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Shawn Wells, R.D.

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10 Superfoods for Superior Joints

Joint discomfort and stiffness impair mobility, adversely affect daily activities, and negatively impact quality of life.1,2 Simply put, tired, worn, and stiff joints can limit you from doing what you love to do and living the life of your dreams. Research shows that 43% of folks between the ages of 45 – 65 years old struggle with joint discomfort.3 Beyond that, it is estimated that 80% of the population will have radiographic (i.e., X-ray) evidence of significant joint breakdown by the age of 65.4

Researchers have found that two major risk factors associated with declining joint health and increased joint discomfort are age and overweight/obesity.5,6 With that said, joint degradation is thought to be precipitated by a number of factors, including oxidative and inflammatory stress.7–9

With regard to the latter, inflammatory stress can result from excess body fat and poor diet. That’s right, body fat is much more than an innate depot for excess energy storage. It is a dynamic tissue that secretes a large number of hormones and chemicals (e.g., cytokines), many of which have a pro-inflammatory effect and favor an inflammatory environment.10–12 As a result, obesity is commonly recognized as a chronic, low-grade inflammatory state.

In addition to excess body fat, excess calorie consumption (which is inherently associated with increasing body fat stores) and poor food choices (typical of the “Standard American Diet” and Western eating practices, which tend to be characterized by high amounts of heavily processed and refined carbohydrates and low-quality, refined oils) also promote both acute and sustained inflammatory stress.13–15 This pattern of eating and its associated dietary composition lead to an overproduction of

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free radicals, which results in oxidative stress and inflammatory stress. On the other hand, diets rich in fruits and vegetables—which are abundant in antioxidants—are inversely associated with inflammatory stress.16

While inflammation is a fashionable “buzzword” with a negative connotation, it should be pointed out that inflammation is the normal, protective, and (usually) temporary response of the immune system to pathogens and injury. In other words, a normal, healthy, and acute inflammatory response is not only a good thing, it’s imperative to optimal human health and function. However, it’s when there’s recurrent stimuli or poor regulation of the system that chronic inflammation—and problems—ensue.

Researchers believe that age may be tied to declining joint health for a number of reasons. One factor that may lead to age-related changes in joint structures is the formation of advanced glycation end-products (AGEs). AGEs are the result of the addition of carbohydrates to proteins or lipids (i.e., fat), and they can be formed both inside and outside the body. For instance, AGEs can be formed during cooking, and they can also be formed by the body after exposure to high levels of blood sugar, which results from regular consumption of simple sugars and refined carbohydrates.17

AGEs can wreak havoc on the body’s tissues, including joint structures. For instance, AGEs can impact the mechanical properties of cartilage, and as a result, increase joint stiffness, increase joint fatigue, and inhibit the building of new, healthy joint tissue.6 What’s more, AGEs increase free radical formation, impair antioxidant defense systems, increase oxidative stress, and promote inflammation.18

Along those lines, excessive free radical production leads to oxidative stress, which is “a disturbance in the balance between the production of reactive oxygen species (i.e., free radicals) and antioxidant defenses.”19 Oxidative stress has long been thought to play a central role in biological aging (i.e., cellular senescence) and the aging of various tissues, including joint structures.20,21 Reactive oxygen species (ROS) appear to play an important role in joint tissue breakdown and promoting inflammatory stress, and as a result, supporting the body’s defense systems through increased antioxidant intake

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seems to be imperative to bolstering joint health.22

Currently, the overwhelming majority of folks turn to options like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) to relieve joint discomfort, reduce stiffness, and improve physical function. While these tend to be effective acutely, regular, consistent use of NSAIDs has been found to be associated with a number of adverse health outcomes, including GI discomfort, enhanced risk for GI bleeding, hypertension, congestive heart failure, renal insufficiency, and more.23–25

With that said, more and more people are recognizing and seeking out the power of dietary factors, functional foods, and nutraceuticals to help nourish joints, improve joint health, and reduce joint discomfort. According to renowned joint health expert Dr. Jason Theodosakis (“Dr. Theo”), “We now know that certain foods can actually help ease and promote joint comfort.”26

Antioxidants are a major help in fighting free radicals, and as mentioned above, excessive free radicals and oxidative stress may be damaging to joints and can contribute to joint discomfort. According to Dr. Theo, foods that contain vitamin A (e.g., beta-carotene), vitamin C, vitamin E, and/or selenium (collectively known as the “ACES”) are powerful weapons for combating free radicals and supporting superior joints.

Speaking of antioxidants, there are a number of phytonutrients (e.g., flavonoids, anthocyanins, carotenoids, plant sterols, glucosinolates) found in an array of plant-based foods that can have a tremendously beneficial effect on joint health by supporting the body’s antioxidant defense systems, reducing oxidative stress, and promoting a healthy inflammatory response. In addition, a number of other micronutrients (e.g., vitamin D, vitamin K, several B vitamins) may play a critical role in optimizing joint health and function.27

What’s more, certain fatty acids (e.g., omega-3 fatty acids) are protective by nature, promote a healthy inflammatory response, and ease joint discomfort.

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With all of that in mind, we’d like to share with you a list of foods that may help nourish joints, support superior joint health, and promote joint comfort. Throughout, you’ll see a common theme of whole foods that are rich in potent antioxidants and support a healthy inflammatory response. Of course, these are not the only foods that may be beneficial, as there is a cornucopia of whole minimally processed foods that can promote joint health.

While the following sections highlight unique attributes of single foods, bear in mind that, in the grand scheme of things, your health, feelings of wellbeing, and performance are the product of your entire body of “nutrition work.” In other words, there’s no single magical food. Instead of viewing foods in isolation as “good” or “bad,” think about “deep health” as the result of practicing healthy eating habits, creating a positive food environment, and choosing high-quality nutritious foods in appropriate amounts regularly and consistently over time. Good nutrition takes practice, and it’s about progress—not perfection—and finding what works best for you.

What’s more, it’s also important to consider your own personal responses to foods. For instance, you might find that an otherwise perfectly healthy food (e.g., FODMAP-containing foods) might result in joint discomfort. While it’s beyond the scope of this report, identifying personal food sensitivities—defined as a negative physiological reaction to a food—can play a critical role in easing joint discomfort, as it’s not at all uncommon for specific foods (on an individual basis) to lead to joint flare-ups.

AvocadosAvocados are a rich source of antioxidants (e.g., chrysanthemaxanthin, neoxanthin, lutein, vitamins C and E) and contain a number of anti-inflammatory compounds (e.g., carotenoids, phytosterols, catechins, procyandins). As mentioned above, declining joint health is thought to be precipitated by a number of factors, including oxidative and

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inflammatory stress,7–9 and as a result, it stands to reason that avocados—with their phytonutrient density—may help ease joint discomfort.

In one study published in the American Journal of Clinical Nutrition, researchers from Oregon Health and Science University found that fruits and vegetables rich in lutein and zeaxanthin (the primary carotenoids in avocados) are associated with decreased risk of cartilage defects.28

A number of studies have demonstrated that supplementation with avocado-soybean unsaponifiables (ASU), which are concentrated extracts rich in the phytosterols from these whole foods, may promote joint comfort.

In one randomized, double-blind, placebo-controlled clinical trial, 164 participants, who regularly used NSAIDs to ease joint discomfort, were divided into two groups. French researchers gave one group an ASU supplement while the other group received a placebo once daily for 6 weeks. At the end of the trial, 26% fewer folks taking the ASU supplement resumed therapy with NSAIDs (compared to the placebo group), and on average, the participants taking ASU experienced a 2.3 times greater improvement in their functional index, which is a composite assessment of joint discomfort, stiffness, and mobility.29

In another study investigating the efficacy of ASU on joint comfort, a group of French researchers administered either an ASU supplement or a placebo to participants for 6 months. At the end of the randomized, double-blind, placebo-controlled trial, the folks taking ASU experienced a 37% reduction in joint discomfort, an improvement 2 times greater than the placebo group. What’s more, the ASU group demonstrated, on average, a 30% improvement in their functional index—6 TIMES better than the placebo group.30

In a recent study, researchers from Johns Hopkins University found that ASU reduces the production of multiple pro-inflammatory compounds (e.g., IL-1ß, TNF-α) and suppresses the activity of two key pro-inflammatory enzymes (i.e., COX-2, iNOS), all of which are closely linked to joint breakdown and discomfort.31 In a recent review published by the

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Cochrane Collaboration, the independent scientific group concluded that there was “moderate to high” evidence to support the use of ASU for easing joint discomfort.32

While it is not completely clear how much avocado or avocado oil may be needed to promote joint comfort, there is substantial enough evidence and rationale to conclude that avocados deserve to be considered a superfood for superior joints. In addition to eating whole avocados, you may also consider trying avocado oil in recipes, salad dressings, etc., as it may provide an even greater concentration of phytosterols.

What’s more, the addition of avocado or avocado oil to other vegetables appears to promote greater absorption of their antioxidant phytonutrients. In a study published in the Journal of Nutrition, researchers from Ohio State University found that when avocado or avocado oil was added to salsa, the absorption of fat-soluble carotenoids was up to four times higher than when the salsa was avocado-free. If that’s not enough, when avocado was added to salads, the researchers found that absorption of carotenoids was up to 15 times higher than when the salads were consumed avocado-free (i.e., fat-free).33

Olive OilExtra-virgin olive oil is naturally abundant in a polyphenol called oleocanthal, which has been shown to promote a healthy inflammatory response. Specifically, oleocanthal acts as a “natural anti-inflammatory compound” by inhibiting the activity of cyclooxygenase (COX) enzymes, a property it shares with the highly-recognizable NSAID ibuprofen.34,35

“By inhibiting these enzymes, inflammation and the increase in pain sensitivity associated with them is dampened,” says Dr. Paul Breslin, co-author of a recent study published in the Journal of Neuroscience in which researchers identified the unique mechanism underlying the oral stinging sensation shared by oleocanthal and ibuprofen.36

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Along those lines, researchers have found that a Mediterranean diet, which is rich in olive oil, confers a number of health benefits, some of which seem to overlap with those attributed to NSAIDs.37,38

In addition to oleocanthal, there are a number of other polyphenols (e.g., oleuropein, hydroxytyrosol) in extra-virgin olive oil that provide antioxidant activity and promote a healthy inflammatory response.39 In fact, Italian researchers have found that oleuropein, a compound that is similar in structure to oleocanthal, exerts anti-inflammatory effects and has the potential to mitigate joint degradation.40 In a recent study published in the Journal of Nutritional Biochemistry, Portuguese researchers found that olive oil fortified with hydroxytyrosol significantly improved the inflammatory response and reduced joint swelling in animals.41

In a study published in the journal Atherosclerosis, researchers examined the antioxidant and anti-inflammatory effects of extra-virgin olive oil. Healthy participants were divided into three groups, each one receiving a meal with a different type of oil: Extra-virgin olive oil (EVOO), olive oil (OO), or corn oil (CO). The researchers found that only when the folks consumed meals with EVOO (not OO or CO), they experienced significant decreases in inflammatory markers (e.g., TXB2, LTB4) along with increases in markers of antioxidant capacity within two hours of the meal.42 While the EVOO and OO had nearly identical fatty acid compositions, the EVOO contained nearly 38 TIMES more health-promoting polyphenols.

In a recent study published in the Journal of Nutritional Biochemistry, researchers from Spain found that extra-virgin olive oil polyphenols reduced joint swelling and protected joints against cartilage and bone degradation through their potent anti-inflammatory activities (e.g., reduced production of pro-inflammatory cytokines).43 Although the study was conducted in mice, the anti-inflammatory and joint protective properties of the extra-virgin polyphenols were so promising that the authors concluded, “These results support the interest of natural diet components in the development of therapeutic products” for promoting joint health.

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In terms of extra-virgin olive oil consumption, the evidence suggests that around 3 tablespoons or so may be needed daily to derive the research-backed benefits. While this may come as somewhat of a surprise, it should be noted that Mediterranean diets typically provide up to 40% of total calorie intake from fats— 50% of which comes from monounsaturated fats (predominantly extra-virgin olive oil).44

CherriesCherries are rich in antioxidants and anti-inflammatory nutrients. In fact, studies have shown that the antioxidant potential of the anthocyanins—phytonutrients that are responsible for the red skin and flesh color of cherries—are superior to vitamin E.45

What’s more, research has shown that these potent polyphenols promote a healthy inflammatory response by inhibiting the activity of a class of enzymes in the body called cyclooxygenase (COX). Inhibition of COX is a common target of NSAIDs to ease joint comfort and reduce stiffness, and the COX inhibitory activities of the anthocyanins from cherries have been shown to be comparable to that of commonly-used NSAIDs.46

Studies dating all the way back to the 1950s have suggested that cherry consumption may play a role in easing joint discomfort, and as a result, cherries have long had a reputation for supporting joint health.47 This long-standing belief was fortified in a study published in the Journal of Nutrition in which researchers found that the consumption of 45 cherries provoked a significant decrease in circulating levels of urate (i.e., uric acid) in women.48 When urate accumulates in joints, it is associated with discomfort, stiffness, and swelling.

In one study published in the Journal of Nutrition, researchers from the University of California-Davis found that men and women who consumed 45 Bing sweet cherries daily for 28 days demonstrated significantly reduced levels of inflammatory markers.49 On average, the participants’ circulating levels of a compound called C-reactive protein

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(CRP), a marker of inflammation, decreased by 25%.

In a study of over 600 participants, researchers from Boston University Medical Center found that cherry intake was associated with reduced risk of joint flare-ups.50 In fact, the researchers found that folks who consumed one or more servings of cherries for two consecutive days experienced a 35 – 48% decrease in joint flare-up occurrences.

In recent years, tart cherry juice has become increasingly common for everything from promoting more restful sleep to helping soothe sore muscles. In a recent study published in the Journal of Functional Foods, British researchers found that consuming 1 – 2 ounces of Montmorency tart cherry concentrate daily significantly reduced blood levels of urate and CRP, which, as mentioned above, are associated with joint stiffness and inflammation, respectively.51 Each 1-ounce serving of the cherry juice concentrate was equivalent to 90 whole Montmorency tart cherries.

In a recent study published in the journal Osteoarthritis and Cartilage, a group of researchers at the Philadelphia VA Medical Center gave 58 study participants either 8 ounces of tart cherry juice or a placebo twice daily for 6 weeks. After a one-week “washout period” (during which they received neither), the folks were then administered the opposite treatment. At the end of the study, the researchers found that when the participants consumed the tart cherry juice, they experienced significantly improved joint comfort, reduced stiffness, and increased physical function.52 Each bottle of cherry juice contained the equivalent amount of anthocyanins found in 50 cherries.

With all of that in mind, it seems as though cherries’ reputation for easing joint discomfort, reducing stiffness, and improving physical function has a solid evidence base, and it appears that these effects can be attributed to the anthocyanin phytonutrients, which promote a healthy inflammatory response, provide antioxidant protection, and decrease blood levels of uric acid.

What’s more, it seems as though a variety of different types of cherries (e.g., tart, Bing sweet), as well as cherry juices and concentrates, may all provide these benefits. While

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the optimal amount or frequency is not completely clear, it appears that regular cherry consumption—either in whole fruit, concentrate, or juice form—may be beneficial to bolster joint health.

ApplesSurely you’ve heard the old adage, “An apple a day keeps the doctor away.” It turns out that’s not just a nice rhyme that mothers use to convince their kids to eat more apples. In fact, there’s plenty of science to support the notion, and there’s evidence that apple consumption can help promote a healthy inflammatory response, which can have a tremendous impact on easing joint discomfort and stiffness.

In a recent study published in the Journal of the Academy of Nutrition and Dietetics, researchers in the Department of Nutrition, Food, and Exercise Sciences at Florida State University conducted a 1-year clinical trial among 160 women to examine the effects of daily apple consumption on a variety of health parameters.53

The study randomly assigned the women to one of two groups: One group received dried apples daily (the equivalent of two medium-sized apples) and the other group ate dried prunes each day for one year. After just 6 months, the women who consumed the apples experienced a 32% reduction in levels of CRP, a marker of systemic inflammation that is commonly elevated in situations involving joint discomfort.54,55

Even though this was not a weight loss study, the women consuming the apples dropped over 3 pounds during the course of the trial. This is noteworthy because being overweight is strongly associated with increased joint discomfort and risk of deteriorating joint health.56,57 Body weight has a direct impact on the amount of pressure placed on joints, and it’s estimated that a force of 3 – 6 times one’s body weight is exerted across the knee when walking. In other words, being just 10 pounds overweight can mean an additional 30 – 60 pounds of force on the knee with each step.58

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Not only that, fat tissue is not inert; it creates and releases chemicals that promote inflammation and exacerbate joint discomfort.59 “These chemicals can influence the development of [joint discomfort],” says Dr. Jeffrey N. Katz, a professor of medicine and Orthopedic surgery at Harvard Medical School and Brigham and Women’s Hospital in Boston.

This effect can be seen in the numerous studies that have linked being overweight to joint discomfort in non-weight-bearing joints (e.g., hands). “Obviously, you don’t walk on your hands, so there may be something that is produced by fat cells in the body that causes the joint to break down more rapidly than it might otherwise,” says Dr. David Felson, a professor of medicine and epidemiology at Boston University School of Medicine.60

While studies show that being overweight can increase joint discomfort, research suggests that even small amounts of weight loss can improve joint comfort.57,61 In fact, researchers have found that, for every 11-pound decrease in body weight, a woman’s risk of osteoarthritis decreases by a whopping 50%.

The skin of apples is rich in antioxidant phytonutrients, including anthocyanins and quercetin.62 Much like the former, quercetin has been shown to promote a healthy inflammatory response that is associated with easing joint discomfort.63 Researchers from La Trobe University in Australia also found that quercetin can prevent the loss of aggrecan, which is a key component of joint tissue structures.64

Not only that, quercetin has been shown to help promote healthy carbohydrate metabolism by inhibiting digestive enzymes like alpha-amylase and alpha-glucosidase, which are responsible for breaking down carbohydrates into absorbable sugars.65 This has implications on joint health because poor carbohydrate management is associated with increased joint discomfort, stiffness, and swelling.66

With all of that in mind, it seems as though the long-standing guidance to consume “an apple a day” may help promote joint health, provide antioxidant protection, and support a healthy inflammatory response.

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Blueberries, Strawberries & Other BerriesJust like cherries, blueberries, strawberries, and other berries get their dark, deeply-colored hues from their concentrations of potent polyphenols called anthocyanins.67–69 Much like cherries, the anthocyanins found in berries have been shown to inhibit COX enzymes, thereby promoting a healthy inflammatory response and easing joint discomfort.46

A number of studies have shown that berry consumption has been associated with reduced markers of systemic inflammation. In one study published in the Journal of the American College of Nutrition, researchers from Harvard examined the dietary habits of nearly 27,000 women as part of the Women’s Health Study. They found that women who consumed two or more servings of strawberries per week (about 16 strawberries) were 14% less likely to have elevated levels of CRP, a marker of inflammatory stress that may be closely related to joint flare-ups.70

In two separate studies, researchers from the Department of Food Science and Nutrition at Laval University in Quebec found that folks who consumed a low-calorie cranberry juice cocktail daily for 4 – 12 weeks showed reduced levels of selected pro-inflammatory markers.71,72 In one of the studies, the men who drank the cranberry juice cocktail daily for 12 weeks demonstrated a 36% reduction in levels of matrix metalloproteinases (MMPs), which are enzymes involved in the breakdown of a variety of tissues in the body and are thought to play a pivotal role in joint degradation.73

Researchers from Texas Women’s University recently demonstrated that the polyphenols in blueberries might play a significant role in reducing body fat, which secretes a number of hormones and chemicals that favor an inflammatory state. Specifically, the researchers found that the blueberry polyphenols inhibited the

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formation of fat cells.74 By reducing body fat, one can promote joint health by reducing inflammatory stress as well as decreasing the physical stress on joints associated with extra body weight.

Blueberries may also help promote joint health by fighting free radicals and promoting a healthy inflammatory response. In one study published in the journal Applied Physiology, Nutrition, and Metabolism, researchers from Appalachian State University found that athletes who consumed about 2 cups of blueberries daily for 6 weeks showed reduced levels of oxidative stress and an increase in anti-inflammatory molecules.75

In a study published in the Journal of the International Society of Sports Nutrition, researchers from New Zealand found that consumption of blueberries may also accelerate recovery, reduce discomfort, and decrease oxidative stress when combined with exercise. Specifically, folks who consumed a blueberry smoothie before and after exercise experienced reduced muscle soreness and accelerated recovery of strength, which translates to more frequent exercise and improved performance.76

Overall, berries contain a number of compounds that support the body’s antioxidant defense systems, promote a healthy inflammatory response, and support weight management. With that in mind, it’s a good idea to consume a wide variety of berries on a regular basis to support superior joints.

Red WineOver the last several years, the health benefits of moderate red wine consumption have become increasingly clear, and among the myriad advantages appears to be joint protective effects. Like many of the other dark, rich-colored fruits already discussed, red wine is a rich source of antioxidant polyphenols, including anthocyanins.77

One of the best-known polyphenols found in red wine is resveratrol. A number of studies have demonstrated the anti-inflammatory

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activity of resveratrol and its ability to promote a healthy inflammatory response.78 Like oleocanthal and a number of the other polyphenols already mentioned, resveratrol seems to exhibit its anti-inflammatory activity mostly through inhibition of the COX enzymes, which has the potential to ease joint discomfort.79 Resveratrol also seems to modulate the body’s inflammatory response by reducing both the production of inflammatory molecules as well as the formation of free radicals.80

A number of studies have demonstrated specific joint-protective benefits when resveratrol has been administered to animals. In one study, researchers from Taiwan found that resveratrol protected joints from cartilage damage associated with AGEs.81 AGEs can reduce collagen synthesis, leading to joint stiffness, as well as increase the activity of MMPs, which are responsible for joint and cartilage breakdown.82,83

While resveratrol seems to be the most popular antioxidant associated with red wine, the beneficial effects of red wine cannot be solely accounted for by this polyphenol due to its low concentration and bioavailability.84 In a recent study published in the journal PLoS One, researchers from Hungary demonstrated that malvidin, the most abundant anthocyanin polyphenol in red wine, possesses potent antioxidant and anti-inflammatory activity, and the effects of malvidin “at least partially account for the positive effects of moderate red wine consumption.”85

This is important to note because it highlights that a combination of red wine polyphenols—not a single isolated compound—may be needed to derive the touted health benefits. Thus, moderate amounts of red wine—1 glass (i.e., 5 ounces) per day for women and 1 – 2 glasses per day for men—may be optimal. It’s important to note, however, that drinking alcohol in excess appears to increase the body’s production of pro-inflammatory molecules, according to researchers from the University of North Carolina.86

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Coldwater FishColdwater fish are abundant in the essential omega-3 fatty acids EPA and DHA. They are considered essential because the body cannot produce them, and they must be consumed through dietary sources. Unfortunately, the modern food supply is largely void of these important healthy fats due to overconsumption of vegetable oils, which are rich in omega-6 fatty acids (e.g., soybean, safflower, sunflower, corn, etc.), meat from feedlot animals (that consume abundant amounts soy and corn), and reductions in healthful seafood consumption.

Experts estimate that throughout human history the optimal ratio for consumption of omega-6 fatty acids (e.g., linoleic acid) to omega-3 fatty acids (e.g., alpha linolenic acid, DHA, EPA) was about 2:1 or 1:1.87 With the contemporary diet, this ratio has shifted dramatically in favor of omega-6 fatty acids to 20:1.88 While there are multiple explanations, researchers attribute this in large part to the ubiquity of vegetable oils (e.g., soybean oil) present in the Western diet.89

This is important for a number of reasons, especially when it comes to promoting a healthy inflammatory response. For example, omega-3 fatty acids have anti-inflammatory effects (e.g., suppress IL-1ß, TNF-α, and IL-6) whereas omega-6 fatty acids do not.90 In fact, studies show that omega-6 fats promote inflammation, particularly when they are consumed in excess of omega-3 fats.91

Omega-3 fatty acids get incorporated into the body’s cell membranes, which keeps them more “fluid.” This ultimately allows for better communication (e.g., hormones, neurotransmitters) and nutrient uptake (e.g., protein synthesis, glycogen synthesis). However, omega-3 fatty acids compete with omega-6 fatty acids (and other fats) for “parking

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spots” within the cell membrane.92 Thus, increasing omega-3 fatty acids (via EPA and DHA)—and subsequently decreasing omega-6 fatty acids—tends to promote a healthy inflammatory response and lead to improvements in a variety of health parameters.

In a study published in the European Journal of Clinical Nutrition, French researchers assessed the effects of a 10-week diet modification to decrease the ratio of omega-6 to omega-3 fats in healthy subjects on various health parameters, including inflammatory markers.93 The researchers found that the diet intervention (i.e., decreased omega-6 and increased omega-3 fatty acids) resulted in significant reductions in TNF-α and “multiple favourable effects on the metabolic and inflammatory profiles.”

As mentioned above, the modern food supply is rife with industrial vegetable oils rich in pro-inflammatory omega-6 fatty acids (e.g., soybean, safflower, sunflower, corn, etc.), and an increase in omega-3 fatty acids (e.g., freshwater fish, fish oil supplements) and a concomitant decrease in omega-6 fatty acids appears crucial in promoting a healthy inflammatory response and supporting joint health. In fact, excessive consumption of omega-6 fatty acids coupled with a deficiency of omega-3 fats is connected to an increase in all conditions characterized by inflammatory stress, including joint discomfort and poor joint health.87,94

In one study, Australian researchers found that improving the ratio between omega-6 and omega-3 fatty acids through EPA and DHA supplementation (i.e., 4 grams total per day) resulted in a substantial decrease in the pro-inflammatory compounds IL-1ß and TNF-α. The researchers reported that the omega-3 fatty acids EPA and DHA help ease joint discomfort through their actions on promoting a healthy inflammatory response.95 In a review study published in the Journal of Clinical Epidemiology, researchers from Harvard Medical School analyzed the data from 10 double-blind, placebo-controlled studies and concluded that supplementation with omega-3 fatty acids significantly reduced joint discomfort and stiffness.96

With all of that in mind, you’d be well-advised to consume coldwater fish on a regular basis to help promote joint health and comfort, and many experts recommend

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consuming at least 4 ounces several times per week. In addition to supplementing with a high-quality fish oil supplement daily, the following are the best sources of fish rich in EPA and DHA:

• Anchovy• Herring• Mackerel• Sardine• Salmon• Trout• Tuna

Broccoli and Other Cruciferous VeggiesGeorge W. Bush once said, “I do not like broccoli. And I haven’t liked it since I was a little kid and my mother made me eat it. And I’m President of the United States and I’m not going to eat any more broccoli.” While the 41st President of the United States got many things right, it’s safe to say that this was not one of his better decisions. Love it or hate it, broccoli is good for you, and it’s packed with nutrients that can promote superior joint health.

Broccoli (along with other cruciferous vegetables) is rich in a compound called sulforaphane, which has been shown to promote a healthy inflammatory response and support joint health.97 In a recent study, a research team from the University of East Anglia led by Dr. Ian Clark found that sulforaphane blocks the action of enzymes (i.e., MMPs) that result in joint tissue breakdown, and what’s more, the researchers also confirmed that sulforaphane provides superior joint protection by reducing inflammation.98

In a series of studies, researchers from Korea have made similar findings,

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demonstrating that sulforaphane effectively inhibits the production of inflammatory molecules and action of enzymes involved in the breakdown of joint structures.99,100

Technically, sulforaphane is an isothiocynate, and broccoli and other cruciferous vegetables are rich in glucosinolates, which are precursors to isothiocynates. For instance, broccoli contains the glucosinolate glucophoranin, and when the vegetable is chopped or chewed, it is exposed to the action of an enzyme myrosinase to yield sulforaphane, the isothiocyanate. With that in mind, it’s a good reminder to eat slowly and take your time chewing your food.

In addition to sulforaphane, broccoli is an excellent source of vitamin C. In fact, among the cruciferous family, which also includes cauliflower, Brussels sprouts, kale, cabbage, and bok choy, broccoli is the most concentrated source of this potent antioxidant, providing over 100% of the daily Dietary Reference Intake (DRI) in single one-cup serving.

As part of the Framingham study, researchers from Boston University Medical Center found that, among 640 men and women, folks with the highest intake of vitamin C showed the greatest joint protective effects and lowest incidence of knee discomfort.101 While vitamin C is typically viewed simply as an antioxidant, it’s important to note that vitamin C plays a significant role in the synthesis of collagen, a major component of many connective tissues including cartilage and bone.102

On top of these joint protective nutrients, broccoli is also an excellent source of vitamin K, providing over 200% of the DRI in a one-cup serving. Vitamin K plays an important role in bone and cartilage mineralization (i.e., the process of creating new bone and cartilage), and several studies have found a link between low levels of vitamin K, poor joint health, and joint discomfort.103–105

With all of this in mind, broccoli and cruciferous vegetables contain an array of joint supernutrients, and the evidence suggests that regular consumption of these superfoods may be helpful in promoting joint health and easing joint discomfort.

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Brazil Nuts and Other NutsBrazil nuts are one of the most concentrated sources of the micronutrient selenium, which serves a critical role in the body’s antioxidant defense systems, and studies have shown that Brazil nut consumption can significantly improve antioxidant status and increase the activity of glutathione peroxidase, a family of enzymes whose main task is to reduce oxidative stress.106–108

While its antioxidant prowess may be reason enough to consume more selenium to support healthy joints, there’s research to suggest that low selenium intake may be linked to poor joint health and joint discomfort. Researchers from the University of North Carolina found that, among over 4,400 participants, folks with the highest selenium intakes had the lowest incidence of joint discomfort. What’s more, they found that the severity of the participants’ joint discomfort was directly related to how low their selenium levels were.109

A number of studies have suggested that health benefits of nuts may be due to their supply of antioxidants and the role that they play in reducing oxidative stress. Of the tree nuts, walnuts and pecans are among the plant-based foods with the highest content of total antioxidants.110 Nuts are among the best sources of vitamin E, and research has shown a connection between vitamin E intake and joint health.101

Walnuts are also one of the better plant-based sources of omega-3 fatty acids, specifically alpha linolenic acid (ALA), which is considered to be the “parent” omega-3 fatty acid to the aforementioned EPA and DHA. It should be noted that ALA must be converted (in the liver) into EPA and DHA, and although the human body has the capability to do this, it has only a very limited capacity do so, as the conversion rate is relatively poor (e.g., 5%).111

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Cashews are an excellent source of copper, which plays an important role in joint health and tissue formation. Specifically, copper is necessary for the synthesis of elastin and collagen, which provide the framework for healthy joint structures, and studies have linked low copper intake to joint discomfort and declining joint health.112,113 Because of their array of antioxidants, vitamins, and minerals, it’s a good idea to consume a variety of nuts on a regular basis to promote superior joints.

Dairy, Yogurt, and Other Fermented FoodsThere’s a common misconception that dairy products may lead to joint discomfort and stiffness. However, the body of evidence suggests otherwise; in fact, there’s a robust body of research to suggest that dairy may ease joint discomfort and reduce joint flare-ups.

This really shouldn’t come as much of a surprise, as higher intakes of specific nutrients from dairy (e.g., calcium, B vitamins, protein, magnesium, vitamin D) are linked to improved bone health and muscle function, which may enhance joint protection.114,115 Not only that, studies show that dairy intake is inversely associated with body fat percentage, abdominal fat, body mass index, waist circumference, and hip circumference.116 As previously alluded to, maintaining a healthy body fat percentage may promote joint health and joint comfort considering the roles that excess body weight and inflammatory compounds (secreted by fat cells) may have on joint discomfort.

In one study published in the journal Clinical and Experimental Rheumatology, researchers from Akdeniz University in Turkey found that among 655 men and women, folks who consumed dairy daily had a significantly lower occurrence of joint discomfort.117

In a recent study, a group of researchers from Harvard Medical School, Tufts University, the University of Massachusetts Medical School, and Brown University found that among 2,148 women, those who drank more milk experienced a significant decrease in

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joint breakdown over time. Specifically, over the course of 4 years, women who drank 7 or more glasses of milk per week demonstrated a 32% improvement in joint health compared to women who drank none.118

In another recent study, a group of researchers from the Bone and Joint Research Group at the University of Auckland in New Zealand found that 3 months of daily milk consumption significantly reduced the number of joint flare-ups among a group of 120 participants.119 The researchers also found that milk fortified with glycomacropeptide (GMP) and G600 milk fat extract led to even greater reductions in flare-ups. GMP and G600 are two components found in dairy that have been shown to help promote a healthy inflammatory response (e.g., inhibit IL-1ß).120 Observational studies have also shown that dairy consumption is associated with lower concentrations of uric acid, which can contribute to joint flare-ups and discomfort.121

While dairy may help ease joint discomfort and promote joint health, fermented dairy (e.g., yogurt, kefir) and other traditionally-fermented foods (e.g., sauerkraut, pickles, miso, tempeh) rich in healthy bacteria may provide even greater benefit. As has been discussed, there are a number of factors (e.g., oxidative stress, inflammation, overweight/obesity, AGEs, aging) that may contribute to declining joint health and joint discomfort, and more and more researchers are beginning to speculate that the gut microbiome may also play a role.

In fact, Dr. Jose Scher, a rheumatologist at New York University, has published a number of studies showing that the gut microbiome of folks who regularly experience joint discomfort and flare-ups is characterized by dysbiosis.122,123 Dysbiosis refers to microbial imbalances on or within the body. In other words, dysbiosis describes the state of an unhealthy imbalance of bacteria in the gut flora, characterized by excessive levels of pathogenic bacteria, inadequate amounts of commensal and probiotic bacteria, and/or reduced bacterial diversity.

This connection between gut dysbiosis and joint discomfort makes sense, as healthy bacteria serve a wide array of functions in the body, including regulating and supporting

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a healthy immune system and promoting a healthy inflammatory response by producing anti-inflammatory cytokines (and down-regulating pro-inflammatory cytokines).124,125

In a double-blind, placebo-controlled study published in the journal Nutrition, researchers from Iran found that folks who supplemented with a probiotic (Lactobacillus casei) daily for 8 weeks significantly improved joint health. What’s more, the folks taking the probiotic also demonstrated significantly reduced markers of several inflammatory chemicals (e.g,. TNF-α, IL-6, IL12) and showed an overall improved inflammatory status.126

Overall, the evidence supports the regular consumption of dairy to ease joint discomfort, reduce joint flare-ups, and promote joint health. What’s more, emerging research suggests that the gut microbiome and establishing a healthy balance of gut bacteria (i.e., symbiosis), which can be promoted by increasing consumption of fermented foods and/or supplementing with probiotics, may play an important role in supporting a healthy immune system and inflammatory response.

Superfoods for Superior JointsAs highlighted above, there are a number of factors that appear to contribute to declining joint health and joint discomfort, and the great news is that research shows that many of these can be managed through dietary choices and lifestyle behaviors. In other words, promoting joint health, supporting joint comfort, improving physical function, reducing joint stiffness, and decreasing joint flare-ups may be well within your control, starting with the food choices that you make.

The superfoods outlined above are nutrient-dense, and they are rife with vitamins, minerals, antioxidant phytochemicals, anti-inflammatory nutrients, healthy bacteria, and more. Consider adding more of these whole foods, which support a strong antioxidant defense system, a healthy inflammatory response, and a robust immune system, to your nutrition arsenal to bolster joint health. Also, pay close attention to how your body responds to your overall diet to help identify if specific foods lead you to experience joint discomfort, flare-ups, and stiffness.

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References:1. Liikavainio T, Lyytinen T, Tyrväinen E, Sipilä S, Arokoski JP. Physical function and

properties of quadriceps femoris muscle in men with knee osteoarthritis. Arch Phys Med Rehabil. 2008;89(11):2185-2194. doi:10.1016/j.apmr.2008.04.012.

2. Phillips S, Dow L. Impact of impaired morning function on quality of life in rheumatoid arthritis: results of an exploratory patient survey. Int J Clin Rheumatol. 2012;7(6):597-606. doi:10.2217/ijr.12.62.

3. Health, United States, 2011: With Special Feature on Socioeconomic Status and Health. National Center for Health Statistics.; 2012. http://www.cdc.gov/nchs/data/hus/hus11.pdf.

4. Green GA. Understanding NSAIDs: from aspirin to COX-2. Clin Cornerstone. 2001;3(5):50-60.

5. Richmond SA, Fukuchi RK, Ezzat A, Schneider K, Schneider G, Emery CA. Are joint injury, sport activity, physical activity, obesity, or occupational activities predictors for osteoarthritis? A systematic review. J Orthop Sports Phys Ther. 2013;43(8):515-B19. doi:10.2519/jospt.2013.4796.

6. Shane Anderson A, Loeser RF. Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol. 2010;24(1):15-26. doi:10.1016/j.berh.2009.08.006.

7. Jacques C, Gosset M, Berenbaum F, Gabay C. The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation. Vitam Horm. 2006;74:371-403. doi:10.1016/S0083-6729(06)74016-X.

8. Goldring MB, Berenbaum F. The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide. Clin Orthop. 2004;(427 Suppl):S37-S46.

9. van der Kraan PM, van den Berg WB. Anabolic and destructive mediators in osteoarthritis. Curr Opin Clin Nutr Metab Care. 2000;3(3):205-211.

26

Hajer GR, van Haeften TW, Visseren FLJ. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008;29(24):2959-2971. doi:10.1093/eurheartj/ehn387.

10. Hummasti S, Hotamisligil GS. Endoplasmic reticulum stress and inflammation in obesity and diabetes. Circ Res. 2010;107(5):579-591. doi:10.1161/CIRCRESAHA.110.225698.

11. Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol. 2011;29:415-445. doi:10.1146/annurev-immunol-031210-101322.

12. Patel C, Ghanim H, Ravishankar S, et al. Prolonged reactive oxygen species generation and nuclear factor-kappaB activation after a high-fat, high-carbohydrate meal in the obese. J Clin Endocrinol Metab. 2007;92(11):4476-4479. doi:10.1210/jc.2007-0778.

13. Aljada A, Mohanty P, Ghanim H, et al. Increase in intranuclear nuclear factor kappaB and decrease in inhibitor kappaB in mononuclear cells after a mixed meal: evidence for a proinflammatory effect. Am J Clin Nutr. 2004;79(4):682-690.

14. Aljada A, Friedman J, Ghanim H, et al. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metabolism. 2006;55(9):1177-1185. doi:10.1016/j.metabol.2006.04.016.

15. Calder PC, Ahluwalia N, Brouns F, et al. Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr. 2011;106 Suppl 3:S5-S78. doi:10.1017/S0007114511005460.

16. Goldin A. Advanced Glycation End Products: Sparking the Development of Diabetic Vascular Injury. Circulation. 2006;114(6):597-605. doi:10.1161/CIRCULATIONAHA.106.621854.

17. Nowotny K, Jung T, Höhn A, Weber D, Grune T. Advanced Glycation End Products and Oxidative Stress in Type 2 Diabetes Mellitus. Biomolecules. 2015;5(1):194-222. doi:10.3390/biom5010194.

27

18. Betteridge DJ. What is oxidative stress? Metabolism. 2000;49(2 Suppl 1):3-8.

19. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11(3):298-300.

20. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408(6809):239-247. doi:10.1038/35041687.

21. Henrotin YE, Bruckner P, Pujol J-PL. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr Cartil OARS Osteoarthr Res Soc. 2003;11(10):747-755.

22. Singh G. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med. 1998;105(1B):31S - 38S.

23. Griffin MR. Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury. Am J Med. 1998;104(3A):23S - 29S; discussion 41S - 42S.

24. Wright JM. The double-edged sword of COX-2 selective NSAIDs. CMAJ Can Med Assoc J J Assoc Medicale Can. 2002;167(10):1131-1137.

25. Theodosakis J, Buff S. The Arthritis Cure: The Medical Miracle That Can Halt, Reverse, and May Even Cure Osteoarthritis. New York: St. Martin’s Press; 2004.

26. Green JA, Hirst-Jones KL, Davidson RK, et al. The potential for dietary factors to prevent or treat osteoarthritis. Proc Nutr Soc. 2014;73(02):278-288. doi:10.1017/S0029665113003935.

27. Wang W, Connor SL, Johnson EJ, Klein ML, Hughes S, Connor WE. Effect of dietary lutein and zeaxanthin on plasma carotenoids and their transport in lipoproteins in age-related macular degeneration. Am J Clin Nutr. 2007;85(3):762-769.

28. Blotman F, Maheu E, Wulwik A, Caspard H, Lopez A. Efficacy and safety of avocado/soybean unsaponifiables in the treatment of symptomatic osteoarthritis of the knee and hip. A prospective, multicenter, three-month, randomized, double-blind, placebo-controlled trial. Rev Rhum Engl Ed. 1997;64(12):825-834.

28

29. Maheu E, Mazières B, Valat JP, et al. Symptomatic efficacy of avocado/soybean unsaponifiables in the treatment of osteoarthritis of the knee and hip: a prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial with a six-month treatment period and a two-month followup demonstrating a persistent effect. Arthritis Rheum. 1998;41(1):81-91. doi:10.1002/1529-0131(199801)41:1<81::AID-ART11>3.0.CO;2-9.

30. Au RY, Al-Talib TK, Au AY, Phan PV, Frondoza CG. Avocado soybean unsaponifiables (ASU) suppress TNF-α, IL-1β, COX-2, iNOS gene expression, and prostaglandin E2 and nitric oxide production in articular chondrocytes and monocyte/macrophages. Osteoarthritis Cartilage. 2007;15(11):1249-1255. doi:10.1016/j.joca.2007.07.009.

31. Cameron M, Chrubasik S. Oral herbal therapies for treating osteoarthritis. In: The Cochrane Collaboration, ed. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2014. http://doi.wiley.com/10.1002/14651858.CD002947.pub2. Accessed October 22, 2015.

32. Unlu NZ, Bohn T, Clinton SK, Schwartz SJ. Carotenoid absorption from salad and salsa by humans is enhanced by the addition of avocado or avocado oil. J Nutr. 2005;135(3):431-436.

33. Beauchamp GK, Keast RSJ, Morel D, et al. Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature. 2005;437(7055):45-46. doi:10.1038/437045a.

34. Vane JR, Botting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res Off J Eur Histamine Res Soc Al. 1995;44(1):1-10.

35. Peyrot des Gachons C, Uchida K, Bryant B, et al. Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. J Neurosci Off J Soc Neurosci. 2011;31(3):999-1009. doi:10.1523/JNEUROSCI.1374-10.2011.

36. Togna GI, Togna AR, Franconi M, Marra C, Guiso M. Olive oil isochromans inhibit human platelet reactivity. J Nutr. 2003;133(8):2532-2536.

37. Chrysohoou C, Panagiotakos DB, Pitsavos C, Das UN, Stefanadis C. Adherence to the Mediterranean diet attenuates inflammation and coagulation process

29

in healthy adults: The ATTICA Study. J Am Coll Cardiol. 2004;44(1):152-158. doi:10.1016/j.jacc.2004.03.039.

38. Bulotta S, Celano M, Lepore SM, Montalcini T, Pujia A, Russo D. Beneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: focus on protection against cardiovascular and metabolic diseases. J Transl Med. 2014;12:219. doi:10.1186/s12967-014-0219-9.

39. Impellizzeri D, Esposito E, Mazzon E, et al. Oleuropein aglycone, an olive oil compound, ameliorates development of arthritis caused by injection of collagen type II in mice. J Pharmacol Exp Ther. 2011;339(3):859-869. doi:10.1124/jpet.111.182808.

40. Silva S, Sepodes B, Rocha J, et al. Protective effects of hydroxytyrosol-supplemented refined olive oil in animal models of acute inflammation and rheumatoid arthritis. J Nutr Biochem. 2015;26(4):360-368. doi:10.1016/j.jnutbio.2014.11.011.

41. Bogani P, Galli C, Villa M, Visioli F. Postprandial anti-inflammatory and antioxidant effects of extra virgin olive oil. Atherosclerosis. 2007;190(1):181-186. doi:10.1016/j.atherosclerosis.2006.01.011.

42. Rosillo MÁ, Alcaraz MJ, Sánchez-Hidalgo M, Fernández-Bolaños JG, Alarcón-de-la-Lastra C, Ferrándiz ML. Anti-inflammatory and joint protective effects of extra-virgin olive-oil polyphenol extract in experimental arthritis. J Nutr Biochem. 2014;25(12):1275-1281. doi:10.1016/j.jnutbio.2014.07.006.

43. Brehm BJ, Lattin BL, Summer SS, et al. One-Year Comparison of a High-Monounsaturated Fat Diet With a High-Carbohydrate Diet in Type 2 Diabetes. Diabetes Care. 2009;32(2):215-220. doi:10.2337/dc08-0687.

44. Wang H, Nair MG, Strasburg GM, et al. Antioxidant and antiinflammatory activities of anthocyanins and their aglycon, cyanidin, from tart cherries. J Nat Prod. 1999;62(2):294-296. doi:10.1021/np980501m.

45. Seeram N. Cyclooxygenase inhibitory and antioxidant cyanidin glycosides in cherries and berries. Phytomedicine. 2001;8(5):362-369. doi:10.1078/0944-7113-00053.

30

46. Blau LW. Cherry diet control for gout and arthritis. Tex Rep Biol Med. 1950;8(3):309-311.

47. Jacob RA, Spinozzi GM, Simon VA, et al. Consumption of cherries lowers plasma urate in healthy women. J Nutr. 2003;133(6):1826-1829.

48. Kelley DS, Rasooly R, Jacob RA, Kader AA, Mackey BE. Consumption of Bing sweet cherries lowers circulating concentrations of inflammation markers in healthy men and women. J Nutr. 2006;136(4):981-986.

49. Zhang Y, Neogi T, Chen C, Chaisson C, Hunter DJ, Choi HK. Cherry consumption and decreased risk of recurrent gout attacks. Arthritis Rheum. 2012;64(12):4004-4011. doi:10.1002/art.34677.

50. Bell PG, Gaze DC, Davison GW, George TW, Scotter MJ, Howatson G. Montmorency tart cherry (Prunus cerasus L.) concentrate lowers uric acid, independent of plasma cyanidin-3-O-glucosiderutinoside. J Funct Foods. 2014;11:82-90. doi:10.1016/j.jff.2014.09.004.

51. Schumacher HR, Pullman-Mooar S, Gupta SR, Dinnella JE, Kim R, McHugh MP. Randomized double-blind crossover study of the efficacy of a tart cherry juice blend in treatment of osteoarthritis (OA) of the knee. Osteoarthritis Cartilage. 2013;21(8):1035-1041. doi:10.1016/j.joca.2013.05.009.

52. Chai SC, Hooshmand S, Saadat RL, Payton ME, Brummel-Smith K, Arjmandi BH. Daily apple versus dried plum: impact on cardiovascular disease risk factors in postmenopausal women. J Acad Nutr Diet. 2012;112(8):1158-1168. doi:10.1016/j.jand.2012.05.005.

53. Tishler M, Caspi D, Yaron M. C-reactive protein levels in patients with rheumatoid arthritis: the impact of therapy. Clin Rheumatol. 1985;4(3):321-324.

54. Otterness IG. The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum. 1994;24(2):91-104.

55. Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthritis of the hand and knee in women: a twin study. J Rheumatol. 1996;23(7):1221-1226.

31

56. Anderson JJ, Felson DT. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work. Am J Epidemiol. 1988;128(1):179-189.

57. Felson DT. Weight and osteoarthritis. J Rheumatol Suppl. 1995;43:7-9.

58. Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc. 2001;60(3):349-356.

59. Kane A. How Fat Affects Arthritis. Arthritis Found. http://www.arthritis.org/living-with-arthritis/comorbidities/obesity-arthritis/fat-and-arthritis.php.

60. Felson DT, Zhang Y, Hannan MT, et al. Risk factors for incident radiographic knee osteoarthritis in the elderly: the Framingham Study. Arthritis Rheum. 1997;40(4):728-733. doi:10.1002/1529-0131(199704)40:4&lt;728::AID-ART19&gt;3.0.CO;2-D.

61. Boyer J, Liu RH. Apple phytochemicals and their health benefits. Nutr J. 2004;3:5. doi:10.1186/1475-2891-3-5.

62. Jackson JK, Higo T, Hunter WL, Burt HM. The antioxidants curcumin and quercetin inhibit inflammatory processes associated with arthritis. Inflamm Res Off J Eur Histamine Res Soc Al. 2006;55(4):168-175. doi:10.1007/s00011-006-0067-z.

63. Lay E, Samiric T, Handley CJ, Ilic MZ. Short- and long-term exposure of articular cartilage to curcumin or quercetin inhibits aggrecan loss. J Nutr Biochem. 2012;23(2):106-112. doi:10.1016/j.jnutbio.2010.11.004.

64. S. A. H, A. A, T. O. M, T. A. A. Quercetin Dampens Postprandial Hyperglycemia in Type 2 Diabetic Patients Challenged with Carbohydrates Load. Int J Diabetes Res. 2012;1(3):32-35. doi:10.5923/j.diabetes.20120103.01.

65. Diabetes and Your Joints. Clin Diabetes. 2001;19(3):136-136. doi:10.2337/diaclin.19.3.136.

32

66. Del Rio D, Borges G, Crozier A. Berry flavonoids and phenolics: bioavailability and evidence of protective effects. Br J Nutr. 2010;104(S3):S67-S90. doi:10.1017/S0007114510003958.

67. Felgines C, Talavéra S, Gonthier M-P, et al. Strawberry anthocyanins are recovered in urine as glucuro- and sulfoconjugates in humans. J Nutr. 2003;133(5):1296-1301.

68. Norberto S, Silva S, Meireles M, Faria A, Pintado M, Calhau C. Blueberry anthocyanins in health promotion: A metabolic overview. J Funct Foods. 2013;5(4):1518-1528. doi:10.1016/j.jff.2013.08.015.

69. Sesso HD, Gaziano JM, Jenkins DJA, Buring JE. Strawberry intake, lipids, C-reactive protein, and the risk of cardiovascular disease in women. J Am Coll Nutr. 2007;26(4):303-310.

70. Ruel G, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C. Low-calorie cranberry juice supplementation reduces plasma oxidized LDL and cell adhesion molecule concentrations in men. Br J Nutr. 2008;99(2):352-359. doi:10.1017/S0007114507811986.

71. Ruel G, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C. Plasma matrix metalloproteinase (MMP)-9 levels are reduced following low-calorie cranberry juice supplementation in men. J Am Coll Nutr. 2009;28(6):694-701.

72. Itoh T, Matsuda H, Tanioka M, Kuwabara K, Itohara S, Suzuki R. The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. J Immunol Baltim Md 1950. 2002;169(5):2643-2647.

73. Moghe SS, Juma S, Imrhan V, Vijayagopal P. Effect of blueberry polyphenols on 3T3-F442A preadipocyte differentiation. J Med Food. 2012;15(5):448-452. doi:10.1089/jmf.2011.0234.

74. McAnulty LS, Nieman DC, Dumke CL, et al. Effect of blueberry ingestion on natural killer cell counts, oxidative stress, and inflammation prior to and after 2.5 h of running. Appl Physiol Nutr Metab Physiol Appliquée Nutr Métabolisme. 2011;36(6):976-984. doi:10.1139/h11-120.

33

75. McLeay Y, Barnes MJ, Mundel T, Hurst SM, Hurst RD, Stannard SR. Effect of New Zealand blueberry consumption on recovery from eccentric exercise-induced muscle damage. J Int Soc Sports Nutr. 2012;9(1):19. doi:10.1186/1550-2783-9-19.

76. Bitsch R, Netzel M, Frank T, Strass G, Bitsch I. Bioavailability and Biokinetics of Anthocyanins From Red Grape Juice and Red Wine. J Biomed Biotechnol. 2004;2004(5):293-298. doi:10.1155/S1110724304403106.

77. de la Lastra CA, Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res. 2005;49(5):405-430. doi:10.1002/mnfr.200500022.

78. Udenigwe CC, Ramprasath VR, Aluko RE, Jones PJH. Potential of resveratrol in anticancer and anti-inflammatory therapy. Nutr Rev. 2008;66(8):445-454. doi:10.1111/j.1753-4887.2008.00076.x.

79. Candelario-Jalil E, de Oliveira ACP, Gräf S, et al. Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia. J Neuroinflammation. 2007;4:25. doi:10.1186/1742-2094-4-25.

80. Liu F-C, Hung L-F, Wu W-L, et al. Chondroprotective effects and mechanisms of resveratrol in advanced glycation end products-stimulated chondrocytes. Arthritis Res Ther. 2010;12(5):R167. doi:10.1186/ar3127.

81. Verzijl N, DeGroot J, Ben ZC, et al. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. Arthritis Rheum. 2002;46(1):114-123. doi:10.1002/1529-0131(200201)46:1<114::AID-ART10025>3.0.CO;2-P.

82. Yammani RR, Carlson CS, Bresnick AR, Loeser RF. Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: Role of the receptor for advanced glycation end products. Arthritis Rheum. 2006;54(9):2901-2911. doi:10.1002/art.22042.

83. Gescher AJ, Steward WP. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer

34

Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2003;12(10):953-957.

84. Bognar E, Sarszegi Z, Szabo A, et al. Antioxidant and anti-inflammatory effects in RAW264.7 macrophages of malvidin, a major red wine polyphenol. PloS One. 2013;8(6):e65355. doi:10.1371/journal.pone.0065355.

85. Crews FT, Bechara R, Brown LA, et al. Cytokines and alcohol. Alcohol Clin Exp Res. 2006;30(4):720-730. doi:10.1111/j.1530-0277.2006.00084.x.

86. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med Maywood NJ. 2008;233(6):674-688. doi:10.3181/0711-MR-311.

87. Simopoulos AP. Overview of evolutionary aspects of omega 3 fatty acids in the diet. World Rev Nutr Diet. 1998;83:1-11.

88. Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, Rawlings RR. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr. 2011;93(5):950-962. doi:10.3945/ajcn.110.006643.

89. Simopoulos AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother Bioméd Pharmacothérapie. 2006;60(9):502-507. doi:10.1016/j.biopha.2006.07.080.

90. Bosma-den Boer MM, van Wetten M-L, Pruimboom L. Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering. Nutr Metab. 2012;9(1):32. doi:10.1186/1743-7075-9-32.

91. Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr. 2006;83(6 Suppl):1467S - 1476S.

92. Guebre-Egziabher F, Rabasa-Lhoret R, Bonnet F, et al. Nutritional intervention to reduce the n-6/n-3 fatty acid ratio increases adiponectin concentration and fatty acid oxidation in healthy subjects. Eur J Clin Nutr. 2008;62(11):1287-1293. doi:10.1038/sj.ejcn.1602857.

35

93. Hibbeln JR, Nieminen LRG, Blasbalg TL, Riggs JA, Lands WEM. Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity. Am J Clin Nutr. 2006;83(6 Suppl):1483S - 1493S.

94. James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis Rheum. 1997;27(2):85-97.

95. Fortin PR, Lew RA, Liang MH, et al. Validation of a meta-analysis: The effects of fish oil in rheumatoid arthritis. J Clin Epidemiol. 1995;48(11):1379-1390. doi:10.1016/0895-4356(95)00028-3.

96. Juge N, Mithen RF, Traka M. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci CMLS. 2007;64(9):1105-1127. doi:10.1007/s00018-007-6484-5.

97. Davidson RK, Jupp O, de Ferrars R, et al. Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo. Arthritis Rheum. 2013;65(12):3130-3140. doi:10.1002/art.38133.

98. Ah Kim H, Yeo Y, Kim W-U, Kim S. Phase 2 enzyme inducer sulphoraphane blocks matrix metalloproteinase production in articular chondrocytes. Rheumatology. 2009;48(8):932-938. doi:10.1093/rheumatology/kep132.

99. Kim H-A, Yeo Y, Jung HA, Jung YO, Park SJ, Kim SJ. Phase 2 enzyme inducer sulphoraphane blocks prostaglandin and nitric oxide synthesis in human articular chondrocytes and inhibits cartilage matrix degradation. Rheumatol Oxf Engl. 2012;51(6):1006-1016. doi:10.1093/rheumatology/ker525.

100. McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 1996;39(4):648-656.

101. Clark AG, Rohrbaugh AL, Otterness I, Kraus VB. The effects of ascorbic acid on cartilage metabolism in guinea pig articular cartilage explants. Matrix Biol J Int Soc Matrix Biol. 2002;21(2):175-184.

36

102. Neogi T, Booth SL, Zhang YQ, et al. Low vitamin K status is associated with osteoarthritis in the hand and knee. Arthritis Rheum. 2006;54(4):1255-1261. doi:10.1002/art.21735.

103. Oka H, Akune T, Muraki S, et al. Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dietary survey in a population-based cohort of the ROAD study. J Orthop Sci Off J Jpn Orthop Assoc. 2009;14(6):687-692. doi:10.1007/s00776-009-1395-y.

104. Misra D, Booth SL, Tolstykh I, et al. Vitamin K Deficiency Is Associated with Incident Knee Osteoarthritis. Am J Med. 2013;126(3):243-248. doi:10.1016/j.amjmed.2012.10.011.

105. Tapiero H, Townsend DM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharmacother Bioméd Pharmacothérapie. 2003;57(3-4):134-144.

106. Tinggi U. Selenium: its role as antioxidant in human health. Environ Health Prev Med. 2008;13(2):102-108. doi:10.1007/s12199-007-0019-4.

107. Huguenin GVB, Oliveira GMM, Moreira ASB, et al. Improvement of antioxidant status after Brazil nut intake in hypertensive and dyslipidemic subjects. Nutr J. 2015;14(1). doi:10.1186/s12937-015-0043-y.

108. Jordan JM. An Ongoing Assessment of Osteoarthritis in African Americans and Caucasians in North Carolina: The Johnston County Osteoarthritis Project. Trans Am Clin Climatol Assoc. 2015;126:77-86.

109. Blomhoff R, Carlsen MH, Andersen LF, Jacobs DR. Health benefits of nuts: potential role of antioxidants. Br J Nutr. 2006;96 Suppl 2:S52-S60.

110. Gerster H. Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)? Int J Vitam Nutr Res Int Z Für Vitam- Ernährungsforschung J Int Vitaminol Nutr. 1998;68(3):159-173.

111. Harris ED, Rayton JK, Balthrop JE, DiSilvestro RA, Garcia-de-Quevedo M. Copper and the synthesis of elastin and collagen. Ciba Found Symp. 1980;79:163-182.

37

112. Kremer JM, Bigaouette J. Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, copper, and magnesium. J Rheumatol. 1996;23(6):990-994.

113. Houston DK, Nicklas BJ, Ding J, et al. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study. Am J Clin Nutr. 2008;87(1):150-155.

114. Janssen HCJP, Samson MM, Verhaar HJJ. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr. 2002;75(4):611-615.

115. Murphy K, Crichton G, Dyer K, et al. Dairy Foods and Dairy Protein Consumption Is Inversely Related to Markers of Adiposity in Obese Men and Women. Nutrients. 2013;5(11):4665-4684. doi:10.3390/nu5114665.

116. Kaçar C, Gilgil E, Tuncer T, et al. The association of milk consumption with the occurrence of symptomatic knee osteoarthritis. Clin Exp Rheumatol. 2004;22(4):473-476.

117. Lu B, Driban JB, Duryea J, McAlindon T, Lapane KL, Eaton CB. Milk Consumption and Progression of Medial Tibiofemoral Knee Osteoarthritis: Data From the Osteoarthritis Initiative: Association of Milk Consumption With Progression of Knee OA. Arthritis Care Res. 2014;66(6):802-809. doi:10.1002/acr.22297.

118. Dalbeth N, Ames R, Gamble GD, et al. Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomised controlled trial. Ann Rheum Dis. 2012;71(6):929-934. doi:10.1136/annrheumdis-2011-200156.

119. Dalbeth N, Gracey E, Pool B, et al. Identification of dairy fractions with anti-inflammatory properties in models of acute gout. Ann Rheum Dis. 2010;69(4):766-769. doi:10.1136/ard.2009.113290.

120. Choi HK, Liu S, Curhan G. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2005;52(1):283-289. doi:10.1002/art.20761.

121. Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife. 2013;2:e01202.

38

doi:10.7554/eLife.01202.

122. Scher JU, Ubeda C, Artacho A, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol Hoboken NJ. 2015;67(1):128-139. doi:10.1002/art.38892.

123. Bahrami B, Macfarlane S, Macfarlane GT. Induction of cytokine formation by human intestinal bacteria in gut epithelial cell lines. J Appl Microbiol. 2011;110(1):353-363. doi:10.1111/j.1365-2672.2010.04889.x.

124. Menard S. Lactic acid bacteria secrete metabolites retaining anti-inflammatory properties after intestinal transport. Gut. 2004;53(6):821-828. doi:10.1136/gut.2003.026252.

125. Vaghef-Mehrabany E, Alipour B, Homayouni-Rad A, Sharif S-K, Asghari-Jafarabadi M, Zavvari S. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutr Burbank Los Angel Cty Calif. 2014;30(4):430-435. doi:10.1016/j.nut.2013.09.007.