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. 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.

  2. Bonnet C, Kaltimbacher V, Ellouze S, Augustin S, Bénit P, Forster V, Rustin P, Sahel JA, Corral-Debrinski M. Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or V subunits. Rejuvenation Res 2007;10(2):127-144. PubMed: 17518546. Categories: MitoSENS

    Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or V subunits.

    Rejuvenation Res 2007;10(2):127-144.

    Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or V subunits.

    Bonnet C, Kaltimbacher V, Ellouze S, Augustin S, Bénit P, Forster V, Rustin P, Sahel JA, Corral-Debrinski M.

    Abstract

    Abstract:

    The possibility of synthesizing mitochondrial DNA (mtDNA)-coded proteins in the cytosolic compartment, called allotopic expression, provides an attractive option for genetic treatment of human diseases caused by mutations of the corresponding genes. However, it is now appreciated that the high hydrophobicity of proteins encoded by the mitochondrial genome represents a strong limitation on their mitochondrial import when translated in the cytosol. Recently, we optimized the allotopic expression of a recoded ATP6 gene in human cells, by forcing its mRNA to localize to the mitochondrial surface. In this study, we show that this approach leads to a long-lasting and complete rescue of mitochondrial dysfunction of fibroblasts harboring the neurogenic muscle weakness, ataxia and retinitis Pigmentosa T8993G ATP6 mutation or the Leber hereditary optic neuropathy G11778A ND4 mutation. The recoded ATP6 gene was associated with the cis-acting elements of SOD2, while the ND4 gene was associated with the cis-acting elements of COX10. Both ATP6 and ND4 gene products were efficiently translocated into the mitochondria and functional within their respective respiratory chain complexes. Indeed, the abilities to grow in galactose and to produce adenosine triphosphate (ATP) in vitro were both completely restored in fibroblasts allotopically expressing either ATP6 or ND4. Notably, in fibroblasts harboring the ATP6 mutation, allotopic expression of ATP6 led to the recovery of complex V enzymatic activity. Therefore, mRNA sorting to the mitochondrial surface represents a powerful strategy that could ultimately be applied in human therapy and become available for an array of devastating disorders caused by mtDNA mutations.

  3. Brindley D, Davie N Regenerative Medicine Through a Crisis: Social Perception and the Financial Reality. Rejuvenation Research 2009, 12(6): 455-461 PubMed: 20041739. Categories: Socioethical

    Regenerative Medicine Through a Crisis: Social Perception and the Financial Reality.

    Rejuvenation Research 2009, 12(6): 455-461

    Regenerative Medicine Through a Crisis: Social Perception and the Financial Reality.

    Brindley D, Davie N

    Abstract

    Abstract:

    The aim of this perspective piece is to highlight how the “social perception” and “financial reality” of regenerative medicine may act to hinder its evolution into the principal health-care option for the future. We also consider the role of the consumer and the need for increased public awareness. Furthermore, we consider the effects of the changing social attitudes toward the field, as well as taking into account the influence of current and future political thinking. From a financial viewpoint, we analyze the compatibility of the current venture capital model with regenerative medicine start-ups and explore approaches to ensure sufficient funding and support throughout all stages of product development, for example, the modularization of funding.

  4. Brindley DA, Wall IB, Bure K. Automation of Cell Therapy Biomanufacturing: Minimizing Regulatory Risks and Maximising Return on Investment Bioprocess International, Supplement; vol. 11, No. S3, March 2013, pp. 18–25.


    Automation of Cell Therapy Biomanufacturing: Minimizing Regulatory Risks and Maximising Return on Investment

    Bioprocess International, Supplement; vol. 11, No. S3, March 2013, pp. 18–25.


    Automation of Cell Therapy Biomanufacturing: Minimizing Regulatory Risks and Maximising Return on Investment

    Brindley DA, Wall IB, Bure K.

    Abstract

    Abstract:

    (No abstract available.)

  5. Brindley DA, Wall IB. The Commercial Manufacture of Cell Therapies In: Standardization in Cell and Tissue Engineering: Methods and Protocols (V. Salih, ed.) Woodhead Publishing, 2012, pp. 212-240.

    The Commercial Manufacture of Cell Therapies

    In: Standardization in Cell and Tissue Engineering: Methods and Protocols (V. Salih, ed.) Woodhead Publishing, 2012, pp. 212-240.

    The Commercial Manufacture of Cell Therapies

    Brindley DA, Wall IB.

    Abstract

    Abstract:

    (No abstract available.)

  6. Bussel II, Stupple A, Moody KJ, Lefkowitz DM. Call to action: medical students for regenerative medicine. Rejuvenation Res. 2010 Feb;13(1):1-2. PubMed: 20230272. Categories: Introductions

    Call to action: medical students for regenerative medicine.

    Rejuvenation Res. 2010 Feb;13(1):1-2.

    Call to action: medical students for regenerative medicine.

    Bussel II, Stupple A, Moody KJ, Lefkowitz DM.

    Abstract

    Abstract:
  7. Chen Y, Ma X, Zhang M, Wang X, Wang C, Wang H, Guo P, Yuan W, Rudolph KL, Zhan Q, Ju Z. Gadd45a regulates hematopoietic stem cell stress responses in mice. Blood. 2014 Feb 6;123(6):851-62. doi: 10.1182/blood-2013-05-504084. PubMed: 24371210.

    Gadd45a regulates hematopoietic stem cell stress responses in mice.

    Blood. 2014 Feb 6;123(6):851-62. doi: 10.1182/blood-2013-05-504084.

    Gadd45a regulates hematopoietic stem cell stress responses in mice.

    Chen Y, Ma X, Zhang M, Wang X, Wang C, Wang H, Guo P, Yuan W, Rudolph KL, Zhan Q, Ju Z.

    Abstract

    Abstract:

    Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia. However, the function of Gadd45a in hematopoietic stem cells (HSCs) remains unknown. Here, we reported that Gadd45a-deficient (Gadd45a(-/-)) mice showed a normal hematologic phenotype under homeostatic conditions. However, following 5-fluorouracil treatment, Gadd45a(-/-) HSCs exhibited a faster recovery, associated with an increase in the proliferation rate. Interestingly, young Gadd45a(-/-) HSCs showed enhanced reconstitution ability in serial transplantation. Following ionizing radiation (IR), young Gadd45a(-/-) HSCs exhibited an increased resistance to IR-induced DNA damage, associated with a decrease in the apoptosis rate and delayed DNA repair. The significantly higher level of DNA damage in Gadd45a(-/-) HSCs ultimately promoted B-cell leukemia in further transplanted recipient mice. In old mice, Gadd45a(-/-) HSCs were functionally equal to wild-type HSCs but exhibited more DNA damage accumulation and increased sensitivity to IR than wild-type HSCs. In conclusion, Gadd45a plays a significant role in HSC stress responses. Gadd45a deficiency leads to DNA damage accumulation and impairment in apoptosis after exposure to IR, which increases the susceptibility of leukemogenesis.

  8. Chen Y, Yang R, Guo P, Ju Z. Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice. Protein Cell. 2014 Jan;5(1):80-9. doi: 10.1007/s13238-013-0017-9. PubMed: 24474198.

    Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice.

    Protein Cell. 2014 Jan;5(1):80-9. doi: 10.1007/s13238-013-0017-9.

    Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice.

    Chen Y, Yang R, Guo P, Ju Z.

    Abstract

    Abstract:

    Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(-/-) HSCs.

  9. Corral-Debrinski M. mRNA specific subcellular localization represents a crucial step for fine-tuning of gene expression in mammalian cells. Biochim Biophys Acta. 2007 Apr;1773(4):473-5. PubMed: 17292980. Categories: MitoSENS

    mRNA specific subcellular localization represents a crucial step for fine-tuning of gene expression in mammalian cells.

    Biochim Biophys Acta. 2007 Apr;1773(4):473-5.

    mRNA specific subcellular localization represents a crucial step for fine-tuning of gene expression in mammalian cells.

    Corral-Debrinski M.

    Abstract

    Abstract:

    mRNA subcellular distribution and translational control are key player mechanisms for post-transcriptional gene expression regulation. In the last decade it has become increasingly clear that these processes are associated with various human diseases. Understanding the interconnected multistep process of mRNA localization and its involvement in organelle biogenesis and in the overall spatial structure of eukaryotic cells will be an important step towards the long-term goal of curing individual molecular defects. In a recent issue, Russo et al. [The 3'-untranslated region directs ribosomal protein-encoding mRNAs to specific cytoplasmic regions, Biochim. Biophys. Acta, Mol. Cell Res. 1763 (8) (2006) 833-843] reported interesting findings on the mechanisms that direct mRNAs encoding different ribosomal proteins to specific cytoplasmic regions in human cells.

  10. Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP, Conboy IM. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun. 2014 Jun 10;5:4082. doi: 10.1038/ncomms5082. PubMed: 24915299. Categories: RepleniSENS

    Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration.

    Nat Commun. 2014 Jun 10;5:4082. doi: 10.1038/ncomms5082.

    Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration.

    Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP, Conboy IM.

    Abstract

    Abstract:

    The regenerative capacity of skeletal muscle declines with age. Previous studies suggest that this process can be reversed by exposure to young circulation; however, systemic age-specific factors responsible for this phenomenon are largely unknown. Here we report that oxytocin-a hormone best known for its role in lactation, parturition and social behaviours-is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age. Inhibition of oxytocin signalling in young animals reduces muscle regeneration, whereas systemic administration of oxytocin rapidly improves muscle regeneration by enhancing aged muscle stem cell activation/proliferation through activation of the MAPK/ERK signalling pathway. We further show that the genetic lack of oxytocin does not cause a developmental defect in muscle but instead leads to premature sarcopenia. Considering that oxytocin is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent skeletal muscle ageing.

  11. Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M. Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction. Am J Hum Genet. 2008 Sep;83(3):373-87. doi: 10.1016/j.ajhg.2008.08.013. PubMed: 18771762. Categories: MitoSENS

    Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.

    Am J Hum Genet. 2008 Sep;83(3):373-87. doi: 10.1016/j.ajhg.2008.08.013.

    Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction.

    Ellouze S, Augustin S, Bouaita A, Bonnet C, Simonutti M, Forster V, Picaud S, Sahel JA, Corral-Debrinski M.

    Abstract

    Abstract:

    Mitochondrial diseases due to mutations in mitochondrial DNA can no longer be ignored in most medical areas. With prevalence certainly higher than one in 6000, they probably represent the most common form of metabolic disorders. Despite progress in identification of their molecular mechanisms, little has been done with regard to therapy. We have recently optimized the allotopic expression for the mitochondrial genes ATP6, ND1, and ND4 and obtained a complete and long-lasting rescue of mitochondrial dysfunction in the human fibroblasts in which these genes were mutated. However, biosafety and benefit to mitochondrial function must be validated in animal models prior to clinical applications. To create an animal model of Leber Hereditary Optic Neuropathy (LHON), we introduced the human ND4 gene harboring the G11778A mutation, responsible of 60% of LHON cases, to rat eyes by in vivo electroporation. The treatment induced the degeneration of retinal ganglion cells (RGCs), which were 40% less abundant in treated eyes than in control eyes. This deleterious effect was also confirmed in primary cell culture, in which both RGC survival and neurite outgrowth were compromised. Importantly, RGC loss was clearly associated with a decline in visual performance. A subsequent electroporation with wild-type ND4 prevented both RGC loss and the impairment of visual function. Hence, these data provide the proof-of-principle that optimized allotopic expression can be an effective treatment for LHON, and they open the way to clinical studies on other devastating mitochondrial disorders.

  12. Kim T, Spiegel DA. The unique reactivity of N-phenacyl-derived thiazolium salts toward alpha-dicarbonyl compounds. Rejuvenation Res. 2013 Feb;16(1):43-50. doi: 10.1089/rej.2012.1370. PubMed: 23186164. Categories: GlycoSENS

    The unique reactivity of N-phenacyl-derived thiazolium salts toward alpha-dicarbonyl compounds.

    Rejuvenation Res. 2013 Feb;16(1):43-50. doi: 10.1089/rej.2012.1370.

    The unique reactivity of N-phenacyl-derived thiazolium salts toward alpha-dicarbonyl compounds.

    Kim T, Spiegel DA.

    Abstract

    Abstract:

    Advanced glycation end-products (AGEs), a heterogenous mixture of compounds formed by non-enzymatic chemical reactions between sugars and the nucleophilic residues of proteins, have been implicated in the pathogenesis of a number of diseases. ALT-711 is an N-phenacyl-derived thiazolium carbene developed as a therapeutic agent for cardiovascular diseases that is proposed to function through cleaving pre-formed AGE-protein crosslinks. However, despite promising results in animal models and clinical trials, its mechanism of action still remains controversial. Herein, we report the first systematic investigations into dicarbonyl cleavage by ALT-711. We demonstrate that it is capable of cleaving α-diketones more efficiently and likely via a distinct mechanism compared with other N-heterocyclic carbene precursors. We also show that ALT-711 reacts rapidly with α-keto aldehydes to form cyclic diol products, and can efficiently scavenge methylglyoxal under physiological conditions to protect E. coli from lethal concentrations of this reactive α-keto aldehyde. This work suggests ALT-711 may be especially suited for α-dicarbonyl clearance in vivo, and supports a mode of action similar to that originally proposed. To this end, our findings may provide insights into the development of next-generation crosslink breakers.

  13. Mathieu J, Schloendorn J, Rittmann BE, Alvarez PJ. Microbial degradation of 7-ketocholesterol. Biodegradation. 2008;19(6):807-13. PubMed: 18344006. Categories: LysoSENS

    Microbial degradation of 7-ketocholesterol.

    Biodegradation. 2008;19(6):807-13.

    Microbial degradation of 7-ketocholesterol.

    Mathieu J, Schloendorn J, Rittmann BE, Alvarez PJ.

    Abstract

    Abstract:

    7-Ketocholesterol (7KC) is an oxidized derivative of cholesterol suspected to be involved in the pathogenesis of atherosclerosis and possibly Alzheimer's disease. While some oxysterols are important biological mediators, 7KC is generally cytotoxic and interferes with cellular homeostasis. Despite recent interest in preventing the accumulation of 7KC in a variety of matrices to avoid adverse biological effects, its microbial degradation has not been previously addressed in the peer-reviewed literature. Thus, the rate and extent of biodegradation of this oxysterol was investigated to bridge this gap. A wide variety of bacteria isolated from soil or activated sludge, including Proteobacterium Y-134, Sphingomonas sp. JEM-1, Nocardia nova, Rhodococcus sp. RHA1, and Pseduomonas aeruginosa, utilized 7KC as a sole carbon and energy source, resulting in its mineralization. Nocardia nova, which is known to produce biosurfactants, was the fastest degrader. This study supports the notion that microbial catabolic enzymes could be exploited to control 7KC levels in potential biotechnological applications for agricultural, environmental, or medical use.

  14. Mathieu JM, Mohn WW, Eltis LD, LeBlanc JC, Stewart GR, Dresen C, Okamoto K, Alvarez PJ. 7-ketocholesterol catabolism by Rhodococcus jostii RHA1. Appl Environ Microbiol. 2010 Jan;76(1):352-5. doi: 10.1128/AEM.02538-09. PubMed: 19880645. Categories: LysoSENS

    7-ketocholesterol catabolism by Rhodococcus jostii RHA1.

    Appl Environ Microbiol. 2010 Jan;76(1):352-5. doi: 10.1128/AEM.02538-09.

    7-ketocholesterol catabolism by Rhodococcus jostii RHA1.

    Mathieu JM, Mohn WW, Eltis LD, LeBlanc JC, Stewart GR, Dresen C, Okamoto K, Alvarez PJ.

    Abstract

    Abstract:

    Oxysterols from steroid autooxidation have numerous harmful effects, but their biodegradation is poorly understood. Microarrays were used to study mineralization of the most common oxysterol, 7-ketocholesterol (7KC), by Rhodococcus jostii RHA1. Growth on 7KC versus growth on cholesterol resulted in 363 differentially expressed genes, including upregulation of two large gene clusters putatively encoding steroid catabolism. Despite this difference, 7KC degradation required key genes involved in cholesterol degradation, indicating a common catabolic route.

  15. Mathieu JM, Schloendorn J, Rittmann BE, Alvarez PJ. Medical bioremediation of age-related diseases. Microb Cell Fact. 2009 Apr 9;8:21. doi: 10.1186/1475-2859-8-21. PubMed: 19358742. Categories: LysoSENS

    Medical bioremediation of age-related diseases.

    Microb Cell Fact. 2009 Apr 9;8:21. doi: 10.1186/1475-2859-8-21.

    Medical bioremediation of age-related diseases.

    Mathieu JM, Schloendorn J, Rittmann BE, Alvarez PJ.

    Abstract

    Abstract:

    Catabolic insufficiency in humans leads to the gradual accumulation of a number of pathogenic compounds associated with age-related diseases, including atherosclerosis, Alzheimer's disease, and macular degeneration. Removal of these compounds is a widely researched therapeutic option, but the use of antibodies and endogenous human enzymes has failed to produce effective treatments, and may pose risks to cellular homeostasis. Another alternative is "medical bioremediation," the use of microbial enzymes to augment missing catabolic functions. The microbial genetic diversity in most natural environments provides a resource that can be mined for enzymes capable of degrading just about any energy-rich organic compound. This review discusses targets for biodegradation, the identification of candidate microbial enzymes, and enzyme-delivery methods.

  16. Mathieu JM, Wang F, Segatori L, Alvarez PJ. Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase. Biotechnol Bioeng. 2012 Sep;109(9):2409-15. doi: 10.1002/bit.24506. PubMed: 22447444. Categories: LysoSENS

    Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase.

    Biotechnol Bioeng. 2012 Sep;109(9):2409-15. doi: 10.1002/bit.24506.

    Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase.

    Mathieu JM, Wang F, Segatori L, Alvarez PJ.

    Abstract

    Abstract:

    7-Ketocholesterol (7KC) is a cytotoxic oxysterol that plays a role in many age-related degenerative diseases. 7KC formation and accumulation often occurs in the lysosome, which hinders enzymatic transformations that reduce its toxicity and increase the sensitivity to lysosomal membrane permeabilization. We assayed the potential to mitigate 7KC cytotoxicity and enhance cell viability by overexpressing 7KC-active enzymes in human fibroblasts. One of the enzymes tested, a cholesterol oxidase engineered for lysosomal targeting, significantly increased cell viability in the short term upon treatment with up to 50 µM 7KC relative to controls. These results suggest targeting the lysosome for optimal treatment of oxysterol-mediated cytotoxicity, and support the use of introducing novel catalytic function into the lysosome for therapeutic and research applications.

  17. Peto MV. Aluminium and iron in humans: bioaccumulation, pathology, and removal. Rejuvenation Res 2010 Oct;13(5):589-98. PubMed: 21142669. Categories: AmyloSENS, LysoSENS, OncoSENS

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Rejuvenation Res 2010 Oct;13(5):589-98.

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Peto MV.

    Abstract

    Abstract:

    It is well known that exposure to various elements has a noticeable effect on human health. The effect of an element is determined by several characteristics, including its similarity to elements of biological necessity, metabolism, and degree of interaction with physiological processes. This review investigates the scientific literature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is reviewed because of its prevalence in daily life, observed interference with several biological processes, controversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these metals has long been investigated for a possible relationship with various pathological states, a substantial volume of research is available regarding the effects of iron and aluminium in biological systems. For both aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility of bioaccumulation, and (3) exploring methods of managing their accumulation.

  18. Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231. PubMed: 24648510. Categories: AmyloSENS

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231.

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S.

    Abstract

    Abstract:

    Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function.

  19. Rebo J, Causey K, Zealley B, Webb T, Hamalainen M, Cook B, Schloendorn J. Whole-animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles. Rejuvenation Res. 2010 Apr-Jun;13(2-3):298-300. doi: 10.1089/rej.2009.0964. PubMed: 20426617. Categories: ApoptoSENS

    Whole-animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles.

    Rejuvenation Res. 2010 Apr-Jun;13(2-3):298-300. doi: 10.1089/rej.2009.0964.

    Whole-animal senescent cytotoxic T cell removal using antibodies linked to magnetic nanoparticles.

    Rebo J, Causey K, Zealley B, Webb T, Hamalainen M, Cook B, Schloendorn J.

    Abstract

    Abstract:

    A major type of unwanted cells that accumulate in aging are anergic cytotoxic T cells. These cells often have virus-specific T cell receptors, as well as other surface markers that distinguish them from their youthful counterparts, and they are thought to play a major role in the decline of the immune system with age. Here we consider two surface markers thought to define these cells in mice, CD8 and Killer cell lectin-like receptor G1 (KLRG1), and a means we developed to remove these cells from the blood of aged C57BL/6 mice. Using antibodies with magnetic nanoparticles linked to their Fc domains, we first developed a method to use magnets to filter out the unwanted cells from the blood and later constructed a device that does this automatically. We demonstrated that this device could reduce the KLRG1-positive CD8 cell count in aged mouse blood by a factor of 7.3 relative to the total CD8 cell compartment, reaching a level typically seen only in very young animals.

  20. Rehki R, Wall I, French A, Bure K, Carr AJ, Brindley DA. Cell Therapy Biomanufacturing Risk Management In: Cell Therapy Translation (D. Williams and D. Scadden, eds.), StemBook, 2014.

    Cell Therapy Biomanufacturing Risk Management

    In: Cell Therapy Translation (D. Williams and D. Scadden, eds.), StemBook, 2014.

    Cell Therapy Biomanufacturing Risk Management

    Rehki R, Wall I, French A, Bure K, Carr AJ, Brindley DA.

    Abstract

    Abstract:

    (No abstract available.)

Pages