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Ending Aging

If you are looking for an accessible description of SENS research, our Chief Science Officer, Dr Aubrey de Grey, together with co-author Michael Rae, has written a book entitled Ending Aging. The book speaks to a broad audience, but it does so without 'dumbing down' the science at all. It is the ideal resource for either the biologist or the non-biologist, whether encountering SENS for the first time or wishing to absorb more of its details. Copies are available from your local bookstore or from Amazon.com. The details are: de Grey ADNJ, Rae M. Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime. New York, NY: St. Martin's Press, 2007, 416pp, hardcover, ISBN 0-312-36706-6; or there is a paperback edition with an additional chapter covering more recent developments, ISBN 0-312-36707-4.


The following list of publications presents, by default, work funded in whole or in part by SENS Research Foundation. To view a much more extensive list of papers relevant to our work, including all papers cited in Ending Aging, alter the value of the "SRF Funded?" filter below.

  1. Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev 2007;21(24):3244-3257. PubMed: 18055696.

    Motif module map reveals enforcement of aging by continual NF-kappaB activity.

    Genes Dev 2007;21(24):3244-3257.

    Motif module map reveals enforcement of aging by continual NF-kappaB activity.

    Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY.

    Abstract

    Abstract:
    Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-kappaB. Inducible genetic blockade of NF-kappaB for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-kappaB blockade and orthogonal cell cycle interventions revealed that NF-kappaB controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-kappaB is continually required to enforce many features of aging in a tissue-specific manner.
  2. Akman K, Haaf T, Gravina S, Vijg J, Tresch A. Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data. Bioinformatics. 2014 Mar 27. [Epub ahead of print] PubMed: 24618468.

    Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data.

    Bioinformatics. 2014 Mar 27. [Epub ahead of print]

    Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data.

    Akman K, Haaf T, Gravina S, Vijg J, Tresch A.

    Abstract

    Abstract:

    SUMMARY:

    Here we present the open-source R/Bioconductor software package BEAT (BS-Seq Epimutation Analysis Toolkit). It implements all bioinformatics steps required for the quantitative high-resolution analysis of DNA methylation patterns from bisulfite sequencing data, including the detection of regional epimutation events, i.e. loss or gain of DNA methylation at CG positions relative to a reference. Using a binomial mixture model, the BEAT package aggregates methylation counts per genomic position, thereby compensating for low coverage, incomplete conversion and sequencing errors.

    AVAILABILITY AND IMPLEMENTATION:

    BEAT is freely available as part of Bioconductor at www.bioconductor.org/packages/devel/bioc/html/BEAT.html. The package is distributed under the GNU Lesser General Public License 3.0.

  3. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM,Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003;425(6961):968-973. PubMed: 14555960. Categories: RepleniSENS

    Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.

    Nature 2003;425(6961):968-973.

    Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.

    Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM,Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A.

    Abstract

    Abstract:
    Recent studies have suggested that bone marrow cells possess a broad differentiation potential, being able to form new liver cells, cardiomyocytes and neurons. Several groups have attributed this apparent plasticity to 'transdifferentiation'. Others, however, have suggested that cell fusion could explain these results. Using a simple method based on Cre/lox recombination to detect cell fusion events, we demonstrate that bone-marrow-derived cells (BMDCs) fuse spontaneously with neural progenitors in vitro. Furthermore, bone marrow transplantation demonstrates that BMDCs fuse in vivo with hepatocytes in liver, Purkinje neurons in the brain and cardiac muscle in the heart, resulting in the formation of multinucleated cells. No evidence of transdifferentiation without fusion was observed in these tissues. These observations provide the first in vivo evidence for cell fusion of BMDCs with neurons and cardiomyocytes, raising the possibility that cell fusion may contribute to the development or maintenance of these key cell types.
  4. Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW. The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation. J Clin Invest 1999;104(1):103-113. PubMed: 10393704. Categories: GlycoSENS

    The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation.

    J Clin Invest 1999;104(1):103-113.

    The myeloperoxidase system of human phagocytes generates Nepsilon-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation.

    Anderson MM, Requena JR, Crowley JR, Thorpe SR, Heinecke JW.

    Abstract

    Abstract:
    Reactive aldehydes derived from reducing sugars and peroxidation of lipids covalently modify proteins and may contribute to oxidative tissue damage. We recently described another mechanism for generating reactive aldehydes from free alpha-amino acids. The pathway begins with myeloperoxidase, a heme enzyme secreted by activated neutrophils. Conversion of alpha-amino acids to aldehydes requires hypochlorous acid (HOCl), formed from H2O2 and chloride by myeloperoxidase. When L-serine is the substrate, HOCl generates high yields of glycolaldehyde. We now demonstrate that a model protein, ribonuclease A (RNase A), exposed to free L-serine and HOCl exhibits the biochemical hallmarks of advanced glycation end (AGE) products -- browning, increased fluorescence, and cross-linking. Furthermore, Nepsilon-(carboxymethyl)lysine (CML), a chemically well-characterized AGE product, was generated on RNase A when it was exposed to reagent HOCl-serine, the myeloperoxidase-H2O2-chloride system plus L-serine, or activated human neutrophils plus L-serine. CML production by neutrophils was inhibited by the H2O2 scavenger catalase and the heme poison azide, implicating myeloperoxidase in the cell-mediated reaction. CML was also generated on RNase A by a myeloperoxidase-dependent pathway when neutrophils were activated in a mixture of amino acids. Under these conditions, we observed both L-serine-dependent and L-serine-independent pathways of CML formation. The in vivo production of glycolaldehyde and other reactive aldehydes by myeloperoxidase may thus play an important pathogenic role by generating AGE products and damaging tissues at sites of inflammation.
  5. Andrews LD, Brizzee KR. Lipofuscin in retinal pigment epithelium of rhesus monkey: lack of diminution with centrophenoxine treatment. Neurobiol Aging 1986;7(2):107-113. PubMed: 3083280. Categories: LysoSENS

    Lipofuscin in retinal pigment epithelium of rhesus monkey: lack of diminution with centrophenoxine treatment.

    Neurobiol Aging 1986;7(2):107-113.

    Lipofuscin in retinal pigment epithelium of rhesus monkey: lack of diminution with centrophenoxine treatment.

    Andrews LD, Brizzee KR.

    Abstract

    Abstract:
    An experiment was performed to test the ability of Centrophenoxine to reduce the amount of lipofuscin (age pigment) in the retinal pigment epithelium (RPE) of aged rhesus monkeys. Centrophenoxine is reputed to have this action in neurons of lower mammals. Quantitative electron microscopic analysis was performed on sections from the perifovea of ten rhesus monkeys, all approximately 20 years of age. Four of the animals received 80 mg/kg Centrophenoxine (IM injection) daily for 12 weeks. No significant difference between the treated and control groups could be demonstrated statistically (Mann-Whitney U-test) either in the fraction of RPE cell cytoplasm occupied by lipofuscin granules or in the average size of the granules.
  6. Asif M, Egan J, Vasan S, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA 2000;97(6):2809-2813. PubMed: 10706607. Categories: GlycoSENS

    An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness.

    Proc Natl Acad Sci USA 2000;97(6):2809-2813.

    An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness.

    Asif M, Egan J, Vasan S, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ.

    Abstract

    Abstract:
    Decreased elasticity of the cardiovascular system is one of the hallmarks of the normal aging process of mammals. A potential explanation for this decreased elasticity is that glucose can react nonenzymatically with long-lived proteins, such as collagen and lens crystallin, and link them together, producing advanced glycation endproducts (AGEs). Previous studies have shown that aminoguanidine, an AGE inhibitor, can prevent glucose cross-linking of proteins and the loss of elasticity associated with aging and diabetes. Recently, an AGE cross-link breaker (ALT-711) has been described, which we have evaluated in aged dogs. After 1 month of administration of ALT-711, a significant reduction ( approximately 40%) in age-related left ventricular stiffness was observed [(57.1 +/- 6.8 mmHg x m(2)/ml pretreatment and 33.1 +/- 4.6 mmHg x m(2)/ml posttreatment (1 mmHg = 133 Pa)]. This decrease was accompanied by improvement in cardiac function.
  7. Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM. Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 2006;355(12):1222-1232. PubMed: 16990385. Categories: RepleniSENS

    Transcoronary transplantation of progenitor cells after myocardial infarction.

    N Engl J Med 2006;355(12):1222-1232.

    Transcoronary transplantation of progenitor cells after myocardial infarction.

    Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM.

    Abstract

    Abstract:
    BACKGROUND: Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown. METHODS: After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were subsequently randomly assigned to receive CPC or BMC, and the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months' follow-up. RESULTS: The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (-0.4 percentage point, P=0.003) or no infusion (-1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly enhanced regional contractility in the area targeted by intracoronary infusion of BMC. The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular function, regardless of whether patients crossed over from control to BMC or from CPC to BMC. CONCLUSIONS: Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months.
  8. Atala A. Tissue engineering and regenerative medicine: concepts for clinical application. Rejuvenation Res 2004;7(1):15-31. PubMed: 15256042. Categories: RepleniSENS

    Tissue engineering and regenerative medicine: concepts for clinical application.

    Rejuvenation Res 2004;7(1):15-31.

    Tissue engineering and regenerative medicine: concepts for clinical application.

    Atala A.

    Abstract

    Abstract:
    Patients suffering from diseased and injured organs may be treated with transplanted organs. However, there is a severe shortage of donor organs that is worsening yearly given the aging population. Scientists in the field of regenerative medicine and tissue engineering apply the principles of cell transplantation, material science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. Therapeutic cloning, where the nucleus from a donor cell is transferred into an enucleated oocyte in order to extract pluripotent embryonic stem cells, offers a potentially limitless source of cells for tissue engineering applications. The stem cell field is also advancing rapidly, opening new options for therapy. This paper reviews recent advances that have occurred in regenerative medicine and describes applications of these new technologies that may offer novel therapies for patients with end-stage organ failure.
  9. Badman MK, Pryce RA, Charge SB, Morris JF, Clark A. Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation. Cell Tissue Res 1998;291(2):285-294. PubMed: 9426315. Categories: AmyloSENS

    Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation.

    Cell Tissue Res 1998;291(2):285-294.

    Fibrillar islet amyloid polypeptide (amylin) is internalised by macrophages but resists proteolytic degradation.

    Badman MK, Pryce RA, Charge SB, Morris JF, Clark A.

    Abstract

    Abstract:
    Pancreatic islet amyloid, formed from islet amyloid polypeptide, is found in 96% of Type II (non-insulin-dependent) diabetic patients. Islet amyloidosis is progressive and apparently irreversible. Fibrils immunoreactive for islet amyloid polypeptide are found in macrophages associated with amyloid, suggesting that deposits can be phagocytosed. To determine the mechanism for the recognition and internalisation of fibrils, mouse peritoneal macrophages were cultured with fibrillar synthetic human islet amyloid polypeptide. Fibrils did not exert a cytotoxic effect over 72 h of culture. The uptake and degradation of fibrils was analysed by quantitative light-and electron-microscopic immunocytochemistry and immunoreactivity was detectable in 86+/-3% cells within 6 h of culture. Neither polyinosinic acid (200 microg/ml) nor nocodazole (10 microg/ml) inhibited fibril uptake, suggesting that internalisation is not blocked by poly-ions and is independent of microtubule assembly. Inhibition of pseudopodia formation by cytochalasin B blocked fibriI uptake. Fibril aggregates became condensed in lysosomes to form protofilaments and were resistant to intracellular proteolysis. Fibrils can be phagocytosed by macrophages in vitro but amyloid-associated factors may block the recognition of fibrils in vivo preventing the removal of islet amyloid in diabetes.
  10. Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dolle ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J. Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 2006;441(7096):1011-1014. PubMed: 16791200. Categories: OncoSENS

    Increased cell-to-cell variation in gene expression in ageing mouse heart.

    Nature 2006;441(7096):1011-1014.

    Increased cell-to-cell variation in gene expression in ageing mouse heart.

    Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dolle ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J.

    Abstract

    Abstract:
    The accumulation of somatic DNA damage has been implicated as a cause of ageing in metazoa. One possible mechanism by which increased DNA damage could lead to cellular degeneration and death is by stochastic deregulation of gene expression. Here we directly test for increased transcriptional noise in aged tissue by dissociating single cardiomyocytes from fresh heart samples of both young and old mice, followed by global mRNA amplification and quantification of mRNA levels in a panel of housekeeping and heart-specific genes. Although gene expression levels already varied among cardiomyocytes from young heart, this heterogeneity was significantly elevated at old age. We had demonstrated previously an increased load of genome rearrangements and other mutations in the heart of aged mice. To confirm that increased stochasticity of gene expression could be a result of increased genome damage, we treated mouse embryonic fibroblasts in culture with hydrogen peroxide. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at a lacZ reporter locus. These results underscore the stochastic nature of the ageing process, and could provide a mechanism for age-related cellular degeneration and death in tissues of multicellular organisms.
  11. Bains, William More than genes and cells: drug discovery in the ECM Drug Discovery World. 2013/14 Winter:65-70 Categories: GlycoSENS

    More than genes and cells: drug discovery in the ECM

    Drug Discovery World. 2013/14 Winter:65-70

    More than genes and cells: drug discovery in the ECM

    Bains, William

    Abstract

    Abstract:

    Drug discovery in the last few decades has focused on the cellular and genetic mechanisms of disease. This has been very successful in cancer, which is a disease of somatic genetics, and moderately successful elsewhere. But the declining productivity of pharmaceutical and biotechnology investment in drug discovery and development suggests that we should be alert to other approaches. One is to look outside the cell, at the extracellular superstructure of the body. Once viewed as an inert structure that is just the biological equivalent of a petri dish, the extracellular milieu is now being seen as a therapeutic target, especially for diseases of old age. Importantly, targeting the scaffold of the body might be a much faster route to treatment for some conditions than attempting to find, and fix, underlying cellular or genetic aetiology of disease.

  12. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011 Nov 2;479(7372):232-6. PubMed: 22048312. Categories: ApoptoSENS

    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

    Nature. 2011 Nov 2;479(7372):232-6.

    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.

    Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM.

    Abstract

    Abstract:
    Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
  13. Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens 2004;17(12 Pt 2):23S-30S. PubMed: 15607432. Categories: GlycoSENS

    Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process.

    Am J Hypertens 2004;17(12 Pt 2):23S-30S.

    Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process.

    Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S.

    Abstract

    Abstract:
    Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress.
  14. Balakrishnan K, Andrei-Selmer LC, Selmer T, Bacher M, Dodel R. Comparison of Intravenous Immunoglobulins for Naturally Occurring Autoantibodies against Amyloid-beta. J Alzheimers Dis. 2010 Feb 17. [Epub ahead of print] PubMed: 20164596. Categories: AmyloSENS

    Comparison of Intravenous Immunoglobulins for Naturally Occurring Autoantibodies against Amyloid-beta.

    J Alzheimers Dis. 2010 Feb 17. [Epub ahead of print]

    Comparison of Intravenous Immunoglobulins for Naturally Occurring Autoantibodies against Amyloid-beta.

    Balakrishnan K, Andrei-Selmer LC, Selmer T, Bacher M, Dodel R.

    Abstract

    Abstract:
    Intravenous immunoglobulins (IVIG) are currently used for therapeutic purposes in autoimmune disorders. Recently, we demonstrated the presence of naturally occurring antibodies against amyloid-beta (nAbs-Abeta) within the pool of IVIG. In this study, we compared different brands of IVIG for nAbs-Abeta and have found differences in the specificity of the nAbs-Abeta towards Abeta_{1-40} and Abeta_{1-42}. We analyzed the influence of a pH-shift over the course of antibody storage using ELISA and investigated antibody dimerization at acidic and neutral pH as well as differences in the IgG subclass distributions among the IVIG using both HPLC and a nephelometric assay. Furthermore, we investigated the epitope region of purified nAbs-Abeta. The differences found in Abeta specificity are not directly proportionate to the binding nature of these antibodies when administered in vivo. This information, however, may serve as a guide when choosing the commercial source of IVIG for therapeutic applications in Alzheimer's disease.
  15. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004;428(6983):668-673. PubMed: 15034594. Categories: RepleniSENS

    Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.

    Nature 2004;428(6983):668-673.

    Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium.

    Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC.

    Abstract

    Abstract:
    Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+-GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.
  16. Bandy B, Davison AJ. Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Radic Biol Med 1990;8(6):523-39. PubMed: 2193852. Categories: MitoSENS

    Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging?

    Free Radic Biol Med 1990;8(6):523-39.

    Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging?

    Bandy B, Davison AJ.

    Abstract

    Abstract:
    The sensitivity of mitochondrial DNA to damage by mutagens predisposes mitochondria to injury on exposure of cells to genotoxins or oxidative stress. Damage to the mitochondrial genome causing mutations or loss of mitochondrial gene products, or to some nuclear genes encoding mitochondrial membrane proteins, may accelerate release of reactive species of oxygen. Such aberrant mitochondria may contribute to cellular aging and promotion of cancer.
  17. Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Beal MF, Moore MA, Studer L. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol 2003;21(10):1200-1207. PubMed: 14502203. Categories: RepleniSENS

    Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice.

    Nat Biotechnol 2003;21(10):1200-1207.

    Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice.

    Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Beal MF, Moore MA, Studer L.

    Abstract

    Abstract:
    Existing protocols for the neural differentiation of mouse embryonic stem (ES) cells require extended in vitro culture, yield variable differentiation results or are limited to the generation of selected neural subtypes. Here we provide a set of coculture conditions that allows rapid and efficient derivation of most central nervous system phenotypes. The fate of both fertilization- and nuclear transfer-derived ES (ntES) cells was directed selectively into neural stem cells, astrocytes, oligodendrocytes or neurons. Specific differentiation into gamma-aminobutyric acid (GABA), dopamine, serotonin or motor neurons was achieved by defining conditions to induce forebrain, midbrain, hindbrain and spinal cord identity. Neuronal function of ES cell-derived dopaminergic neurons was shown in vitro by electron microscopy, measurement of neurotransmitter release and intracellular recording. Furthermore, transplantation of ES and ntES cell-derived dopaminergic neurons corrected the phenotype of a mouse model of Parkinson disease, demonstrating an in vivo application of therapeutic cloning in neural disease.
  18. Barja G. Rate of generation of oxidative stress-related damage and animal longevity. Free Radic Biol Med 2002;33(9):1167-1172. PubMed: 12398924. Categories: MitoSENS

    Rate of generation of oxidative stress-related damage and animal longevity.

    Free Radic Biol Med 2002;33(9):1167-1172.

    Rate of generation of oxidative stress-related damage and animal longevity.

    Barja G.

    Abstract

    Abstract:
    Comparative studies about the relationship between endogenous antioxidant and pro-oxidant factors and maximum longevity of different animal species are reviewed. The majority of studies on antioxidant supplementation indicate that it can increase mean survival without changing maximum longevity. On the other hand, endogenous antioxidants are negatively correlated with maximum longevity. The same is true for the rates of mitochondrial oxygen radical generation, oxidative damage to mitochondrial DNA, and the degree of fatty acid unsaturation of cellular membranes in postmitotic tissues. The lower rate of mitochondrial oxygen radical generation of long-lived animals in relation to that of short-lived ones can be a primary cause of their slow aging rate. This is secondarily complemented in long-lived animals with low rates of lipid peroxidation due to their low degrees of fatty acid unsaturation. These two traits suggest that the rate of generation of endogenous oxidative damage determines, at least in part, the rate of aging in animals.
  19. Barker RW, Brindley DA, Schuh A. Establish good genomic practice to guide medicine forward. Nat Med. 2013 May;19(5):530. doi: 10.1038/nm0513-530. PubMed: 23652098.

    Establish good genomic practice to guide medicine forward.

    Nat Med. 2013 May;19(5):530. doi: 10.1038/nm0513-530.

    Establish good genomic practice to guide medicine forward.

    Barker RW, Brindley DA, Schuh A.

    Abstract

    Abstract:

    (No abstract available.)

  20. Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L. Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J Clin Invest 1998;101(7):1353-1361. PubMed: 9525977. Categories: ApoptoSENS

    Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat.

    J Clin Invest 1998;101(7):1353-1361.

    Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat.

    Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L.

    Abstract

    Abstract:
    Hyperinsulinemia and increased visceral/abdominal fat (VF) are common features of human aging. To examine the relationships among VF, peripheral, and hepatic insulin sensitivity, we studied 4- and 18-mo-old male Sprague-Dawley rats (n = 42) fed ad libitum (4 AL and 18 AL) or moderately calorie restricted (18 CR) up to 18 mo of age. Total fat mass (FM) and VF were decreased in 18 CR to approximately one-third of that of 18 AL (P < 0.001), while lean body mass (LBM) was unchanged. Most important, 18 CR had more FM (65+/-6 vs. 45+/-6 g) but less VF (7.8+/-0.6 vs. 12.3+/-3.3 g) compared with 4 AL (P < 0.01 for both). Thus, the effects of variable VF on HIS could be assessed, independent of FM and age. Marked hepatic insulin resistance ensued with aging (18 AL) and CR restored hepatic insulin sensitivity to the levels of young rats, while peripheral insulin sensitivity remained unchanged (by insulin clamp of 18 mU/kg/min). In fact, the rates of insulin infusion required to maintain basal hepatic glucose production in the presence of pancreatic clamp were 0.75+/-0.10, 1.41+/-0.13, and 0.51+/-0.12 mU/kg . min, in 4 AL, 18 AL, and 18 CR, respectively (P < 0.01 between all groups), and in 18 CR rats infused with insulin at similar rates as in the 18 AL (1.4 mU/kg/min) hepatic glucose production was decreased by 32% (P < 0. 005). Furthermore, when 18 CR rats were fed AL for 14 d, VF rapidly and selectively increased and severe hepatic insulin resistance was induced. We propose that in this animal model the age-associated decrease in hepatic (rather than peripheral) insulin action is the major determinant of fasting hyperinsulinemia and that increased visceral adiposity plays the major role in inducing hepatic insulin resistance. Thus, interventions designed to prevent the accumulation of VF are likely to represent an effective mean to improve carbohydrate metabolism in aging.

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