Julie A Mattison

National Institute on Aging, Baltimore, Maryland, United States

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Publications (78)512.95 Total impact

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    ABSTRACT: Genetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues. CNIO-PI3Ki treatment also ameliorates liver steatosis and decreases glucose serum levels. The above observations have been recapitulated in independent laboratories and using different oral formulations of CNIO-PI3Ki. Finally, daily oral treatment of obese rhesus monkeys for 3 months with low doses of CNIO-PI3Ki decreased their adiposity and lowered their serum glucose levels, in the absence of detectable toxicities. Therefore, pharmacological inhibition of PI3K is an effective and safe anti-obesity intervention that could reverse the negative effects of metabolic syndrome in humans. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Metabolism 06/2015; 21(4):558-570. DOI:10.1016/j.cmet.2015.02.017 · 16.75 Impact Factor
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    ABSTRACT: Although the accumulation of highly-differentiated and granzyme B (GrB)-expressing CD8(+)CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques and mice and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+)CD8(+) T cells by presenting endogenous antigens and utilizing the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and their capacity to evoke the generation of GrB(+)CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4-1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly.
    Blood 07/2014; 124(9). DOI:10.1182/blood-2014-03-563940 · 9.78 Impact Factor
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    Journal of Diabetes 06/2014; 6(6). DOI:10.1111/1753-0407.12178 · 2.35 Impact Factor
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    ABSTRACT: Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. However, no specific therapies to reduce PWV are presently available. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV.
    Cell Metabolism 05/2014; 20(1). DOI:10.1016/j.cmet.2014.04.018 · 16.75 Impact Factor
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    ABSTRACT: To compare gross and histologic patterns of age-related degeneration within the intervertebral disc and adjacent vertebra between rhesus monkeys and humans. We examined age-related patterns of disc degeneration from mid-sagittal sections of the intervertebral disc and adjacent vertebral bodies among six rhesus monkey thoracolumbar and seven human lumbar spines. Gross morphology and histopathology were assessed via the Thompson grading scheme and other degenerative features of the disc and adjacent bone. Thompson grades ranged from 3 through 5 for rhesus monkey discs (T9-L1) and 2 through 5 for the human discs (T12-S1). In both rhesus monkey and human discs, presence of distinct lesions were positively associated with Thompson grade of the overall segment. Degenerative patterns differed for radial tears, which were more prevalent with advanced disc degeneration in humans only. Additionally, compared to the more uniform anteroposterior disc degeneration patterns of humans, rhesus monkeys showed more severe osteophytosis and degeneration on the anterior border of the vertebral column. Rhesus monkey spines evaluated in the present study appear to develop age-related patterns of disc degeneration similar to humans. One exception is the absence of an association between radial tears and disc degeneration, which could reflect species-specific differences in posture and spinal curvature. Considering rhesus monkeys demonstrate similar patterns of disc degeneration, and age at a faster rate than humans, these findings suggest longitudinal studies of rhesus monkeys may be a valuable model for better understanding the progression of human age-related spinal osteoarthritis and disc degeneration.
    Osteoarthritis and Cartilage 05/2014; DOI:10.1016/j.joca.2014.04.027 · 4.66 Impact Factor
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    ABSTRACT: Background Drugs commonly used to sedate non-human primates for physiological sample collection can affect the metabolic system and alter rates of glucose metabolism. This study was designed to compare the physiological and metabolic effects of ketamine/diazepam, telazol, and ketamine/dexmedetomidine. Methods Seven female rhesus monkeys underwent intravenous glucose tolerance testing under each of three anesthesia conditions. Blood glucose, insulin, physiological parameters, and sedation characteristics were measured and recorded. ResultsGlucose and insulin values were both significantly impacted by ketamine/dexmedetomidine sedation while remaining consistent during ketamine and telazol sedation. Heart rate was also significantly lowered during ketamine/dexmedetomidine anesthesia. Though, ketamine/dexmedetomidine resulted in a longer time between induction of anesthesia and need for a supplemental dose of anesthesia drug. Conclusions Telazol and ketamine have minimal cardiorespiratory and metabolic effects compared to ketamine/dexmedetomidine. Although practicably interchangeable, telazol appears to be the most efficient for intravenous glucose tolerance testings with non-human primates.
    Journal of Medical Primatology 02/2014; 43(3). DOI:10.1111/jmp.12104 · 0.89 Impact Factor
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    ABSTRACT: Objective To compare gross and histologic patterns of age-related degeneration within the intervertebral disc and adjacent vertebra between rhesus monkeys and humans. Materials and methods We examined age-related patterns of disc degeneration from mid-sagittal sections of the intervertebral disc and adjacent vertebral bodies among six rhesus monkey thoracolumbar and seven human lumbar spines. Gross morphology and histopathology were assessed via the Thompson grading scheme and other degenerative features of the disc and adjacent bone. Results Thompson grades ranged from 3 through 5 for rhesus monkey discs (T9-L1) and 2 through 5 for the human discs (T12-S1). In both rhesus monkey and human discs, presence of distinct lesions were positively associated with Thompson grade of the overall segment. Degenerative patterns differed for radial tears, which were more prevalent with advanced disc degeneration in humans only. Additionally, compared to the more uniform anteroposterior disc degeneration patterns of humans, rhesus monkeys showed more severe osteophytosis and degeneration on the anterior border of the vertebral column. Conclusions Rhesus monkey spines evaluated in the present study appear to develop age-related patterns of disc degeneration similar to humans. One exception is the absence of an association between radial tears and disc degeneration, which could reflect species-specific differences in posture and spinal curvature. Considering rhesus monkeys demonstrate similar patterns of disc degeneration, and age at a faster rate than humans, these findings suggest longitudinal studies of rhesus monkeys may be a valuable model for better understanding the progression of human age-related spinal osteoarthritis and disc degeneration.
    Osteoarthritis and Cartilage 01/2014; · 4.66 Impact Factor
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    ABSTRACT: Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.
    Cell metabolism 10/2013; 18(4):533-545. DOI:10.1016/j.cmet.2013.09.004 · 16.75 Impact Factor
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    ABSTRACT: microRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate gene expression by targeting specific mRNAs. Altered expression of circulating miRNAs have been associated with age-related diseases including cancer and cardiovascular disease. Although we and others have found an age-dependent decrease in miRNA expression in peripheral blood mononuclear cells (PBMCs), little is known about the role of circulating miRNAs in human aging. Here, we examined miRNA expression in human serum from young (mean age 30 years) and old (mean age 64 years) individuals using next generation sequencing technology and real-time quantitative PCR. Of the miRNAs that we found to be present in serum, three were significantly decreased in 20 older individuals compared to 20 younger individuals: miR-151a-5p, miR-181a-5p and miR-1248. Consistent with our data in humans, these miRNAs are also present at lower levels in the serum of elderly rhesus monkeys. In humans, miR-1248 was found to regulate the expression of mRNAs involved in inflammatory pathways and miR-181a was found to correlate negatively with the pro-inflammatory cytokines IL-6 and TNFα and to correlate positively with the anti-inflammatory cytokines TGFβ and IL-10. These results suggest that circulating miRNAs may be a biological marker of aging and could also be important for regulating longevity. Identification of stable miRNA biomarkers in serum could have great potential as a noninvasive diagnostic tool as well as enhance our understanding of physiological changes that occur with age.
    Aging 09/2013; 5(10). · 4.89 Impact Factor
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    ABSTRACT: The levels of microRNAs (miRNAs) are altered under different conditions such as cancer, senescence, and aging. Here, we have identified differentially expressed miRNAs in skeletal muscle from young and old rhesus monkeys using RNA sequencing. In old muscle, several miRNAs were upregulated, including miR-451, miR-144, miR-18a and miR-15a, while a few miRNAs were downregulated, including miR-181a and miR-181b. A number of novel miRNAs were also identified, particularly in old muscle. We also examined the impact of caloric restriction (CR) on miRNA abundance by reverse transcription (RT) followed by real-time, quantitative (q)PCR analysis and found that CR rescued the levels of miR-181b and chr1:205580546, and also dampened the age-induced increase in miR-451 and miR-144 levels. Our results reveal that there are changes in expression of known and novel miRNAs with skeletal muscle aging and that CR may reverse some of these changes to a younger phenotype.
    Aging 09/2013; · 4.89 Impact Factor
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    ABSTRACT: We previously reported that moderate calorie restriction (CR) has minimal impact on testicular gene expression in young adult rhesus macaques, and no obvious negative impact on semen quality or plasma testosterone levels. We now extend these findings by examining the influence of CR on various aspects of the reproductive axis of older males, including 24-h circulating testosterone levels, testicular gene expression, and testicular morphology. Young adult and old adult male rhesus macaques were subjected to either 30 % CR for 5-7 years, or were fed a standard control diet. Analysis of the 24-h plasma testosterone profiles revealed a significant age-associated decline, but no evidence for CR-induced suppression in either the young or old males. Similarly, expression profiling of key genes associated with testosterone biosynthesis and Leydig cell maintenance showed no significant CR-induced changes in either the young or old animals. The only evidence for CR-associated negative effects on the testis was detected in the old animals at the histological level; when old CR animals were compared with their age-matched controls, there was a modest decrease in seminiferous tubule diameter and epithelium height, with a concomitant increase in the number of depleted germ cell lines. Reassuringly, data from this study and our previous study suggest that moderate CR does not negatively impact 24-h plasma testosterone profiles or testicular gene expression. Although there appear to be some minor CR-induced effects on testicular morphology in old animals, it is unclear if these would significantly compromise fertility.
    Age 07/2013; DOI:10.1007/s11357-013-9563-6 · 3.45 Impact Factor
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    ABSTRACT: Eating a 'Westernized' diet high in fat and sugar leads to weight gain and numerous health problems, including the development of type 2 diabetes mellitus (T2DM). Rodent studies have shown that resveratrol supplementation reduces blood glucose, preserves β-cells in islets of Langerhans, and improves insulin action. While rodent models are helpful for understanding β-cell biology and certain aspects of T2DM pathology, they fail to reproduce the complexity of the human disease as well as non-human primates. Rhesus monkeys were fed a standard diet (SD), or a high fat/ high sugar diet in combination with either placebo (HFS) or resveratrol (HFS+Resv) for 24 months and pancreata were examined before overt dysglycemia occurred. Increased glucose-stimulated insulin secretion and insulin resistance occurred in both HFS and HFS+Resv diets compared to SD. While islet size was unaffected, there was a significant decrease in β-cells and increase in α-cells, containing glucagon and GLP-1, with HFS diets. Islets from HFS+Resv monkeys were morphologically similar to SD. HFS diets also resulted in decreased expression of essential β-cell transcription factors, FOXO1, NKX6-1, NKX2-2, and PDX1 which did not occur with resveratrol supplementation. Similar changes were observed in human islets where the effects of resveratrol were mediated through SIRT1. These findings have implications for the management of humans with insulin resistance, pre-diabetes, and diabetes.
    Diabetes 07/2013; 62(10). DOI:10.2337/db13-0266 · 8.47 Impact Factor
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    ABSTRACT: Metabolic diseases are characterized by the failure of regulatory genes or proteins to effectively orchestrate specific pathways involved in the control of many biological processes. In addition to the classical regulators, recent discoveries have shown the remarkable role of small non-coding RNAs (microRNAs) in the post-transcriptional regulation of gene expression. In this regard, we have recently demonstrated that miR-33a/b, intronic microRNAs (miRNA) located within the sterol regulatory element-binding protein (SREBP) genes, regulate lipid metabolism in concert with their host genes. Here, we show that miR-33b also cooperates with SREBP1 in regulating glucose metabolism by targeting phosphoenolpyruvate carboxykynase (PCK1) and glucose-6-phosphatase (G6PC), key regulatory enzymes of hepatic gluconeogenesis. Overexpression of miR-33b in human hepatic cells inhibits PCK1 and G6PC expression leading to a significant reduction of glucose production. Importantly, hepatic SREBP1c/miR-33b levels correlate inversely with the expression PCK1 and G6PC upon glucose infusion in rhesus monkeys. Taken together, these results suggest that miR-33b works in concert with its host gene to ensure a fine-tuned regulation of lipid and glucose homeostasis, highlighting the clinical potential of miR-33a/b as novel therapeutic targets for a range of metabolic diseases.
    Molecular and Cellular Biology 05/2013; DOI:10.1128/MCB.00016-13 · 5.04 Impact Factor
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    ABSTRACT: Hsa-miR-33a and hsa-miR-33b, intronic microRNAs (miRNAs) located within the sterol regulatory element-binding protein (Srebp)-2 and -1 genes, respectively, have recently been shown to regulate lipid homeostasis in concert with their host genes. Although the functional role of miR-33a/b has been highly investigated, the role of their passenger strands, miR-33a*/b*, remains unclear. Here, we demonstrate that miR-33a*/b* accumulate to steady-state levels in human, mouse and non-human primate tissues and share a similar lipid metabolism target gene network as their sister strands. Analogous to miR-33, miR-33* represses key enzymes involved in cholesterol efflux (ABCA1, NPC1), fatty acid metabolism (CROT, CPT1a) and insulin signaling (IRS2). Moreover, miR-33* also targets key transcriptional regulators of lipid metabolism, including SRC1, SRC3, NFYC, and RIP140. Importantly, inhibition of either miR-33 or miR-33* rescues target gene expression in cells over-expressing pre-miR-33. Consistent with this, over-expression of miR-33* reduces fatty acid oxidation in human hepatic cells. Altogether, these data support a regulatory role for the miRNA* species and suggest that miR-33 regulates lipid metabolism through both arms of the miR-33/miR-33* duplex.
    Molecular and Cellular Biology 04/2013; DOI:10.1128/MCB.01714-12 · 5.04 Impact Factor
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    ABSTRACT: 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.
    Experimental gerontology 01/2013; DOI:10.1016/j.exger.2013.01.001 · 3.53 Impact Factor
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    ABSTRACT: Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate.
    Nature 08/2012; 489(7415):318-21. DOI:10.1038/nature11432 · 42.35 Impact Factor
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    ABSTRACT: 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.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 08/2011; 66(11):1163-8. DOI:10.1093/gerona/glr136 · 4.98 Impact Factor
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    ABSTRACT: 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. 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. At the time of biomarkers evaluation (58-70 yrs), none of the single biomarker levels was 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). In their sixties, long-lived and short-lived individuals do not differ in biomarkers that have been associated with CR in animals. However, difference between the groups was only obtained when multiple biomarker dysregulation was considered.
    Aging clinical and experimental research 04/2011; 23(2):153-8. DOI:10.1007/BF03351078 · 1.14 Impact Factor
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    Heather A Simmons, Julie A Mattison
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    ABSTRACT: Rhesus macaques (Macaca mulatta) are genetically similar to humans and share many characteristics of aging and age-related diseases. They age at approximately three times the rate of humans and develop spontaneous cancers. In both humans and rhesus macaques, cancer incidence increases with age with the greatest incidence in those over 60 years of age and 20 years, respectively. The current survey reports on the incidence of spontaneous neoplasia in two colonies of captive rhesus macaques: the Wisconsin National Primate Research Center colony with 28 years of records and a National Institute on Aging colony with 21 years of records. When categorized by organ and histologic diagnosis, the average age at diagnosis was greater than 20 years for all categories except oral squamous cell carcinoma. Neoplasms of the gastrointestinal system were the most commonly diagnosed, accounting for 48.8% of the cases. Adenocarcinomas of the large intestine were the most prevalent tumor identified. Although there are differences in the biological behavior of cancer in the rhesus macaque when compared with humans, they are a valuable model of comparative oncology.
    Antioxidants & Redox Signaling 01/2011; 14(2):221-7. DOI:10.1089/ars.2010.3311 · 7.67 Impact Factor
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    ABSTRACT: 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.
    Biology of Reproduction 10/2010; 83(4):635-40. DOI:10.1095/biolreprod.110.084186 · 3.45 Impact Factor

Publication Stats

3k Citations
512.95 Total Impact Points

Institutions

  • 2001–2014
    • National Institute on Aging
      • • Laboratory of Experimental Gerontology (LEG)
      • • Laboratory of Cardiovascular Science (LCS)
      • • Laboratory of Neurosciences (LNS)
      Baltimore, Maryland, United States
  • 2013
    • National Institutes of Health
      • Branch of Clinical and Translational Epidemiology
      Maryland, United States
  • 2008–2010
    • Pennington Biomedical Research Center
      • Nutritional Neuroscience and Aging Laboratory
      Baton Rouge, Louisiana, United States
  • 2009
    • The University of Arizona
      • College of Medicine
      Tucson, AZ, United States
  • 1999–2002
    • Southern Illinois University Carbondale
      • • School of Medicine
      • • Department of Physiology
      Illinois, United States
    • Southern Illinois University School of Medicine
      • Department of Physiology
      Springfield, Illinois, United States