The Buck Institute for Research on Aging

Redwood City, CA, United States

The Buck Institute for Research on Aging

Redwood City, CA, United States
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Villarroel-Campos D.,University of Chile | Villarroel-Campos D.,Center for Geroscience | Henriquez D.R.,University of Chile | Bodaleo F.J.,University of Chile | And 7 more authors.
Journal of Neuroscience | Year: 2016

Rab35 is a key protein for cargo loading in the recycling endosome. In neuronal immortalized cells, Rab35 promotes neurite differentiation. Here we describe that Rab35 favors axon elongation in rat primary neurons in an activity-dependent manner. In addition, we show that the p53-related protein kinase (PRPK) negatively regulates axonal elongation by reducing Rab35 protein levels through the ubiquitin-proteasome degradation pathway. PRPK-induced Rab35 degradation is regulated by its interaction with microtubuleassociated protein 1B (MAP1B), a microtubule stabilizing binding protein essential for axon elongation. Consistently, axon defects found in MAP1B knock-out neurons were reversed by Rab35 overexpression or PRPK inactivation suggesting an epistatic relationship among these proteins. These results define a novel mechanism to support axonal elongation, by which MAP1B prevents PRPK-induced Rab35 degradation. Such a mechanism allows Rab35-mediated axonal elongation and connects the regulation of actin dynamics withmembrane trafficking. In addition, our study reveals for the first time that the ubiquitin-proteasome degradation pathway regulates a Rab GTPase. © 2016 the authors.

McClelland L.,University of Rochester | Jasper H.,The Buck Institute for Research on Aging | Biteau B.,University of Rochester
Developmental Biology | Year: 2017

Adult stem cell proliferation rates are precisely regulated to maintain long-term tissue homeostasis. Defects in the mechanisms controlling stem cell proliferation result in impaired regeneration and hyperproliferative diseases. Many stem cell populations increase proliferation in response to tissue damage and reacquire basal proliferation rates after tissue repair is completed. Although proliferative signals have been extensively studied, much less is known about the molecular mechanisms that restore stem cell quiescence. Here we show that Tis11, an Adenine-uridine Rich Element (ARE) binding protein that promotes mRNA degradation, is required to re-establish basal proliferation rates of adult Drosophila intestinal stem cells (ISC) after a regenerative episode. We find that Tis11 limits ISC proliferation specifically after proliferation has been stimulated in response to heat stress or infection, and show that Tis11 expression and activity are increased in ISCs during tissue repair. Based on stem cell transcriptome analysis and RNA immunoprecipitation, we propose that Tis11 activation represents an integral part of a negative feedback mechanism that limits the expression of key components of several signaling pathways that control ISC function and proliferation. Our results identify Tis11 mediated mRNA decay as an evolutionarily conserved mechanism of re-establishing basal proliferation rates of stem cells in regenerating tissues. © 2017.

Brejning J.,University of Aarhus | Norgaard S.,University of Aarhus | Scholer L.,University of Aarhus | Morthorst T.H.,University of Aarhus | And 4 more authors.
Aging Cell | Year: 2014

NDG-4 is a predicted transmembrane acyltransferase protein that acts in the distribution of lipophilic factors. Consequently, ndg-4 mutants lay eggs with a pale appearance due to lack of yolk, and they are resistant to sterility caused by dietary supplementation with the long-chain omega-6 polyunsaturated fatty acid dihommogamma-linolenic acid (DGLA). Two other proteins, NRF-5 and NRF-6, a homolog of a mammalian secreted lipid binding protein and a NDG-4 homolog, respectively, have previously been shown to function in the same lipid transport pathway. Here, we report that mutation of the NDG-4 protein results in increased organismal stress resistance and lifespan. When NDG-4 function and insulin/IGF-1 signaling are reduced simultaneously, maximum lifespan is increased almost fivefold. Thus, longevity conferred by mutation of ndg-4 is partially overlapping with insulin signaling. The nuclear hormone receptor NHR-80 (HNF4 homolog) is required for longevity in germline less animals. We find that NHR-80 is also required for longevity of ndg-4 mutants. Moreover, we find that nrf-5 and nrf-6 mutants also have extended lifespan and increased stress resistance, suggesting that altered lipid transport and metabolism play key roles in determining lifespan. © 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Martins R.,University of Algarve | Lithgow G.J.,The Buck Institute for Research on Aging | Link W.,University of Algarve
Aging Cell | Year: 2016

Aging constitutes the key risk factor for age-related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which "protective genes" are carried by long-lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin-like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed. © 2016 The Anatomical Society and John Wiley & Sons Ltd.

Kwan E.X.,Fred Hutchinson Cancer Research Center | Foss E.J.,Fred Hutchinson Cancer Research Center | Tsuchiyama S.,The Buck Institute for Research on Aging | Alvino G.M.,University of Washington | And 6 more authors.
PLoS Genetics | Year: 2013

Aging and longevity are complex traits influenced by genetic and environmental factors. To identify quantitative trait loci (QTLs) that control replicative lifespan, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard and a laboratory strain. The predominant QTL mapped to the rDNA, with the vineyard rDNA conferring a lifespan increase of 41%. The lifespan extension was independent of Sir2 and Fob1, but depended on a polymorphism in the rDNA origin of replication from the vineyard strain that reduced origin activation relative to the laboratory origin. Strains carrying vineyard rDNA origins have increased capacity for replication initiation at weak plasmid and genomic origins, suggesting that inability to complete genome replication presents a major impediment to replicative lifespan. Calorie restriction, a conserved mediator of lifespan extension that is also independent of Sir2 and Fob1, reduces rDNA origin firing in both laboratory and vineyard rDNA. Our results are consistent with the possibility that calorie restriction, similarly to the vineyard rDNA polymorphism, modulates replicative lifespan through control of rDNA origin activation, which in turn affects genome replication dynamics. © 2013 Kwan et al.

Haines B.,The Buck Institute for Research on Aging | Li P.A.,North Carolina Central University
PLoS ONE | Year: 2012

Mitochondria play a critical role in cell survival and death after cerebral ischemia. Uncoupling proteins (UCPs) are inner mitochondrial membrane proteins that disperse the mitochondrial proton gradient by translocating H + across the inner membrane in order to stabilize the inner mitochondrial membrane potential (ΔΨ m) and reduce the formation of reactive oxygen species. Previous studies have demonstrated that mice transgenically overexpressing UCP2 (UCP2 Tg) in the brain are protected from cerebral ischemia, traumatic brain injury and epileptic challenges. This study seeks to clarify the mechanisms responsible for neuroprotection after transient focal ischemia. Our hypothesis is that UCP2 is neuroprotective by suppressing innate inflammation and regulating cell cycle mediators. PCR gene arrays and protein arrays were used to determine mechanisms of damage and protection after transient focal ischemia. Our results showed that ischemia increased the expression of inflammatory genes and suppressed the expression of anti-apoptotic and cell cycle genes. Overexpression of UCP2 blunted the ischemia-induced increase in IL-6 and decrease in Bcl2. Further, UCP2 increased the expression of cell cycle genes and protein levels of phospho-AKT, PKC and MEK after ischemia. It is concluded that the neuroprotective effects of UCP2 against ischemic brain injury are associated with inhibition of pro-inflammatory cytokines and activation of cell survival factors. © 2012 Haines and Li.

News Article | October 28, 2016

NOVATO, Calif.--(BUSINESS WIRE)--The Buck Institute for Research on Aging (Buck Institute) today announced the appointment of Edward Lanphier as president and chief executive officer. He succeeds Brian Kennedy, Ph.D., who resigned his position in order to devote all of his time to leading his pioneering Geroscience research at the Buck. “The Buck Institute is indebted to Brian for his leadership over the last six years, during which time the Buck developed the nation’s first Ph.D. program in th

Poksay K.S.,The Buck Institute for Research on Aging
Journal of molecular neuroscience : MN | Year: 2012

The presence of misfolded proteins elicits cellular responses including an endoplasmic reticulum (ER) stress response that may protect cells against the toxic buildup of misfolded proteins. Accumulation of these proteins in excessive amounts, however, overwhelms the "cellular quality control" system and impairs the protective mechanisms designed to promote correct folding and degrade misfolded proteins, ultimately leading to organelle dysfunction and cell death. Studies from multiple laboratories have identified the roles of several ER stress-induced cell death modulators and effectors. Earlier, we reported the role of the small co-chaperone protein p23 in preventing ER stress-induced cell death. p23 undergoes caspase-dependent cleavage to yield a 19-kD product (p19), and mutation of this caspase cleavage site not only blocks the formation of the 19-kD product but also attenuates the ER stress-induced cell death process triggered by various stressors. Thus, a critical question is whether p23 and/or p19 could serve as an in vivo marker for neurodegenerative diseases featuring misfolded proteins and cellular stress. In the present study, we used an antibody that recognizes both p23 and p19 as well as a specific neo-epitope antibody that detects only the p19 fragment. These antibodies were used to detect the presence of both these proteins in cells, primary neurons, brain samples from a mouse model of Alzheimer's disease (AD), and fixed human AD brain samples. While patients with severe AD did display a consistent reduction in p23 levels, our inability to observe p19 in mouse or human AD brain samples suggests that the usefulness of the p23 neo-epitope antibody is restricted to cells and primary neurons undergoing cellular stress.

Schreiber K.H.,The Buck Institute for Research on Aging | Ortiz D.,The Buck Institute for Research on Aging | Academia E.C.,The Buck Institute for Research on Aging | Anies A.C.,The Buck Institute for Research on Aging | And 2 more authors.
Aging Cell | Year: 2015

The mechanism by which the drug rapamycin inhibits the mechanistic target of rapamycin (mTOR) is of intense interest because of its likely relevance in cancer biology, aging, and other age-related diseases. While rapamycin acutely and directly inhibits mTORC1, only chronic administration of rapamycin can inhibit mTORC2 in some, but not all, cell lines or tissues. The mechanism leading to cell specificity of mTORC2 inhibition by rapamycin is not understood and is especially important because many of the negative metabolic side effects of rapamycin, reported in mouse studies and human clinical trials, have been attributed recently to mTORC2 inhibition. Here, we identify the expression level of different FK506-binding proteins (FKBPs), primarily FKBP12 and FKBP51, as the key determinants for rapamycin-mediated inhibition of mTORC2. In support, enforced reduction of FKBP12 completely converts a cell line that is sensitive to mTORC2 inhibition to an insensitive cell line, and increased expression can enhance mTORC2 inhibition. Further reduction of FKBP12 in cell lines with already low FKBP12 levels completely blocks mTORC1 inhibition by rapamycin, indicating that relative FKBP12 levels are critical for both mTORC1 and mTORC2 inhibition, but at different levels. In contrast, reduction of FKBP51 renders cells more sensitive to mTORC2 inhibition. Our findings reveal that the expression of FKBP12 and FKBP51 is the rate limiting factor that determines the responsiveness of a cell line or tissue to rapamycin. These findings have implications for treating specific diseases, including neurodegeneration and cancer, as well as targeting aging in general. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

News Article | November 18, 2016

NOVATO, Calif.--(BUSINESS WIRE)--The Buck Institute for Research on Aging today announced the appointment of a new President and Chief Executive Officer and $10 million in pledged gifts from the Institute’s Board of Trustees, the largest single collective gift in the Institute’s history. The two events position the Buck to reach new heights in aging research and discovery of novel therapeutic interventions. The funding also facilitated the hiring of Eric M. Verdin, MD, a world-renowned expert o

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