Dietary Anti-Aging Polyphenols

Dietary Anti-Aging Polyphenols: Comparison

Please note this is a comparison between Version 1 by Dongmin Liu and Version 2 by Lily Guo.

For years, the consumption of a diet rich in fruits and vegetables has been considered healthy, increasing longevity, and decreasing morbidities. With the assistance of basic research investigating the potential mechanisms, it has become clear that the beneficial effects of plant-based foods are mainly due to the large amount of bioactive phenolic compounds contained. Indeed, substantial dietary intervention studies in humans have supported that the supplementation of polyphenols have various health-promoting effects, especially in the elderly population. In vitro examinations on the anti-aging mechanisms of polyphenols have been widely performed, using different types of natural and synthetic phenolic compounds.

Dietary Anti-Aging Polyphenols

1. Introduction

The common understanding of food has evolved from the previous concept “eat to live” to health promotion and disease prevention. Substantial dietary intervention studies and epidemiological surveys have demonstrated that the consumption of a diet rich in fruits and vegetables has health-promoting effects

^[1][2]

. It is estimated that the proportion of people aged 60 and above will increase from 12% in 2015 to 22% in 2050

^[3]

. Thus, delaying or preventing the onset of aging-related diseases due to cellular damage and functional decline would greatly improve life quality and expectancy, as well as mitigate the burden on the current healthcare system.

Despite the debate on the free radical theory of aging for the past decade

^[4]

, it is widely acknowledged that disrupted homeostasis between oxidants and antioxidants would cause cellular damage and even organ dysfunction

^[5]

. To counteract the abnormal oxidative stress and accumulation of excess oxidants such as reactive oxygen species (ROS), which cause DNA damage

^[6]

and cellular senescence

^[7]

, antioxidants bind to the pro-oxidants and abstract hydrogen to form stabilized radicals, hence neutralizing the hazardous effects of oxidants

^[8]

. Oxidative stress plays an important role in aging process and various aging-associated chronic diseases. Reducing ROS has been shown to alleviate oxidative damage and extend the lifespan of various animal species

^[9]

. Thus, phytonutrients with antioxidant property have drawn great attention for their ROS-scavenging actions and anti-aging potential.

Polyphenols are the largest, most studied group of naturally occurring antioxidants, which can be structurally categorized into phenolic acids, flavonoids, stilbenes, lignans, and other polyphenols with hydroxyl group(s) attached to the carbon atom on the aromatic ring (detailed classification and their food sources are listed in

Table 1

)

^[10]

. It was reported that dietary consumption of polyphenols is much higher than the daily intake of several essential micronutrients, such as vitamin C, vitamin E, and carotenoids

^[11]

. Over the past two decades, polyphenolic compounds have attracted considerable research interests because of their wide distribution in different foods and their potent antioxidant properties

^[11]

. In addition, polyphenols were reported to modulate energy metabolism in a manner favorable for well-being and longevity and reduce the risk of aging-related chronic diseases

^{[12][13][14][15]}

. Here, we provide a brief overview of the current understanding of aging and the mechanisms of cellular senescence. We propose to critically review the anti-aging effects of polyphenols and experimental evidence supporting the health-promoting effects against aging-related diseases.

Table 1.

Classification of polyphenols and dietary sources.

Classification	Subgroups	Dietary Sources
Phenolic acids	Hydroxybenzoic acids	Wine, sorghum, dried date, blackberry, apple juice, olive, chicory, black tea, etc.
	Hydroxycinnamic acids
	Hydroxyphenylacetic acids
	Hydroxyphenylpropanoic acids
	Hydroxyphenylpentanoic acids
Flavonoids	Anthocyanins	Soy, bean, wine, berries, grape, plum, pomegranate juice, olive, etc.
	Chalcones
	Dihydrochalcones
	Dihydroflavonols
	Flavanols
	Flavanones
	Flavones
	Flavonols
	Isoflavonoids
Stilbenes	Resveratrol	Grape, wine, lingonberry, etc.
	Dihydroresveratrol
	Pallidol
	Pinosylvin
	Piceatannol
	Pterostilbene
Lignans	Sesamin	Barley, apricot, peach, kiwi, beer, sesame seed, etc.
	Secoisolariciresinol
	Isohydroxymatairesinol
	Conidendrin
	Episesamin
Other polyphenols	Tyrosols	Beer, wine, olive, olive oil, turmeric, curry, etc.
	Phenolic terpenes
	Methoxyphenols
	Hydroxyphenylpropenes
	Curcuminoids
	Alkylphenols

2. Anti-Aging Effects of Polyphenols

2.1. Polyphenols and Longevity

There has been great interest in identifying natural compounds for improving health, preventing chronic diseases, and extending longevity. In this regard, numerous polyphenols, including EGCG, curcumin, and quercetin, have been shown to extend lifespan in various model organisms, including

Caenorhabditis elegans (C.elegan), Drosophila Melanogaster (Drosophila)

, as well as high-fat diet-induced obese rodents

^[15]

. Similarly, dietary resveratrol was shown to promote the health and survival of high-fat diet-induced obese male mice

^[16]

. However, resveratrol treatment failed to extend the lifespan of chow-diet fed C57/B6 mice

^[17]

or heterozygous mice

^[18][19]

. In an animal study, Reutzel et al. reported that administering a mixture of six highly purified olive secoiridoid polyphenols at 50 mg /kg in the diet for six months has a long-term positive effect on cognition and brain energy metabolism in aging mice

^[20]

. In this study, cognition was measured by behavioral tests. Brain ATP level and NADH reductase, cytochrome c oxidase, and citrate synthase mRNA expression levels are the main indicators for mitochondrial dysfunction

^[20]

. Moreover, data from the Aging Intervention Testing Program supported by the National Institute on Aging (USA) showed that the popular anti-aging natural agents, including resveratrol, green tea extract, and curcumin did not affect lifespan of standard chow-diet-fed heterozygous mice

^[19]

. These results suggest that these compounds may only work under certain conditions. In that regard, they may only delay or mitigate aging-associated chronic diseases in inbred mice fed a high-fat diet for a long period of time, which lack genetic diversity and are more susceptible to environment insult-induced pathological changes.

We found that dietary intake of (-)-epicatechin (EC), a flavonoid present in various foods including cocoa (

Theobroma cacao

), chocolate, berries, and tea, greatly increased survival rate in obese diabetic mice (50% and 8.4% mortality in control and EC groups after 15 weeks of treatment, respectively), whereas blood glucose levels and food intake were not modulated, suggesting that the observed effects of EC was not due to the secondary action to the changes of these variables. However, EC treatment improved skeletal muscle stress, reduced systematic inflammation, increased hepatic antioxidant glutathione concentration and superoxide dismutase activity, decreased circulating insulin-like growth factor-1, and improved AMP-activated protein kinase-α activity in the liver and skeletal muscle of diabetic mice. Therefore, EC may be a novel food-derived, anti-aging compound with direct lifespan-extending effect, given that these favorable changes are always associated with a healthier and longer lifespan

^[21]

. Consistently, further study showed that EC (0.1–8 mmol/L) also promoted survival and increased mean lifespan of

Drosophila

^[21]

. To further examine whether EC indeed is able to promote health and lifespan in aged but otherwise healthy mice fed the standard chow diet, we provided 20-month old mice (equivalent of 60-65 years old in humans) with EC in drinking water (0.25% w/v) for 37 weeks, and discovered that EC-treated mice had a strikingly higher survival rate as compared with that in control group (69.7% versus 39.2%)

^[22]

. Remarkably, the universal profiles of the serum metabolites and general mRNA expressions in skeletal muscle of old mice were shifted by EC toward those demonstrated in young mice

^[22]

. These findings suggest that EC may be a novel anti-aging polyphenolic compound that could promote healthy lifespan in normal healthy subjects. Cocoa is particularly rich in flavonoids that include EC, flavanol-3ols, catechin, and oligomeric derivatives, making up 10% of the dry weight of cocoa powder

^{[23][24][25][26]}

. Thus, it is tempting to speculate that cocoa product consumption may extend the lifespan in humans. Epidemiological studies further show that people living on the San Blas Island, who are known to consume large amounts of cocoa beverage daily, have a remarkably longer lifespan than those who live in the mainland of Panama

^[27][28]

. Interestingly, these differences disappeared when people from San Blas island migrated to Panama city where cocoa consumption was considerably reduced

^[29]

. Dietary chocolate intake extended average life expectancy by as much as 4 years in humans

^[30]

. While EC only accounts for 20–30% of total flavanols in cocoa, its oligomers cannot be absorbed into circulation in rodents and humans

^[23][24][25]

. Therefore, it is believed that the monomers might be the predominant form responsible for the beneficial effects of cocoa in vivo. Indeed, EC was found to be the dominant (>96%) flavanol in human circulation with the plasma concentration reaching more than 6 μM after ingestion of cocoa

^[31]

. Therefore, EC may be the primary constituent in cocoa that exerts health benefits and extends lifespan in healthy subjects.

Data from both epidemiological and large randomized clinical studies have demonstrated that Mediterranean diet (MeD) eating pattern was associated with lower risk of major chronic diseases (heart disease, cognitive decline and breast cancer), better quality of life, and longer life expectancy

^[32]

. A 50-year follow-up study found that MeD eating habit contributes 4.4 years longer of life expectancy in Italy

^[33]

, which is similar to other two intervention studies showing that MeD is inversely associated with total mortality in Sweden

^[34]

and the USA

^[35]

. While Mediterranean dietary pattern is characterized by consumption of plant-based foods and olive oil, which may collectively exert health-promoting effects, emerging evidence shows that some polyphenols present in olive and olive oil likely contribute to some observed health benefits of Mediterranean diet consumption. Indeed, olive-derived polyphenols, including hydroxytyrosol, tyrosol, oleuropein, and pinoresionol

^[36][37]

, were reported to improve aging-related dysfunctions of the brain

^[38]

, and heart

^[39]

in mice. Long-term (10 months) dietary intake of extra-virgin olive oil (10% wt/wt dry diet) rich in phenols (total polyphenol dose/day, 6 mg/kg) significantly prevented aging-related impairment in motor coordination in the rotarod test in 10-month old C57BL/6J mice

^[38]

. Dietary intake of 10% olive oil (contains 532 mg gallic acid/kg oil) for 4.5 months significantly reduced oxidative stress in the senescence-accelerated mouse prone 8 (SAMP8) mice, which was mediated by the induction of nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent gene expressions

^[39]

. These results are in line with a new report that dietary intake of extra virgin olive oil for 6 months significantly ameliorated cognition decline in a transgenic mouse model with brain amyloid plaques and neurofibrillary tangles

^[40]

. In a study with diabetic rats, it was also shown that a 3-month treatment with virgin olive oil (0.125 mg/kg phenols per day) displayed a stronger neuroprotective ability than that of aspirin (2 mg/kg per day)

^[41]

. Although the mortality rate was not altered by olive oil intake because of the relatively young age of the mice used in these studies (10-months or 9–10 weeks old), it is tempting to speculate that olive oil polyphenols might have the potential to extend lifespan. Actually, increasing evidence supports that olive oil phenols delay the aging process in cells, animals, and humans

^[42][43]

. Rechtsregulat® (RR) is the fruit and vegetable extract that is rich in polyphenols, including phenolic metabolites such as protocatechuic acid (PCA)

^[44]

. Dilberger

et al

. reported that

C. elegans

administrated with 10% RR or 780 µM PCA showed a significant increase in heat-stress resistance, median lifespan, and activity of mitochondrial respiratory chain complexes. These results suggest that both polyphenols and the PCA can enhance the lifespan and mitochondrial function

^[44]

. The European Food Safety Authority has approved a claim that olive oil polyphenols protect against LDL oxidation at a minimal dose of 5 mg/kg/day hydroxytyrosol

^[45]

2.2. Polyphenols on Aging-Related Diseases

Aging is a well-established risk factor for a wide range of diseases

^[15]

, among which neurodegenerative diseases are highly prevalent since the central nervous system (CNS) is vulnerable to aging-induced cellular malfunction and degenerative damage

^[46]

. In addition, cellular inflammatory response progressively increases with age

^[47]

, which increases the risk for developing chronic inflammation related disease such as atherosclerosis in the elderly

^[48]

. Furthermore, type 2 diabetes (T2D), characterized by insulin resistance and pancreatic β-cell dysfunction, may lead to a complex complications such as vascular tissue damage, depression, cognitive decline, and dementia which are tightly associated with aging

^[13]

. Below we will review studies, mostly in vivo studies, exploring the physiological role of polyphenols in aging-related disease. We aim to critically review the studies using polyphenols as a complementary and alternative medicine that benefits humans.

2.2.1. Polyphenols in Neurodegenerative Diseases

Aging is a major risk factor for developing neurodegenerative diseases, and presently, there is no effective treatment for aging-related neurodegeneration

^[49]

. Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are characterized by the progressive loss of functional neuron cells

^[50]

. The brain requires comparably high amount of oxygen

^[51]

and the impaired oxidative balance in the brain has been substantially determined as the common feature of neurodegenerative diseases

^[52][53]

. Mounting research have reported the utilization of natural polyphenols on neurodegenerative diseases due to their antioxidant and anti-aging properties

^{[54][55][56][57][58]}

. Grape is an evident example of fruits that contain a high content of polyphenols

^[59]

. Dietary supplement of grape polyphenol concentrate at 1.5 mL/kg significantly enhanced memory reconsolidation in transgenic mouse model of PD

^[60]

. Curcumin is a polyphenol present in turmeric (

Curcuma longa

) root, which is a yellow pigment used in curry. In an old aluminum-induced neurotoxical rat model, oral gavage of 30 mg/ml/kg curcumin treatment significantly suppressed the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione-s-transferase (GST), protein kinase C (PKC), and Na

⁺

, K

⁺

-ATPase, thereby protecting the brain against aluminum toxicity in aging rats

^[61]

. Supplementation of EC (10 mg/kg) per day for two weeks significantly ameliorated 6-hydroxydopamine (OHDA)-lesioned PD behavior, including increased locomotor activity and decreased rotational behavior, as compared with sham operated control group in male rats, suggesting a neuroprotective property of this compound

^[62]

. Sugarcane (

Saccharum officinarum

L.) top ethanolic extract was reported to contain several polyphenols with strong antioxidant effects, including 3-caffeoylquinic acid (CQA), 5-CQA, 3-O-feruloylquinic acid (FQA), and isoorientin

^[63]

. CQA provided at 5 mg/kg for 30 days was reported to enhance brain function of SAMP8 mice as demonstrated in the Morris water maze test

^[64]

. Consistently, microarray analysis showed that sugarcane top ethanolic extract regulated neuron development-associated genes in the cerebral cortex of SAMP8 mice

^[63]

. Isoorientin is a naturally occurring

-glycosyl flavone and exists in several dietary plants, including corn silks

^[65]

, rooibos tea

^[66]

, and buckwheat

^[67]

. Interestingly, although isoorientin showed lower antimycobacterial activity in virulent strain

^[68]

, it remarkably protected human neuroblastoma SH-SY5Y cells from 6-OHDA-induced toxicity via the AMPK/Akt/Nrf2 signaling pathway

^[69]

. Olive polyphenols are components of the Mediterranean diet. Grewal et al. examined the effects of purified olive secoiridoid derivatives and their metabolites on mitochondrial function in SH-SY5Y-APP695 cells, a cellular model of early AD

^[70]

. An aging mouse model (Female NMRI mice, aged 12 months) was used to further examine the effects of purified secoiridoids (oleocanthal and ligstroside) in vivo. Results of in vitro studies showed that purified ligstroside protected against mitochondrial dysfunction by restoring ATP levels in models of early AD

^[70]

. Female NMRI mice supplemented with oleocanthal or ligstroside (6.25 mg/kg b.w) for six months showed improved spatial working memory and ATP levels in the brain

^[70]

. These results indicate that ligstroside can expand the lifespan in aging mice and enhance cognitive function. The ortho-diphenol hydroxytyrosol (HT) is one of the main components of extra virgin olive oil, which is an important part of the Mediterranean diet. Schaffer et al. reported that HT-rich olive mill wastewater extract (HT-E) and its main constituent HT were found to protect against ferrous iron or sodium nitroprusside-induced cytotoxicity in PC 12 neuronal cells

^[71]

. The same group further demonstrated that HT-E also protects isolated brain cells against oxidative stress after subchronic oral administration of the extract to mice, suggesting the neuroprotective potential of HT-E

^[72]

. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) is one of the polyphenolic compounds and is naturally present in

Godmania aesculifolia

Tridax procumbens,

and in leaves of Primroses

^[73]

. Rho proteins, including the small GTPase Rac1 are essential regulators of neuronal synaptic plasticity. Interestingly, the levels of Rac1 and Rab3A were restored in membrane isolated from brains of aged mice when treated with 7,8-DHF at 100 mg /kg body weight once daily for a total of 21 days via oral gavage

^[73]

. Quercetin is one of the polyphenols found in many foods and vegetables, such as red wine, green tea, apples, and berries. Quercetin at 1 µM was found to prevent glucose-induced lifespan reduction of

C. elegans mev-1

mutants

^[74]

. The results of this study further demonstrated that the sirtuin SIR-2.1, the nuclear hormone receptor DAF-12, and MDT-15 are essential for the effect of quercetin

^[74]

Although the etiology of AD is still elusive, the production of amyloid β (Aβ) peptides via β-secretase and γ-secretase cleavage are the pathological hallmarks of AD

^[75]

. In addition, abnormal phosphorylation and aggregation of tau protein in neuronal cells also lead to the progression of AD

^[76]

. As mentioned above, isoorientin is a naturally occurring polyphenol with strong antioxidant property and it has been demonstrated to protect human neuroblastoma SH-SY5Y cells from β-amyloid induced tau hyperphosphorylation, thereby exerting neuroprotective potential

^[65]

. Treatment with green tea polyphenols significantly protected primary rat prefrontal cortical neuron cells from Aβ-induced neurotoxicity via the protein kinase B (PKB, also known as Akt) signaling pathway

^[77]

. In addition to green tea, coffee is also a popular beverage worldwide. Epidemiological studies have shown the lifespan-extending benefits of coffee-consuming habits

^[78]

and the potential of coffee consumption in alleviating the severity of PD

^[79]

. Chlorogenic acid largely presents in both caffeinated and decaffeinated coffee, with a potent free radical scavenging activity and antioxidant effects

^[80]

. Treatment of chlorogenic acid (40 mg/kg bw) significantly improved spatial memory in the Morris water maize test and alleviated neuron damage in an AD mouse model

^[81]

. The biosynthetic compound 3’-

-methyl-epicatechin-5-

-glucuronide, which is a grape derived polyphenol, improved basal synaptic transmission and cognitive functions in a mouse model of AD

^[82]

. Catechins are a group of bioactive polyphenols found in green tea leaves, among which (+)-catechin, EC, and (-)-epigallocatechin gallate (EGCG) are the most abundant and well-known compounds

^[83]

. These polyphenols also can be found in other fruits and vegetables such as cocoa beans and berries

^[84]

. In a mice model with an early appearance of learning and memory decline and an increased production of Aβ peptides, 0.05–0.1% catechin treatment decreased Aβ peptides and enhanced mice behavior in spatial learning and memory capacity tests

^[85]

. As aforementioned, resveratrol was quite a hot topic among scientists because of the “French Paradox” a decade ago. A comprehensive review paper summarized that resveratrol extends model organisms life expectancy by up to 60% depending on the dosage, gender, genetic background, and diet composition

^[86]

. In an intracerebroventricular injection of streptozotocin-induced brain insulin resistant rat model, 30 mg/kg/day resveratrol treatment significantly increased brain Sirt1 activity, reversed the hyperphosphorylation of tau, and enhanced the cognitive capability as compared with age-matched control rats

^[87]

. The pathophysiology of neurodegenerative diseases has a complex mechanism and as the elderly population gets larger, aging-related neurodegenerative diseases become a major worldwide public health concern. The available in vivo and in vitro studies indicate a possible role of polyphenols in improving cognitive function and neurodegenerative diseases, future clinical trials are needed to assess the possibility using natural polyphenols as a therapeutic strategy.

2.2.2. Polyphenols in Aging-Related Inflammatory Diseases

Despite the enormous complexity of aging, one of the key features is chronic inflammation

^[88]

. A recent retrospective study testing the effects of resveratrol in AD patients (aged 50 and above) reported that 52 weeks of resveratrol treatment (1 g by mouth twice daily) significantly decreased levels of plasma inflammatory markers and induced the adaptive immune response, suggesting a promising role of resveratrol against inflammation

^[89]

. Nuclear factor kappa light chain enhancer of activated B cells (NF-κB) is a ubiquitous transcription factor, which can be activated by acetylation and phosphorylation, thereby initiates the transcriptional cascade of a large variety of target genes that are involved in inflammation and innate immunity in mammalian cells

^[90]

. EGCG, the major polyphenol found in green tea, was reported to extend rat median lifespan from 92.5 weeks to 105 weeks and significantly decrease the mRNA and protein levels of NF-κB, improving aging-induced oxidative status in rat liver and kidney

^[91]

. In a randomized controlled clinical trial, consumption of turmeric extracts curcumin at 1.5 g/day for four weeks alleviated pain and swelling with minimal side effects in osteoarthritis patients (aged 50 and above)

^[92]

. Similarly, quercetin, one of the most studied polyphenol found in various fruits

^[93]

, efficiently reduced the severity and sickness period in older patients with upper respiratory tract infection at a dose of 1 g per day for 12 weeks

^[94]

. Treatment of isoorientin effectively inhibited the release of inflammatory cytokines in high fructose-fed mice

^[95]

. Recently, we reported for the first time that curcumin (1 μM) and luteolin (0.5 μM) synergistically (combination index is 0.60) inhibited TNF-α-induced monocyte adhesion to human EA.hy926 endothelial cells while the individual chemicals did not have such effect at the selected concentrations

^[96]

. Collectively, studies in both humans and animals have shown the potential of polyphenols in modulating aging-related inflammatory disorders and further analyses of the detailed mechanisms can be useful to guide clinicians and health care providers to consider polyphenols in their approach to intervene aging-associated inflammatory responses.

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