3
Physiology and Aging

The session opened with moderator Gordon Jensen of Pennsylvania State University, University Park, Pennsylvania, remarking on the challenge of differentiating between aging and the multitude of chronic diseases that accompany aging. He then introduced the first of three speakers, Simin Nikbin Meydani of the Jean Mayer U.S. Department of Agriculture (USDA) Human Nutrition Research Center on Aging (HNRCA) at Tufts University, Boston, Massachusetts, who spoke about changes in the immune system that accompany aging and the importance of considering underlying genetic variation in immunity when evaluating nutrition in aging populations. Meydani emphasized the distinction between incidence of infectious disease and severity of illness resulting from infection. Meydani also presented evidence from a series of recent studies demonstrating how macro- and micro-nutritional supplementation can compensate for some of the immunological changes that accompany aging. Jensen himself then spoke about the gastrointestinal (GI) system and how it remains largely unchanged with aging, with most major changes being related to underlying conditions. He emphasized, however, that oral health is one component of the GI system that does typically decline with aging, with many older adults suffering from poor diet quality and micronutrient deficiencies as a result. Finally, Marcia Pelchat of the Monell Chemical Sciences Center, Philadelphia, Pennyslvania, discussed food-related sensory perception changes with age and the consequences of these changes.



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3 Physiology and Aging T he session opened with moderator Gordon Jensen of Pennsylva- nia State University, University Park, Pennsylvania, remarking on the challenge of differentiating between aging and the multitude of chronic diseases that accompany aging. He then introduced the first of three speakers, Simin Nikbin Meydani of the Jean Mayer U.S. Department of Agriculture (USDA) Human Nutrition Research Center on Aging (HNRCA) at Tufts University, Boston, Massachusetts, who spoke about changes in the immune system that accompany aging and the importance of considering underlying genetic variation in immunity when evaluating nutrition in ag- ing populations. Meydani emphasized the distinction between incidence of infectious disease and severity of illness resulting from infection. Meydani also presented evidence from a series of recent studies demonstrating how macro- and micro-nutritional supplementation can compensate for some of the immunological changes that accompany aging. Jensen himself then spoke about the gastrointestinal (GI) system and how it remains largely unchanged with aging, with most major changes being related to underlying conditions. He emphasized, however, that oral health is one component of the GI system that does typically decline with aging, with many older adults suffering from poor diet quality and micronutrient deficiencies as a result. Finally, Marcia Pelchat of the Monell Chemical Sciences Center, Philadel- phia, Pennyslvania, discussed food-related sensory perception changes with age and the consequences of these changes. 

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40 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE IMMUNE STATUS OF AgINg POPULATIONS AND METHODS OF MODULATINg SUSCEPTIBILITY Presenter: Simin nikbin Meydani Meydani began by commenting on how scientists have recently learned that dysregulation of immune and inflammatory response with aging not only contributes to greater susceptibility to infectious diseases and cancer, but also greater susceptibilities to other chronic diseases such as cardiovas- cular disease, Alzheimer’s disease, osteoporosis, and type 2 diabetes. She remarked that most of her talk, however, would focus on the former: how dysregulation of the immune and inflammatory systems, most of which is associated with changes in T-cell-mediated function, contribute to an in- creasing incidence of infectious diseases and cancer with aging. Aging and Infectious Diseases Aging is associated with a higher incidence of morbidity and mortality from a number of different types of infectious diseases (e.g., pneumonia, tuberculosis, GI infections, urinary tract infections, and Herpes zoster). For example, pneumonia and influenza together are the fourth leading cause of death among older adults. Even when a diagnosis is cardiovascular disease, the cause of death is often pneumonia. While the incidence of GI infections is not necessarily any greater in the elderly population, morbidity and mor- tality from GI infections is much higher in older adults. For example, when a food poisoning episode occurs in a nursing home, the younger caregivers can usually recover, but the elderly people often suffer greater complications that may result in death. To illustrate the impact that aging has on the severity of infectious disease, Meydani described a Salmonella typhimurium study that she and her colleagues conducted using a murine model system (Ren et al., 2009). They examined colonization of Salmonella after both young and old mice had been exposed to Salmonella. While in the beginning (one day post- infection), the young animals showed a higher colonization rate, the older animals showed a much higher colonization rate as their infections pro- gressed (2–4 days post-infection). This was true at both low and high doses of exposure. Even early on, when the colonization rates were higher in the younger animals, the older animals nonetheless experienced greater weight loss because of the severity of the infection. Meydani emphasized that the last observation is important to consider in relation to food safety because often efforts are directed toward prevent- ing exposure to foodborne infectious agents without enough consideration

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4 PHySIology And AgIng about whether and how host response to infection could be improved to make older adults less susceptible to morbidity and mortality resulting from an infection once it does take hold.1 Meydani gave several reasons that might explain why susceptibility to infectious disease increases with age: • Impaired immune response, which occurs mostly because of changes in T cell-mediated functions. For example, in the same murine system previously described, Meydani and colleagues found that production of Interferon (IFN)-g is the same in young and old uninfected mice but that young infected animals show a significantly greater produc- tion of IFN-g than old infected animals. These results suggest that younger animals are more capable of mounting an effective immune response against Salmonella typhimurium. In humans, any of a number of T cell-mediated functions could be contributing to the link between aging and infectious diseases (as well as between aging and cancer), including decreased antibody production, a decreased delayed-type hypersensitivity (DTH) response, an increase in the percentage of memory cells and corresponding decrease in the per- centage of naïve cells (thereby decreasing an individual’s ability to re- spond to new infections), a decrease in the number of T-helper cells, etc. In addition to changes in the T cells themselves, other changes such as increased macrophage production of various suppressive factors can also lead to a decline in T cell-mediated function. • Increased pathogen virulence in aged hosts. For example, Meydani described work by Melinda Beck, University of North Carolina, and colleagues on the coxsackie B3 (CVB3) virus. There are two types of CVB3 virus: one avirulent (CVB3/0 does not cause disease), the other virulent (CVB3/20 can cause myocarditis in animals and is known to be associated with Keshan disease, a cardiomyopathy associated with dietary deficiencies in selenium [Se]). Beck and col- leagues showed that the avirulent version injected into Se-deficient mice will evolve into the virulent version (Beck et al., 1994). When the researchers separated the virus from the host and injected it back into another young animal that was not Se-deficient, the latter ani- mal nonetheless developed myocarditis, suggesting that the normally mild virus had somehow become virulent in the Se-deficient mice. When the researchers sequenced the virus, they found mutations that resembled those of the virulent form. Suspecting that perhaps the 1 Steven Gendel also elaborated on the distinction between incidence of foodborne infection and the severity of the consequences of infection during his presentation later in the workshop, as summarized in Chapter 4.

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4 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE change was associated with increased oxidative stress in the Se-defi- cient animals, the researchers questioned whether they might find the same phenomena on mice similarly stressed in other ways. Indeed, they showed the same occurrence in animals fed diets deficient in vitamin E. Meydani and her colleagues wondered if the same might be true of aging, given that aging is also known to be associated with an increase in oxidative stress. So they did a similar passage experiment where they injected avirulent virus into both young and old animals (Gay et al., 2006). As expected, the young animals had low titers (i.e., little infection). However, the old animals not only showed higher titers but also more pathology and even some mor- tality. After avirulent strain was injected into old animals and then back into the young animals, suddenly the previously healthy young animals developed high titers, high pathology, and this virus exhib- ited numerous base changes in its nucleotide sequences, which made it similar to the virulent strain. These observations suggested that, as with a Se-deficient diet, there is something about the aging host that caused a normally mild virus to become virulent. So in addition to immunological changes that occur with aging, which make older individuals more susceptible to infection or more severe infections, unknown changes in the host environment might also be causing mutations that make pathogens more virulent. • Changes in gut microflora. A limited number of studies (e.g., Hop- kins and Macfarlane, 2002) have shown that structural changes can occur in the gut that result in a decrease in the number and diver- sity of beneficial bacteria (e.g., bifidobacteria) and a correspond- ing increase in the number and diversity of harmful bacteria (e.g., clostridia, enterobacteria). The reason for this change is unclear, although Meydani speculated that perhaps the same type of evo- lutionary change that the CVB3 virus appears to undergo could be occurring with bacteria as well. • genetics and other physiological changes. Differences in genetic background may be related to variation in response to nutritional interventions as described in the next section on nutrition supple- mentation. Meydani also suggested that micronutrient status in older adults could be a determinant of susceptibility to infectious disease. Taken together, all of these changes that occur with aging raise the question: Can something be done to prevent age-associated immune dys- function and/or viral evolution? What is the role of nutrition?

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4 PHySIology And AgIng The Effect of Nutrient Supplementation on Susceptibility to Infectious Disease For the remainder of her talk, Meydani described a series of studies on how supplementation with various micronutrients (vitamin E, zinc, vitamin B6), macronutrients (fish oil), and caloric restriction can impact suscepti- bility to infectious disease. Meydani argued that taken together, all of this evidence suggests that nutritional manipulation can decrease susceptibility to infections in older adults. Vitamin E In a double-blind, placebo-controlled study, Meydani and colleagues demonstrated that supplementation with vitamin E can significantly im- prove immune response, particularly T cell-mediated response, in healthy older adults (Meydani et al., 1997). Meydani and colleagues fed healthy older adults different levels of vitamin E for six months and then examined, as an indication of immune response, the participants’ abilities to produce antibodies against hepatitis B, tetanus toxoid, and pneumococcal vaccine, as well as in vivo cell-mediated immunity. At the workshop, she shared only the results relating to changes in antibody response to hepatitis B. All three vitamin E-fed groups (60, 200, and 800 international units [IU]), but partic- ularly the 200 IU group, showed an increase in both antibody response and DTH diameter. The 200 IU group showed a 19.9 U/ml antibody response (compared to 3.3 U/ml in the control group) and a 65 percent change in DTH diameter of induration (compared to 18 percent among controls). Pallast et al. (1999) confirmed the findings. Meydani and colleagues asked whether this improved immune response from vitamin E supplementation is also associated with an actual de- crease in susceptibility to infection. They conducted another double-blind, placebo-controlled study (Meydani et al., 2004). Based on a year’s worth of data from 617 nursing home residents, they found that older adults supplemented with vitamin E had significantly lower risk of acquiring upper but not lower respiratory infections. Upper respiratory infections tend to be viral, whereas lower respiratory infections tend to be bacterial. However, in these various studies, not all of the older adults who received vitamin E supplementation showed improvements in immune re- sponse. There were responders and non-responders. Meydani and col- leagues speculated that some of this variability may be due to genetic differences among the older adults. Knowing that host genetics influence cytokine production, they wondered if variation in cytokine genetics in par- ticular could explain variability in response to vitamin E. Indeed, Belisle et

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44 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE al. (2009) found that vitamin E supplementation did not have a significant effect on tumor necrosis factor (TNF)-α production in individuals with a G/G genotype (TNF-α-308G>A) but significantly reduced TNF-α produc- tion in individuals with an A/G or A/A genotype. Meydani said that, inter- estingly, people with an A/G or A/A genotype normally produce a higher level of TNF-α, and vitamin E supplementation appears to be effective at reducing cytokine production only in individuals with initially high levels of cytokine. Zinc Also in Meydani et al. (2004), Meydani and colleagues measured the blood levels of various other micronutrients, including zinc. They were surprised to find that 30 percent of the participants were deficient in zinc (i.e., defined as less than 70 µg/dL). Knowing that zinc has been shown to play an important role in resistance to pneumonia, they questioned whether there might be a relationship between serum zinc levels and pneumonia. Not surprisingly, in a subsequent study, they found that the incidence of pneumonia in older adults with adequate zinc serum levels was half of what it was among older adults with low zinc serum levels (Meydani et al., 2007). Individuals with adequate zinc levels who did develop pneumonia had illnesses of shorter duration, fewer antibiotic prescriptions, and shorter durations of antibiotic use. These associations suggest that zinc status could be an important determinant of susceptibility to pneumonia among older adults. Meydani emphasized that so far she and her colleagues have detected only an association between zinc and pneumonia. The next step is to deter- mine whether zinc supplementation in older adults with initially low serum zinc levels actually reduces the incidence of pneumonia. She also mentioned that this high level of zinc deficiency is not unique to nursing home resi- dents; in another study, she and her colleagues found that 22 percent of independently living older adults had low serum zinc levels.2 Vitamin B Meydani described a study that she conducted in collaboration with Rob Russell (Meydani et al., 1990) on the effect of vitamin B6 depletion and supplementation on immune response in the elderly. They found that depletion results in a significant reduction of lymphocyte percentage and that supplementation partially reversed the downward trend. However, the final lymphocyte percentage was still significantly lower than the initial 2 These data are unpublished from Rall and colleagues.

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4 PHySIology And AgIng baseline value. In terms of functionality, for example with respect to the availability of lymphocytes for interleukin 2 production and lymphocyte proliferation, they observed the same pattern. Vitamin B6 depletion was fol- lowed by significant reductions in both measures of functionality. Although supplementation partially reversed this trend, they were not able to bring the levels back up to what they were at baseline. Meydani explained that this inability to raise the levels to baseline could have been a function of the duration of supplementation (i.e., perhaps they needed to supplement for a longer period of time) and that the results nonetheless suggest that the status of vitamin B6 is clearly important for healthy immune system functioning. Fish oil Fish oil contains the n-3 polyunsaturated fatty acids, eicosapentae- noic acid (EPA), and docosahexaenoic acid (DHA).3 Meydani explained that EPA has been shown to replace arachidonic acid (AA)4 in membrane phospholipids in cells, thereby reducing the formation of pro-inflammatory lipids such as prostaglandin E2 (PGE2). Prostaglandins have been shown to have a suppressive effect on T cell function. Knowing that aging is as- sociated with an increased production of PGE2, Meydani and colleagues questioned whether a reduction in PGE2 might have an impact—not just by reducing inflammation in older adults but also by affecting cell-medi- ated immunity. They conducted a study whereby they fed older adults with either a low-level fish oil diet (0.13 percent of calories) or a high-level fish oil diet (0.54 percent of calories) for six months and showed that, yes, diets enriched with fish-derived polyunsaturated fatty acids significantly reduced production of PGE2 as well as production of the pro-inflammatory cytokines interleukin 1β, TNF, and interleukin 6 (Meydani et al., 1993). Surprisingly, in the same study, the researchers also found a significant reduction in DTH, which is not a desirable effect as DTH is an index of T cell-mediated function. They suspected that this adverse effect might be related to the increased need for antioxidant nutrients when consuming a high polyunsaturated fat diet. In a subsequent study, they showed that by consuming both supplemental fish oil and vitamin E in combination, older adults derive the beneficial anti-inflammatory effect of fish oil but without the adverse effect on T cell-mediated function that occurs when fish oil is administered alone (Wu et al., 2006) (see Figure 3-1). 3 EPA and DHA are omega-3 fatty acids. 4 AA is an omega-6 fatty acid.

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4 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE High Fish * High Fish Low Fish Low Fish (a) Baseline 3-mo 50 48 h induration (mm) * * 45 Figure 3-1a, fixed * 40 35 30 25 20 15 10 5 0 Vit E 100 Vit E 200 Vit E 400 (b) Supplementation groups FIgURE 3-1 (a) When fish oil alone is administered to older adults, delayed-type hypersensitivity (DTH) levels decrease. (b) When administered in combination with vitamin E, DTH levels increase. Figure 3-1b, editable NOTE: (a) * = significantly different from before; (b) Mean ± SE, n = 8 to 10/group; *p < 0.05 compared to the baseline SOURCES: Meydani et al., 1993; Wu et al., 2006.

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4 PHySIology And AgIng Caloric Restriction Finally, Meydani commented on a recent study on the effects of caloric restriction in humans. While there are plentiful data showing that caloric restriction can extend life in animals, data on its biological effects in hu- mans are sparse.5 Funded by the National Institute on Aging, CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) is a multi-center study on the effects of 2 years of caloric restric- tion in humans. The Jean Mayer USDA HNRCA at Tufts University is one of the participating centers. Data collection was conducted in two phases. Meydani described results from the first (pilot) phase (Hayek et al., 1994). The design was randomized, controlled, and single-blinded; the participants were men and women between the ages of 25 and 45 and with a body mass index between 25 and 29 kg/m2 (evidence suggests that the earlier caloric restriction is started, the more effective it will be); participants were exposed to either 10 percent or 30 percent reduced calorie diets; and DTH was used as an indicator of immune response and measured at both baseline and after 6 months. Among other findings, the study showed that both the 10 percent and 30 percent reduced calorie diets led to significant improvements in immune responses based on DTH measurements. Both diets also led to significant increases in concanavalin A and phytohemagglutinin-induced lymphocyte proliferation. However, only the 30 percent reduced calorie diet was effective at increasing anti-CD3-induced lymphocyte proliferation levels and reducing PGE2 production. Meydani cautioned that while the data suggest that caloric restriction could be effective in humans, this does not necessarily mean that caloric restriction “is good for the frail elderly.” Participants in that study were between the ages of 25 and 45 and slightly overweight. She said that caloric restriction might, however, be beneficial in older adults who are overweight. Conclusion In conclusion, Meydani listed other dietary components that have been shown to be effective in improving or having some impact on the immune response in older adults: glutathione, conjugated linoleic acid, mushroom- derived glycopolysaccharide, and probiotics. 5 For more detailed discussion on other recent studies on the effect of caloric restriction on aging, see the summary of Luigi Fontana’s presentation in Chapter 5.

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4 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE gASTROINTESTINAL SYSTEM CHANgES WITH AgE Presenter: gordon Jensen Jensen began by commenting on the fact that there has not been much recent research on GI function in aging, probably because GI function is largely preserved over time in healthy adults—most dysfunction is an indication of an underlying condition. The remainder of his talk was an overview of the changes that occur along the GI tract with aging, beginning with the oropharynx and ending with the colorectum. The most important clinically relevant changes that occur in healthy older adults are in the oropharynx, with poor oral health being associated with poor diet quality, micronutrient deficiencies, involuntary weight loss, and an increased risk of cardiovascular disease. Oropharynx Some of the most important changes that occur with aging and that impact nutritional status occur in the oropharynx. Teeth become stained and worn and their roots become fragile and susceptible to fracture; and periodontal disease and tooth loss are common. In fact, many older adults are edentulous (without teeth) and without dental care insurance or en- titlement programs for dental care. Many older adults also lack or have poor-fitting dentures. Other oropharyngeal changes known to occur with aging include swallowing dysfunction (15 percent of community-dwelling older adults have reported concerns); reduction in mastication and tongue muscle mass; dry mouth (40 percent of older persons complain of this) and decreased saliva production (which is usually caused by medical condi- tions, medications, or dehydration); delay in pharyngeal swallowing and decreased peristaltic amplitude and velocity; impairment of the laryngeal swallowing reflex; and a modestly increased risk of aspiration (which can lead to aspiration pneumonia). Jensen and colleagues have found that the persistence of oral health problems in older adults is associated with various comorbidities (e.g., diabetes, obesity), impaired diet health quality (as measured by the Healthy Eating Index), and micronutrient deficiencies (Bailey et al., 2004). Citing work by Dennis Sullivan at the University of Arkansas, Little Rock, and colleagues, he stated that oral health problems are also known to be as- sociated with significant involuntary weight loss in older adults (Sullivan et al., 1993). Periodontal disease in particular is also known to be associ- ated with an increased risk of cardiovascular disease, probably because it reflects what Jensen described as a “smoldering inflammatory state.” He explained that individuals with periodontal disease often have elevated C-

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4 PHySIology And AgIng reactive protein levels and that this same inflammatory state probably also injures the vascular endothelium and predisposes affected individuals to an increased risk of cardiovascular disease. Esophagus Significant impairment in the esophagus (i.e., impaired motility) usu- ally reflects an underlying disease or condition, such as the presence of a tumor. Aging itself typically is associated with only more modest change, with many older adults showing decreased upper and lower sphincter pres- sures, reduced amplitude of peristaltic contractions, incomplete sphincter relaxation, delayed esophageal emptying, frequent tertiary contractions, esophageal dilation, and decreased neurons in the myenteric plexus. Unless there is an underlying disease or condition, these changes are usually not clinically symptomatic. Stomach While gastric acid secretion (both basal and stimulated) is generally well preserved in older adults, about one-third of older adults have atrophic gastritis (chronic inflammation of the stomach mucosa) and associated hypo- chlorhydria or achlorhydria (little or no gastric acid production, respectively). Atrophic gastritis is associated with a loss of gastric folds. Non-steroidal anti-inflammatory drugs (NSAID) gastropathy is even more common than atrophic gastritis, not just because of increased NSAID use among older adults but also because of impaired mucosal defense mechanisms in the aging stomach. Finally, gastric emptying tends to become delayed with mixed or solid meals but not with liquid meals, although a clinically significant delay usually reflects an underlying disease condition (e.g., diabetes). Liver The liver decreases in size with aging as a consequence of reduced hepa- tocyte regeneration. Blood flow to the liver declines as well. These changes result in a reduced capacity to metabolize many drugs, which has important implications for drug dosing in older adults. Aging livers also often demon- strate increased expression of inflammation-related genes. However, liver function tests are generally well preserved with the exception of albumin synthesis, which tends to decrease slightly. But it is difficult to attribute the change in albumin synthesis to aging alone because any smoldering inflam- matory state could also induce the same change. Reduced albumin levels are better indicators of an underlying inflammatory state or chronic disease condition, and generally are not valid indicators of nutritional status.

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0 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE Pancreas The weight of the pancreas decreases with aging, with increased duc- tal epithelial hyperplasia leading to a narrowing of the ducts and lobular fibrosis. However, as with other GI organs and despite decreases in trypsin and lipase, the exocrine functions of the pancreas remain adequate unless there is some underlying serious disease (e.g., chronic pancreatitis). While decreased insulin secretion has been demonstrated in aging rodents, it is not clear whether this is true of humans. It conceivably could play a role in late-onset diabetes. Small Intestine As with most other sections of the GI tract, significant alterations in small bowel motility, transit, or function likely reflect underlying disease. The structure and absorptive functions of the small intestine are generally well preserved with aging. Small intestine surface area, crypt depth, villous height, enterocytes, and brush border show little change, and brush border enzyme activity for glucose transport is well maintained. While lactase ac- tivity declines, sucrase and maltase activities are unaffected. By and large, small intestinal integrity remains largely intact in healthy older adults, with normal mannitol absorption measurements.6 While decreased nutrient absorption is exhibited with aging, Jensen reiterated that significant changes in absorption of any nutrient usually reflect an underlying pathology. High on the list of nutrients with decreased absorption levels is vitamin B12, which Jensen explained is often a result of achlorhydria. Others include lactose, calcium, vitamin D (which shows a decrease in active transport as well as a decrease in receptors), iron, zinc, and magnesium. On the other hand, most macronutrients (protein, fat, and carbohydrate) and some vita- mins (riboflavin and vitamin B6) exhibit little change in absorption. Absorp- tion of vitamin A increases with aging. Colorectum Unlike most other sections of the GI tract, the large bowel undergoes some significant structural changes with aging. These include increased col- lagen, elastic, elaunin, and oxytalan fibers; and decreased neuronal density. Postprandial augmentation of mass movements and segmented contractions of the colon, on the other hand, usually change only modestly, supporting a 6 Mannitol is a common intestinal permeability probe. Malabsorption of mannitol is con- sidered to be an indication of impaired functional integrity of the small intestine and of small intestinal diseases, such as celiac disease.

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 PHySIology And AgIng normal transit in most healthy older adults. However, certain dietary factors, diseases, medications (e.g., narcotics), and inactivity can nonetheless create significant clinical issues. In fact, self-reported constipation and laxative use increase with aging and are more prevalent among women. Other typical changes include an increased pressure threshold for eliciting a sense of rectal filling, decreased rectal elasticity, a thickening of the internal anal sphincter, and impairment in anal canal resting and maximal squeeze pressures. While older adults, especially women, report an increased frequency of fecal incon- tinence, this is usually associated with colorectal surgery or disease. Microbiota Again, GI microbiota appear to be relatively stable throughout adult life. Measurable changes are usually attributable to changes in diet, changes in GI function, or changes in the host immune system. Jensen cited Wood- mansey (2007) and referred to Meydani’s comments about studies that have shown an increase in the number and diversity of facultative anaer- obes with aging and a corresponding decrease in the number and diversity of beneficial lactobacilli and bifidobacteria (Figure 3-2). Conceivably, this change in GI microbiota could lead to an increased risk of gastroenteritis and Clostridium difficile infection (which is an issue for hospitalized or chronic care facility patients who are administered antimicrobials that disrupt their normal bowel flora) and an increased risk of translocation of harmful bacteria. Jensen remarked that there are a number of therapeutic strategies for intervening and favorably impacting altered microbiota (i.e., prebiotics, FIgURE 3-2 Key changes in intestinal microflora with aging. NOTE: ABE = antibiotic-treated elderly; SCFA = short chain fatty acids. SOURCE: Woodmansey, 2007. Figure 3-2, fixed

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 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE probiotics, and synbiotics) and that our European colleagues “are prob- ably at least a decade ahead of us in this very interesting area of research.” Prebiotics are food ingredients that favor the growth of desirable bacteria (e.g., oligofructosaccharides). Probiotics are live microbial supplements (e.g., lactobacilli, bifidobacteria). Synbiotics are combinations of prebiotics and probiotics. Benefits have been reported (mostly from small, poorly con- trolled clinical trials) for the prevention of antibiotic-associated diarrhea, relapsing C. difficile colitis, traveler’s diarrhea, and food-borne pathogen exclusion as well as the reduction of H. pylori-associated gastritis (McFar- land, 2006, 2010). Conclusion In conclusion, Jensen emphasized the following: • The aging GI system remains largely intact and functional. • Clinical dysfunction usually reflects underlying disease or chronic conditions. Because absorptive functions remain intact in most healthy older adults, many nutritional supplements (e.g., those discussed during this workshop, such as vitamin E supplementation) are likely to be assimilated. • Oral health in older adults, however, is a critical concern, with poor oral health leading to poor diet quality, micronutrient deficiencies, and involuntary weight loss. SENSORY PERCEPTION CHANgES WITH AgINg Presenter: Marcia Pelchat Pelchat presented an overview of the major taste, olfactory, and other food-related changes in sensory perception that typically occur with aging. Age-Related Changes in Sense of Taste Age-related loss of taste sensitivity is a well-known phenomenon, with the degree of sensory loss varying across compounds. Sensitivity to sweet is the most likely taste to be spared with aging, although even it can be af- fected. Most of the change in taste sensitivity that occurs with aging is not a consequence but rather a correlate of aging, due in part to commonly used medications, such as those for cardiovascular problems (e.g., see Schiffman, 2009). Consequently, much of the loss of taste that accompanies aging is

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 PHySIology And AgIng potentially reversible through change either in medication or medication formulation. Pelchat said that according to her Monell colleague Beverly Cowart, the most disturbing changes in sense of taste with aging are distortions and phantoms. Distortions are changes in the way a stimulus tastes when it is in the mouth, for example when a sweet food tastes bitter or metallic. Phantoms are persistent taste sensations that are present all the time. In some cases, distortions and phantoms are medication-related. However, aging is almost never accompanied by a complete loss of taste. Pelchat explained that the sense of taste is “organized extremely redundantly,” with three different cranial nerves serving the taste buds on the tongue. Rarely are all three nerves impacted. When a complete loss of taste does occur (e.g., as it can following head and neck radiation), it is devastating for the individual and makes it almost impossible to eat. With only a reduced sense of taste, eating is still possible. Sense of Olfaction Pelchat explained that while only a small number of taste qualities (i.e., about four to six) exist, individuals nonetheless experience “thousands upon thousands of different flavors” because of olfaction. Compared to taste, changes in olfaction are generally much more pronounced with aging. She said that the prevalence of presbyosmia (the diminution or loss of the sense of smell with aging) is “definitely the rule rather than the exception” (Cain and Stevens, 1989). For example, the National Geographic Smell Sur- vey, a classic study conducted in the 1980s, demonstrated higher thresholds among older adults for several different odorants (Wysocki and Gilbert, 1989). National Geographic Magazine included a set of six scratch-and- sniff odor samples (both food and non-food stimuli: androstenone, amyl acetate, galaxolide, eugenol, mercaptans, and rose) in an issue of the maga- zine, eliciting 1.42 million respondents worldwide. The results are shown in Figure 3-3. This was followed by a smaller, scientifically recruited sample of around 25,000 individuals. The results were the same: As aging increased, ability to detect odor declined. Even above the detection threshold, odors become less intense with aging. The data also showed gender differences, with men experiencing more olfactory loss than women. Also, very importantly and as Pelchat and colleagues subsequently dem- onstrated (2001), not only does the rate of loss vary across odorants, but it also varies among individuals, particularly among the “young elderly.” For example, one person might show an early decline in his or her sensitivity to vanilla but not rose, while somebody else shows the opposite. This makes it difficult to increase odorants in foods in order to make them more palat- able. Pelchat stated that over the age of 80, however, sensitivity to odors

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4 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE Female Male 90 100 80 95 70 90 60 PERCENTAGE ABLE TO SMELL 85 50 ANDROSTENONE AMYL ACETATE 40 80 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 90 100 80 95 70 90 60 85 50 GALAXOLIDE EUGENOL 40 80 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 100 100 95 95 90 90 85 85 MERCAPTANS ROSE 80 80 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 DECADE OF LIFE FIgURE 3-3 Comparison of an older population’s ability to smell six different compounds. SOURCE: Wysocki and Gilbert, 1989. Figure 3-3, editable tends to decline “across the board,” making it a little easier to increase palatability through odorant supplementation. In a more recent epidemiological study, the Beaver Dam Study, which was mostly focused on hearing but also involved collecting olfactory data, over 60 percent of the people involved in the study over the age of 80 years had impaired sense of smell, and close to 25 percent of people over the age of 50 years were affected (Murphy et al., 2002). For Pelchat, one of the most important findings from that study was that self-report values dramatically underestimated the degree of loss (when compared to labora- tory measures) (Shu et al., 2009). That is, when asked about their sense of smell, most older adults respond “it is just fine.” Indeed, when the change is gradual, many people are not even aware of it.

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 PHySIology And AgIng In sum, although both aging-related loss of taste and smell vary across compounds and individuals, loss of olfactory sensitivity is more pronounced than loss of gustatory sensitivity. The Sense of “Chemical Feeling” There is a third food-related sense, which Pelchat said is sometimes referred to as “chemical feeling.” It is the desirable irritation produced by carbonation and spices (e.g., chili pepper, ginger, and cinnamon) and which is not detected by the gustatory or olfactory systems but by a part of the nervous system more closely related to the skin senses. Pelchat explained that the same types of nerve endings that indicate when something hot has touched your cheek or that a foreign object is in your eye also innervate inside the nose and mouth and detect these “desirable irritants.” So far, there is no evidence for a decline in chemical feeling with age. For example, with carbonation, Pelchat and her group found that sensitivity (intensity of feeling) increased with increasing concentrations of carbon- ation, and that they did so for all age groups (young, middle-aged, and el- derly).7 In fact, elderly participants showed the greatest increase in intensity of feeling at the highest carbonation concentration levels. It is not clear why this is the case. There may be age-related changes in the oral mucosa that make it easier for these irritants to access the nerve endings. Pelchat said that preservation of the sense of chemical feeling with aging could be perceived as either “good” or “bad.” On one hand, for baby boom- ers who enjoy eating spicy Mexican or Thai food, it could serve as a form of oral stimulation that can be used to replace some of the other sensory losses. On the other hand, most flavorings are combinations of odorants, tastes, and irritants, and therefore adding more irritant can have an unpleasant burning effect unless the intensities of other flavor compounds are increased as well. Most Older Adults Enjoy Eating Despite chemosensory losses, most older adults nonetheless enjoy eat- ing. While in the event of an upper respiratory infection or under other circumstances, chemosensory changes can be sudden and noticeable, most chemosensory loss with normal aging is gradual and undetectable. People compensate in unnoticeable ways, for example by leaving teabags to steep for longer periods of time. Pelchat and her colleagues have demonstrated that it is difficult to identify people with severe olfactory losses if they are eating familiar foods. For example, people who know that they are eating pear puree will say that what they are eating tastes like pear. But if they don’t 7 These data are unpublished from Pelchat.

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 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE know that they are eating a pear puree, they are very likely to misidentify the pear taste. This suggests that when people are in control of their purchase and preparation of food, their chemosensory losses may not have much effect. But if they are in a nursing home and eating a pureed diet without visual or textural cues, they may not know what they are eating. Loss of gate-Keeping Function Pelchat said that importantly, a decreased intensity of flavor causes a shift toward something known as hedonic neutrality: pleasant flavors be- come less pleasant and unpleasant flavors become less unpleasant. Because of something known as negativity bias, people pay more attention to harm- ful experiences than to potentially beneficial experiences. So the effect of chemosensory loss is much greater for unpleasant flavors, which leads to a potential loss in what are known as gate-keeping functions, for example the ability to detect spoiled food or salt. Pelchat described the results of a study demonstrating that older adults living in institutionalized settings prefer saltier foods than younger adults living in the community, because of a loss in gate-keeping function (Figure 3-4).8 Conclusion In summary, Pelchat emphasized the following: • The elderly experience declines in sensitivity of all the chemical senses. • Olfactory sensitivity declines the most. • Most older adults are not aware of their loss of chemosensitivity. • Loss of chemosensitivity is especially hard to detect in community- living elderly. • Loss of chemosensitivity leads to a loss in gate-keeping functions. QUESTIONS AND DISCUSSION The three presentations sparked questions from the audience on vita- min E supplementation, differences in physiology between the 65-and-over and 85-and-over populations, the gate-keeping function of the mouth, epi- genetics and the reality that aging is a lifetime process, and the association between loss of smell and Alzheimer’s disease and other dementias. 8 These data are unpublished from Pelchat.

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 PHySIology And AgIng 4.00 2.40 Salt Preference/Liking 0.80 old-inst -0.80 young -2.40 -4.00 0.00 0.10 0.20 0.30 0.40 0.50 concentration (M) FIgURE 3-4 Loss in olfactory sensitivity with aging typically leads to a loss of gate-keeping function, with one of the manifestations being a decreased ability to detect salt. SOURCE: Pelchat, unpublished data, 1993. Vitamin E Supplementation Figure 3-4, editable The first two questions were directed to Meydani, with the questioner asking about the benefits of vitamin E in middle-aged vs. older adults and the connection between vitamin E and omega-3 supplementation. Meydani explained that most of her studies have been with older adults. She recalled only one study involving both younger and older adults, which demon- strated some improvement in the younger adults but not to the degree seen in the older adults. Additionally, many animal model studies have shown that the benefit is greater for older ages. Without further studies in young adults, she said that she would be hesitant to recommend vitamin E supple- mentation to adults below the age of 50. With regard to the connection between vitamin E and fish oil, she said that most of those studies were done nearly 30 years ago, when there was considerable interest in fish oil. Both animal (rodent, primate) and human studies showed that fish oil must be combined with vitamin E in order to avoid the adverse effects associated with cell-mediated immunity. She said that the requirement for vitamin E is likely dependent on the type of fatty acid supplement. Physiological Differences Among Different Older Age groups An audience member asked whether there are any differences in phys- iology between the 65-and-over versus 85-and-over populations. Most reports lump all older adults together into the 65-and-over category, but is this appropriate? Should this lumping be split into 65-and-over and 85-

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 PRoVIdIng HEAltHy And SAFE FoodS AS WE AgE and-over categories? Jensen responded, “That is a terrific question.” He said that, as a clinician, he has observed tremendous variation between “old older persons” and “young older persons.” Of course there are exceptions, and genetic imperative makes a tremendous difference as well. He described the differences as a continuum, and said “Drawing a line in the sand at a particular age is very challenging.” Meydani agreed and added that the degree of change in immune system dysfunction during aging depends to some extent on the decade of age, and that there are differences between people in their 60s, for example, and people in their 90s. The gate-Keeping Function of the Oral Cavity Another audience member asked Pelchat to elaborate on the concept of gate-keeping. Pelchat described the mouth as “the guardian of the body.” She explained, “When you eat, you are potentially taking things into the body. One of the functions of the mouth is evaluating those things. . . . If there is a deep freeze in this guardianship, there may be more risk for adverse outcomes.” Meydani added that loss of regulatory capacity dur- ing aging seems to be a common theme for many different functions. For example, older adults are often not able to detect hydration in the mouth, and they are less able to develop a response to infection (e.g., by develop- ing a fever). Aging as a Lifetime Process The presenters were asked if they had given any consideration to whether epigenetics plays a role in aging-related physiological change. Does variation in early-life exposure (e.g., place of birth, nutrition during formative years) mean that different people have different optimal diets later in life? If so, how might this impact public policy around nutrition in aging populations? Meydani replied, “That is an excellent question.” She said that she is considering that question in her own research, specifically how nutrition during early fetal life and during childhood could impact the development of chronic and infectious diseases later in life. It raises an important point: aging is a lifelong process, not just something that occurs in old age. Loss of Smell The last question was about the association between loss of smell and Alzheimer’s disease. Pelchat replied that there is a very good correlation between loss of smell and Alzheimer’s (and, more controversially, other de-

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 PHySIology And AgIng mentias as well), as many of the changes associated with Alzheimer’s begin in parts of the olfactory cortex. Prospective studies have found that people with severe olfactory loss develop more memory deficits in general, even if they do not develop Alzheimer’s per se. However, she noted, “it is much more common to have a loss of sense of smell than to have Alzheimer’s!”

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