consumption (e.g. fatty acid and cholesterol biosynthesis) to active ATP production (e.g. fatty acid and glucose oxidation). These events are rapidly initiated and are referred to as short-term regulatory processes. The activation of AMPK also exerts long-term effects at the level of both gene expression and protein synthesis. Other important activities attributable to AMPK are regulation of insulin synthesis and secretion in pancreatic islet β-cells, modulation of hypothalamic functions involved in the regulation of satiety (the sensation of being full), and regulation of the cellular process called autophagy. Autophagy literally means "self-eating" and is the process whereby damaged cellular components (e.g. proteins) and organelles can be degraded and the constituent parts (e.g. amino acids) reutilized. Abnormal autophagy is associated with increased cell death as well as numerous pathogies.
The cellular signaling cascades initiated by the activation of AMPK exert effects on glucose and lipid metabolism, gene expression, protein synthesis, and cellular responses to various forms of stress. These effects are most important for regulating metabolic events in the liver, skeletal muscle, heart, adipose tissue, and pancreas but are also critical for cellular survival pathways.
Demonstration of the central role of AMPK in the regulation of metabolism in response to events such as nutrient- or exercise-induced stress. Several of the known physiologic targets for AMPK are included as well as several pathways whose flux is affected by AMPK activation. Arrows indicate positive effects of AMPK, whereas, T-lines indicate the resultant inhibitory effects of AMPK action.
Stress and exercise are powerful inducers of AMPK activity in skeletal muscle. Additional regulators of AMPK activity have been identified such as the insulin-sensitizing drugs of the thiazolidinedione (TZD) family as well as the biguanide class of hypoglycemia drugs (predominantly metformin). Both of these classes of drug exert a portion of their effects through increaing the activity of AMPK.
In the context of cellular aging, two major pathways are central in the regulation of the processes of responding to cellular damage and death. These pathways are called apoptosis (programmed cell death) and autophagy ("self-eating"). The process of apoptosis is designed to remove cells from tissues when their usefulness has been exceeded or something pathological has occurred which could render the tissue dysfunctional should the abnormal cell(s) be allowed to remain. The process of autophagy is activated as a means to clear out abnormal proteins and/or organelles within cells in order to maintain the viability of the cells. Of course if the damage is severe enough autophagy is insufficient and the apoptotic program will likely be activated.
A central regulator of the signaling pathways that triggers autophagy is the serine and threonine kinase called mTOR (mechanistic target of rapamycin). This enzyme is the principal component of both the mTOR complex 1 (mTORC1) and mTORC2 protein complexes. The mTORC1 is the major mTOR-containing complex that regulates cellular responses to growth factor signaling, nutrient deprivation, and various forms of cellular stress all of which are contribute to cellular aging. Activation of the the kinase activity of mTOR results in the activation of the autophagy program. More detailed information on the role of mTORC1 in autophagy can be found in The Medical Biochemistry Page. Several other serine and threonine kinases regulate the kinase activity of mTOR either positivly or negatively. Under conditions of energy depletion, such as nutrient starvation, the master metabolic regulatory kinase, AMPK, is activated which phosphorylates and inhibits the kinase activity of mTOR. When mTOR is inactivated by AMPK there is an induction of autophagy which will prevent the accumulation of damaged proteins, thereby ensuring cell survival and tissue viability.
From the perspective of anti-aging, the benefits of dietary supplements for the activation of AMPK are that cells can more effectively prevent the damaging effects of the cellular aging processes. Several dietary supplements have been touted as AMPK activators, and therefore sold as anti-aging supplements and science behind these claims will be examined in the subsequent sections.back to the top
Resveratrol is a chemical compound that is a member of a family of polyphenols called viniferins. The compound was first isolated from the roots of Veratrum grandiflorum (white hellebore). The chemical name for resveratrol is trans-3,4,5'-trihydroxystilbene (or also 3,4',5-stilbenetriol). Resveratrol is also a phytoalexin ("defender of the plant"). Phytoalexins are antimicrobial substances synthesized de novo by plants that accumulate rapidly at areas of pathogen infection. Resveratrol is produced in plants via the action of the enzyme stilbene synthase not only in response to pathogen invasion but also in response to ozone exposure, heavy metals, sunlight, and changes in climate. Resveratrol exists in nature in both the trans- and cis-stereoisomeric forms with heat and ultraviolet radiation inducing the trans– to cis– isomerization. Both the cis– and the tans– forms of resveratrol exhibit the same level of biological activity. However, in studies on the biological effects of resveratrol it is the trans– form that is most used.
Structure of Resveratrol
The range of action of resveratrol is broad. This compound has been shown to exert anti-inflammatory, anti-carcinogenic, anti-tumorigenic, and anti-aging effect. In addition, resveratrol inhibits platelet aggregation, a process required for blood coagulation, and as such plays a significant role in the cardioprotective activities of the compound. Resveratrol also acts as a phytoestrogen. Phytoestrogens are plant-derived compounds that can either mimic or inhibit the female sex hormone, estrogen.
Most recently resveratrol has been shown to ameliorate metabolic defects that occur as a consequence of normal aging processes. These "age restricting" effects on metabolism exerted by resveratrol are the result of its ability to activate the sirtuins (described above) as well as to inhibit a class of enzymes known as phosphodiesterases. These latter enzymes normally degrade the intracellular "second messenger" cAMP (cyclic adenosine monophosphate). Therefore, the action of resveratrol results in elevated cAMP levels with concomitant increases in events downstream of this signaling molecule. One important effect is the prevention of diet-induced obesity, increased lipid oxidation due to enhanced mitochondrial function, and increased glucose tolerance.
More detailed information on the activities of resveratrol as well as excellent sources of bioavailable resveratrol are found in the Resveratrol page of this website.back to the top
Curcumin (chemical name diferuloylmethane) is the yellow compound found in the spice turmeric. Turmeric is derived from the rhizomes (the horizontal stem of a plant found underground: picture the ginger root you find in the grocery store) of the perennial herb, Curcuma longa Linn, a member of the ginger family (Zingerberaceae).
Structure of Curcumin
When curcumin is eaten very little is actually absorbed from the gut. In studies where from 2 to 10 grams of curcumin were eaten alone (i.e. without other foods) there was undetectable to very low levels of the compound detected in the serum. When in the gut, curcumin is unstable and the traces that do pass through the gut are taken up by the liver and rapidly degraded or are conjugated to glucuronic acid and subsequently excreted. Glucuronidation is a typical means by which the liver detoxifies lipid soluble compounds, making them soluble and easily excretable (see The Medical Biochemistry Page).
Curcumin has been shown to suppress tumor promotion and proliferation, inflammatory signaling, and angiogenesis (the development of new blood vessels). It should be noted that solid tumors cannot grow unless they can promote the development of new blood vessels to bring oxygen-rich blood to the cancerous tissue. Therefore, the antiangiogenic properties of curcumin could play a significant part in its anticancer activity. The anti-inflammatory activity of curcumin is, in part, due to its ability to inhibit enzymes that are necessary for the synthesis of lipid mediators of inflammation. In particular, curcumin inhibits cyclooxygenase-2 (COX-2: this is the same enzyme that is inhibited by the NSAID drug Celebrex®) and lipoxygenase. For details on the synthesis and activities of the products of these two enzymes visit The Medical Biochemistry Page. Curcumin also inhibits inflammatory responses initiated by various stimuli that result in the activation of white blood cells such as macrophages and T-cells, both of which are potent inflammatory mediators. In studies on the effects of curcumin using human cells in culture it has been shown that the compound blocks the release of inducible nitric oxide synthase (iNOS) and COX-2 from airway epithelial cells, prevents COX-2 expression in mammary epithelial cells, inhibits cytiokine secretion from macrophages, and blocks the release of cytokines and ROS from arterial cells. Curcumin also exerts cytoprotective effects that enhance cellular survival. Much of this activity is due to the antioxidant properties of curcumin.
Previous in vivo studies have demonstrated that administration of curcumin can lead to decreases in the level of cholesterol in the blood. These effects of curcumin on cholesterol levels were thought to be related to upregulation of LDL receptor. However, since plasma cholesterol levels are also influenced by the uptake of cholesterol in the gut, which is mediated by a specific transporter Niemann-Pick C1-like 1 (NPC1L1) protein, it is possible that curcumin exerts its cholesterol lowering effects via inhibition of this intestinal cholesterol uptake mechanism. Indeed, in a study using an intestinal cell culture system (Caco-2 cells) it was shown that treatment with curcumin results in a down-regulation of the expression of the NPC1L1 gene resulting in reduced levels of the protein present in the membrane of Caco-2 cells. The NPC1L1 protein is also highly expressed in human liver. The hepatic function of NPC1L1 is presumed to limit excessive biliary cholesterol loss. NPC1L1-dependent sterol uptake is regulated by cellular cholesterol content. Recently studies have shown that NPC1L1 inhibition results in beneficial effects on components of the metabolic syndrome, such as obesity, insulin resistance, and fatty liver, in addition to atherosclerosis. Therefore, consumption of curcumin may have clinical benefits in the mangement of the metabolic syndrome and its associated cardiovascular complications.
In patients suffering from inflammatory bowel disease, taking 550mg curcumin twice daily resulted in significant amelioration of inflammatory symptoms. In another study, patients with rheumatoid arthritis took 1220mg daily and experienced a reduction in inflammatory symptoms.back to the top
Berberine is an ammonium salt compound of the protoberberine group of benzylisoquinoline alkaloids. Berberine is found in numerous plants of the Berberis genus of evergreen shrubs that are more commonly called barberry. The most common member of the genus is Berberis vulgaris but there are numerous popularly cultivated members such a Berberis thunbergii, Berberis candidula, Berberis thunbergii, and Berberis canadensis (American barberry). In addition to being found in Berberis, berberine is present in plants of the Coptis genus (such as Coptis chinensis: Chinese goldthread), Oregon grape (Mahonia aquifolium, goldenseal (Hydrastis canadensis), and yellowroot (Xanthorhiza simplicissma). Coptis teeta has been used in China and in eastern India as a medicinal herb for treating malarial fever. Numerous parts of the Berberis plant have been used for a variety of medicinal purposes including the roots, the bark, and the fruit.
The biggest limitation to the use of berberine supplements is the low bioavailability of the compound. Intestinal absorption of berberine is very low such that the vast majority of that consumed is eliminated, thus limiting its oral bioavailability. In addition, any berberine that is absorbed into intestinal cells is rapidly pumped back out into the lumen of the intestines via the action of a membrane transporter of the P-glycoprotein family. P-glycoprotein is also known as multidrug resistance protein 1 (MDR1). Finally, any berberine delivered to the blood from the intestines is rapidly taken up by the liver where the same membrane transporter, P-glycoprotein, pumps the berberine into the bile circulation where it is returned to the intestines for excretion.back to the top
Quercetin [chemical name is 2-(3,4-dihydroxypheny)-3,5,7-trihydroxy-4H-1-benzopyran-4-one] is one of the most potent antioxidant polyphenols which explains its use as a dietary supplement. Quercetin is found in numerous foods such as brassica vegetables (e.g. broccoli, cauliflower, cabbage, brussel sprouts, bok choy), apples, berries, red onions, citrus fruits, and tea made from Camellia sinensis, as well as many seeds, nuts, leaves, barks, and flowers. Very high concentrations of quercetin are found in capers and lovage (Levisticum officinale, similar in appearance and taste to celery), on the order of 2mg per gram of plant. Quercetin is available in highly purified extracts for sale as a dietary supplement which allow for the consumption of 500–1000mg per day. This is the equivalent of eating 5–10 kilograms (11–22 pounds) of apples each day.
Structure of Quercetin
The sugar conjugated quercetin compounds are very hydrophilic (meaning they do not interact with water) and were thought to be poorly absorbed from the gut following consumption. However, evidence shows that around 50% of quercetin glycosides are absorbed versus 25% for the aglycon form (sugar molecule removed). The biochemical basis for this absorption difference is believed to be due to the intestinal uptake process that involves a carrier-mediated transport or a coupled deglycosylation transport mechanism. After uptake by carrier-mediated processes quercetin glycosides have their sugar molecule removed by intracellular glycosides (enzymes that hydrolyze glycosidic bonds). Following absorption quercetin is metabolized by the small intestine, colon, liver, and kidney. In animal models of quercetin absorption and tissue distribution, highest concentrations were found in the lung, liver, and kidney. Because the half-life of quercetin in the plasma and tissues is long (on the order of 28 hours), repeated intake with supplements can lead to considerable plasma levels of the compound.
In addition to antioxidant activity (but likely related to this activity) quercetin exhibits anti-inflammatory, antiproliferative and apoptotic effects both on cells in culture as well as when ingested. In addition to cancer, quercetin is active in many processes of diseases related to ageing such as cardiovascular and neurodegenerative disorders. Many studies have looked at the effects of quercetin in the treatment of breast, ovarian, and colon cancers and leukemias. The anti-tumor properties of quercetin are diverse and include the ability to modulate the metabolism of carcinogens through inhibition and/or induction of enzymes that are involved in their conversion to non-toxic compounds. This latter process is referred to as xenobiotic metabolism. Research into the anti-cancer effects of quercetin have shown that the compound can induce cell cycle arrest and DNA strand breakage resulting in apoptosis.
A gene that is found mutated in numerous types of cancer is called p53 (see The Medical Biochemistry Page for details) whose protein product functions to regulate the progression of cells through the cell cycle. Quercetin has been shown to down regulate the expression of mutant p53 in breast cancer cells to nearly undetectable levels. The effect of this down regulation is the arrest of cells at the point in the cell cycle prior to cell division. Of significance is the fact that quercetin has a much reduced effect on the expression of the normal p53 gene.
Quercetin has also been shown, in animal models, to lower blood pressure and ameliorate hyperglycemia and conditions resulting from hyperglycemia. In a trial involving pre-hypertensive and stage 1 hypertensive patients, the consumption of 730mg per day of quercetin for 4 weeks led to a reduction in blood pressure but did not have any effect on the parameters of oxidative stress. Oxidative stress is referred to as an imbalance between the production of, and protection against, reactive oxygen species (ROS) and can result from overproduction of ROS and/or impairment of the endogenous antioxidant defense systems in the body.
Additional activities attributed to quercetin include regulation of caspase-3 (involved in triggering apoptosis), telomerase (an enzyme of DNA replication), lymphocyte tyrosine kinase (kinase are enzymes that add a phosphate moiety to their substrate), and other tyrosine kinases and serine/threonine kinases. Tyrosine, serine, and threonine are amino acids found in proteins. Quercetin increases the activity of superoxide dismutase, catalase, and glutathione peroxidase explaining its powerful antioxidant properties. One major benefit of the increase in these latter enzymes is a significant decrease in the oxidation and peroxidation of membrane lipids, thereby, preventing cell damage leading to premature initiation of apoptosis.back to the top
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Huang, W-Y and Cai, Y-Z 2010. Natural phenolic compounds from medicinal herbs and dietary plants: potential use for cancer prevention. Nutr. and Cancer 62(1):1-20.
Bisht, K, Wagner, K-H and Bulmer, AC 2010 Curcumin, resveratrol and flavonoids as anti-inflammatory, cyto- and DNA-protective dietary compounds. Toxicology 278(1):88-100
Boots, AW, Haenen, GRMM and Bast, A 2008 Health effects of quercetin: from antioxidant to nutraceutical. Eur. J. Pharm. 585:325-337
Bischoff, SC 2008 Quercetin: potentials in the prevention and therapy of disease. Curr. Opin. Clin. Nutr. Metab. Care 11:733-740.
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Last modified: February 22, 2017