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To investigate the effects of dietary iron (Fe) and age on Fe metabolism, we used 36 weaned barrows in a 2 x 3 design with 2 concentrations of dietary Fe [97 (control) and 797 (high Fe) mg Fe/kg dry matter] and 3 time points of tissue collection (after 21,42, or 63 d on diets). Pigs were weighed and bled on d 0, 20, 41, and 62. High Fe reduced feed efficiency but did not affect pig weight gain. Blood hemoglobin concentrations and Fe concentrations of liver, intestine, and heart were increased by high dietary Fe on all days. Concentrations of liver and heart Fe increased with age. As determined by quantitative real- time PCR, hepatic expression of hepcidin (HAMP) in pigs given the high-Fe diet was 6.25-fold that of control pigs. In the intestine, relative mRNA levels of ferroportin, divalent metal transporter 1, and transferrin receptor were downregulated by high Fe. Expression of an alternative route of Fe absorption, solute carrier family 39 member 14 (SLC39A14), was downregulated in the intestine of pigs fed high dietary Fe. Additionally, duodenal mRNA level of certain genes including scavenger receptor class A, member 5, and frataxin decreased with age of the animal. Our findings indicate new roles in Fe metabolism for several mineral metabolism-associated genes and that some of these genes, such as SLC39A14, may be regulated in response to dietary Fe in pigs. Additionally, the expression of some genes examined in this study was affected by age, suggesting age dependency of Fe metabolism in pigs. J. Nutr. 140: 271-277, 2010. doi: 10.3945/jn.109.112722.

The antioxidant properties of North American ginseng (Panax quinquefolium) were investigated in young and old rats fed a ginseng-supplemented diet for 4 mo. Female Fischer 344 rats at 4 (Y, n = 38) or 22 (O, n = 25) mo of age were randomly divided into three groups and fed either a AIN-93G formula-based control diet (C) or a diet containing 0.5 g/kg (low dose, L) or 2.5 g/kg (high dose, H) dry ginseng power for 4 mo. Oxidant generation, measured with 2'7'-dichlorofluorescin (DCFH), was significantly lowered with ginseng feeding in the homogenates of heart, soleus, and the deep portion of vastus lateralis muscle (DVL) (P < 0.05) in both Y and O rats, and the effects were dose dependent. Superoxide dismutase activity was elevated in heart and DVL of H rats, and in soleus of L rats (P < 0.05). H rats showed higher glutathione peroxidase activity in DVL and soleus muscle (P < 0.05), and elevated citrate synthase activity in the heart of both age groups and DVL of Y rats (P < 0.05). Neither the H nor L diet affected age-dependent lipid peroxidation in the heart or muscle, but protein carbonyl content was attenuated with the H diet in the heart (P < 0.05) and with both the L and H diets in DVL (P < 0.01). We conclude that ginseng supplementation can prevent age-associated increase in oxidant production and oxidative protein damage in rats. These protective effects are explained in part by elevated antioxidant enzyme activities in the various tissues. KEY WORDS: * antioxidant enzyme * free radical * ginseng * oxidative stress * rats

The main objective of this study was to resolve the issue of whether the amounts of Coenzyme Q (CoQ), which is endogenously synthesized in cells, can be elevated in tissues and mitochondria of young mice by dietary supplementation with Co[Q.sub.10]. The prevalent view is that the uptake of exogenous CoQ by tissues other than plasma and liver either does not occur or is quite minimal. Mice, 6 mo of age, were fed 0, 148 or 654 mg Co[Q.sub.10]/(kg body * d) in their diets for 11 wk. Co[Q.sub.10] intake enhanced both Co[Q.sub.9] and Co[Q.sub.10] homologues in the plasma, and in homogenates and mitochondria of liver, heart and skeletal muscle. CoQ was elevated in brain mitochondria, but not in the brain homogenate. The uptake of exogenous CoQ was higher in mitochondria of heart and skeletal muscle than those in liver. Co[Q.sub.10] administration also elevated the [alpha]-tocopherol concentration in tissue homogenates and their mitochondria, thereby providing an in vivo indication of the 'sparing' effect of CoQ on [alpha]-tocopherol. Results of this study demonstrate that, contrary to the historical view, both total and mitochondrial CoQ concentrations in the heart and skeletal muscle and in the mitochondria of brain of young mice can be augmented by dietary supplementation. Furthermore, CoQ intake enhances the antioxidative potential of tissues by elevating the endogenous amounts of [alpha]-tocopherol. J. Nutr. 133: 3175-3180, 2003. KEY WORDS: * coenzyme Q * mitochondria * [alpha]-tocopherol * aging * oxidative stress * antioxidants

Oxidative stress is thought to be a factor in the progression of chronic diseases, and even the aging process itself. We examined the effect of two moderate vitamin, mineral and phytochemical supplements and a dietary intervention on markers of oxidative stress and antioxidant status in older humans. Subjects (n=60, 65-85 y old) were enrolled in a 5-wk, double-blind, placebo-controlled study. The subjects were randomly assigned to a group with one of four interventions: antioxidant supplement capsule, antioxidant supplement tablet, high carotenoid diet or placebo. Postintervention serum levels of some of the supplemented carotenoids and [alpha]-tocopherol were higher in all treated groups compared with the placebo group and with preintervention levels within groups. Markers of oxidative stress or antioxidant capacity were not significantly different from preintervention levels, although the diet and supplement capsule groups had lower levels of some of those markers than the placebo group postintervention. The results suggest that both moderate antioxidant supplementation and a diet high in carotenoids elevate serum carotenoids and antioxidant levels in an older adult population, although with different specific effects. J. Nutr. 133:3117-3123, 2003. KEY WORDS: * oxidative stress * carotenoids * antioxidant supplemetns * oxygen radical absorptive capacity (ORAC) * high carotenoid diet

There is conflicting evidence as to whether the age-related decline in resting energy expenditure (REE) can be attributed to i) absolute changes in fat-free mass (FFM), ii) alterations in the composition of FFM or iii) decreasing organ metabolic rates. This study directly addressed the first and second hypotheses by quantification of metabolically active components of FFM assuming constant tissue respiration rates to calculate REE (REEc). REE was measured (REEm) in 26 young (13 females, 13 males, age 22-31 y) and 26 elderly subjects (15 females, 11 males, age 60-82 y) by indirect calorimetry and detailed body composition analysis was obtained using bioelectrical impedance analysis (BIA), dual energy X-ray absorptiometry (DXA), and MRI. Specific organ metabolic rates were taken from the literature. REEm adjusted for differences in FFM was lower in older subjects than in younger control subjects (5.43 [+ or -] 0.61 MJ/d compared with 6.37 [+ or -] 0.48 MJ/d; P < 0.001). Skeletal muscle mass plus liver mass accounted for 86% and 48% of the variance in REE in young and elderly subjects, respectively. The difference between REEm and REEc was 0.03 [+ or -] 0.40 MJ/d and -0.36 [+ or -] 0.70 MJ/d in young and elderly subjects, respectively. In the elderly 58% of the difference in variance was attributed to heart mass. REEm -REEc was -1.40 [+ or -] 0.44 MJ/d in subjects with hypertensive cardiac hypertrophy, i.e., heart mass > 500 g, suggesting a decrease in heart metabolic rate with increasing heart mass. Excluding five elderly subjects with cardiac hypertrophy resulted in agreement between REEm and REEc in the elderly (-0.10 [+ or -] 0.48 MJ/d). We concluded that the age-related decline in REE is attributed to a reduction in FFM as well as in proportional changes in its metabolically active components. There is no evidence for a decreasing organ metabolic rate in healthy aging. KEY WORDS: * aging * dual energy X-ray absorptiometry * magnetic resonance imaging * organ mass * resting energy expenditure

Acute leucine supplementation of the diet has been shown to blunt defects in postprandial muscle protein metabolism in old rats. This study was undertaken to determine whether the effect of leucine persists in a 10-d experiment. For this purpose, adult (9 mo) and old (21 mo) rats were fed a semiliquid 18.2 g/100 g protein standard diet during the 8-h dark period for 1 mo. Then, each group was given either a leucine-supplemented meal or an alanine-supplemented meal (as the control meal) for 1 h and the standard diet the rest of the feeding period. On d 10, rats were fed either no food (postabsorptive group) or the supplemented meal for 1 h. Muscle protein synthesis was assessed in vivo 90-120 min after meal distribution using the flooding dose method (1-[sup.13]C phenylalanine). Leucinemia was similar in rats of both ages in the postabsorptive state. Postprandial plasma leucine concentrations were one- to twofold greater after the leucine meal than after the control meal. In the postabsorptive state, leucine supplementation did not modify the muscle protein synthesis rate in old rats but enhanced it to the postprandial rate in adult rats. As expected, muscle protein synthesis was stimulated by the control meal in adult rats but not in old rats. The leucine meal restored this stimulation in old rats but did not further stimulate muscle protein synthesis in adult rats. In conclusion, the beneficial effect of leucine supplementation on postprandial muscle protein anabolism persists for at least 10 d. The long-term utilization of leucine-rich diets may therefore limit muscle protein wasting during aging. J. Nutr. 133: 1198-1205, 2003. KEY WORDS: * aging * muscle protein synthesis * leucine * chronic * rats

Aging induces a dysregulation of immune and inflammation functions that may affect protein synthesis rates in lymphoid tissue and plasma proteins. We quantified in vivo synthesis rates of thymus, spleen and plasma proteins, including albumin and acute phase proteins, in adult (8 mo old) and old (22 mo old) rats using the flooding dose method [L-(1-[sup.13]C) phenylalanine]. Immunosenescence was reflected by thymus atrophy and spleen hypertrophy in old rats but not in adult rats. A low albumin plasma level associated with high concentrations of fibrinogen, [[alpha].sub.2]-macroglobulin, [[alpha].sub.1]-acid glycoprotein and proteins other than albumin revealed a low grade inflammation in old rats. Protein fractional synthesis rates (FSR) and protein synthesis efficiencies of thymus were 29 and 26% lower in old than in adult rats, respectively; these variables did not differ in spleen. Protein absolute synthesis rates (ASR) of the thymus and spleen were 76% lower and 67% greater in old than adult rats, respectively. The FSR and ASR of albumin and other plasma proteins were greater in old than in adult rats. Protein synthesis measurement is a valuable nonimmunological tool to assess, in vivo, immune and inflammatory variables. Alterations in secondary lymphoid organs and plasma protein synthesis may contribute to the significant repartitioning of amino acids in old compared with adult rats and may be involved in sarcopenia. KEY WORDS: * aging * inflammation * lymphoid tissues * protein synthesis * rats

Cytosine guanine dinucleotide (CpG) island methylation is a known mechanism of epigenetic inheritance in postmeiotic cells. Through associated chromatin changes and silencing, such epigenetic states can influence cellular physiology and affect disease risk and severity. Our studies of CpG island methylation in normal colorectal mucosa revealed progressive age-related increases at multiple gene loci, suggesting genome-wide molecular alterations with potential to silence gene expression. However, there was considerable variation in the degree of methylation among individuals of comparable ages. Such variation could be related to genetic factors, lifestyle, or environmental exposures. Studies in ulcerative colitis and hepatocellular cirrhosis and neoplasia revealed that chronic inflammatory states are accompanied by marked increases in CpG island methylation in normal-appearing tissues, confirming the hypothesis that proinflammatory exposures could account for part of the epigenetic variation in human populations. Preliminary data also suggest potential influences of lifestyle and exposure factors on CpG island methylation. It is suggested that epigenetic variation related to aging, lifestyle, exposures and possibly genetic factors, is one of the modulators of acquired, age-related human diseases, including neoplasia. KEY WORDS: * epigenetics * DNA methylation * aging * CpG islands * CpG island methylator phenotype

DNA methylation is a major epigenetic modification of the genome that has the potential to silence gene expression. Recently, the role of epigenetic alteration as a distinct and crucial mechanism to regulate genes governing cell proliferation in atherosclerosis has emerged. Aberrant methylation is related to aging, and, because it affects a large number of CpG islands, age-related methylation may be an important contributor to increased atherosclerosis among older individuals by upregulating atherosclerosis-susceptible genes and downregulating atherosclerosis-protective genes. Further dissection of epigenetic alterations in atherosclerosis and aging will lead to the identification of novel epigenetic modifiers and improved diagnosis and treatment for atherosclerosis-related diseases. KEY WORDS: * DNA methylation * atherosclerosis * aging

DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of autoimmunity, aging and cancer. Evidence for a role in autoimmunity comes from studies demonstrating that inhibiting T lymphocyte DNA methylation causes autoreactivity in vitro and a lupus-like disease in vivo. The autoimmunity is due in part to the heterodimeric [[beta].sub.2] integrin lymphocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) overexpression, and T lymphocytes from lupus patients hypomethylate the same CD11a promoter sequences, overexpress LFA-1 and demonstrate the same autoreactivity. Procainamide and hydralazine, two drugs that cause a lupus-like disease, also inhibit T cell DNA methylation, increase LFA-1 expression and induce autoreactivity in vitro and autoimmunity in vivo, supporting the association of DNA hypomethylation and autoimmunity. Methylation patterns also change with age in T lymphocytes as well as other tissues, typically with an overall decrease in methylcytosine content, but with increases in some cytosine guanine dinucleotide (CpG) islands. Age-dependent hypomethylation contributes to LFA-1 overexpression with aging, which may play a role in the development of autoimmunity in the elderly and age-dependent methylation of CpG islands in the promoters of tumor suppressor genes is an early event in the development of some cancers. DNA hypomethylation also may contribute to carcinogenesis by promoting overexpression of proto-oncogenes, chromosomal translocations and loss of imprinting. The mechanisms causing altered DNA methylation in autoimmunity, aging and carcinogenesis are incompletely characterized but include exposure to environmental agents and drugs, diet, altered signaling in pathways regulating DNA methyltransferase expression and changes in endogenous regulatory mechanisms. Other mechanisms are likely to be identified as well. KEY WORDS: * aging * lupus * carcinogenesis

Physiologic adaptation to the high calcium demand during pregnancy and lactation may be different in adolescents than in adults, particularly at low calcium intake. The aim of this cross-sectional study was to compare biochemical markers of calcium and bone metabolism between adolescent (14-19 y) and adult (21-35 y) women with calcium intake ~500 mg/d, in three different physiologic states, i.e., control (nonpregnant, nonlactating; NPNL), pregnant and lactating. Markers of calcium metabolism [serum Ca, P and intact parathyroid hormone (iPTH); urinary Ca and P] and of bone turnover [urinary deoxypyridinoline (D-Pyr) and plasma bone alkaline phosphatase (BAP)] were measured in NPNL (adolescents, n = 12 and adults, n = 25), pregnant (adolescents, n = 30 and adults, n = 36) and lactating (adolescents, n = 19 and adults, n = 26) women. In the NPNL women, iPTH, D-Pyr and BAP were higher (P < 0.001) and urinary Ca was lower (P < 0.001) in adolescents than in adults. Serum iPTH was higher (P < 0.001) and urinary Ca was lower (P < 0.01) in adolescents than in adults also in pregnancy and lactation. Compared with NPNL women, serum Ca decreased (P < 0.001) with pregnancy in adolescents but not in adults. The increase in D-Pyr with pregnancy and lactation was very pronounced in adults (~130%, P < 0.001) but less in adolescents ( KEY WORDS: * calcium * adolescence * pregnancy * lactation * bone turnover

The aim of this investigation was to see whether aging influences feeding behavior in cats. Two studies were carried out. In the first study, a standard canned cat food was fed to six young adult and six senior cats for 10 d on an ad libitum basis. Feeding behavior was monitored during the final 5 d. In the second study, diets enriched with beef tallow, olive oil or sunflower oil were fed at an equivalent energy intake for 21 d. Feeding behavior was monitored during the final 5 d. The results of both studies indicated no significant differences between the young and old cats in the number of meals consumed, the amount consumed at each meal or the duration of each meal when fed either ad libitum or at equivalent energy intakes. Daily feeding patterns were similar for each of the 5 d for each cat, with cats tending to consume regular small meals throughout the day and night. The only significant differences noted were among the fat-enriched diets. The diet enriched with beef tallow had fewer refusals compared to the diets enriched with olive oil and sunflower oil, indicating a possible palatability differential. It was concluded that cats of all ages are habitual feeders with similar daily feeding patterns, which may be altered only with a change in diet. Given that no differences were seen between the young and senior cats, it cannot be assumed that feeding patterns are responsible for the previously observed age-related decreases in apparent digestibility. KEY WORDS: * feeding behavior * feline * digestibility * age * energy intakes

Increasing evidence suggests involvement of free-radical species in the development of oxidative DNA damage, the consequences of which have been implicated in a number of degenerative disorders associated with the aging process. Here we report the application of a single-cell gel electrophoresis (comet) assay for assessing levels of DNA damage in canine and feline leukocytes. Leukocytes were collected from 24 healthy adult cats and dogs and subjected to DNA damage ex vivo by exposure to a range of hydrogen peroxide ([H.sub.2 O.sub.2]) concentrations (0-250 [micro]mol/L). The optimal concentration of([H.sub.2 O.sub.2]) to induce a significant increase in DNA damage was 100 [micro]mol/L for both canine and feline leukocyte samples. Levels of DNA damage were assessed and quantified by visual and computer image analysis. The results obtained showed high correlations between visual scoring and computer image analysis for feline samples (percentage DNA in tail, R[sup.2] > 0.99; tail moment, R[sup.2] > 0.95; tail length, R[sup.2] > 0.90) and canine samples (percentage DNA in tail, R[sup.2] > 0.97; tail moment, R[sup.2] > 0.95; tail length, R[sup.2] > 0.91). In conclusion, this method provides a way of assessing levels of DNA damage utilizing visual and/or computer image analysis in the feline and canine systems. With the capacity of the comet assay to be able to measure end products of free-radical reactions, it is a useful tool for determining the optimal effects of dietary antioxidants on a reliable biomarker of oxidative stress such as cellular DNA status in cats and dogs. Key Words: * DNA damage * comet assay * leukocytes * canine * feline

We studied the effects of feeding an antioxidant blend of vitamins, minerals and carotenoids to a mixed adult dog population (n = 40, mean 4.4 [+ or -] 1.85 y) for a 16-wk period. Compared to the control group of dogs (n = 20), the antioxidant (AOX)-supplemented group of dogs (n = 20) demonstrated significant increases in plasma levels of vitamin E and taurine by 4 wk of supplementation (P < 0.01) and total antioxidant activity (as measured by ferric-reducing antioxidant power assay) by 8 wk of supplementation (P < 0.05). Following 8 wk of supplementation, the AOX-supplemented dogs also showed significant reductions in both endogenous and exogenous DNA damage (P < 0.005) compared to that of the control dogs, as measured by the comet assay. Over an 8-wk rabies vaccination course that started at 8 wk supplementation, the AOX-supplemented dogs also demonstrated significantly higher vaccine-specific virus-neutralizing antibody levels at 2, 4 and 6 wk postvaccination (P < 0.05) and a tendency toward establishing a vaccine-specific antibody response quicker than did the control group of dogs. These findings in dogs suggest that antioxidant supplementation can achieve sustained increases in circulating levels of antioxidants that exert a protective effect by a decrease in DNA damage, leading to improved immunological performance. These findings also have implications in a wider context where free-radical damage has been associated with a variety of degenerative disorders and the aging process in general. KEY WORDS: * dogs * antioxidants * DNA damage * comet assay * vaccination

The process of neurodegeneration displays some common morphological characteristics, most of which are jointly observed in the brains of most mammalian species. In the canine brain, neurodegeneration is frequently typified by an extensive [beta]-amyloid (A[beta]) deposition (mainly of the C-terminal A[beta]1-42 form) within the neurones and at the synaptic regions, in the early stages of the process. These deposits subsequently appear to give rise to the formation of senile plaques of the diffuse (non-[beta]-sheet) subtype, which tend to develop spontaneously but rarely proceed to form neuritic plaques. Additional features accompanying neurodegeneration include accumulations of the 'aging pigment,' lipofuscin, intraneuronal changes in the cytoskeleton, vascular changes in the cerebrum, cortical cerebral atrophy, enlargement of the ventricles and increased concentration of oxidative stress markers, many of which are perceived as cardinal features of extensive dysfunction in the protein turnover network. The involvement of ubiquitin is discrete but consistent in many of these molecular structures and seems to account for some critical aspects of the associated neuropathology. Irrespective of these, though, the degenerated canine brain seems to be devoid of neurofibrillary tangle formation, a manifestation commonly observed in the brain of both aged (cognitively normal) and Alzheimer-affected human subjects. The fact that canines exhibit clear symptoms of an age-related cognitive decline pertains to the concept of A[beta] playing a central role in age-related cognitive dysfunction and neurodegeneration. Key Words: * [beta]-amyloid (A[beta]) * neurodegeneration * aging

Aging is characterized by a progressive loss of muscle mass. A decrease of muscle protein synthesis stimulation has been detected in the postprandial state and correlated to a decrease of muscle protein synthesis sensitivity to leucine in vitro. This study was undertaken to examine the effect of a leucine-supplemented meal on postprandial (PP) muscle protein synthesis during aging. Adult (8 mo old) and old (22 mo old) rats were fed a semiliquid 18.2% protein control diet for 1 mo. The day of the experiment, rats received no food (postabsorptive group) or either an alanine or leucine-supplemented meal for 1 h (postprandial groups: PP and PP + Leu groups, respectively). Muscle protein synthesis was assessed in vivo 90-120 min after the meal distribution using the flooding dose method (1-[sup.13]C phenylalanine). Plasma leucine concentrations were significantly greater in the PP + Leu group compared with the PP group at both ages. Muscle protein synthesis was significantly greater in the adult PP group, whereas it was not stimulated in the old PP group. When supplemented with leucine, muscle protein synthesis in old rats was stimulated and similar to that observed in adults. We conclude that acute meal supplementation with leucine is sufficient to restore postprandial stimulation of muscle protein synthesis in old rats. Whether chronic leucine meal supplementation may limit muscle protein wasting during aging remains to be verified. KEY WORDS: * aging * protein synthesis * leucine * muscle * rats

Reduction in klotho gene expression causes accelerated senescence in klotho mutant mice. We have now found two key substances, phosphorus and zinc, which affect the appearance of klotho phenotypes. Klotho mutant homozygotes fed nonpurified diet with a phosphorus concentration of 1.03 g/100 g showed typical klotho phenotypes. However, most of the klotho phenotypes no longer appeared in male homozygotes fed a 0.4 g/100 g phosphorus diet. These homozygotes were capable of spermatogenesis. In the kidneys of the rescued male homozygotes, klotho protein expression was clearly detected. On the other hand, female klotho mice required supplementation of 0.25 g/100 g zinc orotate to the 0.4 g/100 g phosphorus diet to be rescued. Unlike in the rescued male mice, klotho protein levels in the kidneys of the rescued females were quite low. Wild-type (C3H/He) mice fed 1.5 or 1.0 g/100 g phosphorus diets had lower klotho protein expression in the kidneys than those fed a 0.4 g/100 g phosphorus diet (Kruskal-Wallis test, P < 0.05). These results indicate that dietary phosphorus and zinc modulate the phenotypes of klotho mice, and that klotho expression in the kidneys is regulated not only in klotho mutant mice, but also in wild-type mice. KEY WORDS: * klotho * phosphorus * zinc orotate * mice

Lactase-phlorizin hydrolase (LPH) and sucrase-isomaltase (SI) are intestinal microvillus membrane hydrolases that play important roles in carbohydrate digestion. Although the expression of these enzymes during postnatal development has been characterized, the effect of old age on disaccharidase activity is poorly understood. In the present investigation, we examined the effect of aging on lactase and sucrase activities and their mRNA levels in the small intestines of 3-, 12- and 24- mo-old rats by sampling from nine equidistant segments of small intestine. Total intestinal disaccharidase activity or mRNA abundance was determined from areas under the proximal-to-distal curves. Rats 24 mo of age had total intestinal lactase and sucrase activities that were 12 and 38% lower, respectively, than the 3-mo-old animals (P < 0.05). In contrast, total LPH and SI mRNA abundance did not change significantly. Thus, total intestinal lactase and sucrase activities decrease with age in a manner that likely involves a posttranscriptional process. The age-related decline in disaccharidase activity, if extrapolated to humans, may have important implications for the digestion of carbohydrate contained in the diet of the elderly. KEY WORDS: lactase-phlorizin hydrolase; sucrase-isomaltase; aging; rats; disaccharidase

The capacity of older men and women to adapt to regularly performed exercise has been demonstrated by many laboratories. Aerobic exercise results in improvements in functional capacity and reduced risk of developing type II diabetes in the elderly. High intensity resistance training (above 60% of the 1 repetition maximum) causes large increases in strength in the elderly, and resistance training significant increases muscle size. Resistance training also significantly increases energy requirements and insulin action of the elderly. We recently demonstrated that resistance training has a positive effect on multiple risk factors for osteoporotic fractures in previously sedentary post-menopausal women. Because the sedentary lifestyle of individuals in a long-term care facility may exacerbate losses of muscle function, we applied this same training program to frail, institutionalized elderly men and women. In a population of 100 nursing home residents, a randomly assigned high intensity strength training program resulted in significant gains in strength and functional status. In addition, spontaneous activity, measured by activity monitors, increased significantly in those participating in the exercise program; there was no change in the sedentary control group. Before the strength training intervention, the relationship of whole-body potassium and leg strength was relatively weak ([r.sup.2] = 0.29, P < 0.001), indicating that in very old persons muscle mass is an important but not the only determiner of functional status. Thus exercise may minimize or reverse the syndrome of physical frailty prevalent among very old individuals. Because of their low functional status and high incidence of chronic disease, there is no segment of the population that can benefit more from exercise training than the elderly. KEY WORDS: sarcopenia; muscle mass; aging muscle strength exercise

Despite general information that skeletal muscle mass is the largest organ in the body and despite increased awareness of the importance of skeletal muscle in biological function, methods and techniques for its routine assessment in humans are generally lacking. One important reason for the paucity of assessment tools is the relative lack of direct data on anatomical skeletal muscle mass in humans. KEY WORDS: sarcopenia; muscle mass; aging

The purpose of this study was to determine if food restriction alters the age-related decline in heat shock protein 70 (hsp70) expression in lymphocytes from male Fischer 344 rats. Spleen lymphocytes were isolated from young (6 mo) and old (24 mo) rats that had free access to food (control group) and from food-restricted old (24 mo) rats that, beginning at 6 wk of age, were fed 60% (40% food restriction) of the diet consumed by the control rats. Lymphocytes were either heat shocked (42.5 [degrees] C for 1 h) or maintained at 37 [degrees] C (control). The levels of hsp70 protein and mRNA and the induction of interleukin-2 (IL-2) mRNA by concanavalin A (conA) were measured in these rats. In addition, the percentage of viability (as an index of thermosensitivity) of the lymphocytes from these rats was also measured after exposure of cells to different temperatures (first at 42.5 [degrees] C and then 45 [degrees] C). We found that the induction of hsp70 protein and mRNA in lymphocytes isolated from control old rats and food-restricted old rats was lower (P [less than] 0.001) than that in control young rats. However, the levels of hsp70 and mRNA in lymphocytes isolated from food-restricted old rats were similar to the levels in age-matched control rats. Lymphocytes from both control old rats and food-restricted old rats were more thermosensitive than lymphocytes from control young rats; however, thermosensitivity of lymphocytes from food-restricted old rats was similar to that of age-matched control rats. The induction of IL-2 mRNA levels by conA was significantly (P < 0.001) lower in old than in young control rats. In contrast to hsp70, which was not affected by food restriction, the induction of IL-2 mRNA was higher (P < 0.05) in food-restricted old rats than in age-matched control rats. Therefore, food restriction has a differential effect on gene expression. J. Nutr. 126: 2069-2075, 1996. INDEXING KEY WORDS: * food restriction * heat shock proteins * lymphocyte * aging * rats

To determine the effect of age on the regulation of intestinal nutrient absorption, we fed young (7.6-mo-old) and aged (24.8-mo-old) C57BL mice diets designed to stimulate in vitro sugar or amino acid uptake in the isolated small intestine. In each age group, diet had no effect on feeding rates and body weights. D-Glucose and D-fructose uptakes by the small intestine each increased by about two times in young and 1.5 times in aged mice fed high carbohydrate diets as compared with those fed no carbohydrate. Adaptive increases in uptake by the aged group were not only reduced but also restricted to more proximal regions of the small intestine. In both age groups, diet-stimulated increases in D-glucose transport were accompanied by parallel increases in number of Na+-D-glucose cotransporters as estimated by specific phlorizin binding. Diet had no effect on transporter K(sub d) for phlorizin, turnover rate of each transporter, mucosal mass or mucosal permeability. A high protein diet stimulated the uptake of L-aspartate and L-proline in young mice and of only L-aspartate in aged mice. Uptake of essential amino acids and of nonessential amino acids sharing transporters with essential ones were not regulated. Although aged mice possess adaptive mechanisms to diet that are similar to those in young mice, the effectiveness of these mechanisms may be impaired with age and may result in malabsorption symptoms so prevalent in the elderly. J. Nutr. 123: 502-511, 1993.

We investigated the importance of adaptive variations in energy expenditure in the regulation of energy balance in young and elderly men of normal body weight leading unrestricted lives. Changes were measured in total and resting energy expenditure and body composition in response to overeating by approximately 4.2 MJ/d or undereating by 3.3 MJ/d for 21 d in 39 young and elderly men consuming a typical diet. In the young men, an average of 85-90% of the excess energy intake during overeating was deposited. During underfeeding, mobilization of body energy compensated for an average of 65% of the energy deficit in these subjects. The resting metabolic rate, averaged for fasting and fed states, increased during overfeeding (+0.63 plus or minus 0.20 MJ/d, P < 0.01) and decreased during underfeeding (-0.42 plus or minus 0.12 MJ/d), but at least some of these changes were due to the obligatory expenditure associated with nutrient assimilation. There was no significant change in energy expenditure for physical activity or thermoregulation from overfeeding or underfeeding. Preliminary results indicate that aging had no effect on responses to overfeeding or underfeeding. These findings suggest that adaptive variations in energy expenditure are not the major determinant of energy regulation in young adults of normal body weight and that, instead, energy balance is maintained on a day-to-day basis through the control of nutrient intakes.

Loss of lean body mass (LBM) is a hallmark of aging and of acute and chronic illness. Loss of more than 40% of lean mass is not compatible with life. The causes of loss of LBM in aging remain obscure, although changes in growth hormone production, physical activity and the cytokines interleukin-1 beta and tumor necrosis factor-alpha may play a role. The usefulness of a disease model based on rheumatoid arthritis (RA) is considered, in which all these changes occur to a greater degree and independently of age. RA is a common autoimmune condition in which cytokine production is increased, LBM is reduced and mortality is greatly accelerated. These observations suggest that, with respect to body composition at least, RA represents a model of 'accelerated' aging. A hypothesis is presented that unifies metabolic and immunologic observations and changes in body composition. The interrelationship of the immune system and body composition is an important area that deserves further investigation.

Advancing adult age is associated with profound changes in body composition. One of the most prominent of these changes is sarcopenia, defined as the age-related loss in skeletal muscle mass, which results in decreased strength and aerobic capacity and thus functional capacity. Sarcopenia is also closely linked to age-related losses in bone mineral, basal metabolic rate and increased body fat content. Through physical exercise and training, especially resistance training, it may be possible to prevent sarcopenia and the remarkable array of associated abnormalities, such as type II diabetes, coronary artery disease, hypertension, osteoporosis and obesity. Using an exercise program of sufficient frequency, intensity and duration, it is quite possible to increase muscle strength and endurance at any age. There is no pharmacological intervention that holds a greater promise of improving health and promoting independence in the elderly than does exercise.

This study examined the effects of diet restriction and exercise training during aging on adipocyte size and number in male Wistar rats. An average of 30 weanling rats each were assigned to one of four experimental groups: ad libitum access to food, nonexercised; diet restricted, nonexercised; ad libitum access to food, exercised; diet restricted, exercised. Diet-restricted groups were allowed free access to food every other day, and, over the course of the study, they consumed 18-25% less than the groups allowed ad libitum access. Exercise training consisted of swimming on alternate days for up to 3 h per exercise period. Fat cell size, number and fat depot mass were determined in the inguinal, epididymal and perirenal fat depots at 12 mo of age and every 4 mo thereafter until 28 mo of age. Fat cell number was not influenced by age, exercise or food restriction in the epididymal or perirenal fat depots. Inguinal cell number was lower (P < 0.05) in the diet-restricted, exercised group at all ages compared with all other treatments. Dietary restriction and exercise training significantly decreased fat depot mass and fat cell size, with dietary restriction having the greatest effect. A bimodal distribution of adipocytes was observed in the epididymal, perirenal and inguinal depots of animals allowed ad libitum access to food. The presence of a large population of small fat cells ( < 35 micrometer) indicated that even in the very aged animal there was the propensity for large variations in fat pad mass. The influence of diet restriction, exercise and aging on adipocyte cell size was highly variable and these effects were dependent on adipose tissue depot location. J. Nutr. 123: 52-58, 1993.

Milk was obtained from nonimmunized cows and cows immunized with a mixture of various human gut bacteria. Each milk was administered orally to 2-mo-old C57BL/6 mice at a dose of 150 [g.kg.sup.-1][.d.sup.-1] for either 6 or 16 mo. The study group had fewer enteric bacteria and a lower concentration of the serum antibodies against enteric bacteria compared with the control group at 8 and 18 mo of age. Furthermore, the study group at 18 mo old had a higher redirected cytotoxicity of intestinal intraepithelial lymphocytes, a higher proliferative response of mesenteric lymph nodes cells against mitogenic or alloantigenic stimulation and a greater ability of the spleen celis to produce anti-sheep erythrocytes IgG antibody after systemic immunization with sheep erythrocytes. A lower level of autoantibodies was observed at 8 mo and 18 mo of age in the study group compared with the control group. These results suggest that the senescence of the murine immune system may be delayed by consumption of milk from immunized cows. J. Nutr. 122: 1875-1883, 1992. INDEXING KEY WORDS: * aging * immune system * milk * mice * antibody, Immune competence of aging mice was evaluated by testing the protective effects of ingested cows milk immunized against enteric bacteria. Blood antibodies and intestinal tissue lymphocytes were analyzed to determine immune capacity. Results showed that immunized cows milk offered higher antibody activity and enteric bacterial inhibition. An increased thymocyte activity was also noted and cytolytic activity of gut-associated lymphocytes was enhanced in rats fedimmunized milk. It also suppressed the formation of autoantibodies and immunoglobulin levels remained constant.

In vitro and in vivo studies of human tissues have demonstrated telomeric attrition with age and have linked this attrition to cellular senescence and aging. Telomere studies in canine subjects have not thus far consistently uncovered the same pattern of telomere attrition that would be expected because of the end replication problem. In this report we describe the investigation of telomere lengths in a broad age range of dogs from three different breeds: the Labrador Retriever, Miniature Schnauzer and Beagle. Peripheral blood mononuclear cell-derived DNA samples were subjected to terminal restriction fragment (TRF) analysis and demonstrated a range of mean TRFs from 9.7 to 22.3 kbp. Telomeric attrition tended to be associated with increasing donor age (P = 0.06). Interbreed differences in mean TRF values were also noted (P = 0.006). These results warrant further investigation of possible interbreed differences, given that shorter telomeres may contribute to differing life expectancy between breeds. KEY Words: * telomere * dog * age

The use of the term sarcopenia to describe the age-related loss in skeletal muscle and its functional consequences is relatively recent. However, interest in the relationship of muscle mass to strength and function predates the concept of sarcopenia as researchers have attempted to understand differences in mass and strength between men and women, young and old. Most of these studies are cross-sectional comparisons in which muscle mass and strength tend to be linearly related, so that those with more muscle tend to be stronger. This article focuses instead on some potential problems with the sarcopenia-function association in old age and presents what little data exist from longitudinal population studies addressing the effect of sarcopenia over time. KEY WORDS: sarcopenia; muscle mass; aging

Human skeletal muscle undergoes major structural and functional changes with advancing age. A progressive degeneration of the nervous system is now considered a major factor underlying these alterations. This review will briefly describe the changes that occur in the human motor unit with increasing age and focus specifically on the changes that relate to a degeneration of the nervous system. KEY WORDS: aging; central nervous system; muscle mass; motor neurons; humans

The idea that aging should be linked to energy expenditure has a long history that can be traced to the late 1800s and the industrial revolution. Machines that are run fast wear out more quickly, so the notion was born that humans and animals might experience similar fates: the faster they live (expressed as greater energy expenditure), the sooner they die. Evidence supporting the 'rate-of-living' theory was gleaned from the scaling of resting metabolism and life span as functions of body mass. The product of these factors yields a mass-invariant term, equivalent to the 'amount of living.' There are at least four problems with this evidence, which are summarized and reviewed in this communication: 1) life span is a poor measure of aging, 2) resting metabolism is a poor measure of energy expenditure, 3) the effects are confounded by body mass and 4) the comparisons made are not phylogenetically independent. We demonstrate that there is a poor association between resting metabolic rate (RMR) and daily energy expenditure (DEE) measured using the doubly labeled water (DLW) method at the level of species. Nevertheless, the scaling relation between DEE and body mass still has the same scaling exponent as the RMR and body mass relationship. Thus, if we use DEE rather than RMR in the analysis, the rate-of-living ideas are still supported. Data for 13 species of small mammal were obtained, where energy demands by DLW and longevity were reliably known. In these species, there was a strong negative relationship between residual longevity and residual DEE, both with the effects of body mass removed (r[sup.2] = 0.763, F = 32.1, P < 0.001). Hence, the association of energy demands and life span is not attributed to the confounding effects of body size. We subjected these latter data to an analysis that extracts phylogenetically independent contrasts, and the relationship remained significant (r[sup.2] = 0.815, F = 39.74, P < 0.001). Small mammals that live fast really do die young. However, there are very large differences between species in the amounts of living that each enjoy and these disparities are even greater when other taxa are included in the comparisons. Such differences are incompatible with the 'rate-of-living' theory. However, the link between energetics and aging across species is reconcilable within the framework of the 'free-radical damage hypothesis' and the 'disposable soma hypothesis.' Within species one might anticipate the rate-of-living model would be more appropriate. We reviewed data generated from three different sources to evaluate whether this were so, studies in which metabolic rate is experimentally increased and impacts on life span followed, studies of caloric restriction and studies where links between natural variation in metabolism and life span are sought. This review reveals that there might be contrasting effects of resting and nonresting energy expenditure on aging, with increases in the former being protective and increases in the latter being harmful. Key Words: * metabolic rate * body mass * aging * survival * energetics * doubly labeled water * phylogenetics

The effect of aging on energy regulation remains controversial. We compared the effects of underfeeding on changes in energy expenditure and respiratory quotient in young normal weight men and women [YNW, age 25.7 [+ or -] 3.2 y(SD), body mass index (BMI) 23.1 [+ or -] 1.6 kg/[m.sup.2], young overweight men and women (YOW, age 26.1 [+ or -] 3.5 y, BMI 27.7 [+ or -] 2.1 kg/[m.sup.2]) and older (OLD) men and women (age 68.4 [+ or -] 3.3 y, BMI 27.4 [+ or -] 3.4 kg/[m.sup.2]). The thermic effect of feeding (TEF) during weight maintenance, and changes in resting energy expenditure (REE) and respiratory quotient were determined in response to undereating by an average 3.75 MJ/d for 6 wk. In addition, body composition was measured. No significant differences among the groups were observed in TEF, fasting and postprandial respiratory quotient, or the change in fasting respiratory quotient with underfeeding. However, REE adjusted for fat-free mass and fat mass was significantly lower in OLD subjects compared with YNW and YOW subjects (P [is less than] 0.05). In addition, the REE response to weight change was significantly attenuated in the OLD subjects (P = 0.023). These data suggest that the responsiveness of energy expenditure to negative energy balance is attenuated in old age, and provide further support for the hypothesis that mechanisms of energy regulation are broadly disregulated in old age. J. Nutr. 131: 1833-1838, 2001. KEY WORDS: * aging * energy metabolism * humans * respiratory quotient * body composition

This study examined the effect of S-allylcysteine (SAC), a major thioallyl compound found in aged garlic extract, on the memory deficit and age-related changes of senescence-accelerated mice. Senescence-accelerated prone P8 mice fed a diet supplemented with 40 mg SAC/kg diet for 8 mo had a significantly attenuated decrease in the conditioned avoidance response compared with those not given SAC. In the elevated plus-maze test using senescence-accelerated prone P10 mice, the percentage of time spent on the open arm was greater compared with the senescence-resistant control mice. Chronic dietary treatment with 40 mg SAC/kg diet decreased the time in the open arm in senescence-accelerated prone P10 mice. These studies suggest that diet supplementation with SAC may reduce age-related learning disabilities and cognitive disorders in senescence-accelerated mice. J. Nutr. 131: 1093S-1095S, 2001. KEY WORDS: * senescence-accelerated mice * S-allylcysteine * garlic * learning * memory

During the next 12 y, the National Cancer Institute-sponsored PCPT-2 SELECT trial will study [is greater than] 32,000 men to determine whether daily supplementation with selenium with and without vitamin E decreases the incidence of prostate cancer. However, the molecular mechanisms by which supranutritional selenium modulates key events in multistep prostate carcinogenesis remains unclear. We used the dog model to test the hypothesis that supranutritional selenium exerts a DNA damage-sparing effect on the aged prostate. Elderly (9-10.5-y) male beagle dogs were randomly assigned to groups: no treatment (sexually intact controls; n = 4 dogs), selenomethionine at 3 [micro]g [multiplied by] [kg.sup.-1] [multiplied by] [d.sup.-1] (n = 5 dogs) and selenomethionine at 6 [micro]g [multiplied by] [kg.sup.-1] [multiplied by] [d.sup.-1] (n = 5 dogs). After 7 mo of treatment, dogs were killed and single-cell gel electro-phoresis (alkaline comet assay) was used to measure basal levels of DNA damage in freshly harvested prostate tissue. Mean ([+ or -] SD) percentage of cells with extensively damaged DNA was compared between treatment groups by using ANOVA. Dogs in the low- and high-dose selenium groups had significantly reduced basal levels of DNA damage compared with age-matched controls. Mean ([+ or -] SD) percentage of cells with extensive DNA damage was 81% [+ or -] 3% and 54% [+ or -] 5% for control dogs and selenium-supplemented dogs, respectively (P [is less than] 0.0001). There was no significant difference in mean serum glutathione peroxidase activity between the control and selenium-supplemented groups. These data show that supranutritional selenium exerts a DNA damage-sparing effect within the aged prostate. This model enables us to study the mechanism of selenium supplementation in a model of selenium adequacy, which is the case for almost all healthy Americans, including those who will participate in the SELECT trial. [Supported in part by a grant from the USAMRMC Prostate Cancer Research Program (PC-970492 awarded to DJW).]

The introduction of high fructose corn syrup as a substitute sweetener for sucrose in the mid-1970s has contributed to a general increase in fructose consumption in the U.S. diet. Although several previous investigations suggested that dietary fructose increases serum triglyceride concentration and body fat, these studies have, in general, evaluated this effect in young rats fed the experimental diets for a relatively short period of the life span of the animals. Moreover, these investigations did not control for the possible effects that increased adiposity due to fructose feeding may have on serum triglyceride concentration. The purpose of the current investigation was to describe the long-term effects of specific dietary carbohydrates on serum lipid concentrations and body composition. To this end, we measured serum triglyceride, total cholesterol and HDL cholesterol concentrations and body composition of rats aged 9, 18 and 26 mo that had free access to or were restricted to 60% of free access intake of one of five diets that varied in carbohydrate source (cornstarch, sucrose, glucose, fructose or equimolar fructose plus glucose) starting at 3 mo of age. Dietary fructose significantly increased serum triglyceride concentration across the life span in rats that had free access to food or were calorie restricted. The source of dietary carbohydrate did not have a significant effect on body composition, total cholesterol or the distribution of the cholesterol fractions. These data suggest that dietary fructose per se and not the interaction between fructose and the energy content of the diet increases serum triglyceride concentration in rats. J. Nutr. 130: 3077-3084, 2000. KEY WORDS: * aging * body composition * calorie restriction * cholesterol * fructose * triglyceride * rats

We investigated the effects of a mixture of dietary nucleosides and nucleotides (NS + NT) on memory in 1- and 7-mo-old senescence-accelerated mice (SAM). Memory retention was studied with passive avoidance (step-through) and active avoidance (shuttle) tests. For 14 wk, mice in the control groups were fed a 20 g of casein/100 g diet, whereas the NS + NT groups were fed this diet supplemented with a 0.5 g of NS + NT mixture/100 g. All mice were killed at wk 14, and we studied the brain histopathology. Lipofuscin, monovacuoles and multiple vacuoles of various brain regions were measured. Body weight, food intake and ambulatory activity did not differ between the control and NS + NT groups. In old mice, the time of passive avoidance was significantly higher in the NS + NT group than in the control group at d 1 and 7 (P [is less than] 0.05). However, such an effect of NS + NT was not observed in young mice. In the active avoidance test, the incidence of successful avoidance in old mice was higher in the NS + NT group than in the control group at d 1 and 2 (P [is less than] 0.05). The percentages of specific brain cells containing lipofuscin were lower in NS + NT groups than in the control groups in both young and old mice (P [is less than] 0.05). The number of monovacuoles and multiple vacuoles in specific brain regions tended to be lower (P = 0.1-0.25) in NS + NT than in control groups, with significant differences in the microvacuoles of the middle cortex of young mice and in the multiple vacuoles in the hind cortex of old mice (P [is less than] 0.05). These results suggest that increased dietary NS + NT may be associated with decreases in the age-induced deterioration of brain morphology and certain memory tasks. J. Nutr. 130: 3085-3089, 2000. KEY WORDS: * age * nucleosides * nucleotides * memory * mice

Aging is characterized by a decrease of muscle mass associated with a decrease in postprandial anabolism. This study was performed to gain a better understanding of the intracellular mechanisms involved in the stimulation of muscle protein synthesis by amino acids and their role in the decrease of muscle sensitivity to food intake during aging. The effects of amino acids or leucine alone were assessed in vitro on epitrochlearis muscle from young, adult and old rats. Protein synthesis was assessed by incorporation of radiolabeled phenylalanine into protein and p70 S6 kinase activity by incorporation of [sup.32]p into a synthetic substrate. Amino acids, at physiologic concentrations, stimulated muscle protein synthesis (P [is less than] 0.05) and leucine reproduced this effect. The intracellular targets of amino acids were phosphatidylinositol 3' kinase and the rapamycin-sensitive pathways mammalian target of rapamycin (mTOR)/p70 S6 kinase. In old rats, the sensitivity of muscle protein synthesis to leucine was lower than in adults (P [is less than] 0.05) and this paralleled the lesser ability of leucine to stimulate the rapamycin-sensitive pathways (P [is less than] 0.05). We demonstrated that amino acids and leucine stimulate muscle protein synthesis and that aging is associated with a decrease in this effect. However, because aged rats are still able to respond normally to high leucine concentrations, we hypothesize that a nutritional manipulation increasing the availability of this amino acid to muscle could be beneficial in maintaining the postprandial stimulation of protein synthesis. J. Nutr. 130: 2630-2635, 2000. KEY WORDS: * rats * protein synthesis * leucine * age * muscle

Arginine supplementation enhances in vitro lymphocyte proliferation in healthy adult humans and in rodent models. Studies examining the effect of arginine supplementation on in vivo immune responses are lacking. The purpose of this study was to determine whether arginine supplementation could enhance in vivo immune responses in adult mice and reverse known age-associated alterations in immune function of young and aged mice. Mice (1, 10 and 33 mo old) were fed a 2% arginine or an isonitrogenous diet for 2 wk. Delayed-type hypersensitivity to 2,4-dinitrofluorobenzene--challenged ears and changes in popliteal lymph node weights to injected sheep red blood cells were measured. The mean percentage of increase in ear thickness in challenged vs. unchallenged ears was 27, 35 and 24% with arginine supplementation and 7, 12 and 0% with the isonitrogenous diet in the 1-, 10- and 33-mo-old mice, respectively (P [is less than or equal to] 0.05 for each age). Across all ages, the mean differences in popliteal lymph node weights were 1.9 [+ or -] 0.3 vs. 1.0 [+ or -] 0.3 mg with the arginine and isonitrogenous diets, respectively (P [is less than or equal to] 0.05). Only the 33-mo-old mice fed the isonitrogenous diet did not respond to this immune challenge. These findings suggest that arginine supplementation may enhance in vivo immune responses and/or reverse age-associated changes. J. Nutr. 130: 1827-1830, 2000. KEY WORDS: * mice * arginine * aged * immune function * delayed-type hypersensitivity

The Age-Related Eye Disease Study includes a clinical trial of high dose antioxidant and zinc supplements for age-related macular degeneration and a clinical trial of high dose antioxidants for cataract. The clinical trials were initiated largely because of the widespread public use in the United States of commercially available pharmacological doses of vitamins and minerals to treat these two eye conditions and the absence of definitive studies on the safety and efficacy of their use. This report focuses on the clinical trial of zinc and the possibility that this elderly study cohort, who were randomly assigned in a factorial design to receive zinc, antioxidants and placebo, could be assessed for zinc effects other than those currently addressed by the trial. J. Nutr. 130: 1516S-1519S, 2000. KEY WORDS: * zinc * age-related macular degeneration * cataract * clinical trial * antioxidants * vitamin C * vitamin E * beta-carotene

It is currently unknown whether the capacity of the liver to esterify and store vitamin A (VA) changes as a function of long-term VA intake or age. The objective of this study was to investigate whether age and/or VA status are factors for the hepatic expression of cellular retinol-binding protein (CRBP), the esterification of retinol by lecithin:retinol acyltransferase (LRAT) and the accumulation of VA and lipids in liver. Two factors, VA intake and age, were studied in a 3 x 3 design. Diets denoted as VA-marginal, control and supplemented contained 0.35, 4 and 25 mg retinol equivalents/kg diet, respectively; male Lewis rats were fed these diets from weaning until the ages of 2-3 mo (young), 8-10 mo (middle-aged) and 18-20 mo (old) (n = 6/group. Liver CRBP mRNA differed (two-way ANOVA) with dietary VA (P [is less than] 0.0001) and age (P [is less than] 0.05). Hepatic LRAT activity increased with dietary VA (P [is less than] 0.0001). Age was not a factor (P [is less than] 0.47) although there was an interaction of age and dietary VA (P [is less than] 0.0001). Hepatic LRAT activity was correlated (r = 0.633, P [is less than] 0.0001) with plasma retinol at physiologic concentrations. In VA-supplemented rats of all ages, the plasma molar ratio of total retinol:retinol-binding protein (RBP) exceeded 1, and liver VA and total lipid concentrations were elevated. However, tests of liver function had previously been shown to be within normal values. Thus, the capacity of the liver for retinol esterification by LRAT was not diminished by age or the accumulation of VA and other lipids. We conclude the following: 1) hepatic LRAT activity is regulated across a broad, physiologic range of dietary VA; 2) LRAT activity is regulated throughout life; and 3) the capacity for hepatic VA storage is high throughout life. J. Nutr. 130: 1280-1286, 2000. KEY WORDS: * aging * vitamin A * lecithin * retinol acyltransferase * cellular retinol-binding protein * retinyl esters * rats

We tested the hypothesis that nonmuscle lean tissue mass and its rate of protein catabolism remain constant with aging despite changes in the proportional contribution of these tissues to whole-body protein metabolism. Whole-body protein kinetics, using the 60-h oral [[sup.15] N]glycine method, and muscle and nonmuscle protein catabolism, based on protein kinetic data, urinary [N.sup.[Tau]]-methylhistine excretion and lean tissue volumes defined by whole-body magnetic resonance imaging, from eight healthy elderly subjects (5 females and 3 males, mean age 71.5 y) were compared with those of seven young persons (3 females and 4 males, mean age 28 y). There were no significant age or gender effects on rates of protein kinetics per L total lean tissue. There was a lower (P [is less than] 0.004) rate of muscle protein catabolism in the elderly (1.8 [+ or -] 0.2 vs. 2.6 [+ or -] 0.1 g [multiplied by] [L.sup.-1] [multiplied by] [d.sup.-1]) and a trend (P = 0.08) for lower muscle volume (19.7 [+ or -] 1.5 vs. 25.0 [+ or -] 2.4 L). This contrasted with intraabdominal lean tissue, where the rate of protein catabolism (13.8 [+ or -] 0.6 vs. 13.2 [+ or -] 0.9 g [multiplied by] [L.sup.-1] [multiplied by] [d.sup.-1]) and volume (7.5 [+ or -] 0.3 vs 8.0 [+ or -] 0.5 L) did not differ between age groups. Thus, the decrease in the contribution by muscle to whole-body protein metabolism with age is associated with an increase from 62 to 74% (P [is less than] 0.001) in the contribution by nonmuscle lean tissues. These findings have potential implications for the nutrition of both normal and sick elderly persons. J. Nutr. 130: 784-791, 2000. KEY WORDS: * protein turnover * aging * [N.sup.[Tau]]-methylhistidine * magnetic resonance imaging * elderly humans

The senescence-accelerated mouse (SAMP8) is an animal model used in studies of aging. This study was undertaken to investigate the effects of dietary PUFA on longevity (Experiment 1) and serum lipid concentrations (Experiment 2) in SAMP8 mice. Male mice were fed either an (n-3) PUFA-rich (9 g/100 g perilla oil) or an (n-6) PUFA-rich (9 g/100 g safflower oil) diet beginning at 6 wk of age. Experiment 1: The groups did not differ in body weight gain, but those fed perilla oil had significantly lower scores of senescence relative to those fed safflower oil (P [is less than] 0.05). The mean life span of mice fed perilla oil was 357 [+ or -] 21d and of those fed safflower oil, 426 [+ or -] 24 d (P [is less than] 0.05). Pathological studies revealed that the incidence of tumors was significantly lower in the perilla oil group than in the safflower oil group (P [is less than] 0.05). Approximately half the mice fed perilla oil had died after 10 mo, and the direct causes closely connected with death could not be specified. Experiment 2: The serum total cholesterol, HDL cholesterol, triglyceride and phospholipid concentrations were significantly lower in the perilla oil group than in the safflower oil group (P [is less than] 0.01). A marked decrease of serum HDL cholesterol and apolipoprotein A-II (ApoA-II)concentrations in advanced age were observed in the mice fed perilla oil (P [is less than] 0.01). Ten-month-old mice fed perilla oil had a significantly greater ratio of apolipoprotein A-I (ApoA-I) to ApoA-II than those fed safflower oil. Separation of HDL subfractions revealed that the smaller HDL species were much more abundant than the larger HDL species in both dietary oil groups. These findings suggest that dietary (n-3) and (n-6) PUFA differ in their effects on serum lipid metabolism which may modulate the mean life span of SAMP8 mice fed each dietary oil. J. Nutr. 130: 221-227, 2000. KEY WORDS: * senescence-accelerated mouse (SAM) * [Alpha]-linoleic acid * linoleic acid * serum lipids * longevity

This presentation reflects on the origins of the term sarcopenia. The Greek roots of the word are sarx for flesh and penia for loss. The term actually describes important changes in body composition and related functions. Clearly defining sarcopenia will allow investigators to appropriately classify patients and examine underlying pathogenic mechanisms and will allow funding agencies to appropriately target research funds to a taxonomically distinct syndrome. KEY WORDS: sarcopenia; lean body mass; aging

At the present time, there is only limited understanding of the public health significance of sarcopenia. The well-recognized functional consequences of sarcopenia include gait and balance problems and increased risk for fall. Ultimately, these impairments can lead to the loss of physical functional independence. However, sarcopenia may also contribute to an increased risk for chronic diseases such as diabetes and osteoporosis. Future studies of the pathophysiologic significance of sarcopenia need to consider the contribution(s) of muscle properties (e.g., muscle fiber composition, muscle blood flow, fatigue characteristics, innervation) to alterations in physical performance, metabolism and physiology, and skeletal health. More comprehensive studies on the sequelae of sarcopenia are critical to an accurate assessment of the public health burden that sarcopenia poses to the elderly population. KEY WORDS: sarcopenia; aging; muscle mass

The results obtained by the studies conducted on the effect of feeding restriction on longevity fail to disprove the conclusion that metabolic rate reduction induced by chronic energy restriction does not retard aging in Fischer-344 rats. Both studies suffer from flaws in the interpretation of published data and fail to provide sufficient evidence to contradict the original findings. While it is possible for certain tissues to play a role in regulation and prolong life span when they have reduced metabolic rates, further research is necessary to identify these tissues and obtain conclusive evidence.

Food restriction in mice decreased metabolic rate by limiting oxygen consumption without altering body weight. This decrease in oxygen utilization of cells purportedly increased the life span of mice. Oxygen consumption should be equated with metabolic mass and it was shown that obese mice have reduced metabolic efficiency. The genetic and metabolic effects of food restriction resulted from decreased cellular redox potential and tissue damage. Aging therefore could be correlated with alterations in activities of metabolic organs.

Energy restriction repeatedly and strongly increases maximum life span in rodent models while retarding the appearance of age-associated pathologic and biological changes. Three main questions concerning energy restriction and aging will be addressed: 1) By what mechanisms does energy restriction retard aging and disease processes in rodents? Mechanistic insight was gained by using oligonucleotide microarrays by which we described the gene expression profile of aging skeletal muscle (1) and brain (2) in mice and its alteration by energy restriction. 2) Will energy restriction exert similar actions in primates? Two ongoing studies in rhesus monkeys subjected to energy restriction as well as limited human epidemiologic data support the notion of human translatability. 3) Can substances be identified that mimic the beneficial actions of energy restriction? The search for such substances is rapidly becoming an active area of inquiry and may benefit from genomic- and proteomic-based approaches.

Curcumin, the yellow pigment of the rhizome of Cucuma longa Linn., has antioxidative, anti-inflammatory and chemopreventive activities. The effect of aging on the inhibition of early-stage colon cancer by curcumin was examined in young (6 wk), mature (12 mo) and old (22 mo) Sprague-Dawley male rats. Rats in each age group were fed either the AIN-93 containing 0.6% curcumin or AIN-93 control diet. Aberrant crypt foci (ACF) were induced by two weekly subcutaneous injections of azoxymethane (15 mg/kg body). After an additional 3 mo of consuming the diets, the number, multiplicity (number of crypts per foci) and distribution of ACF were evaluated. In rats fed the AIN-93 control diet, the number of ACF with a multiplicity [greater than or equal to] 2 was 100.3 [+ or -] 28.1 in young rats, 76.2 [+ or -] 32.7 in mature rats and 76.7 [+ or -] 19.8 in old rats. Addition of curcumin to the diet reduced the number of ACF to 51.0 [+ or -] 14.5 (49% reduction) in young rats and 34.7 [+ or -] 15.0 (55% reduction) in old rats. However, surprisingly, no reduction of ACF (78.5 [+ or -] 28.0) was found in mature rats fed curcumin. Inhibition of large ACF also appeared to be affected by age, with the greatest reduction of large ACF occurring in old rats. Distribution of ACF was not altered by age. These results indicate that aging may play a significant role in the efficacy of chemoprevention of colon cancer by curcumin. Potential mechanisms responsible for these observations are currently under investigation in our laboratory. [Supported by the American Institute for Cancer Research.]