Longevity - Extending the lifespan of long-lived mice

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62803/1/414412a0.pd

Comparative Proteomic Analyses of the Parietal Lobe from Rhesus Monkeys Fed a High-Fat/Sugar Diet With and Without Resveratrol Supplementation, Relative to a Healthy Diet: Insights Into the Roles of Unhealthy Diets and Resveratrol on Function

A diet consisting of a high intake of saturated fat and refined sugars is characteristic of a Western-diet and has been shown to have a substantial negative effect on human health. Expression proteomics were used to investigate changes to the parietal lobe proteome of rhesus monkeys consuming either a high fat and sugar (HFS) diet, a HFS diet supplemented with resveratrol (HFS+RSV), or a healthy control diet for 2 years. Here we discuss the modifications in the levels of 12 specific proteins involved in various cellular systems including metabolism, neurotransmission, structural integrity, and general cellular signaling following a nutritional intervention. Our results contribute to a better understanding of the mechanisms by which resveratrol functions through the up- or down-regulation of proteins in different cellular sub-systems to affect the overall health of the brain

Resveratrol Supplementation Confers Neuroprotection in Cortical Brain Tissue of Nonhuman Primates Fed a High-Fat/Sucrose Diet

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress

When a calorie is not just a calorie : Diet quality and timing as mediators of metabolism and healthy aging

Funding Information: We thank Dr. Yih-Woei Fridell of the National Institute on Aging for organizing the meeting, as well as the NIA Division of Aging Biology for their support. We thank Dr. Gino Cortopassi for his edits and suggestions. The figures were created with BioRender.com. The Mihaylova lab is supported in part by the NIA (R00AG054760), Office of the NIH Director (DP2CA271361), the American Federation for Aging Research, the V Foundation, Pew Biomedical Scholar award, and startup funds from the Ohio State University. The Delibegovic lab is funded by the British Heart Foundation, Diabetes UK, BBSRC, NHS Grampian, Tenovus Scotland, and the Development Trust (University of Aberdeen). J.J.R. is supported by NIA PO1AG062817, R21AG064290, and R21AG071156. Research support for J.B. was from NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK127800, R01DK113011, R01DK090625, and R01DK050203 and the National Institute on Aging (NIA) grants R01AG065988 and P01AG011412, as well as the University of Chicago Diabetes Research and Training Center grant P30DK020595. This work was supported by NIH grants AG065992 to G.M. and AG068550 to G.M. and S.P. as well as UAB Startup funds 3123226 and 3123227 to G.M. R.S. is supported by NIH grants RF1AG043517, R01AG065985, R01DK123327, R56AG074568, and P01AG031782. Z.C. is primarily funded by The Welch Foundation (AU-1731-20190330) and NIH/NIA (R01AG065984, R56AG063746, RF1AG061901, and R56AG076144). A.C. is supported by NIA grant R01AG065993. W.W.J. is supported by the NIH (R01DC020031). M.S.-H. is supported by NIH R01 R35GM127049, R01 AG045842, and R21 NS122366. The research in the Dixit lab was supported in part by NIH grants AG031797, AG045712, P01AG051459, AR070811, AG076782, AG073969, and AG068863 and Cure Alzheimer's Fund (CAF). A.E.T.-M. is supported by the NIH/NIA (AG075059 and AG058630), NIAMS (AR071133), NHLBI (HL153460), pilot and feasibility funds from the NIDDK-funded UAB Nutrition Obesity Research Center (DK056336) and the NIA-funded UAB Nathan Shock Center (AG050886), and startup funds from UAB. J.A.M. is supported by the Intramural Research Program, NIA, NIH. The Panda lab is supported by the NIH (R01CA236352, R01CA258221, RF1AG068550, and P30CA014195), the Wu Tsai Human Performance Alliance, and the Joe and Clara Tsai Foundation. The Lamming lab is supported in part by the NIA (AG056771, AG062328, AG061635, and AG081482), the NIDDK (DK125859), startup funds from UW-Madison, and the U.S. Department of Veterans Affairs (I01-BX004031), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government. D.W.L. has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases. S.P. is the author of the books The Circadian Code and The Circadian Diabetes Code. Funding Information: We thank Dr. Yih-Woei Fridell of the National Institute on Aging for organizing the meeting, as well as the NIA Division of Aging Biology for their support. We thank Dr. Gino Cortopassi for his edits and suggestions. The figures were created with BioRender.com . The Mihaylova lab is supported in part by the NIA ( R00AG054760 ), Office of the NIH Director ( DP2CA271361 ), the American Federation for Aging Research , the V Foundation , Pew Biomedical Scholar award, and startup funds from the Ohio State University . The Delibegovic lab is funded by the British Heart Foundation , Diabetes UK , BBSRC , NHS Grampian , Tenovus Scotland , and the Development Trust ( University of Aberdeen ). J.J.R. is supported by NIA PO1AG062817 , R21AG064290 , and R21AG071156 . Research support for J.B. was from NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK127800 , R01DK113011 , R01DK090625 , and R01DK050203 and the National Institute on Aging (NIA) grants R01AG065988 and P01AG011412 , as well as the University of Chicago Diabetes Research and Training Center grant P30DK020595 . This work was supported by NIH grants AG065992 to G.M. and AG068550 to G.M. and S.P., as well as UAB Startup funds 3123226 and 3123227 to G.M. R.S. is supported by NIH grants RF1AG043517 , R01AG065985 , R01DK123327 , R56AG074568 , and P01AG031782 . Z.C. is primarily funded by The Welch Foundation ( AU-1731-20190330 ) and NIH/NIA ( R01AG065984 , R56AG063746 , RF1AG061901 , and R56AG076144 ). A.C. is supported by NIA grant R01AG065993 . W.W.J. is supported by the NIH ( R01DC020031 ). M.S.-H. is supported by NIH R01 R35GM127049 , R01 AG045842 , and R21 NS122366 . The research in the Dixit lab was supported in part by NIH grants AG031797 , AG045712 , P01AG051459 , AR070811 , AG076782 , AG073969 , and AG068863 and Cure Alzheimer's Fund (CAF). A.E.T.-M. is supported by the NIH/NIA ( AG075059 and AG058630 ), NIAMS ( AR071133 ), NHLBI ( HL153460 ), pilot and feasibility funds from the NIDDK -funded UAB Nutrition Obesity Research Center ( DK056336 ) and the NIA -funded UAB Nathan Shock Center ( AG050886 ), and startup funds from UAB . J.A.M. is supported by the Intramural Research Program, NIA, NIH . The Panda lab is supported by the NIH ( R01CA236352 , R01CA258221 , RF1AG068550 , and P30CA014195 ), the Wu Tsai Human Performance Alliance , and the Joe and Clara Tsai Foundation . The Lamming lab is supported in part by the NIA ( AG056771 , AG062328 , AG061635 , and AG081482 ), the NIDDK ( DK125859 ), startup funds from UW-Madison , and the U.S. Department of Veterans Affairs ( I01-BX004031 ), and this work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work does not represent the views of the Department of Veterans Affairs or the United States Government.Peer reviewedPostprin

Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise

Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.This research was funded in part by the Intramural Research Program of the NIA/NIH. E.M.M was supported by a postdoctoral grant of the Research Foundation—Flanders (FWO/12R2415N—http://www.fwo.be/en/). I.W. was supported by the Bundesministerium für Bildung und Forschung (BMBF 01GM1113B; mitoNET—Deutsches Netzwerk für mitochondriale Erkrankungen), by the Cluster of Excellence Frankfurt Macromolecular Complexes at the Goethe University Frankfurt DFG project EXC 115 and by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 815, project Z1 (Redox-Proteomics). And partly by the European Union’s Seventh Framework Programme (FP7) under Grant agreement no.. 223576 (MYOAGE) to C.F. J.M.V. was supported by the Spanish Ministerio de Economía y Competitividad (grants BFU2011-23578 and BFU2015-64630-R). We thank the personnel from the Servicio Centralizado de Apoyo a la Investigación (SCAI, University of Córdoba) for technical support.Peer reviewe

Translational models for vascular cognitive impairment: a review including larger species.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required

Physiological effects of alfaxalone anesthesia on rhesus monkeys during intravenous glucose tolerance testing.

Laboratory animal research with nonhuman primates (NHPs) requires anesthesia for most procedures to ensure safety and consistency in sample collection. However, anesthesia drugs can have adverse effects on the physiological measures of interest. Alfaxalone, most notably used in dogs and cats, offers rapid onset, short duration of action, and has a high safety margin. Here, we compared our current anesthesia protocol using Telazol, to three different doses of alfaxalone during a one-hour intravenous glucose tolerance test, the standard evaluation of glucose metabolism in NHPs. Results indicate there are no differences in the rate of glucose metabolism, anesthesia depth measurements, or total duration of sedation, but induction, number of supplemental doses required, and recovery time to eating were affected by the different doses of alfaxalone. Cardiovascular measures showed variability between the four protocols in respiratory rate and systolic blood pressure rates only. These results indicate that alfaxalone can produce a reliable state of anesthesia, similar to our current protocol, and confers minimal cardiovascular or metabolic disturbance, as well as enhanced recovery characteristics. As such, alfaxalone is a promising anesthetic for use in laboratory animals and further investigation is warranted

Detection of Noroviruses in Ready-To-Eat Foods by Using Carbohydrate-Coated Magnetic Beads ▿

This study used histo-blood group antigen-conjugated beads to detect norovirus (NoV) in contaminated strawberries, green onions, lettuce, and deli ham. In addition, multiple strains of NoV from genogroups I and II were recovered. This provides an effective protocol for food testing in the investigation of suspected NoV outbreaks