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Obesity-Related Inflammation:Implications for Older AdultsAmy Ellis PhD, RD, LD a , Kristi Crowe PhD, RD, LD a & JeannineLawrence PhD, RD, LD aa Department of Human Nutrition , University of Alabama ,Tuscaloosa , Alabama , USAPublished online: 13 Nov 2013.

To cite this article: Amy Ellis PhD, RD, LD , Kristi Crowe PhD, RD, LD & Jeannine Lawrence PhD,RD, LD (2013) Obesity-Related Inflammation: Implications for Older Adults, Journal of Nutrition inGerontology and Geriatrics, 32:4, 263-290, DOI: 10.1080/21551197.2013.842199

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Review

Obesity-Related Inflammation: Implicationsfor Older Adults

AMY ELLIS, PhD, RD, LD, KRISTI CROWE, PhD, RD, LD, andJEANNINE LAWRENCE, PhD, RD, LD

Department of Human Nutrition, University of Alabama, Tuscaloosa, Alabama, USA

The combination of age-related increases in obesity and inflam-mation can lead to chronic disease, decreased strength, and physicaldisability. Lifestyle interventions that include moderate caloric restric-tion along with aerobic and resistance exercise have shown improve-ments inmetabolic outcomes, strength, and physical function in obeseolder adults. Although few weight loss studies have addressed dietquality, evidence summarized in this review suggests that encour-aging intake of antioxidant-rich fruits and vegetables, high-qualityprotein, low-glycemic index carbohydrates, and omega-3 fattyacids may further ameliorate obesity-related inflammation. Futurecontrolled trials are indicated to examine the effects of incorporatingthese foods into multimodal weight loss interventions.

KEYWORDS diet quality, inflammation, obesity, oxidative stress,visceral adipose tissue

BACKGROUND: AGE-RELATED INCREASES IN ADIPOSITYAND INFLAMMATION

Increases in Adiposity With Aging

Aging is characterized by an increase in fat mass, representing only one ofseveral age-related body composition changes that can negatively impactoverall health. Body composition is most commonly defined by a two-compartment model that divides body tissue into fat mass (mainly adiposetissue) and fat-free mass (muscle, bone, and body water) (1). With aging,

Address correspondence to Amy Ellis, PhD, RD, LD, Department of Human Nutrition,University of Alabama, 405 Russell Hall, Box 870311, Tuscaloosa, AL 35487, USA. E-mail:aellis@ches.ua.edu

Journal of Nutrition in Gerontology and Geriatrics, 32:263–290, 2013Copyright # Taylor & Francis Group, LLCISSN: 2155-1197 print=2155-1200 onlineDOI: 10.1080/21551197.2013.842199

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a progressive loss of fat-free mass is concomitant with the accrual of fat mass.In addition to increases of overall adiposity, a redistribution of fat mass alsooccurs. Body fat is stored primarily as triglycerides in subcutaneous adiposetissue (SAT), located beneath the skin, and visceral adipose tissue (VAT), sur-rounding internal organs deeper within the abdominal cavity. With advancedage, SAT decreases while VAT increases. Increased accumulation of triglycer-ides in nonadipose tissues is also observed such that both intramuscular andintrahepatic fat increase with age (2–4).

Although the technical definition of obesity is excess fat mass,robust assessment of fat mass and fat-free mass requires expensive methodssuch as dual-energy x-ray absorptiometry (DEXA) or air displacementplethysmography that are not routinely available in clinical settings. Differ-entiation between SAT and VAT requires even more expensive methods suchas magnetic resonance imaging or computed tomography (CT), as well astrained personnel for measurement and interpretation (5–7). Thus, obesityis usually quantified by body mass index (BMI), calculated as weight inkilograms divided by height in meters squared. The World Health Orga-nization and National Institutes of Health define underweight status asBMI<18.5 kg=m2, overweight status as BMI 25–29.9 kg=m2, and obesity asBMI�30 kg=m2. The criteria further delineate Class I Obesity as BMI30–34.9 kg=m2, Class II Obesity as BMI 35–39.9 kg=m2, and Class III Obesityas �40 kg=m2 (8). By this classification, approximately 35% of adults aged 65years and older in the United States were obese in 2007–2010. Obesity rateswere similar between men and women, but the prevalence among indivi-duals aged 65–74 years was higher (40.8%) than for those aged 75 yearsand older (27.8%) (9).

Despite its common use, many experts have criticized the application ofBMI to classify weight status of older adults. While BMI is highly correlatedwith percent body fat in younger adults (10), age-related changes in bodycomposition may confound the association in older adults. For example,vertebral compression alters height so that the BMI equation may overestimatefat mass in some individuals. Alternatively, because the equation does not dif-ferentiate fat mass and fat-free mass, the loss of lean mass and gain of fat massassociated with aging could result in the underestimation of body fat. Further-more, BMI also fails to account for the age-related increase in VAT (3, 5, 11).Although the same BMI criteria are used to classify all adults aged 20 yearsand older, evidence suggests that the optimal BMI for older adults is higherthan that for younger adults. Recent papers have identified the lowest ratesof mortality among older adults with BMI in the range of 27–30 kg=m2 (12)and the lowest rates of physical disability among those with BMI values25–29.9 kg=m2 (13). Note, however, that while overweight status does notappear to increase risk for physical disability, several studies have confirmedhigher rates of physical disability among those classified as obese (14–18).Additionally, obesity is a known risk factor for other chronic comorbidities

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common to older adults such as cardiovascular disease, type 2 diabetes,certain cancers, osteoarthritis, and cognitive dysfunction (4, 5, 11, 19).

The controversy surrounding the optimal BMI for older adults has led tosuggestions that waist circumference (WC) may be a better indicator ofobesity and associated risks for this population (5, 16, 20). For example, higherWC in older adults has been associated with frailty (14) and all-cause mortality(20) independent of BMI. WC provides a proxy measure of VAT, and VAT inparticular has been most strongly associated with metabolic and cardiovascularrisk in both younger and older adults (19, 21). Along with hypertension, glucoseintolerance, reduced high density lipoprotein (HDL)-cholesterol levels, andhypertriglyceridemia, an elevated WC (>102cm in men and>88cm in women)is one feature among a clustering of risk factors known as the metabolic syn-drome. As defined by the National Cholesterol Education Panel, presence ofthree or more of those criteria constitutes metabolic syndrome, and individualswith metabolic syndrome have an elevated risk for cardiovascular disease andtype 2 diabetes (22). The prevalence of metabolic syndrome increases with age,and elevated WC is the most commonly occurring criterion (23).

Increases in Inflammation with Aging

Aging is also characterized by chronic, low-grade inflammation. In a review ofepidemiological studies of aging, Singh and Newman identified interleukin-6(IL-6), tumor necrosis factor-alpha (TNF-a), and C-reactive protein (CRP) as themost commonly measured serum biomarkers of inflammation (24). Circulatinglevels of each of these proinflammatory cytokines increases with age (4, 25, 26).During a normal cellular response to injury, IL-6, TNF-a, and other proinflamma-tory molecules are released by cells. IL-6 then stimulates secretion of the acutephase protein, CRP, from hepatocytes. Together, these cytokines attract macro-phages to the site of injury, and activated macrophages secrete additional proin-flammatory compounds. Although this cascade results in production of freeradicals and reactive oxygen species (ROS), which cause minimal damage tosurrounding healthy tissue, the acute inflammatory response is beneficial toeliminate infection and facilitate tissue repair (27, 28). Conversely, prolongedelevations of circulating cytokines, as seen with aging, leads to degradation ofskeletal muscle (26), damage to vasculature (29), and impairment ofinsulin-mediated glucose uptake (30). Furthermore, prolonged periods ofincreased ROS overwhelm homeostatic antioxidant defenses, leading to oxidat-ive stress within cells. Operating under a positive feedback mechanism,increased ROS results in the production of more circulating proinflammatorycytokines (31). Like obesity, the chronic, low-grade inflammation typical ofadvanced age increases the risk of chronic conditions such as cardiovascular dis-ease, type 2 diabetes, and cognitive dysfunction (32–37). Large longitudinal stu-dies have also shown associations between circulating levels of proinflammatorycytokines and all-cause mortality in adults aged 65 years and older (38–40).

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INTERRELATIONSHIPS BETWEEN INCREASES INVISCERAL ADIPOSE TISSUE AND SYSTEMIC INFLAMMATION

WITH AGING

Obesity amplifies oxidative stress and inflammation. It is well-known thatadipocytes secrete a variety of proinflammatory cytokines including IL-6and TNF-a, among others (41), and production of these adipokines increaseswith accumulation of adipose tissue (16). Adipocytes also secrete the hormoneleptin, which increases inflammation by stimulating monocytes to produce IL-6,TNF-a, and interleukin-12. Circulating leptin levels rise with increasingadiposity (4, 26), thereby exacerbating inflammation. Systemic inflammationis further upregulated when hypertrophied adipocytes attract macrophages(26), which then secrete even more proinflammatory mediators (32).

When comparing types of adipose tissue, VAT secretes more inflamma-tory adipokines than SAT (11, 41, 42), and activated macrophages from VATin particular secrete copious amounts of TNF-a, IL-1, and IL-6 (26, 28).Accordingly, several large population studies have associated elevated WC,indicative of VAT, with higher levels of circulating inflammatory biomarkersin community-dwelling adults aged 65 years and older (43–45). Correlationsbetween central obesity and systemic inflammation in adults aged 65 to 80years have also been confirmed by studies measuring truncal fat by DEXA(46) and abdominal VAT by CT scans (47, 48).

Interrelationships between VAT and chronic inflammation are associa-ted with age-related metabolic disturbances. Accumulation of VAT in theabdominal cavity is thought to promote hepatic insulin resistance partly bythe release of adipokines into the hepatic portal vein (49). Proinflammatorycytokines generated from VAT also promote peripheral insulin resistancein older adults by interfering with insulin signaling pathways (30, 32).Moreover, accumulation of intramuscular lipid disrupts mitochondrialfunction and increases production of ROS in skeletal muscle, furtherimpeding insulin-mediated glucose uptake (4).

CONNECTIONS BETWEEN OBESITY, INFLAMMATION, ANDAGE-RELATED DECLINE IN MUSCLE MASS, STRENGTH,

AND PHYSICAL FUNCTION

Chronic low-grade inflammation and disrupted redox balance of skeletalmuscle also affect muscle mass, strength, and physical function in older adults.Sarcopenia is the term used to describe the loss of muscle mass and functionwith aging (7). Although the etiology of sarcopenia is multifactorial, inflam-mation has been identified as a key contributing factor (7, 50). TNF-a, IL-6,and IL-1 have a catabolic effects on skeletal muscle (11, 25). Fittingly, TNF-ais also sometimes called ‘‘cachectin’’ because of its association with muscle

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wasting in individuals with cachexia (28). Among 3075 men and womenaged 70 to 79 years from the Health ABC Study, participants with highercirculating levels of IL-6 and TNF-a had less muscle mass as measured by CT(51). Additionally, in longitudinal analyses of thousands of Health ABC Studyparticipants, higher serum levels of IL-6, CRP, and TNF-a at baseline predictedgreater declines in muscle mass and strength (52) as well as mobility(53) and physical function (54). Other longitudinal studies of community-dwelling adults aged 65 years and older have likewise shown associationsbetween circulating proinflammatory cytokines and loss of muscle mass(55), decline in grip strength (56), and incident mobility problems (57). Severalcross-sectional studies have also reported inverse associations betweenmarkers of inflammation and physical function in older adults (58–61).

Sarcopenic obesity was first defined by Baumgartner and colleagues asdecreased muscle mass concomitant with BMI> 30 kg=m2 (62). Althoughseveral different definitions have been applied to quantify low muscle mass withcoexistent excess adipose tissue (63), studies have repeatedly shown higherrates of physical disability among sarcopenic obese individuals compared toolder adults with either sarcopenia or obesity alone (7, 16, 62). A study examin-ing 1,127 men and women aged 60 years and older from the National Healthand Nutrition Examination Survey (NHANES 1999–2002) revealed that parti-cipants with the sarcopenic obese phenotype also had the highest levels of cir-culating CRP (64). Among 2,822 older adults in the Health ABC Study, increasedWC was associated with decreased physical performance, and the inflammatorybiomarkers IL-6 and CRP partially accounted for the association (43). Com-parably, data from the InCHIANTI Study also revealed a similar interactionbetween WC, markers of inflammation, and muscle strength. Among 871men and women aged 65 years and older, WC was associated with severalproinflammatory cytokines including IL-6 and CRP. In turn, higher levels ofproinflammatory cytokines were associated with lower grip strength (65).

OBESITY TREATMENTS FOR OLDER ADULTS

Given the deleterious effects of obesity, particularly central obesity, andassociated inflammation, it seems intuitive that weight reduction may beindicated to reduce the inflammatory burden of obese older adults. However,the topic of weight loss interventions for older adults remains controversial.Part of the controversy involves the ‘‘obesity paradox,’’ or the observation thatolder adult patients with higher BMI values and chronic diseases such as heartfailure, end-stage renal disease, and chronic obstructive pulmonary diseaseoften experience lower mortality rates compared to lean patients with theseconditions (11, 13, 19). However, critics argue that obesity itself is often a con-tributing factor to these chronic conditions (19). Another argument againstweight reduction stems from numerous epidemiological studies relating

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weight loss to increased mortality in older adults. Several review papers fromthe 1990s summarized these associations (66–68). Although not all studiesdifferentiated lean and obese participants, some researchers have reportedassociations between weight loss and increased mortality risk regardless ofbaseline BMI (69–71). Unfortunately, many epidemiological studies reportingthis association have not distinguished between intentional weight loss andunintentional weight loss. Observational studies that have differentiated thetwo have predominantly associated unintentional, but not intentional, weightloss with increased mortality (72–75), suggesting that unintentional weightloss may actually be indicative of other underlying disease states that affectmortality risk. In addition, some researchers have questioned whether physi-cal function, metabolic outcomes, and quality of life may be better outcomesto measure than total mortality. If epidemiological studies relating weight lossto total mortality statistically adjust for obesity-related comorbidities, thenbenefits of weight loss may not be articulated (16, 19).

Another possible contraindication for weight loss is the concern that it willexacerbate age-related losses ofmuscle andbone (6). For bothyounger andolderadults, weight loss results in reduction of fat-free mass along with fat mass (76). Afour-year follow-up of 2,163 older adults in the Health ABC Study demonstratedthat significant amounts of muscle and bone can be lost when older obese adultsintentionally lose weight, and the loss of fat-free mass with weight reductionexceeds the gain of fat-free mass with weight gain (77). Furthermore, althoughobesity is correlated with knee osteoarthritis in older adults (78–80), it is thoughtto be protective against osteoporosis and fracture risk because increased bodyweight is associated with increased bone mineral density (81).

Considering the potential risks and potential benefits of weight loss, in2005 the Obesity Society and the American Society for Nutrition issued a jointposition statement concerning weight management for older adults. In thisreport, they proposed that weight loss therapy may be advantageous forolder adults with obesity-related comorbidities, including impaired physicalfunction or chronic health conditions. The authors emphasized that treatmentshould be individualized and should encompass a multimodal lifestyleintervention including modest caloric restriction (500–750 kcals=day) andan exercise program that includes aerobic activity, stretching, and strengthtraining. The position paper also highlighted the need for randomizedcontrolled trials to evaluate these lifestyle interventions (5).

RANDOMIZED CONTROLLED TRIALS EVALUATINGMULTIMODAL LIFESTYLE INTERVENTIONS FOR

WEIGHT LOSS IN OLDER ADULTS

Since publication of the previously described 2005 position statement(5), several randomized controlled trials have evaluated the effects of

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diet-induced weight loss, with and without exercise, in obese adults aged 60years and older (78–80, 82–84) and aged 65 years and older (85–93). Resultsof these trials have been summarized in several comprehensive reviewpapers (94–97). Together, this body of literature provides evidence thatweight loss of 8%–10% is achievable for obese (BMI �30) older adultsthrough lifestyle interventions with modest caloric reduction (�750 kcals=d). Moreover, gradual controlled weight loss appears to improve both physicalfunction and metabolic parameters. Addition of aerobic and resistance exerciseimproves functional performance (79, 80, 85, 89) and muscle strength (83, 85,87, 89, 91, 92) while greatly attenuating loss of muscle (83, 85, 89, 91–93) andbone (84, 87, 90). Although research regarding postintervention weight main-tenance is limited, one study followed participants for 30 months aftercompletion of a diet and exercise program. Formerly obese adults aged 65years and older were able to maintain reduced weight and BMI measuressignificantly below baseline (P< 0.05), and no changes in appendicular leanmass or physical function were observed from the study’s completion throughthe 30-month follow-up. In addition, participants retained improvements ininsulin sensitivity and blood pressure throughout the follow-up period. Thisstudy provides promise that long-term weight maintenance is an achievablegoal for obese older adults after completion of weight loss programs (98).

EFFECTS OF LIFESTYLE INTERVENTIONS FOR WEIGHTREDUCTION ON MARKERS OF INFLAMMATION

Several randomized, controlled weight loss trials have demonstratedimprovement in markers of inflammation in older adults. The Arthritis, Diet,and Activity Promotion Trial (ADAPT) enrolled sedentary older adults aged60 years and older with a BMI �28 kg=m2 and diagnosed osteoarthritis. Part-icipants were randomized to diet-induced weight loss, diet and exercise, orcontrol groups for 18 months. Weight loss, with or without exercise, resultedin decreases in leptin (82), CRP, IL-6, and TNF-a soluble receptor-1 (78). Tenyears after the ADAPT trial, investigators used public records to examineassociations between intentional weight loss and mortality among the cohortof older adults who had completed the study. Participants from the weightloss arms of the original intervention (diet only or diet=exercise) demon-strated lower mortality rates than those who had been in the control group(99). In a separate clinical trial, frail sedentary adults aged 65 years and olderwith a BMI �30 kg=m2 were randomized to diet=exercise or control groupsfor six months. The number of participants meeting the criteria for metabolicsyndrome decreased significantly (P< 0.05) in the weight loss group, withconcomitant decreases in circulating CRP and IL-6 (86). Another study com-pared the effects of diet-induced weight loss without exercise to exercisewithout weight loss. Frail, obese men and women aged 65 years and older

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were randomized to caloric restriction or resistance=aerobic exercise for 12weeks. Both groups demonstrated reductions in circulating high-sensitivityC-reactive protein (HsCRP), but only the exercise group showed reducedskeletal muscle mRNA expression of several inflammatory proteins (suchas IL-6 and TNF-a) (92).

Other studies support the notion that exercise alone, independent ofweight loss, can ameliorate inflammation in older adults. Among cohortsof men and women aged 70 to 79 years (100) and postmenopausal womenaged 50 to 79 years (101), participants with higher levels of self-reportedphysical activity had lower levels of circulating CRP and IL-6. Anothercross-sectional analysis of 54 Brazilian women aged 60 years and oldercompared circulating cytokines of participants who had performed resist-ance exercise training over the previous eight months to those who weresedentary. Women in the resistance training group had significantly lowercirculating levels of IL-6, interferon-c, and TNF-a at month 8 (102). Note,however, serum markers in this study were not measured at baseline beforethe women began the exercise intervention. Given the considerableinterindividual variation of these cytokines (103), intraindividual changesin these biomarkers over time provide stronger evidence for risk reduction.For example, in a longitudinal study of healthy adults aged 50 to 76 years,two months of aerobic exercise training reduced gene expression ofmultiple markers of inflammation in peripheral blood mononuclear cells(104). Another randomized control trial assigned 45 men and women aged65 years and older to 16 weeks of aerobic training, resistance exercise, ora sedentary control group. Both aerobic and resistance training resultedin reductions in circulating HsCRP while no change was observed in thecontrol group (105).

DIET QUALITY AND OBESITY-RELATED INFLAMMATION

Antioxidant Micronutrients

To date, intervention trials targeting obese older adults have not emphasizeddiet quality. However, it is likely that bioactive food components withantioxidant capacity may act synergistically to influence inflammation bydecreasing oxidative stress. The relationship between inflammation andincreased ROS production is cyclical such that oxidative stress caused bythe accumulation of ROS augments chronic inflammation, and thoseinflammatory processes, in turn, weaken cellular antioxidant capacity(106). At the cellular level, endogenous antioxidant enzymes along with diet-ary compounds are responsible for protecting the body by halting the radicalreactions initiated by ROS, thus decreasing systemic inflammation (107).

Within adipocytes, antioxidant capacity decreases while ROS increasein parallel with fat accumulation (108). To illustrate, results of the

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cross-sectional ATTICA Study demonstrated that overweight or obese men(N¼ 1,518, 46� 13 years of age) had 6% lower serum antioxidant capacity(P¼ 0.03) compared to normal weight men, while overweight or obesewomen (N¼ 1,528, 45� 13 years of age) had 10% lower serum antioxidantcapacity (P¼ 0.02) compared to normal weight women. Associationsbetween serum antioxidant capacity and central adiposity were morepronounced than the associations between serum antioxidant capacity andgeneral obesity (109). Studies of younger adults have also reported inverseassociations between obesity and serum concentrations of lipid-solubleantioxidant micronutrients. For instance, a comparison of 180 lean and obesepremenopausal women aged 35 to 46 years revealed significantly lower(P< 0.05) serum carotenoids among obese subjects when compared to leansubjects (110). Another study of 3,128 French men and women aged 45 to 60years revealed lower serum concentrations of b-carotene and vitamin C amongobese participants compared to those with BMI values <30kg=m2 (111).

Although similar studies among obese older adults are lacking, theWomen’s Health and Aging Studies provide evidence that decreased anti-oxidant defenses and concomitant increased inflammation are associatedwith decreases in strength and function. In women aged 65 years and older,circulating levels of selenium, a-carotene, and total carotenoids wereinversely correlated with serum IL-6 at baseline. Over two years, participantswith the lowest levels of a-carotene, b-carotene, lutein=zeaxanthin, and totalcarotenoids experienced the greatest increases in circulating IL-6 (112). Inanother cross-sectional analysis of women aged 70 to 79 years from theWomen’s Health and Aging Studies, low serum carotenoids and low seruma-tocopherol were associated with poor muscle strength (113). Longitudinalanalysis of this cohort also revealed that women with the lowest levels ofserum carotenoids were more likely to develop mobility disability overa 36-month follow-up (114). Similarly, among 986 InCHIANTI studyparticipants aged 65 years and older, plasma a-tocopherol and c-tocopherolwere positively correlated with lower-extremity muscle strength, and plasmaa-tocopherol was associated with better physical performance (115). Together,these observations suggest that dietary compensation with antioxidant-richfoods may attenuate obesity-induced inflammation while improving strengthand performance.

Among dietary compounds with antioxidant activity, the most highlyresearched nutrients and non-nutrients are vitamins C and E, flavonoids,and the carotenoids beta-carotene and lycopene. Each compound differsin its chemical structure, which influences both its ability to stabilize freeradicals as well as its solubility in biological systems. While vitamin C andflavonoids are water-soluble compounds with strong activity in aqueousenvironments, carotenoids and vitamin E exhibit greater action against lipidoxidation in cellular membrane bilayers. Despite these very basic differences,the synergy between the hydrophilic and lipophilic compounds is

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remarkable. For example, vitamin C has been shown to regenerate vitamin Eand enhance the antioxidant effect of carotenoid compounds (116). Like-wise, research has shown that flavonoids, classified as non-nutritive phenoliccompounds, act synergistically with vitamin E to prevent low-density lipo-protein (LDL) oxidation (117). Collectively, dietary and endogenous antiox-idants impact inflammatory mediators, ROS production, and ROS quenching(31). As such, the resulting interactions often provide greater capacity forsustained antioxidant effect than individual antioxidants alone. For thisreason, numerous studies are now evaluating the antioxidant capacity ofplasma or serum in order to better understand the potential benefit to bederived from the interactions of all antioxidants in situ (118). Whether it isthe interaction between different dietary antioxidants or between dietaryantioxidants and endogenous antioxidant enzymes, achieving recommendedintake levels of vitamin C, vitamin E, carotenoids, and flavonoids mayrepresent an efficacious non-pharmacological therapeutic approach for miti-gating the effects of obesity-induced inflammation in an aging population.

Intake of Compounds With Antioxidant Functionality: FoodVersus Supplement

Improving dietary antioxidant intake may be accomplished through foodsources and=or supplements. In the United States, there is a growing trendamong consumers to increasingly rely on dietary supplements (119), withadults 51 and older reporting greater supplement use than younger adults(120). Unfortunately, antioxidant supplementation trials have shown a greatdegree of variability and limited success, and some trials have even suggestedpossible harm in specific subgroups (121–123). Several factors may underliethe limited success of supplementation trials. First, the supra-physiologicalconcentrations of single antioxidants may cause these compounds to reacha point of saturation in the body or within target tissues, thus limiting thepotential benefits (124, 125). Additionally, by isolating individual com-pounds, the absorption and metabolism of some antioxidants, particularlyphytochemicals, may be reduced when consumed as supplements ratherthan within a food matrix. Lastly, the use of synthetic forms of antioxidantsmay have different biological activity than natural forms, which may influ-ence effectiveness.

Beyond supplementation trials, an epidemiological study of supplementintake also revealed associations between several commonly used vitaminand mineral supplements and increased total mortality risk among olderwomen (N¼ 38,772) (126). Likewise, an earlier systematic review ofsupplemental antioxidant intake suggested that supplementation with beta-carotene, vitamin A, and vitamin E does not reduce the risk of developingcardiovascular disease, but rather supplementation with these vitamins canincrease all-cause mortality risk (127). In contrast to these results concerning

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antioxidants in the supplement form, epidemiological studies continue toreport inverse correlations between consumption of foods containing highlevels of antioxidants, primarily from fruit and vegetables, and risk of variouschronic diseases or biomarkers of inflammation and oxidative stress (128–131). At first glance, the research on antioxidant intake may appear to beconflicting, yet these studies underscore the difference in the vehicle ofantioxidant delivery—supplement versus food. In contrast to findings withsupplements, nutrient toxicity resulting from food intake has rarely beenreported (132). Thus, the combined effects of the macro-, micro-, andnon-nutrients within food directly influence the absorption, bioavailability,and functionality of these compounds, and they also indirectly influencethe consumable dose of bioactive ingredients. Although supplementationmay be necessary for certain individuals who are unable to meet micronutri-ent needs by food alone, there is insufficient data to justify routine supple-mentation of dietary antioxidants for all older adults. Hence, dietaryapproaches that encourage intake of foods rich in vitamin C, vitamin E,carotenoids, and flavonoids may mitigate oxidative stress and inflammationwithout posing undue risks to older adults. Table 1 highlights food sourcesof these dietary antioxidants.

Comparison of the Typical Dietary Intake of Antioxidants byOlder Adults to the Optimal Intake

Unfortunately, even when meeting or exceeding their energy requirements,older adults are not necessarily consuming high-quality diets appropriatefor meeting their micronutrient needs. Gao and colleagues assessed dietquality using the Healthy Eating Index (HEI) scoring, a system that awardsup to 20 points (on a 100-point scale) for fruit and vegetable intake (133).In a multi-ethnic group of 6,236 middle-aged and older adults, researchersfound that poorer diet quality was associated with both increasing BMIand WC, even after adjusting for energy requirements. Also, the HEI was pre-dictive of obesity in Whites and Hispanics, such that a 3% decrease in obesityrisk was shown with each one-unit increase in HEI score. This associationbetween lower diet quality and obesity is particularly problematic when con-sidering the typical fruit and vegetable intake of older adults is well belowthe recommended intake. The Dietary Guidelines for Americans are issuedevery five years as a joint effort between the U.S. Department of Healthand Human Services’ Office of Disease Prevention and Health Promotionand the Department of Agriculture’s Center for Nutrition Policy andPromotion (134). Dietary recommendations categorized by age group areavailable to the public via ChooseMyPlate.gov (135). The 2010 DietaryGuidelines recommend that older adult (defined as ages �51 years) womenconsume a minimum of six servings of fruits and vegetables daily (or theequivalent of approximately 1.5 cups of fruit and 2 cups of vegetables)

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and men consume a minimum of nine total servings per day (or approxi-mately 2 cups of fruit and 2.5 cups of vegetables) (134). However, thisrecommendation is in stark contrast to the actual fruit and vegetable intakeof older adults. Data from the 2009 Behavioral Risk Factor SurveillanceSystem, the most recent edition with dietary data available, suggest thatadults aged 65 years and older consume far fewer than the recommendedservings of fruits and vegetables, with 74% of men and 65% of womensurveyed consuming fewer than five total servings per day (136). This obser-vation is supported by data from an earlier analysis of 547 adults aged 67 to93 years participating in the 1988–1989 Framingham Heart Study. Among thiscohort, women consumed a mean of 5.1 fruit and vegetables serving perday, while men consumed a significantly (P< 0.05) lower average of 4.1servings (137). Not surprisingly, suboptimal intake of fruits and vegetablescorresponds to intake of individual micronutrients by older adults. EstimatedAverage Requirements (EARs) for micronutrients are defined by the Instituteof Medicine’s Dietary Reference Intakes. For adults aged 19 years and older,the EAR for vitamin C is 60–75mg=day (for women and men, respectively),and the EAR for vitamin E is 12 mg=day (138). However, a study examiningdietary intake of 2179 older adults who did not use dietary supplementsreported that 43% (�3.1) of men aged 51 to 70 years and 48% (�3.3) ofmen aged 71 years and older did not meet the EAR for vitamin C. Womenexhibited a lesser disparity between EAR and dietary intake of vitamin C,such that 39% (�2.7) of women aged 51 to 70 years and 37% (�5.0) inwomen aged 71 years and older did not meet the EAR. After all sources ofvitamin E intake were converted to a-tocopherol equivalents, data from thisstudy revealed that 90% (�2.4) of men aged 51 to 70 years and 93% (�2.3) ofmen aged 71 years and older failed to meet the EAR for vitamin E. The per-centage of older adult women failing to meet the EAR for vitamin E exceeded97% (no SEM given) for both age groups (139). Overall, surveys of dietaryintake suggest that underconsumption of fruits and vegetables by older

TABLE 1 Dietary Sources Rich in Vitamins C and E, Carotenoids, and Flavonoids (164–167)

Vitamin C Vitamin E Carotenoids Flavonoids

Dark, leafy greensCitrus fruitStrawberriesKiwiBell peppersBroccoliCauliflowerBrussels sproutsTomatoes

Wheat germ oilSunflower seeds

& oilAlmondsHazelnutsPeanuts & peanut

butterSpinachBroccoliCorn oil

Sweet potatoSpinachCarrotsTomatoesApricotsMangosMilkRicotta cheeseFortified cerealsSquashSalmonTuna

Berries, all typesRed & purple grapesRed wineGreen & black teaApplesCitrus fruitsOnionsBroccoliSoybeans & soy

foodsLegumes

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adults may be compromising their intake of the majority of antioxidantvitamins and phytonutrients from dietary sources.

Dietary Reference Intakes have not been established for carotenoids orflavonoids. Nonetheless, while recognizing a role for supplements inspecified circumstances, the 2010 Dietary Guidelines recommend that micro-nutrients are best ingested as foods in order to maximize intake of othernon-nutrients with health-promoting properties (134). Despite the presentlack of guidelines for recommended intake, researchers have describedpatterns of carotenoid and flavonoid intake among different populations.Assessment of dietary intake data from the 1988–1989 FraminghamHeart Study revealed considerable variance for carotenoid intake amongparticipants aged 67 to 93 years. In this cohort, intake of a-carotene rangedfrom 656 mg=day (�605; men) to 862 mg=day (�781; women), and dietaryb-carotene intake ranged from 3520mg=day (�2,474; men) to 4216mg=day(�2,609; women). Among men and women, predominant food sources ofthese two carotenoids were carrots, mixed vegetables, cantaloupe, spinach,and sweet potatoes (137). Analysis of total flavonoid intake of adults in theUnited States revealed that some older adults have a higher dietary intakeof flavonoids than their younger counterparts. Using 24-hour dietary recallscollected from the NHANES 1999–2002 cohort, researchers estimated thedaily dietary flavonoid intake of 8,809 adults. In this population, older adultsaged 51 to 70 years consumed a mean flavonoid intake of 215.4 (�16.8) mg=day, as compared to the 173.5 (�17.5) mg=day for adults aged 19 to 30 yearsand 192.0 (�13.0) mg=day for adults 31 to 50 years. However, among those70 years and older, flavonoid intake dropped to 150.0 (�11.4) mg=day (140).

Although the average intake of high-antioxidant foods (primarily fruitsand vegetables) typically falls below the recommended levels in the olderadult population, interventions targeted at improving fruit and vegetableintake have shown success. Diet education programs that provided writteninstructions and recipes, group information and support sessions, and=orperiodic supportive newsletters have demonstrated increased fruit andvegetable consumption by older adults (141, 142). Alternatively, a recentsystemic review suggests that novel food or beverage products such asmixed fruit=vegetable juices may also be a viable manner for improvingintake of b-carotene and vitamins C and E. Interventions designed toincrease dietary intake of these nutrients from fruit and vegetable concen-trates also reported increased serum concentrations of antioxidants as wellas decreased biomarkers of inflammation and oxidative stress (143).Although evidence is still insufficient to recommend ‘‘functional foods’’ for-tified with antioxidants, studies to date do support the concept that dietaryapproaches for improving antioxidant intake are a practical way to modulateinflammation.

The idea that even obese older adults who are exceeding theirenergy requirements are not consuming high-quality diets or meeting

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recommendations for antioxidant micronutrients is troubling. Just as a strongbody of literature has now established that obesity may mask the presence ofsarcopenia (7), it is entirely possible that obesity may also mask inadequatedietary intake of anti-inflammatory micronutrients. Moreover, obese olderadults may likely require higher intakes of dietary antioxidants than leanolder adults in order to offset decreases in oxidative capacity and increasesin production of ROS and proinflammatory adipokines. Further researchis needed to explore these inter-relationships and to establish practicalguidelines for dietary intake.

Evidence That Macronutrient Profiles May Favorably InfluenceBody Composition and Reduce Inflammation

In addition to micronutrients and dietary antioxidants, previous studiessuggest that macronutrient composition of the diet may also affect bodycomposition and inflammation in older adults. It is well-established thatadequate protein is essential for preservation of lean body mass. Studies haverepeatedly confirmed a blunted response of aging skeletal muscle to theanabolic effects of ingested amino acids (144). Thus, compared to youngeradults, older adults are less able to utilize the amino acids they ingest fromprotein foods for muscle protein synthesis. Although the RecommendedDietary Allowance for protein is the same for adults of all ages (0.8 g=kg),several researchers have recommended intakes of 1.0–1.5 g=kg or �15-20%of total energy intake for older adults (145–147). In a review of dietary pro-tein intake and skeletal muscle metabolism in older adults, Paddon-Jones andRasmussen recommended a distribution of 25–30 g of high-quality protein ateach meal (148). Among 598 men and women aged 65 years and older fromthe InCHIANTI Study, low protein intake was associated with greater declinein muscle strength over three years only in individuals with high serum levelsof CRP, IL-6, and TNF-a. Although participants in this study were not obese,the authors surmised that older adults with higher levels of proinflammatorycytokines may require additional protein to overcome the catabolic effects ofinflammation on muscle tissue (149).

If total energy intake is reduced, caloric restriction may need to bepaired with increased protein intake to offset muscle catabolism (4, 11). Ina study of eight obese older adults, Villareal and colleagues used the robustmethod of stable isotope tracers to demonstrate that muscle protein synthesisis not impaired by weight loss. The authors concluded that the loss of musclemass observed with caloric restriction is mainly due to muscle proteolysisrather than any change in muscle protein synthesis (150). In a weight losstrial of frail, obese older adults, Villareal and colleagues assigned participantsin the treatment group to meet weekly with a dietitian to achieve a 750 kcalenergy deficit while maintaining 20% total kcals from protein (85). After sixmonths of diet and exercise, these participants demonstrated decreases in fat

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mass as well as circulating CRP and IL-6 without significant change in fat-freemass (85, 86).

In addition to adequate protein, manipulation of dietary glycemic loadmay also be beneficial to reduce obesity-related inflammation in older adults.The glycemic index of a particular food compares its postprandial effects onblood glucose to that of pure glucose or starch. The glycemic load of a foodis then calculated by multiplying its glycemic index and the amount ofcarbohydrate in the food (151). It has been proposed that sharp rises inblood glucose induced by high glycemic loads may lead to an overpro-duction of ROS and increased inflammation (152). Two large cross-sectionalstudies reported associations between dietary glycemic load and circulatingCRP in healthy women aged 45 years and older (153, 154). Another studyof 902 diabetic women older than 50 years also found that dietary glycemicload was positively associated with plasma CRP and TNF-a receptor2. Con-versely, intake of low glycemic load whole grains and bran was inverselyassociated with those circulating markers of inflammation (155). A rando-mized crossover study compared the effects of a 10-day low glycemic indexdiet to a high glycemic index diet in overweight and obese young men (aged18–35 years). The low glycemic index diet resulted in higher total antioxidantcapacity as measured by the oxygen radical absorbance capacity assay (152).Although glycemic index studies in older adults are few, one randomizedcontrolled trial assigned obese adults aged 65 years and older with insulinresistance to either a low glycemic index diet or a high glycemic index dietfor 12 weeks. All participants engaged in one hour of aerobic exercise fivedays per week. Both groups lost similar amounts of weight and demonstratedreductions in fasting glucose and insulin, but only the low glycemic indexgroup showed improved response to an oral glucose tolerance test anddecreased secretion of IL-6 and TNF-a from peripheral blood mononuclearcells. The authors concluded that a low glycemic index diet combined withaerobic exercise may be an effective strategy to improve glucose homeostasisand reduce inflammation in obese older adults (156). Because calculating theglycemic index and glycemic load of each food at each meal would be atedious process in a real-world setting, it may be more practical to teacholder adults to select carbohydrate foods with more fiber rather than simplesugars and refined grains.

The amount and types of dietary fat can also influence postprandialinflammatory responses. Although not specific to older adults, a recentreview paper provides evidence that a high ratio of omega-3 to omega-6 fattyacids at meals decreases postprandial serum cytokines as well as adhesionmolecules and other biomarkers of oxidant=antioxidant balance (157). Onerandomized, double-blind, placebo-controlled trial examined omega-3 fattyacid supplementation in 138 overweight and obese middle-aged and olderadults. Participants were randomized to 2.5 g=d omega-3 fatty acids, 1.25 g=d omega-3 fatty acids, or placebo for four months. Serum IL-6 increased in

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the placebo group, but both supplemental groups showed similar decreasesin IL-6 of 10%–12% (158). In another sample of 1,123 males and females aged20 to 98 years, higher plasma omega-3 fatty acid concentrations were associa-ted with lower levels of proinflammatory cytokines as well as higheranti-inflammatory markers such as interleukin-10 (159). Based on a largebody of evidence supporting the anti-inflammatory effects of omega-3 fattyacids, the current recommended ratio of omega-6:omega-3 is 2-5:1, withthe optimum intake dependent on the presence of comorbidities (160).Unfortunately, the average ratio of intake in the United States is approxi-mately 10 times higher in omega-6 than omega-3 fatty acids (161). Omega-6fatty acids are widespread in the typical American diet as they are present inmany vegetable oils. Omega-3 fatty acids can be consumed as alpha-linolenicacid in flaxseed, walnuts, and canola oil, while fatty cold-water fish such assalmon, mackerel, herring, and trout are rich in the omega-3 fatty acids eico-sapentanoic acid and docosahexanoic acid (157, 162).

An overall dietary pattern that emphasizes food sources of vitamin C,vitamin E, carotenoids, and flavonoids along with generous protein, lowerglycemic index carbohydrates, and omega-3 fatty acids may be optimal toreduce obesity-related inflammation and favorably impact body compositionof older adults; however, no studies to date have examined all of thesedietary components in synergy. One observational study of 1,751 adults aged70 to 79 years from the Health ABC Study cohort did examine relationshipsbetween dietary patterns and systemic inflammation. Dietary patterns wereascertained by food frequency questionnaires and cluster analysis. A ‘‘healthyfood cluster’’ consisting of higher intakes of vegetables, fruits, fish, poultry,low-fat dairy foods, and whole grains and lower consumption of red meat,added fats, and sugar-sweetened beverages was associated with lowercirculating IL-6 compared with other groups. TNF-a and CRP displayedthe same patterns, but the differences were not statistically significant(163). This study supports the idea that the combined effects of foods andtheir bioactive components may favorably impact inflammatory profiles.

Summary

Figure 1 displays interrelationships between diet, physical activity, bodycomposition, and inflammation. As more middle-aged adults enter their‘‘golden years’’ with pre-existing obesity, interventions to address obesity-related inflammation will become even more imperative. While caloricrestriction appears to be contraindicated for older adults who are overweightbut not obese (13, 96), moderate caloric restriction and gradual weight lossmay improve physical function, metabolic outcomes, and inflammatory pro-files among obese older adults. Importantly, exercise is a beneficial compo-nent of any lifestyle intervention because it decreases inflammation whileattenuating loss of muscle and bone. Supplements may be needed to ensure

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adequate intake of micronutrients among select individuals; however, foodssuch as fruits and vegetables are the optimal source of micronutrients anddietary antioxidants.

Even in the absence of caloric restriction, an integrative lifestyle programthat emphasizes multimodal exercise and diet quality may be effective toreduce obesity-related inflammation and consequent comorbidities. An idealmeal pattern may include �20% of calories from high-quality protein evenlydistributed throughout the day, emphasis on omega-3 fatty acids as a sourceof dietary fat, and replacement of simple sugars and refined carbohydrateswith vegetables and fruits that are rich in vitamin C, vitamin E, carotenoids,and flavonoids. Future trials are warranted to evaluate the effects of sucha program on physical function, chronic disease risk factors, and quality of life.

TAKE AWAY POINTS

. Interventions to address obesity-related inflammation are increasinglyneeded as more people enter old age with pre-existing obesity.

. For elderly adults who are obese, moderate caloric restriction and gradualweight loss may improve physical function, metabolic outcomes, andinflammatory profiles.

. Exercise is a beneficial component of any lifestyle intervention, andsupplements may be needed to ensure adequate intake of micronutrients;however, foods such as fruits and vegetables are the optimal source ofmicronutrients and dietary antioxidants.

. In view of existing evidence, a meal pattern including about 20% of caloriesfrom high-quality protein evenly distributed throughout the day, emphasison omega-3 fatty acids as a source of dietary fat, and replacement ofsimple sugars and refined carbohydrates with vegetables and fruits that arerich in vitamin C, vitamin E, carotenoids, and flavonoids appears optimal.

FIGURE 1 Interrelationships between diet, activity, body composition, and inflammation.

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