September 2019 Issue

CPE Monthly: Health Benefits of Apples
By Kristin Sementelli, MS, RD, LDN
Today’s Dietitian
Vol. 21, No. 9, P. 46

Suggested CDR Learning Codes: 2020, 4040
Suggested CDR Performance Indicators: 7.2.6, 8.1.5, 8.4.2, 9.4.5
CPE Level 2

Take this course and earn 2 CEUs on our Continuing Education Learning Library

The World Health Organization estimates that by 2020, chronic disease prevalence is expected to increase by 57% and will account for almost three-quarters of deaths worldwide.1 Fortunately, chronic diseases are largely preventable, with diet playing a key role as a modifiable risk factor.

High intakes of fruits and vegetables consistently have been shown to reduce risk of chronic disease; however, most Americans aren’t achieving the recommended intake of either. In fact, less than 50% of Americans meet the guidelines for fruit consumption as set forth by the 2015–2020 Dietary Guidelines for Americans.2

Apples are the most commonly consumed fruit in the United States when considering their intake in all forms, including fresh, canned, frozen, dried, and juice.3 Because of their popularity and high nutritional content, apples have been a focus of much scientific research on the prevention of chronic diseases. Their consumption has been linked to positive outcomes for a variety of diseases including cancer, diabetes, osteoporosis, CVD, and cognitive and pulmonary disorders.4 As it turns out, eating an apple a day really might keep the doctor away.

This continuing education course examines the nutritional content of apples, exploring their potential role in moderating chronic diseases, culinary uses for the fruit, and practical guidelines for recommending apples to patients.

Nutrition
Apples are a nutrient-dense food primarily composed of water (85%) and carbohydrates (14%); they’re also rich in vitamins, minerals, fiber, and phytochemicals.5

Vitamins/Minerals
Of the many vitamins and minerals they contain, apples are highest in vitamin C (14% DV) and potassium (6% DV).6 Vitamin C, an important water-soluble nutrient, plays an essential role in immune function and iron absorption. It’s necessary for the synthesis of certain neurotransmitters and L-carnitine, which plays an important role in metabolism and energy production. Vitamin C also is required for synthesis of collagen, a component in connective tissue, and often is used as a supplement in the clinical setting due to its role in wound healing.7 In addition, it’s a potent antioxidant, a factor that contributes greatly to the disease-fighting power of apples that will be discussed further in this article.

In addition to their vitamin C content, apples contain some potassium, an electrolyte that can help maintain a healthy blood pressure because of its role in maintaining fluid balance in the body. Potassium intake lessens the effect of sodium by causing sodium loss through the urine. The mineral also is a potent vasodilator, causing relaxation of blood vessels, which further regulates blood pressure.8 One of the key messages of the DASH diet is to choose foods that are high in potassium to reduce hypertension. Other functions of potassium include muscle contraction, membrane transport, and transmission of nerve impulses.

Apples also contain a variety of other vitamins and minerals including vitamin A (2% DV), folate (1% DV), calcium (1% DV), and iron (1% DV).6

Fiber
Apples are a good source of fiber, containing an average of 4 g (18% DV) per medium apple—about 3 g insoluble fiber and 1 g soluble fiber, each of which conveys its own health benefits.6 Insoluble fiber helps regulate the digestive system by increasing stool bulk and speeding transit time through the bowels. This promotes overall health of the colon by reducing constipation, removing toxins from the system more quickly, and maintaining an appropriate pH level.

The soluble fiber in apples has been partially credited for many of their heart-healthy benefits. Soluble fiber binds to bile acids in the intestines, causing the bile to be excreted. This lowers serum cholesterol because cholesterol is needed to replete the bile acid pool. In addition, soluble fiber is rapidly and completely fermentable in the colon, producing short-chain fatty acids that inhibit cholesterol synthesis. A diet high in soluble fiber can help control diabetes and manage weight because it slows gastric emptying, thus slowing the rise in blood sugar and promoting fullness.

Phytochemicals
Phytochemicals are compounds found in plants that aren’t considered essential nutrients but are associated with health benefits of fruits and vegetables beyond their vitamin and mineral content. Research on phytochemicals is considered to be fairly new, so not enough evidence is available to provide specific recommendations for intake. Although specific amounts can’t be recommended, strong research suggests a protective benefit for many chronic diseases.

Apples are abundant in two particular classes of phytochemicals: polyphenols and phenolic acids. Flavonoids are a subclass of polyphenols that are further divided into specific compounds abundant in apples, including anthocyanidins (1.6 mg per medium apple), flavanols (105 mg), flavones (0.1 mg), and flavonols (4.2 mg). Further classifications of phenolic acids include hydroxybenzoic acids (1.1 mg) and hydroxycinnamic acids (17.9 mg).9 Many of the health benefits of apples have been attributed to the high concentration of these phytochemicals.

Disease Prevention
Apples have been widely studied for their potential role in preventing and managing several chronic diseases, including cancer, diabetes, bone disorders, cognitive decline, CVD, and pulmonary disorders.

Cancer
Apples appear to reduce the risk of multiple types of cancers. A 2016 meta-analysis investigated the link between cancer and apple consumption by analyzing a total of 41 case-control or prospective study designs. When combining data from both types of studies, researchers found significant reductions in cancer risk in those with the highest apple intake compared with the lowest. Specifically, there was a 12% reduction in lung cancer, 28% reduction in digestive tract cancers, and an 11% reduction in breast cancer when comparing groups with the highest intake with the group with the lowest intake of apples. Given the nature of the research, however, no dose-dependent relationship could be established, so it’s difficult to say what number of apples would need to be eaten on a daily basis to receive the benefit. In addition, not every study in the meta-analysis adjusted for intake of other fruits and vegetables, which likely would influence the data.10

To further establish a relationship between apple consumption and cancer risk, animal studies have examined models of colon and breast cancer in rats. In one study, researchers chemically induced colon cancer in rats using the carcinogen azoxymethane. Rats that subsequently were given extracts of apple procyanidins, a subclass of flavonoids, had 50% fewer aberrant cysts in comparison with the controls. The authors established that the amount of procyanidins given to rats would be the equivalent of two apples per day in humans.4

Another study used another method of cancer induction, 1,2-dimethylhydrazine. Rats developed premalignant hyperproliferative as well as aberrant crypts, which are indicators of cancer pathogenesis and often progress to malignancy. Rats were given preparations of apple juice in either a clear or cloudy (higher procyanidin and pectin) form, both of which reduced DNA damage and lowered the number of large aberrant crypts in the distal colon. A follow-up study used similar methods but isolated components of apple juice in different treatment groups and found that whole apple juice was more effective at reducing markers of colon cancer compared with its individual components, including polyphenol extracts, suggesting the components have a synergistic relationship.4

To examine the effects of apple consumption on breast cancer, Liu and colleagues induced mammary tumors in rats that were then fed whole apples by gavage in varying doses equivalent to one, three, or six apples per day. This resulted in a significant reduction in tumor incidence by 25%, 25%, and 61%, respectively, over the course of 24 weeks.4

To further establish the mechanisms through which cancer risk is reduced, numerous in vitro studies have been conducted. It’s been recognized that oxidative stress is related to cancer initiation and advancement by causing DNA damage and mutations as well as increasing cell proliferation. Antioxidants, which are found in high concentrations in apples through their vitamin C, vitamin E, and phytonutrient content, reduce damage from oxidative stress by scavenging free radicals.

One in vitro study cited in a 2011 review took polyphenolic mixtures extracted from apple juice and examined their effects on oxidative markers in cultured human colonic cell lines. All extracts significantly reduced oxidative damage, regardless of concentration or apple type. This study further found that in many of the preparations, longer exposure to apple polyphenols in vitro resulted in more potent antioxidant activity. This suggests that the metabolic products formed from the parent phytochemicals may offer improved antioxidant potential.4

In addition to their antioxidant activity, apple polyphenols may decrease cell proliferation. One study published in the International Journal of Oncology demonstrated that phloretin, a polyphenolic compound found in high concentrations in apples, reduced proliferation of cancer cells in a dose-dependent manner. While this study didn’t isolate the phloretin from apples, it was noted in the study that phloretin is one of the major phenolic compounds found in apples and therefore apple intake also could offer this benefit.11 Another study looked at the effect of apple juice from three separate types of commercially available apple cultivars in Italy and found that the juice of Pelingo apples inhibited breast cancer cell proliferation significantly more than did other types of apple juice.12 This particular cultivar of apple contains a considerable amount of polyphenols in the pulp, showing good antioxidant activity in comparison with other types of apples. While promising, this study didn’t compare the reduction in cell proliferation with a control. In addition, Pelingo apples are a newly identified cultivar and thus aren’t yet widely consumed. Considering the promising evidence that’s been found in regard to apple consumption and decreased cancer risk, more research is needed to establish other possible mechanisms through which apple consumption may reduce cancer risk.

Diabetes
In addition to their role in decreasing cancer risk, apples have been demonstrated to lower the risk of type 2 diabetes. With the rates of type 2 diabetes increasing exponentially in the past few decades, this relationship is particularly important. One study collected diet histories and other baseline information from more than 10,000 Finnish men and women whose outcomes were followed over 28 years. A significant inverse relationship was found between apple intake and risk of type 2 diabetes. This relationship was attributed to the large amount of the flavonols quercetin and myricetin in apples.13 Conversely, another study that used data obtained from the 39,876 women participating in the Women’s Health Study completed at Brigham and Women’s Hospital didn’t find a relationship between flavonols and incidence of type 2 diabetes. The researchers, however, did find that the risk of type 2 diabetes decreased by 27% in women consuming more than one apple per day compared with those who didn’t consume any. This finding suggests there are other components in apples that contribute to their ability to protect against diabetes.14

The mechanism through which apples show a protective effect on diabetes was studied both in vivo and in vitro in obese rat models of diabetes by Manzano and colleagues. Rats who were given a single dose of apple polyphenol extract showed a significant reduction in glycemic response after a meal challenge, a finding that was attributed to the inhibition of glucosidases. This inhibits a spike in blood sugar by preventing the digestion of complex carbohydrates into simple sugars in the intestine. The same study also tested longer-term supplementation with apple polyphenol extract in a dose of 128 mg/kg body weight over four weeks. Rats whose diets were supplemented with apple polyphenol extract showed a lower insulinemic and glycemic response compared with controls. Insulin sensitivity was then tested in these rats, and the results showed a better ability of the peripheral tissues to respond to glucose uptake upon the release of insulin. It was theorized that this is due to the facilitated translocation of GLUT4 to the plasma membrane, which is a necessary step for glucose uptake into the muscles. Western blot analysis further confirmed the involvement of the PI3K and PPAR gamma signaling pathways on this effect.15 Other studies have theorized that an alternate mechanism in the improvement of diabetes markers is the slowing of glucose absorption due to the pectin in apples, but this hasn’t yet been well studied.5

Bone Health
Osteoporosis, a condition in which bones weaken and increase their susceptibility to fractures and breaks, affects 10 million Americans older than age 50. Research is starting to explore the potential link between fruit and vegetable consumption and bone health. In one study, 15 female participants ate three test meals consumed over different occasions. The meals contained either freshly peeled apples (311 g or approximately two medium apples), unsweetened canned apple sauce (877.5 g or approximately 3 1/2 cups), or candy (53 g), but were then adjusted to provide a comparable amount of calories and macronutrients. Net acid excretion, which is implicated in bone loss because it’s positively associated with urinary calcium loss, was significantly lower in the fresh and processed apple groups compared with the group given candy, as evidenced by urinary samples collected at 1.5, three, and 4.5 hours post meal. In addition, both apple groups showed significantly lower calcium loss at these time intervals when compared with the candy group.4

Another study was performed on rats whose ovaries were removed and that were subjected to inflammation as a model of the postmenopausal state in women. Postmenopause is a critical time to study bone health, as hormonal changes during this time, especially a decline in estrogen production, disrupt the bone-building process and cause inflammation. In a study cited by Hyson and colleagues, the flavonoid phloridzin was extracted from the wood of apple trees and given to rats in an amount equal to about six apples per day. After 80 days of treatment, phloridzin improved femoral bone mineral density and other markers of bone turnover. While promising, the amount of apples consumed in this study is much higher than that which would realistically be consumed by the average person.4

Cognitive Issues
Cognitive decline in older adults is one of the biggest concerns among the aging population, yet it remains one of the least understood. Causes of cognitive impairment are multifactorial, and impairment can manifest in many ways, ranging from mild memory loss or motor skills impairment to dementia or Alzheimer’s disease. As cited in a comprehensive review, Shea and colleagues performed a series of studies in mice that were induced with oxidative stress and demonstrated cognitive impairment. In one such study, mice that had been fed a pro-oxidant diet to induce cognitive impairment were given the human equivalent of two to three 8-oz glasses of apple juice per day for one month. The rats fed juice showed significant improvement in cognitive performance and reduced oxidative stress compared with controls. A similar study by the same author, this time using a different method of inducing oxidative stress in mice, also demonstrated that one month of supplementation with apple juice concentrate resulted in a decreased accumulation of reactive oxygen species in brain tissue and lessened cognitive impairment.4

The antioxidant capacity of apples has been suggested as a mechanism for improving the markers of cognitive function. Oxidative stress induces a compensatory increase of the endogenous antioxidant glutathione in the brain as a protective measure. In further research by Shea and colleagues, apple juice intake reduced this effect in mice, likely indicating that the antioxidant potential of apples provided a protective effect, a finding that also was echoed by Viggiano and colleagues.4

Beyond their antioxidant effects, additional mechanisms by which apples exert a neuroprotective effect have been examined. Early research in mice suggests that apple juice concentrate prevents a decline in the neurotransmitter acetylcholine, which is involved with muscle activation, memory, and overall brain function. Its depletion is associated with decreased cognitive performance and is linked with neurological disorders such as attention deficit disorder and Alzheimer’s disease. Amyloid beta peptide is the main component of amyloid plaques, which are aggregates of proteins found in the brains of those with Alzheimer’s disease. Cognitively impaired mice who were given apple juice concentrate demonstrated suppression of proteins involved with amyloid beta production as well as reduced neurotoxicity of amyloid beta peptide.4

Further research by Viggiano and colleagues tested the effects of fresh apple intake on aged rats over a 10-week period. Apple consumption was shown to improve performance in maze tasks as well as restore synaptic function, which is involved in memory formation, to levels seen in younger mice.4 Synaptic function also has been shown to improve with consumption of fruit flavonoids. Although the earlier research isn’t specific to apples, apples remain one of the highest sources of fruit flavonoids.16

CVD
CVD is the leading cause of death of men and women in the United States and worldwide and costs the nation $320 billion annually.17 Therefore, there’s a deep-seated interest in managing risk factors and outcomes of the disease. In one observational study of 34,489 postmenopausal women in the Iowa Women’s Health Study, mortality rates for coronary heart disease and overall CVD were reduced by 15% and 13%, respectively, in the group consuming the most apples and pears (greater than once per week) compared with those consuming the least (less than once per week).18 Another study of more than 5,000 Finnish men and women corroborated these results; the relative risk of coronary mortality in the highest quartile of apple intake compared with the lowest was 0.81 and 0.57 in men and women, respectively.19 A random sampling of more than 10,000 participants in another study also showed an inverse association with apple intake and relative risk of stroke.13

It’s been accepted that eating more fruits and vegetables can ameliorate high blood pressure, a risk factor for CVD. In one study, mice were randomized into one of five diet groups: normal, high fat, and high fat supplemented with either healthy apple peel, dehydrated apple peel, or damaged apple peel for 43 days. The mice in the high fat group had significantly higher systolic blood pressure compared with the controls; however, this was mitigated by consumption of any type of apple peel.20

A randomized, controlled, crossover study in 30 men and women demonstrated that eating whole apples resulted in lower systolic blood pressure, especially. The study attributed this finding to an increase in the vasodilator nitric oxide.5 A similar study using 25 healthy subjects also showed increased plasma nitric oxide levels six hours after consuming apple purée, but no effect was seen after daily consumption for two weeks.21 While promising, both of these studies only provide evidence for short-term consumption and used relatively small sample sizes.

High cholesterol is another factor contributing to CVD that may be lowered by apple consumption; however, evidence is mixed. On the one hand, a review of nine human studies found that daily intake of approximately three apples resulted in an 8% reduction in total cholesterol levels. Apple juice had no effect on cholesterol levels and in fact caused an increase in triglycerides. Another study added 75 g of dried apple daily to the typical diet of postmenopausal women and found total cholesterol and LDL cholesterol were decreased by 9% and 16%, respectively, at three months compared with baseline and increased to 13% and 24% after six months.5 Contradicting these studies was a study on 46 Iranian men aged 30–50 who either were given 300 g of whole apples daily (about two medium) or no apples at all. No difference in total, LDL, or HDL cholesterol was seen at the end of the eight-week study. While there are additional studies to support this finding,21 the majority of research as presented provides evidence that apple consumption leads to a desirable lipid profile.

Apples’ high fiber content, specifically pectin, has been attributed to their cholesterol-lowering effects. Studies comparing the cholesterol-lowering effects of whole apples vs apple juice, which doesn’t have any fiber and doesn’t seem to lower cholesterol, support this theory. Fiber lowers total cholesterol by binding to bile in the digestive tract, causing it to be excreted. Bile is made partially from cholesterol, so the body uses serum cholesterol to help replenish the bile acid pool. Pectin also can bind to cholesterol directly, decreasing its absorption and increasing its excretion. Finally, soluble fiber also exhibits a cholesterol-lowering effect by fermenting to short-chain fatty acids in the gut, which inhibits cholesterol synthesis. Studies have suggested that the polyphenols in apples may work in synergy with fiber; however, the exact mechanism behind this effect is unclear.5

Pulmonary Function
There’s been a recent increase in asthma and other respiratory disorders that has largely been credited to a change in environmental factors, including chemical agents, tobacco smoke, pollution, and high ozone levels. Recent research has provided evidence that apple consumption may improve pulmonary function due to the antioxidant effects associated with their high phytonutrient content. An observational study of 68,535 French women revealed an inverse relationship between apple intake and asthma prevalence. Interestingly, fruits with citrus and fruits with beta-carotene also were studied and showed no relationship.22 Another study of 1,600 adults in Australia similarly showed a significant inverse relationship between apple and pear consumption and asthma risk—a decrease that wasn’t found with total fruit and vegetable intake. A study of 10,000 Finnish men and women produced similar findings. Finally, reduced asthma incidence and higher dietary intake of apples was demonstrated in a study of 1,500 adults in the United Kingdom. Unlike the other studies, this survey showed a weak relationship between total fruit and vegetable intake and asthma incidence. However, consumption of apples independently, totaling two per week, proved to decrease asthma incidence in this population.23

In contrast to the research discussed above, one cross-sectional study in 2,600 children in the United Kingdom didn’t demonstrate a relationship between apple consumption and decreased risk of asthma or its symptoms. Drinking apple juice from concentrate was, however, significantly and dose-dependently associated with reduced wheezing. No relationship was found between consumption of apple juice from concentrate and asthma incidence.24

Apple consumption also has been demonstrated to have beneficial effects on pulmonary function and pulmonary disorders other than asthma. A study of more than 13,000 Dutch men and women showed apple and pear consumption to be inversely associated with COPD.25 Lung function, as measured by forced expiratory volume in one second, was positively correlated with intake of five or more apples per week in a study of 2,500 Welsh men aged 45–59.26

Increasing Apple Intake
Apples are found in a variety of forms in the grocery store, including fresh, frozen, juice, canned, and dried, making it easy to incorporate them into the diet. Clients should be encouraged to eat the whole fruit instead of drinking apple juice, however, as juicing removes the fiber and some of the phytonutrients of the fruit. Without the fiber, the remaining juice can cause a spike in blood sugar, won’t promote satiety, and isn’t likely to convey cardioprotective effects. Therefore, it should be incorporated sparingly. The following are all ways RDs can advise clients to include apples in their diets:

• Have an apple as a snack, on its own or paired with peanut butter or cheese.
• Dice and put apples into oatmeal or pancakes for breakfast.
• Bake diced apples or applesauce into whole grain muffins.
• Use fresh or frozen apples in smoothies.
• Add fresh apple slices or dried apple to salads or sandwiches for a sweet crunch.
• Bake apples with fall vegetables such as sweet potatoes or butternut squash as a side dish.
• Sprinkle baked apples with cinnamon for a light dessert.
• Make applesauce and enjoy as a snack.
• Poach apples in apple cider and serve with vanilla yogurt.
• Grate and incorporate apples into coleslaw.
• Add diced or grated apples into burgers.
• Incorporate apples into stuffing.
• Use dried apples in granola or cereals.
• Purée apples and add them to soups.
• Top pancakes or waffles with warm canned or baked apples.
• Pair apples with proteins such as pork or chicken.

Putting It Into Practice
Research strongly suggests that apples play a role in reducing chronic diseases, such as cancer, diabetes, and CVD, with earlier research suggesting they also may be beneficial for bone health, cognitive disorders, and pulmonary disorders. With Americans falling far short of the recommended daily amount of fruit and vegetable intake, clients should be encouraged in general to increase their intake of these food groups. Because apples usually are well liked among Americans, recommending that clients boost their intake of produce by focusing on this particular fruit may be well received.

The amount of apples needed to be consumed on a daily or weekly basis for maximum health benefits varies among the research; however, RDs can safely suggest that most clients should include an apple per day in addition to a variety of other fruits and vegetables to obtain the health benefits discussed in this article.

— Kristin Sementelli, MS, RD, LDN, is a personal trainer and freelance writer based in Boston.

Learning Objectives
After completing this continuing education course, nutrition professionals should be better able to:
1. Translate the nutritional components of apples.
2. Assess the benefits of apple consumption in the management of chronic disease.
3. Distinguish between the nutritional benefits of various components of apples.
4. Compare the nutritional differences between forms of apple processing and recommend culinary preparations.

CPE Monthly Examination

1. Which of the following vitamins and minerals are most plentiful in apples?
a. Vitamin A and iron
b. Vitamin C and potassium
c. Vitamin A and potassium
d. Vitamin C and magnesium

2. Apples are high in which of the following two phytochemicals?
a. Carotenoids and allium
b. Lycopene and resveratrol
c. Quercetin and lutein
d. Polyphenols and phenolic acids

3. Which of the following components of apples has been most strongly associated with their cardioprotective effects?
a. Flavonoids
b. Potassium
c. Pectin
d. Sodium

4. Which of the following components of apples isn’t considered an antioxidant?
a. Vitamin C
b. Vitamin E
c. Phytochemicals
d. Magnesium

5. Which of the following hasn’t been suggested as a reason why apples may improve cognitive function?
a. They improve blood flow to brain.
b. They reduce oxidative stress in the brain.
c. They prevent a decline in the neurotransmitter acetylcholine.
d. They improve synaptic function.

6. Which of the following flavonols has been attributed to the relationship between apple intake and decreased risk of type 2 diabetes?
a. Quercetin and myricetin
b. Quercetin and allium
c. Myricetin and polyols
d. Polyols and flavones

7. What percentage of Americans eat the recommended amount of fruits?
a. 100%
b. 75% to 99%
c. 50% to 75%
d. Less than 50%

8. Apples have been shown to decrease the risk of mortality in which chronic disease?
a. Irritable bowel syndrome
b. CVD
c. Alzheimer’s disease
d. Type 2 diabetes

9. Which of the following hasn’t been suggested as a mechanism by which apple intake reduces diabetes incidence?
a. Facilitated translocation of the GLUT4 transporter to the plasma membrane
b. Increased involvement of the PI3K and PPAR gamma pathways
c. Higher insulin secretion
d. Slowed glucose absorption

10. Which of the following forms of apples should be consumed minimally?
a. Apple juice
b. Applesauce
c. Whole apples
d. Frozen apples

References
1. The global burden of chronic. World Health Organization website. http://www.who.int/nutrition/topics/2_background/en/. Accessed February 27, 2018.

2. U.S. diets are out of balance with Federal recommendations. US Department of Agriculture website. https://www.ers.usda.gov/data-products/chart-gallery/gallery/chart-detail/?chartId=58334. Updated September 14, 2017. Accessed February 16, 2018.

3. Oranges and apples are America’s top fruit choices. US Department of Agriculture website. https://www.ers.usda.gov/data-products/chart-gallery/gallery/chart-detail/?chartId=58322. Updated September 14, 2017. Accessed February 18, 2018.

4. Hyson D. A comprehensive review of apples and apple components and their relationship to human health. Adv Nutr. 2011;2(5):408-420.

5. Bondonno NP, Bondonno CP, Ward NC, Hodgson JM, Croft KD. The cardiovascular health benefits of apples: whole fruit vs. isolated compounds. Trends Food Sci Technol. 2017;69(B):243-256.

6. Apples and more. University of Illinois Extension. https://extension.illinois.edu/apples/nutrition.cfm. Published August 2018. Accessed November 18, 2018.

7. Vitamin C: fact sheet for health professionals. National Institutes of Health website. https://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/. Updated September 18, 2018.

8. Potassium. American Heart Association website. http://www.heart.org/HEARTORG/HealthyLiving/HealthyEating/Potassium_UCM_306021_Article.jsp#. Updated May 4, 2015. Accessed February 18, 2018.

9. Bhagwat S, Haytowitz DB, Holden JM; US Department of Agriculture, Agricultural Research Service. USDA database for the flavonoid content of selected foods. https://www.ars.usda.gov/ARSUserFiles/80400525/Data/Flav/Flav_R03-1.pdf. Updated May 2014. Accessed February 20, 2018.

10. Fabiani R, Minelli L, Rosignoli P. Apple intake and cancer risk: a systematic review and meta-analysis of observational studies. Public Health Nutr. 2016;19(14):2603-2617.

11. Ma L, Wang R, Nan Y, Li W, Wang Q, Jin F. Phloretin exhibits an anticancer effect and enhances the anticancer ability of cisplatin on non-small cell lung cancer cell lines by regulating expression of apoptotic pathways and matrix metalloproteinases. Int J Oncol. 2016;48(2):843-853.

12. Schiavano GF, De Santi M, Brandi G, et al. Inhibition of breast cancer cell proliferation and in vitro tumorigenesis by a new red apple cultivar. PLoS One. 2015;10(8):e0135840.

13. Knekt P, Kumpulainen J, Järvinen R, et al. Flavonoid intake and risk of chronic diseases. Am J Clin Nutr. 2002;76(3):560-568.

14. Song Y, Manson JE, Buring JE, Sesso HD, Liu S. Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis. J Am Coll Nutr. 2005;24(5):376-384.

15. Manzano M, Giron MD, Vilchez JD, et al. Apple polyphenol extract improves insulin sensitivity in vitro and in vivo in animal models of insulin resistance. Nutr Metab (Lond). 2016;13:32.

16. Spencer J. The impact of fruit flavonoids on memory and cognition. Br J Nutr. 2010;104:S40-S47.

17. Heart disease and stroke cost America nearly $1 billion a day in medical costs, lost productivity. CDC Foundation website. https://www.cdcfoundation.org/pr/2015/heart-disease-and-stroke-cost-america-nearly-1-billion-day-medical-costs-lost-productivity. Published April 29, 2015. Accessed May 15, 2018.

18. Mink PJ, Scrafford CG, Barraj LM, et al. Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women. Am J Clin Nutr. 2007;85(3):895-909.

19. Knekt P, Järvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996;312(7029):478-481.

20. Gonzalez J, Donoso W, Sandoval N, et al. Apple peel supplemented diet reduces parameters of metabolic syndrome and atherogenic progression in ApoE−/− mice. Evid Based Complement Alternat Med. 2015;2015:918384.

21. Koutsos A, Tuohy KM, Lovegrove JA. Apples and cardiovascular health — is the gut microbiota a core consideration? Nutrients. 2015;7(6):3959-3998.

22. Romieu I, Varraso R, Avenel V, Leynaery F, Kuffmann F, Clavel-Chapelon F. Fruit and vegetable intakes and asthma in the E3N study. Thorax. 2006;61(3):209-215.

23. Boyer J, Liu R. Apple phytochemicals and their health benefits. Nutr J. 2004;3(5):1-15.

24. Okoko B, Burney P, Newson R, Potts J, Shaheen S. Childhood asthma and fruit consumption. Eur Respir J. 2007;29(6):1161-1168.

25. Tabak C, Arts IC, Smit HA, Heederik D, Kromhout D. Chronic obstructive pulmonary disease and intake of catechins, flavonols, and flavones: the MORGEN Study. Am J Respir Crit Care Med. 2001;164(1):61-64.

26. Butland B, Fehily A, Elwood P. Diet, lung function, and lung function decline in a
cohort of 2512 middle aged men. Thorax. 2000;55(2):102-108.