Robert and Arlene Kogod Center on Aging

Rochester, MN, United States

Robert and Arlene Kogod Center on Aging

Rochester, MN, United States
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News Article | December 19, 2016
Site: www.eurekalert.org

ROCHESTER, Minn. -- In a recent Science Advances article, Mayo Clinic researchers show how hungry human liver cells find energy. This study, done in rat and human liver cells, reports on the role of a small regulatory protein that acts like a beacon to help cells locate lipids and provides new information to support the development of therapies for fatty liver disease. "Between 30 and 40 percent of our population have, or are leading toward getting, nonalcoholic fatty liver disease," says Mark McNiven, Ph.D., senior author on the paper and director of Mayo Clinic's Center for Biomedical Discovery. "And that is not including those with alcohol-induced fatty liver; that is also quite prevalent." While the mechanisms involved in fat accumulation are the usual targets of research for fatty liver disease, clarifying the cell's mechanism for breaking down fat also could provide valuable information to fuel the discovery of breakthrough treatments in the future. In a well-fed cell, fat deposits, called lipid droplets, are nutritional insurance. They are ignored by the cell as it fuels growth and division via its normal pathway. But, in a starving cell, the normal pathway switches off, and a recycling process, called autophagy, switches on. Autophagy is a way for cells to break down macromolecules, such as protein and fat, into their component parts to be used in cell processes. Under starvation conditions, the cell's recycling pathway directs specialized vessels to engulf lipid droplets. These vessels, called autophagosomes, then link with another organelle, called a lysosome, which is filled with acidic enzymes. When these two merge, the resulting structure is called an autolysosome. Within the autolysosome, the enzymes break apart the fat droplet free fatty acids. Zhipeng Li, first author and a student at Mayo Clinic Graduate School of Biomedical Sciences, noticed that, within the hungry cells, one protein, called Rab10, was intimately associated with many of the lipid droplets. Rab proteins operate like switches; when bound to a substance, they switch on and facilitate interactions in the cell. There are more than 60 different Rab switches, or small regulatory GTPases, in the human genome. "In this paper, we show that, when Rab10 is switched on, it will bind to a lipid droplet and cause the autophagosome to dock on the droplet surface, recruit other proteins, and digest the lipid into a free fatty acid energy source," says Li. Dr. McNiven explains that cells have sensors that detect low energy levels and respond. "Rab10 switches on and builds up around the lipid droplet," says Dr. McNiven. "Then, the cell activates its lysosomes that then targets these lipid droplets and goes after them. So this was an important step that we provided between the sensing mechanism of starvation and how that is signaling to this switch to go after lipid droplets." This study was funded by two National Institutes of Health grants to Dr. McNiven, the Robert and Arlene Kogod Center on Aging, and the Optical Morphology Core of the Mayo Clinic Center for Cell Signaling in Gastroenterology. The authors report no conflicts of interest. Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. For more information, visit mayoclinic.org/about-mayo-clinic or newsnetwork.mayoclinic.org.


Tchkonia T.,Robert and Arlene Kogod Center on Aging | Thomou T.,Harvard University | Zhu Y.,Robert and Arlene Kogod Center on Aging | Karagiannides I.,University of California at Los Angeles | And 3 more authors.
Cell Metabolism | Year: 2013

Fat distribution is closely linked to metabolic disease risk. Distribution varies with sex, genetic background, disease state, certain drugs and hormones, development, and aging. Preadipocyte replication and differentiation, developmental gene expression, susceptibility to apoptosis and cellular senescence, vascularity, inflammatory cell infiltration, and adipokine secretion vary among depots, as do fatty-acid handling and mechanisms of enlargement with positive-energy and loss with negative-energy balance. How interdepot differences in these molecular, cellular, and pathophysiological properties are related is incompletely understood. Whether fat redistribution causes metabolic disease or whether it is a marker of underlying processes that are primarily responsible is an open question. © 2013 Elsevier Inc.


LeBrasseur N.K.,Robert and Arlene Kogod Center on Aging | Walsh K.,Boston University | Arany Z.,Beth Israel Deaconess Medical Center
American Journal of Physiology - Endocrinology and Metabolism | Year: 2011

Skeletal muscle exhibits remarkable plasticity with respect to its metabolic properties. Recent work has shown that interventions such as resistance training, genetic alterations and pharmacological strategies that increase muscle mass and glycolytic capacity, and not necessarily oxidative competence, can improve body composition and systemic metabolism. We review here recent advances in our understanding of the signaling and transcriptional regulatory pathways of this strategy and review new evidence obtained from mice and humans that supports the notion that increasing muscle mass and glycolytic capacity may effectively counter insulin resistance and type 2 diabetes mellitus. Copyright © 2011 the American Physiological Society.


Poland G.A.,Mayo Clinic Vaccine Research Group | Ovsyannikova I.G.,Mayo Clinic Vaccine Research Group | Kennedy R.B.,Mayo Clinic Vaccine Research Group | Lambert N.D.,Mayo Clinic Vaccine Research Group | Kirkland J.L.,Robert and Arlene Kogod Center on Aging
Current Opinion in Immunology | Year: 2014

Aging can lead to immunosenescence, which dramatically impairs the hosts' ability to develop protective immune responses to vaccine antigens. Reasons for this are not well understood. This topic's importance is reflected in the increases in morbidity and mortality due to infectious diseases among elderly persons, a population growing in size globally, and the significantly lower adaptive immune responses generated to vaccines in this population. Here, we endeavor to summarize the existing data on the genetic and immunologic correlates of immunosenescence with respect to vaccine response. We cover how the application of systems biology can advance our understanding of vaccine immunosenescence, with a view toward how such information could lead to strategies to overcome the lower immunogenicity of vaccines in the elderly. © 2014 Elsevier Ltd.


LeBrasseur N.K.,Robert and Arlene Kogod Center on Aging | LeBrasseur N.K.,Mayo Medical School
Diabetologia | Year: 2012

The obesity epidemic is an overwhelming global health concern. Interventions to improve body weight and composition aim to restore balance between nutrient intake and energy expenditure. Myostatin, a powerful negative regulator of skeletal muscle mass, has emerged as a potential therapeutic target for obesity and type 2 diabetes mellitus because of the prominent role skeletal muscle plays in metabolic rate and insulin-mediated glucose disposal. In fact, inhibition of myostatin by genetic manipulation or pharmacological means leads to a hypermuscular and very lean build in mice. The resistance of myostatin-null mice to diet-induced obesity, fat mass accumulation and metabolic dysfunction has been presumed to be a result of their large skeletal muscle mass; however, in this issue of Diabetologia, Zhang et al. (doi:10.1007/s00125-011-2304-4) provide evidence that myostatin inhibition also significantly impacts the phenotype of white adipose tissue (WAT). The authors reveal elevated expression of key metabolic genes of fatty acid transport and oxidation and, intriguingly, the presence of brown adipose tissue-like cells in WAT of myostatin-null mice. They also show that pharmacological inhibition of myostatin replicates several of the protective benefits conveyed by its genetic inactivation. Herein, these data, areas in need of further investigation and the evidence that implicates myostatin as a target for obesity and type 2 diabetes mellitus are discussed. © 2011 Springer-Verlag.


White T.A.,Robert and Arlene Kogod Center on Aging | Lebrasseur N.K.,Robert and Arlene Kogod Center on Aging | Lebrasseur N.K.,Mayo Medical School
Gerontology | Year: 2014

The progressive loss of skeletal muscle mass, strength and/or function with advancing age, termed sarcopenia, poses a major threat to independence and quality of life. Therefore, there is significant merit in better understanding the biology of sarcopenia and developing therapeutic interventions to prevent, slow or reverse its progression. Since the discovery of myostatin, a potent negative regulator of growth that is highly enriched in skeletal muscle, there has been great interest in it as a potential mediator of sarcopenia as well as a therapeutic target. The complex biology of myostatin, the promise of myostatin inhibition as an effective means to counter sarcopenia, and the challenges facing its clinical translation are reviewed herein. © 2014 S. Karger AG, Basel.


Kirkland J.L.,Robert and Arlene Kogod Center on Aging
Experimental Gerontology | Year: 2013

Recently, lifespan and healthspan have been extended in experimental animals using interventions that are potentially translatable into humans. A great deal of thought and work is needed beyond the usual steps in drug development to advance these findings into clinical application. Realistic pre-clinical and clinical trial paradigms need to be devised. Focusing on subjects with symptoms of age-related diseases or frailty or who are at imminent risk of developing these problems, measuring effects on short-term, clinically relevant outcomes, as opposed to long-term outcomes such as healthspan or lifespan, and developing biomarkers and outcome measures acceptable to regulatory agencies will be important. Research funding is a major roadblock, as is lack of investigators with combined expertise in the basic biology of aging, clinical geriatrics, and conducting investigational new drug clinical trials. Options are reviewed for developing a path from the bench to the bedside for interventions that target fundamental aging processes. © 2012 Elsevier Inc.


Scrable H.,Robert and Arlene Kogod Center on Aging
Science Translational Medicine | Year: 2012

Research reported in this issue of Science Translational Medicine illustrates the benefits of short-term food withdrawal (fasting) in the treatment of cancer. Fasting exploited fundamental differences in the way tumor cells and normal cells respond to stress, simultaneously strengthening normal cell function and weakening tumor cell survival in the presence of toxic doses of chemotherapeutic drugs.


Kirkland J.L.,Robert and Arlene Kogod Center on Aging
Cold Spring Harbor Perspectives in Medicine | Year: 2016

Life and health span have been extended in experimental animals using drugs that are potentially translatable into humans. Considerable effort is needed beyond the usual steps in drug development to devise the models, and realistic preclinical and clinical trial strategies are required to advance these agents into clinical application. It will be important to focus on subjects who already have symptoms or are at imminent risk of developing disorders related to fundamental aging processes, to use short-term, clinically relevant outcomes, as opposed to long-term outcomes, such as health span or life span, and to validate endpoint measures so they are acceptable to regulatory agencies. Funding is a roadblock, as is shortage of investigators with combined expertise in the basic biology of aging, clinical geriatrics, and investigational new drug clinical trials. Strategies for developing a path from the bench to the bedside are reviewed for interventions that target fundamental aging mechanisms. © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.


Oursler M.J.,Robert and Arlene Kogod Center on Aging
Journal of Cellular Biochemistry | Year: 2010

Bone marrow macrophages fuse on the bone surface to form multinucleated osteoclasts that then organize to efficiently resorb bone. Many, if not all, of the stages of macrophage fusion involve cytoskeletal components that reorganize the cells. Recruitment may involve chemotactic responses to bone matrix protein and calcium ion gradients and/or chemokine production by bone forming osteoblasts. The roles of integrins vary, depending on the particular subunits with some interfering with fusion and others having a participatory role. RANKL is essential for fusion and many identified modulators of fusion influence RANKL signaling pathways. Tetraspanins have been implicated in fusion of macrophages and myoblasts, but differences in impacts exist between these two cell types. Macrophage recruitment to apoptotic cells prior to their engulfment is driven by the exposed phospholipids on the external surface of the apoptotic cells and there is evidence that this same identification mechanism is employed in macrophage fusion. Because loss of cadherin or ADAM family members suppresses macrophage fusion, a crucial role for these membrane glycoproteins is evident. The Ig membrane glycoprotein superfamily members CD200 and MFR/ SIRPa are involved in macrophage fusion, although their influences are unresolved. Differential screenings have identified the structurally related membrane proteins DC-STAMP and OC-STAMP as required components for fusion and the contributions to fusion remain active areas of investigation. While many of the key components involved in these processes have been identified, a great deal of work remains in resolving the precise processes involved and the interactions between key contributors to multinucleated osteoclast formation. © 2010 Wiley-Liss, Inc.

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