Introduction

Aging is an accumulation of detrimental changes in tissues that hastens morbidity and mortality. Some of these changes are accelerated by Advanced Glycation End products (AGEs). These are created through a reaction between sugars and proteins, lipids, or DNA. Not only are AGEs implicated in aging, but they play critical roles in the development of diabetes, atherosclerosis, chronic kidney disease and Alzheimer's disease. Over time, AGEs build up in organs and tissues causing cross-linking of collagen. Extensive cross-linking reduces elasticity in soft tissues such as skin and blood vessel walls. The loss of elasticity has serious health consequences. In the muscles, collagen cross-linking causes muscle stiffness. Up to 30% of total protein in the body is made of collagen – a tissue predominant in many vital organs including the heart, bone, kidneys. It is the primary reason that collagen cross-linking can adversely affect all major organs and tissues.[1] As one ages, there is a progressive accumulation of AGEs in the internal organs: younger people have less than middle-aged who had less than the older groups. A comparative study disclosed that AGEs accumulation in the kidneys and liver of younger people was lower than the middle-aged which was in turn lower than the aged group. In addition to collagen cross-linking, AGEs stimulate free radical (ROS) formation and inflammation. The corollary is also true: chronic tissue inflammation due to aging favors AGEs production and in turn accelerate the aging process.

[1] Alfonso Gautieri, Alberto Redaelli, Markus J. Buehler, Simone Vesentini. 2014. Age- and diabetes-related nonenzymatic crosslinks in collagen fibrils: Candidate amino acids involved in Advanced Glycation End-products. Matrix Biology. 34:89–95

AGE-RAGE Interaction

When AGEs bind to cell receptors a RAGE complex is formed (R(eceptor)+AGEs). As one ages, RAGE activity increases in all organs including the kidneys and liver. AGE-RAGE interactions induce inflammation which induces more ROS formation and thus more oxidative stress. This AGE-RAGE interplay activates inflammatory factors such as NF-κB which induces the formation of amyloid β plaques, a major causal suspect in Alzheimer’s disease. Although both the liver and kidneys are sites for clearance of circulating AGEs, they are also be targets organs.

Glyoxalase1 (GLO1) is a ubiquitous enzyme. It nullifies the effects of AGEs which in turn reduces protein modification, oxidative stress, and apoptosis.[1] Besides, GLO1 decreases levels of inflammatory protein in organs and tissues. Regrettably, GLO1 decreases with age resulting in corresponding accumulation of AGEs in tissues. Hence, older groups have less than their younger counterparts. Aging influences the release of inflammatory mediators such as TNF-α, IL-1β, IL-6 and NFκB. The latter is known to trigger inflammation through the generation of ROS. Moreover, AGEs potentiate RAGE expression. The interplay between these two components (AGE-RAGE) accelerates the rate of aging in humans and other animals. Activity at this interface also favors the development of age-related inflammation and oxidative stress. This AGE-RAGE interaction accelerates migration of M1-macrophage (WBC) migration. In the processes they express inflammatory factors. Infiltration of M1-macrophage into the organs also increase with advancing age. On the other hand, activity of M2-macrophage class decreases with age. They produce anti-inflammatory factors which reduces inflammation and tumor growth. They contribute to wound healing and tissue repair. In inflammatory states, most of the macrophages at affected sites are of the M1 class. The M2-macrophages, which are anti-inflammatory, encourage tissue repair and wound healing, but do decrease with age. Together, the data suggest a deleterious role of M1 macrophages in the aging process but a curative role of M2. Of note is that M2 activity is enhanced by vitamin D commonly found in dairy products. Of course, basking in the glow of sunlight helps enormously.[2]^,[3]

[1]Margaret G. Distler and Abraham A. Palmer. 19 November 2012. Role of Glyoxalase 1 (Glo1) and methylglyoxal (MG) in behavior: recent advances and mechanistic insights. Front. Genet. 2012https://www.frontiersin.org/articles/10.3389/fgene.2012.00250/full

[2] Lopa M. Das, Amy M. Binko, Zachary P. Traylor, Han Peng and Kurt Q. Lu. 2019. Vitamin D improves sunburns by increasing autophagy in M2 macrophages. Autophagy. 15(5): 813–826.

[3] Myeongjoo Son, Wook-Jin Chung, Seyeon Oh, Hyosang Ahn, Chang Hu Choi, Suntaek Hong, Kook Yang Park, Kuk Hui Son^, and Kyunghee Byun. 2017. Age dependent accumulation patterns of advanced glycation end product receptor (RAGE) ligands and binding intensities between RAGE and its ligands differ in the liver, kidney, and skeletal muscle. Immun Ageing. 14: 12.

The Impact of AGEs Reduction on Health

If AGEs are a health risk, it begs the question how can AGEs be reduced. In part, the answer resides in the type of food ingested. There are two known sources of AGEs. Internally (endogenously), AGEs are spontaneously generated by glycation: a spontaneous reaction of sugars with proteins, nucleic acids and fatty tissues. This reaction is facilitated by ROS and/or a high sugar environment.[1] More importantly, are the external (exogenous) sources. Most of the AGEs are derived from ingestion of processed foods. Dry heat increases the amount of AGEs by 10–100 times than that of uncooked foods. Hence foods exposed to grilling, frying, toasting, barbecuing, roasting, baking, frying and sautéing are higher in AGES. Animal foods that are high in fat and protein, are more susceptible to AGEs formation during cooking. Foods highest in AGEs include meat, certain cheeses, fried eggs, butter, cream cheese, margarine and mayonnaise. High levels of AGEs are causally associated with chronic diseases. These include heart disease, diabetes, liver disease, Alzheimer’s, arthritis, kidney failure, and high blood pressure. Limiting dietary AGEs has been shown to reduce levels of inflammation and oxidative stress, thus lowering the risk of chronic disease.[2] Highly processed sugared products are dangerously high in AGEs and should be studiously avoided. Consequently, to reduce AGEs intake stewing, poaching, boiling, and steaming are preferable cooking methods. Cooking with moist heat, at lower temperatures, for shorter periods diminish AGEs formation. Glycation is irreversible. Hence anti-wrinkling creams are an abject waste of resources. Though preventable, the sugar attachment cannot be undone.

[1] Chan-Sik Kim, Sok Park, and Junghyun Kim . 2017. The role of glycation in the pathogenesis of aging and its prevention through herbal products and physical exercise. J Exerc Nutrition Biochem. Sep 30; 21(3): 55–61

[2] https://www.healthline.com/nutrition/advanced-glycation-end-products#bottom-line retrieved October 11 2020

Anti-aging, Antioxidant and anti-AGEs Foods

Among the best anti-aging, high antioxidant but low AGEs foods are:

Red bell pepper: They are high in biologically active plant compounds often referred to as phytochemicals. These phytochemicals have anti-cancer and anti-inflammatory properties. Red bell peppers are an abundant source of vitamin A, B6 and C. They are packed with polyphenol antioxidants.[1] B6 helps the body store energy from protein and carbohydrates and is critical to the formation of the oxygen-transporting protein, hemoglobin. Whereas vitamin A helps with vision, vitamin C protects against cardiovascular disease, eye disease and skin wrinkling. Magnesium, on the other hand, regulates muscle and nerve function. In addition to regulation of blood sugar levels, magnesium contributes to the synthesis of protein, bone and DNA.

Watercress. This vegetable abounds in vitamin K and C. As with other cruciferous vegetables, watercress contains glucosinolates, which are precursors of sulforaphane and phenethyl isothiocyanate (PEITC). Both PEITC and sulforaphane were found to suppress the growth of breast cancer cells. High in antioxidants - beta carotene, zeaxanthin and lutein - watercress can prevent diseases such as diabetes, cancer, heart disease and lower the risk of strokes. Nitrates found in this vegetable relax blood vessels lowering blood pressure and reducing the amount of oxygen needed during exercise.[2]

Broccoli: Sulforaphane is found in cruciferous vegetables like broccoli, Brussel sprouts, cabbage, cauliflower and kale. The compound neutralizes free radicals, increases insulin sensitivity, protects against damage to blood vessel linings and diminishes CVD-related problems. It also lessens inflammation, boosts liver detoxification and improves glutathione levels. This antioxidant prevents damage caused by ROS and heavy metals. A cause-effect relationship has been established between glutathione (GSH) metabolism and diseases, such as diabetes, cystic fibrosis, cancer, neurodegenerative diseases, HIV and aging.[3] In addition, broccoli contains isothiocyanates and indole-3-carbinol. Both chemical compounds boost the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. Sulforaphane prevents adherence of Helicobacter pylori bacteria to the stomach and duodenal linings, reducing the risk of gastric and peptic ulcers. In addition, this phytochemical is able to revive declining Nrf2,[4] which protects against oxidative damages but declines with age. In effect, increasing Nrf2 concentrations prevents premature age-related diseases.[5] Other anti-inflammatory compounds in broccoli are omega-3 fatty acids. As a result of the many phytochemicals, this inexpensive vegetable has the potential to alleviate arthritis, allergies, Alzheimer’s and autoimmune diseases. High in soluble fibers, broccoli inhibits the absorption of dietary cholesterol from the gut. The B-complex content regulate excessive homocysteine build-up. This accumulation is causally related to arterial damage and blood clots in the blood vessels. Also found in broccoli are significant levels of lutein and zeaxanthin. Both compounds are potent antioxidants and protect against macular degeneration and cataracts. The flavonoid kaempferol, found in a host of other fruits and vegetables including broccoli, lessens the impact of allergens and reduces chronic inflammation.[6]

Kale: Kale is a rich source of vitamins A, C, E and the B-complex vitamins (B1, B2, B5, B6, B9). The vegetable is also an ample source of dietary minerals, including manganese iron, calcium, potassium, and phosphorus. Kale contains high levels of several antioxidants including carotenoids, lutein and zeaxanthin. A deficiency of either lutein and zeaxanthin due to natural aging causes the macula to lose yellow pigment making it difficult to filter out blue light. As with broccoli and other cruciferous vegetables, kale contains glucosinolate compounds, which contributes to the formation of sulforaphane.[7]

Spinach: High in insoluble fibers, spinach advances gastrointestinal health. In addition to potassium and magnesium, spinach contains vitamins B6, B9 and E. This vegetable boasts an abundance of the antioxidants. They include lutein, kaempferol, zeaxanthin and quercetin. The latter, also found plentifully in green tea, is known to improve mental and physical performance. As an antioxidant, quercetin is anti-carcinogenic and anti-inflammatory. It inhibits blood clotting and lipid peroxidation: a process that results in cell toxicity, protein and DNA damage.[8] Studies show that lutein and zeaxanthin reduce the risk of chronic eye diseases, including age-related macular degeneration and cataracts. Whereas cataracts are a leading cause of blindness due to clouding of the clear lens of the eye, macular degeneration is deterioration of the functional center of the light sensitive retina, the macula. High antioxidant levels also regulate blood pressure and play a role in cancer and inflammation suppression.[9]

Papaya: Papayas are dense in antioxidants. They contain a carotenoid antioxidant that reduces inflammation and skin wrinkling. The pink coloration of tomatoes, pink grapefruit, squash and other vegetables are due to the presence of carotenoids. Papayas are a plentiful source of lycopene. Studies suggest that dietary lycopene prevents cancer and reduces the risk of cardiovascular diseases.[10] The ability of lycopene to sequester iron reduces the accumulation of free radical levels in the system. Rich in vitamin C, papayas improve heart health by their anti-inflammatory properties. A powerful digestive enzyme, the papain in papayas aids digestion of protein, reduces constipation and alleviates symptoms of Irritable Bowel Syndrome (IBS): a disorder affecting the large intestine causing cramping, abdominal pain, bloating, gas, and diarrhea.[11]

Blueberries: Blueberries along with kale and onions rank among the highest in content of the flavonoid antioxidants. Studies indicate that the flavonoid oxidants in blueberries reduce DNA damage, a potent precursor of aging, cancer and other inflammatory diseases. Flavonoids prevent oxidation of LDL cholesterol hence they reduce high blood pressure and other CVD-related diseases. Several studies demonstrate that anthocyanins – a chemical compound that provides the deep coloration in plants - in blueberries improve insulin sensitivity thereby lowering blood sugar levels.

Avocado: Rich in vitamin B, C, E, and K, avocado also contains copper and comparatively more potassium than a banana. The fruit is abundant in lutein and zeaxanthin antioxidants. Among the diverse fats, the MUFA in avocados includes oleic acid, palmitic acid and linoleic acid.[12]^,[13]

Nuts: Nuts contains monounsaturated fatty acids (MUFA) such as α-linolenic acid (ALA), an omega-3 fatty acid. Effectively, they lower the bad cholesterol (LDL) but increase the good cholesterol (HDL). Studies have shown that MUFAs reduce blood pressure, coronary artery disease, strokes, breast, colon and prostate cancers. MUFA alleviate inflammatory conditions such as rheumatoid arthritis and degenerative neurological disorders including Schizophrenia and Alzheimer’s disease. In addition to MUFA, nuts and seeds are storehouses of the flavonoid class of antioxidants including carotenes, lutein and cryptoxanthin. These compounds afford protection against cancers, heart disease and degenerative neurological conditions. Also found in peanuts, pistachios and grapes is the antioxidant resveratrol. Scientific data suggest that resveratrol intake reduces stroke risk through decreased activity of angiotensin (a hormone that induce blood vessel constriction) and increased production of the vasodilating neurotransmitter, nitric oxide. The synergistic action of resveratrol on both angiotensin and nitric oxide effectively decreases hypertension. Besides, nuts are a rich source of vitamins and minerals like manganese, potassium, calcium, iron, magnesium, zinc, fluoride and selenium. Manganese is a critical component in the functioning of superoxide dismutase enzyme, a very powerful free radical scavenger. Potassium is involved in regulating heart rate, blood pressure and is essential to transmission of nerve impulses. Copper and iron are required for the production of red blood cells while fluoride is a component of bones and teeth.[14] Seeds and nuts contain healthful levels of vitamin-E, a powerful lipid soluble antioxidant. For maintenance of the integrity of mucus membranes and skin, Vitamin-E is essential. Moreover, seeds and nuts contain B-complex groups of vitamins such as thiamine (B1) riboflavin(B2), niacin (B3), pantothenic acid (B5), pyridoxine (B-6), and folacin (B9).

[1] Vitamin B6: Vitamin B6, regulates levels of homocysteine in the blood and reduces susceptibility to heart disease and stroke. B6 is used to make several neurotransmitters and it is needed for the absorption of Vitamin B12.

[2] https://www.healthline.com/nutrition/watercress-benefits#TOC_TITLE_HDR_12 Retrieved October 11, 2020.

[3] https://en.wikipedia.org/wiki/Glutathione#In_plants

[4] Nrf2: Regulates antioxidant proteins and protects against oxidative damage.

[5] Roberto Santín-Márquez, Adriana Alarcón-Aguilar, Norma Edith López-Diazguerrero, Niki Chondrogianni and Mina Königsberg. 2019. Sulforaphane - role in aging and neurodegeneration. GeroScience. 2019 Oct; 41(5): 655–670.

[6] Jie Ren Yifei Lu Yanhong Qian Bozhou Chen Tao Wu Guang Ji. 2019. Recent progress regarding kaempferol for the treatment of various diseases (Review). Experimental and Therapeutic Medicine. August 13, 2019. 2759-2776

[7] https://en.wikipedia.org/wiki/Kale#Nutritional_value

[8] Yao Li, Jiaying Yao, Chunyan Han, Jiaxin Yang, Maria Tabassum Chaudhry, Shengnan Wang, Hongnan Liu, and Yulong Yin 2016. Quercetin, Inflammation and Immunity. Nutrients. 8(3): 167.

[9] https://www.healthline.com/nutrition/foods/spinach#downsides sept 19 2020

[10] Erica N. Story, Rachel E. Kopec, Steven J. Schwartz, and G. Keith Harris. 2013. An Update on the Health Effects of Tomato Lycopene. Annu Rev Food Sci Technol. 2010:1.

[11] https://www.healthline.com/nutrition/8-proven-papaya-benefits#TOC_TITLE_HDR_10

[12] https://www.healthline.com/nutrition/advanced-glycation-end-products#what-they-are

[13] https://en.wikipedia.org/wiki/Avocado#Nutritional_value September 19 2020

[14] https://www.nutrition-and-you.com/nuts_nutrition.html Sept 19 2020

Conclusion

Undoubtedly, the presence vitamins, minerals, antioxidants and other phytochemicals in fruit and vegetables reduce disease sates and extend life. Among some of the more prominent antioxidants mentioned are, lutein, zeaxanthin, anthocyanins, kaempferol, and quercetin. Also vital for robust health are the antioxidant vitamins, A, C and E. Sulforaphane in broccoli prevents adherence of Helicobacter pylori bacteria to the stomach and duodenal linings, reducing the risk of gastric and peptic ulcers. In addition, this phytochemical is able to stimulate an endogenous Nrf2 protein which inhibits the onset of premature age-related diseases. The iron sequestering properties of lycopene prevents the development of free radicals whereas resveratrol, found in the skins of dark fruits like grapes, blueberries, and raspberries, promotes good health. Among other curative properties is that it stimulates the release of nitric oxide which reduces blood pressure. The fruits and vegetables mentioned above is not an exhaustive list but a select few. There are many more. For example, animal studies have shown that some natural plant phenols can reduce the negative health effects of AGEs. The compound curcumin, found in turmeric, is known for its anti-inflammatory properties.[1]^,[2]

[1] https://www.healthline.com/nutrition/advanced-glycation-end-products#bottom-line retrieved October 11 2020

[2] Susan J. Hewlings and Douglas S. Kalman. 2017. Curcumin: A Review of Its’ Effects on Human Health. Foods. 2017 Oct; 6(10): 92-