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1.  Development of a water-escape motivated version of the Stone T-maze for mice 
Neuroscience  2009;166(1):61-72.
Mice provide a highly valuable resource for investigating learning and memory processes; however, many of the established tasks for evaluating learning and memory were developed for rats. Behaviors of mice in these tasks appear to be driven by different motivational factors, and as a result, they often do not perform reliably on tasks involving rewards traditionally used for rats. Because of difficulties in measuring learning and memory in mice as well as the need to have a task that can reliably measure these behavioral processes, we have developed a mouse version of the Stone T-maze utilizing what appears to be the primary motivation of mice, escape to a safe location. Specifically, we have constructed a task that requires the mouse to wade through water to reach a dark and dry goal box. To escape this aversive environment, the Stone T-maze requires learning the correct sequence of 13 left and right turns to reach the goal box. Through a series of experiments examining a variety of protocols, it was found that mice will reliably perform this task. This task can be used to assess learning and memory without the potential performance confounds that can affect performance of mice in other tasks. We believe this task offers a valuable new tool for evaluating learning and memory in mice not previously available to researchers.
doi:10.1016/j.neuroscience.2009.12.029
PMCID: PMC4255268  PMID: 20026250
Mice; learning; memory; maze; water-motivated
2.  Dietary resistant starch improves selected brain and behavioral functions in adult and aged rodents 
Molecular nutrition & food research  2013;57(11):2071-2074.
Resistant starch (RS) is a dietary fiber that exerts multiple beneficial effects. The current study explored the effects of dietary RS on selected brain and behavioral functions in adult and aged rodents. Because glucokinase (GK) expression in hypothalamic arcuate nucleus and area postrema of the brainstem is important for brain glucose sensing, GK mRNA was measured by brain nuclei microdissection and PCR. Adult RS-fed rats had a higher GK mRNA than controls in both brain nuclei, an indicator of improved brain glucose sensing. Next, we tested whether dietary RS improve selected behaviors in aged mice. RS-fed aged mice exhibited (1) an increased eating responses to fasting, a behavioral indicator of improvement in aged brain glucose sensing; (2) a longer latency to fall from an accelerating rotarod, a behavioral indicator of improved motor coordination; and (3) a higher serum active GLP-1. Third, GLP-1 receptor null (GLP-1RKO) mice were used to test the role of GLP-1 in brain glucose sensing, and they exhibited impaired eating responses to fasting. We conclude that in rodents (1) dietary RS improves two important indicators of brain function: glucose sensing and motor coordination, and that (2) GLP-1 is important in the optimal feeding response to a fast.
doi:10.1002/mnfr.201300135
PMCID: PMC3892668  PMID: 23818307
Aging; Brain function; GK; Glucose sensing; GLP-1; Resistant Starch
3.  Dehydroepiandrosterone sulfate (DHEAS) as an endocrine marker of aging in calorie restriction studies 
Experimental gerontology  2013;48(10):1136-1139.
The adrenal steroid, dehydroepiandrosterone sulfate (DHEAS), is generally regarded as being a reliable endocrine marker of aging, because in humans and nonhuman primates its circulating concentrations are very high during young adulthood, and the concentrations then decline markedly during aging. Despite promising results from early studies, we were recently surprised to find that caloric restriction (CR) did little to prevent or delay the decline of DHEAS concentrations in old rhesus macaques. Here we summarize the use of circulating DHEAS concentrations as a biomarker of aging in CR studies and suggest reasons for its limited value. Although DHEAS can reliably predict aging in animals maintained on a standard diet, dietary manipulations may affect liver enzymes involved in the metabolism of steroid hormones. Consequently, in CR studies the reliability of using DHEAS as a biomarker of aging may be compromised.
doi:10.1016/j.exger.2013.01.001
PMCID: PMC3641169  PMID: 23318475
Adrenal gland; Biomarker; Cortisol; DHEAS; Rhesus macaque
4.  Canonical Nlrp3 inflammasome links systemic low grade inflammation to functional decline in aging 
Cell metabolism  2013;18(4):519-532.
SUMMARY
Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in elderly, the immune sensors that causally link systemic inflammation to aging remain unclear. Here we detail a mechanism that the Nlrp3 inflammasome controls systemic low grade age-related ‘sterile’ inflammation in both periphery and brain independently of the non-canonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome and astrogliosis. Consistent with the hypothesis that systemic low grade inflammation promotes age-related degenerative changes, the deficient Nlrp3 inflammasome mediated caspase-1 activity improved glycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer innovative therapeutic strategy to lower Nlrp3 activity to delay multiple age-related chronic diseases.
doi:10.1016/j.cmet.2013.09.010
PMCID: PMC4017327  PMID: 24093676
Inflammation; T cells; brain; macrophages; Pycard; IL-1β; aging; caspase-1; ASC; LPS; dementia; Lipotoxicity; complement; interferon; dentate gyrus
5.  Chronic caloric restriction partially protects against age-related alteration in serum metabolome 
Age  2012;35(4):1091-1104.
Calorie restriction (CR) remains the most robust metabolic intervention to extend lifespan and improve healthspan in several species. Using global and targeted mass spectrometry-based metabolomics approaches, here we show that chronic CR prevents age-related changes in specific metabolic signatures. Global metabolomic analysis using ultra-performance liquid chromatography–tandem mass spectrometry detected more than 7,000 metabolites in sera from ad-libitum-fed young, aged, and aged C57BL/6 mice maintained on 40 % CR. Multivariate statistical analysis of mass spectrometry data revealed a clear separation among the young, aged, and aged–CR mice demonstrating the potential of this approach for producing reliable metabolic profiles that discriminate based on age and diet. We have identified 168 discriminating features with high statistical significance (p ≤ 0.001) and validated and quantified three of these metabolites using targeted metabolite analysis. Calorie restriction prevented the age-related alteration in specific metabolites, namely lysophosphatidylcholines (16:1 and 18:4), sphingomyelin (d18:1/12:0), tetracosahexaenoic acid, and 7α-dihydroxy-4-cholesten-3-one, in the serum. Pathway analysis revealed that CR impacted the age-related changes in metabolic byproducts of lipid metabolism, fatty acid metabolism, and bile acid biosynthesis. Our data suggest that metabolomics approach has the potential to elucidate the metabolic mechanism of CR’s potential anti-aging effects in larger-scale investigations.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9430-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9430-x
PMCID: PMC3705111  PMID: 22661299
Metabolomics; Calorie restriction; Aging; Serum; Ultra-performance liquid chromatography; Mass spectrometry
6.  Metformin improves healthspan and lifespan in mice 
Nature communications  2013;4:2192.
Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
doi:10.1038/ncomms3192
PMCID: PMC3736576  PMID: 23900241
7.  Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats 
Toxicology and applied pharmacology  2009;243(3):332-339.
Calorie restriction (CR), the purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway rats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound.
doi:10.1016/j.taap.2009.11.025
PMCID: PMC2830378  PMID: 20026095
Deoxyglucose; Calorie restriction; Lifespan; Mortality; Cardiac vacuolarization
9.  Effect of calorie restriction and refeeding on skin wound healing in the rat 
Age  2011;34(6):1453-1458.
Calorie restriction (CR) is a reliable anti-aging intervention that attenuates the onset of a number of age-related diseases, reduces oxidative damage, and maintains function during aging. In the current study, we assessed the effects of CR and other feeding regimens on wound healing in 7-month-old Fischer-344 rats from a larger cohort of rats that had been fed either ad libitum (AL) or 40% calorie restricted based on AL consumption. Rats were assigned to one of three diet groups that received three skin punch wounds along the dorsal interscapular region (12-mm diameter near the front limbs) of the back as follows: (1) CR (n = 8) were wounded and maintained on CR until they healed, (2) AL (n = 5) were wounded and maintained on AL until wound closure was completed, and (3) CR rats were refed (RF, n = 9) AL for 48 h prior to wounding and maintained on AL until they healed. We observed that young rats on CR healed more slowly while CR rats refed for 48 h prior to wounding healed as fast as AL fed rats, similar to a study reported in aged CR and RF mice (Reed et al. 1996). Our data suggest that CR subjects, regardless of age, fail to heal well and that provision of increased nutrition to CR subjects prior to wounding enhances the healing process.
doi:10.1007/s11357-011-9321-6
PMCID: PMC3528375  PMID: 22037865
Aging; Calorie restriction; Refeeding; Wound healing
10.  Impact of caloric restriction on health and survival in rhesus monkeys: the NIA study 
Nature  2012;489(7415):10.1038/nature11432.
Life extension by calorie restriction (CR) has been widely reported in a variety of species and remains on the forefront of anti-aging intervention studies. We report healthspan and survival effects of CR from a 23-year study in rhesus macaques conducted at the National Institute on Aging (NIA). CR initiated at older ages did not increase survival relative to Controls; however, CR monkeys demonstrated an improved metabolic profile and may have less oxidative stress as indicated by plasma isoprostane levels. When initiated in young monkeys, there was a trend (p=0.06) for a delay in age-associated disease onset in CR monkeys; but again, survival curves were not improved, in contrast to another study reported in the literature. This suggests that the effects of CR in a long-lived animal are complex and likely dependent on a variety of environmental, nutritional, and genetic factors.
doi:10.1038/nature11432
PMCID: PMC3832985  PMID: 22932268
11.  Age-Associated Learning and Memory Deficits in Two Mouse Versions of the Stone T-maze 
Neurobiology of aging  2012;33(10):2431-2439.
We have previously reported that a modified Stone T-maze (STM), using escape from water as motivation, was effective in evaluating learning and memory ability in young C57/BL6 mice. Here we report on the effectiveness and sensitivity of the STM in the assessment of age-related learning and memory deficits in mice using either escape from foot shock or water as the motivational manipulations. C57BL/6Nia mice 7-, 12-, 20- and 24-mo old received 15 massed trials in the escape from foot shock motivated STM while C57BL/6Nia mice 5-, 12-, and 25-mo old were tested in the escape from water STM. Analysis of errors, the main performance variable, revealed similar results in both versions of the task with younger mice making fewer errors. Notably mice of all ages in the water-motivated version moved quickly through the maze, while all ages of mice in the shock-motivated version tended to wait for shock to be initiated to move forward. Overall, both versions of the STM appear to be sensitive to age-related changes in learning and memory and provide an alternative to other testing paradigms such as the Morris water waze which are susceptible to performance confounds which can lead to uninterpretable results.
doi:10.1016/j.neurobiolaging.2011.12.004
PMCID: PMC3321391  PMID: 22217418
Aging; mice; learning; memory; maze
12.  Overview of aging research using nonhuman primate models 
Age  2011;34(5):1047-1049.
doi:10.1007/s11357-011-9370-x
PMCID: PMC3448985  PMID: 22207280
13.  The interplay among dietary fat, sugar, protein and açai (Euterpe oleracea Mart.) pulp in modulating lifespan and reproduction in a Tephritid fruit fly 
Experimental Gerontology  2012;47(7):536-539.
Macronutrient balance is a critical contributor in modulating lifespan and health. Consumption of diets rich in fruits and vegetables provides numerous health benefits. The interactions among macronutrients and botanicals and how they influence aging and health remain elusive. Here we employed a nutritional geometry approach to investigate the interplay among dietary fat, sugar, protein and antioxidant- and polyphenolic-rich freeze-dried açai pulp in modulating lifespan and reproductive output in the Mexican fruit fly, Anastrepha ludens (Loew). Individual flies were cultured on one of the 24 diets made from a combination of 1) sugar and yeast extract (SY) at four ratios, 2) palmitic acid, a saturated fat, at two concentrations and 3) freeze-dried açai pulp at three concentrations. Fat addition decreased lifespan in females on the sugar only diet and the diet with a low SY ratio, while decreasing lifetime reproductive output in flies on the diet with the low SY ratio when compared to SY ratio-matched low fat controls. Açai supplementation promoted survival, while decreasing lifetime reproductive output, in flies on diets with high fat and high sugar but not other diets when compared to diet-matched non-supplemented controls. These findings reveal that the impact of fat and açai on lifespan and reproductive output depends on the dietary content of other macronutrients. Our results reveal the intricate interplay among macronutrients and nutraceuticals, and underscore the importance of taking macronutrient balance into consideration in designing dietary interventions for aging and health.
doi:10.1016/j.exger.2012.05.001
PMCID: PMC3368065  PMID: 22580089
Palmitic acid; Lifespan; Dietary intervention; Nutraceutical; Palm fruit; Anastrepha ludens
14.  Brain Injury Caused by HIV Protease Inhibitors: role of Lipodystrophy and Insulin Resistance 
Antiviral Research  2012;95(1):19-29.
HIV-associated neurocognitive disorders (HAND) remain prevalent even with widespread use of combination antiretroviral therapy (ART), suggesting a potential role for co-morbidities in neurologic decline. Indeed, it is well established that ART drugs, particularly HIV protease inhibitors, can induce hyperlipidemia, lipodystrophy, and insulin resistance; all of which are associated with neurologic impairment. This study was designed to determine how metabolic dysfunction might contribute to cognitive impairment and to reveal specific metabolic co-morbidities that could be targeted to preserve brain function. Adult male C57BL/6 mice were thus treated with clinically relevant doses of lopinavir/ritonavir for 4 weeks, and subjected to thorough metabolic, neurobehavioral, and biochemical analyses. Data show that lopinavir/ritonavir resulted in manifestations of lipodystrophy, insulin resistance, and hyperlipidemia. Evaluation of neurologic function revealed cognitive impairment and increased learned helplessness, but not motor impairment following treatment with lopinavir/ritonavir. Further analyses revealed a significant linear relationship between cognitive performance and specific markers of lipodystrophy and insulin resistance. Finally, analysis of brain injury indicated that lopinavir/ritonavir treatment resulted in cerebrovascular injury associated with decreased synaptic markers and increased inflammation, and that the cerebral cortex was more vulnerable than the cerebellum or hippocampus. Collectively, these data reveal an intimate link between metabolic co-morbidities and cognitive impairment, and suggest that remediation of selective aspects of metabolic syndrome could potentially reduce the prevalence or severity HIV-associated neurocognitive disorders.
doi:10.1016/j.antiviral.2012.04.010
PMCID: PMC3400265  PMID: 22580130
HAND; HIV co-morbidities; HIV protease inhibitors; insulin resistance; lipodystrophy; metabolic syndrome
15.  Feed efficiency, food choice, and food reward behaviors in young and old Fischer rats 
Neurobiology of aging  2010;33(1):206.e41-206.e53.
Increased susceptibility to energy imbalance and anorexia in old age are risk factors for malnutrition during aging, but the underlying mechanisms are not well understood. Here, we explored changes in taste-guided hedonic value (“liking”) and motivation to obtain (“wanting”) palatable foods as potential mediators of age-associated anorexia and weight loss in old Fischer-344 rats. “Liking” as measured by the number of positive hedonic orofacial responses to sucrose and corn oil was not different in old compared with young rats. Taste-guided, low effort “wanting” as measured by the number of licks per 10 seconds was also not different, although old rats exhibited a slight oromotor impairment as revealed by significantly increased interlick intervals. Medium effort “wanting” as measured by performance in the incentive runway was significantly decreased in old versus young rats. Although decreased net running speed was partially accountable, significantly increased duration of distractions suggested additional deficits in motivation and/or reinforcement learning. Together with early satiation on corn oil but not sucrose in aged rats, these changes are likely to have resulted in the significantly greater sucrose preference of old rats in 12-hour tests, and may ultimately lead to reduced energy intake and weight loss.
doi:10.1016/j.neurobiolaging.2010.09.006
PMCID: PMC3617984  PMID: 20970890
Aging; Anorexia; Palatability; Appetite; Gustation; Reward; Wanting; Licking; Learning
16.  Prolongevity effects of a botanical with oregano and cranberry extracts in Mexican fruit flies: examining interactions of diet restriction and age 
Age  2011;34(2):269-279.
Botanicals rich with phytochemicals have numerous health benefits. Dietary restriction (DR) extends lifespan in diverse species. We previously demonstrated that an oregano–cranberry (OC) mixture can promote longevity in the Mexican Fruit fly (Mexfly, Anastrepha ludens Loew). However, little is known about the interaction between botanicals and DR, and the age-dependent effect of botanicals on lifespan and reproduction. Here we investigated these issues by feeding Mexflies a full or DR diet supplemented with or without 2% OC. Lifespan and daily egg production of individual flies were recorded. The effect of short-term OC supplementation was evaluated by implementing the supplementation at three age intervals—young, middle, and old age. We found that OC increased lifespan of Mexflies on the full or DR diet when compared to their respective controls. OC increased reproduction of females on the full diet and, to a lesser extent, on the DR diet. Short-term OC supplementation was not sufficient to extend lifespan for males at all three age intervals nor for females at young and old age intervals. However, OC supplementation at the middle age interval was sufficient to extend lifespan in females, while only OC supplementation at the young age interval increased reproduction in females. Our findings suggest that OC extends lifespan and promotes reproduction partly through DR-independent pathways, and short-term supplementation have varied impact on longevity and reproduction. This also suggests a positive interaction between non-genetic interventions in promoting longevity and provides guidance for using botanicals as aging interventions in humans.
doi:10.1007/s11357-011-9230-8
PMCID: PMC3312627  PMID: 21455602
Lifespan; Cranberry; Oregano; Dietary restriction; Reproduction; Aging intervention; Dietary nutrient; Anastrepha ludens Loew
17.  Telomere Dynamics in Rhesus Monkeys: No Apparent Effect of Caloric Restriction 
The role of telomere attrition in limiting the replicative capacity of cells in culture is well established. In humans, epidemiologic evidence suggests telomere length (TL) in leukocytes is highly variable at birth and inversely related to age. Although calorie restriction (CR) significantly increases life span in most rodent models, its association with TL is unknown. Using linear regression analysis, TLs (as measured by Southern blot analysis) of skeletal muscle (a postmitotic tissue that largely represents early development TL), fat, leukocytes, and skin were tested for effects of age, sex, and diet in 48 control and 23 calorie restriction rhesus monkeys. After controlling for the individual's muscle mean TL, differences between leukocytes muscle and skin muscle were significantly associated with age (p = .002; p = .002) and sex (p = .003; p = .042), but not calorie restriction (p = .884; p = .766). Despite an age-dependent shortening of TL in leukocytes and skin, calorie restriction did not significantly affect TL dynamics in these samples.
doi:10.1093/gerona/glr136
PMCID: PMC3193524  PMID: 21860014
Telomere; Macaca mulatta; Aging; Caloric restriction; Rhesus monkeys
18.  Adiponectin protects rat hippocampal neurons against excitotoxicity 
Age  2010;33(2):155-165.
Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin.
doi:10.1007/s11357-010-9173-5
PMCID: PMC3127462  PMID: 20842535
Adiponectin; Neuroprotection; Hippocampus; Kainic acid; AMPK
19.  Metabolic and Neurologic Consequences of Chronic Lopinavir/Ritonavir Administration to C57BL/6 mice 
Antiviral research  2010;88(3):334-342.
It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5 to 200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function revealed that even the lowest dose of lopinavir/ritonavir caused significant cognitive impairment assessed in multi-unit T-maze, but did not affect motoric functions assessed as rotarod performance. Collectively, our results indicate that repeated lopinavir/ritonavir administration produces cognitive as well as metabolic impairments, and suggest that the development of selective aspects of metabolic syndrome in HIV patients could contribute to HIV-associated neurocognitive disorders.
doi:10.1016/j.antiviral.2010.10.006
PMCID: PMC2991583  PMID: 20970459
HIV-associated neurocognitive disorders; HIV protease inhibitors; hypertriglyceridemia; metabolic syndrome
20.  Effects of Moderate Calorie Restriction on Testosterone Production and Semen Characteristics in Young Rhesus Macaques (Macaca mulatta)1 
Biology of Reproduction  2010;83(4):635-640.
We have previously reported a modest influence of moderate calorie restriction (CR) on testicular gene expression in young adult rhesus macaques (Macaca mulatta); however, it is unclear if these modifications correspond to subsequent changes in testicular function or sperm physiology. This study extends our earlier findings to examine potential physiological differences due to this differential gene expression. Animals were subjected to 30% CR (CR, n = 5) or were fed a standard control diet (CON, n = 5) starting during their peripubertal period. Circulating testosterone (T) levels were measured across a 24-h period after 7 yr of dietary treatment and were found to be similar in CR and CON males; however, maintenance of daily minimum T levels was significantly higher in the CR animals. Semen collection was performed on the same cohort of animals three times per male (CR, n = 4; CON, n = 4) after 8 yr of treatment, and samples were assessed by a variety of measures. Parameters, including semen quality and sperm cell viability and function, showed less variability in semen samples taken from CR males, but overall testicular function and sperm quality were comparable regardless of diet. There is mounting evidence that CR may promote health and longevity in a wide range of organisms, including nonhuman primates. Importantly, our data suggest that moderate CR has no obvious lasting detrimental effect on testicular function and sperm parameters in young adult primates and may in fact help maintain higher levels of circulating T.
Moderate calorie restriction does not impact sperm parameters or semen characteristics in young adult rhesus macaques.
doi:10.1095/biolreprod.110.084186
PMCID: PMC2957152  PMID: 20610809
calorie restriction; rhesus macaque; semen collection; sperm; testis; testosterone
21.  Relationship between Plasma Ghrelin, Insulin, Leptin, IL6, Adiponectin, Testosterone and Longevity in the Baltimore Longitudinal Study of Aging 
Background and Aims
Caloric Restriction (CR) is the most robust and reproducible intervention for slowing aging, and maintaining health and vitality in animals. Previous studies found that CR is associated with changes in specific biomarkers in monkeys that were also associated with reduced risk of mortality in healthy men. In this study we examine the association between other potential biomarkers related to CR and extended lifespan in healthy humans.
Methods
Based on the Baltimore Longitudinal Study of Aging, “Long-lived” participants who survived to at least 90 years of age (n=41, cases) were compared with “Short-lived” participants who died between 72–76 years of age (n=31, controls) in the nested case control study. Circulating levels of ghrelin, insulin, leptin, interleukin 6, adiponectin and testosterone were measured from samples collected between the ages 58 to 70 years. Baseline differences between groups were examined with t-test or Wilcoxon test, and mixed effects general linear model was used for a logistic model to differentiate the two groups with multiple measurements on some subjects.
Results
At the time of biomarkers evaluation (58–70 years), none of the single biomarker levels were significantly different between the two groups. However, after combining information from multiple biomarkers by adding the z-transformed values, the global score differentiated the long-and short-lived participants (p=0.05).
Conclusions
In their sixties, long lived and short lived individuals do not differ in biomarkers that have been associated with caloric restriction in animals. However, difference between the groups was only obtained when multiple biomarker dysregulation was considered.
PMCID: PMC3180822  PMID: 21743292
caloric restriction; aging; longevity; biomarkers
22.  A Blueberry-Enriched Diet Attenuates Nephropathy in a Rat Model of Hypertension via Reduction in Oxidative Stress 
PLoS ONE  2011;6(9):e24028.
Objective and Background
To assess renoprotective effects of a blueberry-enriched diet in a rat model of hypertension. Oxidative stress (OS) appears to be involved in the development of hypertension and related renal injury. Pharmacological antioxidants can attenuate hypertension and hypertension-induced renal injury; however, attention has shifted recently to the therapeutic potential of natural products as antioxidants. Blueberries (BB) have among the highest antioxidant capacities of fruits and vegetables.
Methods and Results
Male spontaneously hypertensive rats received a BB-enriched diet (2% w/w) or an isocaloric control diet for 6 or 12 weeks or 2 days. Compared to controls, rats fed BB-enriched diet for 6 or 12 weeks exhibited lower blood pressure, improved glomerular filtration rate, and decreased renovascular resistance. As measured by electron paramagnetic resonance spectroscopy, significant decreases in total reactive oxygen species (ROS), peroxynitrite, and superoxide production rates were observed in kidney tissues in rats on long-term dietary treatment, consistent with reduced pathology and improved function. Additionally, measures of antioxidant status improved; specifically, renal glutathione and catalase activities increased markedly. Contrasted to these observations indicating reduced OS in the BB group after long-term feeding, similar measurements made in rats fed the same diet for only 2 days yielded evidence of increased OS; specifically, significant increases in total ROS, peroxynitrite, and superoxide production rates in all tissues (kidney, brain, and liver) assayed in BB-fed rats. These results were evidence of “hormesis” during brief exposure, which dissipated with time as indicated by enhanced levels of catalase in heart and liver of BB group.
Conclusion
Long-term feeding of BB-enriched diet lowered blood pressure, preserved renal hemodynamics, and improved redox status in kidneys of hypertensive rats and concomitantly demonstrated the potential to delay or attenuate development of hypertension-induced renal injury, and these effects appear to be mediated by a short-term hormetic response.
doi:10.1371/journal.pone.0024028
PMCID: PMC3174132  PMID: 21949690
23.  High Fat Diet Increases Hippocampal Oxidative Stress and Cognitive Impairment in Aged Mice: Implications for decreased Nrf2 signaling 
Journal of neurochemistry  2010;114(6):1581-1589.
Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either “Western Diet” (WD, 41% fat), very high fat lard diet (HFL, 60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the HFL diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in Nrf2 levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.
doi:10.1111/j.1471-4159.2010.06865.x
PMCID: PMC2945419  PMID: 20557430
High fat; oxidative stress; aging; cognition
24.  OVARIAN RESERVE TESTS AND THEIR UTILITY IN PREDICTING RESPONSE TO CONTROLLED OVARIAN STIMULATION IN RHESUS MONKEYS 
American journal of primatology  2010;72(8):672-680.
Controlled ovarian stimulation (COS) is an alternative to natural breeding in nonhuman primates; however, these protocols are costly with no guarantee of success. Toward the objective of predicting COS outcome in rhesus monkeys, the current study evaluated three clinically used ovarian reserve tests (ORTs): day 3 (d3) follicle-stimulating hormone (FSH) with d3 inhibin B (INHB), the clomiphene citrate challenge test (CCCT), and the exogenous FSH Ovarian Reserve Test (EFORT). A COS was also performed and response was classified as either successful (COS+) or unsuccessful (COS−) and retrospectively compared to ORT predictions. FSH and INHB were assessed for best hormonal index in conjunction with the aforementioned tests. INHB was consistently more accurate than FSH in all ORTs used. Overall, a modified version of the CCCT using INHB values yielded the best percentage of correct predictions. This is the first report of ORT evaluation in rhesus monkeys and may provide a useful diagnostic test prior to costly follicle stimulations, as well as predicting the onset of menopause.
doi:10.1002/ajp.20823
PMCID: PMC2909193  PMID: 20336797
inhibin; ovarian reserve; follicular response; peri-menopause; hormone predictors of fertility
25.  NOX Activity in Brain Aging: Exacerbation by High Fat Diet 
This study describes how age and high fat diet affect the profile of NADPH oxidase (NOX). Specifically, NOX activity and subunit expression were evaluated in the frontal cerebral cortex of 7-, 16-, and 24-month old mice following a 4-month exposure to either Western diet (WD, 41% calories from fat) or very high fat lard diet (VHFD, 60% calories from fat). Data reveal a significant effect of age in on NOX activity, and show that NOX activity was only increased by VHFD, and only in 24-month old mice. NOX subunit expression was also increased by diet only in older mice. Quantification of protein carbonyls revealed significant age-related increases in protein oxidation, and indicate that only aged mice respond to high fat diet with enhanced protein oxidation. Histological analyses indicate prominent neuronal localization of both NOX subunits and protein carbonylation. Finally, data indicate that changes in reactive microgliosis, but not astrocytosis, mirror the pattern of diet-induced NOX activation and protein oxidation. Collectively, these data show that both age and dietary fat drive NOX activation, and further indicate that aged mice are preferentially sensitive to the effects of high fat diet. These data also suggest that high fat diets might exacerbate age-related oxidative stress in the brain via increased NOX.
doi:10.1016/j.freeradbiomed.2010.03.006
PMCID: PMC2875353  PMID: 20347034
metabolic dysfunction; neurodegeneration; obesity; oxidative stress; Western diet

Results 1-25 (59)