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  • Bains, W. More than genes and cells: drug discovery in the ECM. Drug Discovery World. 2013/14 Winter:65-70. Read on external site. 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, W.

    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.

  • Brindley DA, Barker RW, Lachmann PJ. Health care: Better drug access for terminal patients. Nature. 2013 Oct 3;502(7469):38. doi: 10.1038/502038c. PubMed: 24091972. Categories: Beyond the Bench

    Health care: Better drug access for terminal patients.

    Nature. 2013 Oct 3;502(7469):38. doi: 10.1038/502038c.

    Health care: Better drug access for terminal patients.

    Brindley DA, Barker RW, Lachmann PJ.

    Abstract

    Abstract:

    The late statistician Les Halpin was the founder of the Empower: Access to Medicine campaign to improve the availability of experimental therapies and to accelerate drug approval and licensing for people with life-threatening illnesses.  His campaign has enabled drugs to get to market faster and more cheaply.

  • Wang T, Douglass EF Jr, Fitzgerald KJ, Spiegel DA. A "turn-on" fluorescent sensor for methylglyoxal. J Am Chem Soc. 2013 Aug 21;135(33):12429-33. doi: 10.1021/ja406077j. Epub 2013 Aug 9. PubMed: 23931147. Categories: GlycoSENS

    A "turn-on" fluorescent sensor for methylglyoxal.

    J Am Chem Soc. 2013 Aug 21;135(33):12429-33. doi: 10.1021/ja406077j. Epub 2013 Aug 9.

    A "turn-on" fluorescent sensor for methylglyoxal.

    Wang T, Douglass EF Jr, Fitzgerald KJ, Spiegel DA.

    Abstract

    Abstract:

    Methylglyoxal (MGO), a dicarbonyl metabolite produced by all living cells, has been associated with a number of human diseases. However, studies of the role(s) MGO plays biologically have been handicapped by a lack of direct methods for its monitoring and detection. To address this limitation, we have developed a fluorescent sensor (methyl diaminobenzene-BODIPY, or "MBo") that can detect MGO under physiological conditions. We show that MBo is selective for MGO over other biologically relevant dicarbonyls and is suitable for detecting MGO in complex environments, including that of living cells. In addition, we demonstrate MBo's utility in estimating plasma concentrations of MGO. The results reported herein have the potential to advance both clinical and basic science research and practice.

  • Brindley DA, Wall IB. Commercial Manufacture of Cell Therapies. In: Standardization in Cell and Tissue Engineering: Methods and Protocols (V. Salih, ed.) Woodhead Publishing, 2012, pp. 212-240. Read on external site. Categories: Beyond the Bench

    Commercial Manufacture of Cell Therapies.

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

    Commercial Manufacture of Cell Therapies.

    Brindley DA, Wall IB.

    Abstract

    Abstract:

    (No abstract available.)

  • Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe JP, Rodier F, Campisi J. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol 2013;201(4):613-29. PubMed: 23649808. Categories: ApoptoSENS

    p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

    J Cell Biol 2013;201(4):613-29.

    p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

    Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe JP, Rodier F, Campisi J.

    Abstract

    Abstract:

    Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.

  • 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.)

  • French A, Buckler RL, Brindley DA. Commercialization of regenerative medicine: learning from spin-outs. Rejuvenation Res 2013;16(2):164-70. PubMed: 23470045. Categories: Beyond the Bench

    Commercialization of regenerative medicine: learning from spin-outs.

    Rejuvenation Res 2013;16(2):164-70.

    Commercialization of regenerative medicine: learning from spin-outs.

    French A, Buckler RL, Brindley DA.

    Abstract

    Abstract:

    The meeting "Commercialization of Your Regenerative Medicine Research: Lessons from Spin Out Successes" was hosted by the Oxbridge Biotech Roundtable (OBR) (Oxford, UK) at the University of Oxford in February, 2013, and attracted a multi-stakeholder audience spanning academia and industry. The event featured case studies from Gregg Sando, CEO, Cell Medica (London, UK), John Sinden, CSO, Reneuron (Guilford, UK), and Paul Kemp, CEO and CSO, Intercytex (Manchester, UK). OBR is a student-led initiative with over 7000 members across eight different UK and US locations with a mission to foster a conversation about the healthcare and life sciences industry. Here we review the main themes of the meeting and the major questions facing the regenerative medicine industry and its rapidly emerging subsets of cellular and gene therapies. Notably, we discuss the compatibility of regenerative therapies to the existing healthcare infrastructure, biomanufacturing challenges (including scalability and comparability), and the amenability of regenerative therapies to existing reimbursement and investment models. Furthermore, we reiterate key words of advice from seasoned industry leaders intended to accelerate the translation path from lab bench to the marketplace.

  • 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.
 Read on external site. Categories: Beyond the Bench

    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.)

  • 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.

  • Bates RC, Stith BJ, Stevens KE. Chronic central administration of valproic acid: Increased pro-survival phospho-proteins and growth cone associated proteins with no behavioral pathology. Pharmacol Biochem Behav 2012;103(2):237-44. PubMed: 22960225.

    Chronic central administration of valproic acid: Increased pro-survival phospho-proteins and growth cone associated proteins with no behavioral pathology.

    Pharmacol Biochem Behav 2012;103(2):237-44.

    Chronic central administration of valproic acid: Increased pro-survival phospho-proteins and growth cone associated proteins with no behavioral pathology.

    Bates RC, Stith BJ, Stevens KE.

    Abstract

    Abstract:

    Valproic acid (VPA) is the most widely prescribed antiepileptic drug due to its ability to treat a broad spectrum of seizure types. However, potential complications of this drug include anticonvulsant polytherapy metabolism, organ toxicity and teratogenicity which limit its use in a variety of epilepsy patients. Direct delivery of VPA intracerebroventricularly (ICV) could circumvent the toxic effects normally seen with the oral route of administration. An additional potential benefit would be significantly reduced dosing while achieving high brain concentrations. Epileptogenic tissue from patients with intractable seizures has shown significant cell death which may be mitigated by maximizing cerebral VPA exposure. Here we show ICV administration of VPA localized to the periventricular zone increased pro-survival phospho-proteins (pAkt(Ser473), pAkt(Thr308), pGSK3β(Ser9), pErk1/2(Thr202/Tyr204)) and growth cone associated proteins (2G13p, GAP43) in a whole animal system. No significant changes in DCX, NeuN, synaptotagmin, and synaptophysin were detected. Assessment of possible behavioral alterations in rats receiving chronic central infusions of VPA was performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the drug infusion process.

  • Johnson AA, Akman K, Calimport SR, Wuttke D, Stolzing A, de Magalhães JP. The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuvenation Res 2012;15(5):483-94. PubMed: 23098078. Categories: OncoSENS

    The role of DNA methylation in aging, rejuvenation, and age-related disease.

    Rejuvenation Res 2012;15(5):483-94.

    The role of DNA methylation in aging, rejuvenation, and age-related disease.

    Johnson AA, Akman K, Calimport SR, Wuttke D, Stolzing A, de Magalhães JP.

    Abstract

    Abstract:

    DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-L-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

  • Zealley B, de Grey ADNJ. Strategies for engineered negligible senescence. Gerontology. 2013;59(2):183-9. Epub 2012 Oct 1. PubMed: 23037635. Categories: SENS Overviews

    Strategies for engineered negligible senescence.

    Gerontology. 2013;59(2):183-9. Epub 2012 Oct 1.

    Strategies for engineered negligible senescence.

    Zealley B, de Grey ADNJ.

    Abstract

    Abstract:

    In this viewpoint, we describe the strategies for engineered negligible senescence (SENS) concept--a simple and appealing model for the design of therapeutic interventions able to meaningfully and persistently reverse the deleterious effects of aging. We go on to outline how current or foreseeable biotechnologies could feasibly be employed to repair every currently identified category of pathogenic damage that accumulates over a human lifespan. Then, briefly, we explain why this goal is not only ethically sound, but can in fact be considered to verge on an ethical obligation. Finally, we review recent progress in some key areas of the SENS platform, including proof-of-concept research sponsored by the SENS Foundation, a charity based in California.

  • 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.

  • Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C. A decade of cell therapy clinical trials (2000–2010). Regen Med. 2012 Jul;7(4):455-62. PubMed: 22817619. Categories: Delivery Mechanisms

    A decade of cell therapy clinical trials (2000–2010).

    Regen Med. 2012 Jul;7(4):455-62.

    A decade of cell therapy clinical trials (2000–2010).

    Culme-Seymour EJ, Davie NL, Brindley DA, Edwards-Parton S, Mason C.

    Abstract

    Abstract:

    The cell therapy industry (CTI) is presently a small but potentially rapidly growing new global healthcare sector. Success is totally dependent on resolving a number of factors unique to cells as therapies, including: manufacturing, enabling technologies, regulation, reimbursement and essential infrastructure. To understand how to solve these challenges in a timely and cost-effective manner, it is essential to be able to forecast the size and resource demands of the sector for a least the next decade. Due to the highly regulated nature of medicines, one predictive method is to analyze the candidate therapies that are currently undergoing clinical trials (i.e., the future pipeline). A search was performed on the website ClinicalTrials.gov using the embedded search engine and key terms relating to ‘cell therapy’. A total of 17,362 files were extracted (27 June 2010) and individually checked for relevance using the British Standard Institute (BSI) definition of ‘cell therapy’. The resulting 2724 trials were then categorized and core information collated, including: trial phase, cell source (autologous/allogeneic), current activity of the trial and responsible national regulatory agency. Key results included: near equal numbers of autologous (46%) and allogeneic (41%) trials; many of the trials are in the later stages – Phase I (49%), Phase II (40%) or Phase III (10%); and there are significantly larger numbers of transient cell therapies (50%) as opposed to permanent cell replacement (5%). This is the first time that the number and composition of all the cell therapy trials on ClinicalTrials.gov has been researched at the level of individual entries, analyzed and published. These data have important planning and resource allocation implications for translational scientists, clinicians, healthcare providers, businesses and governments.

  • Wang T, Kartika R, Spiegel DA. Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones. J Am Chem Soc. 2012 May 30;134(21):8958-67. PubMed: 22591136. Categories: GlycoSENS

    Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones.

    J Am Chem Soc. 2012 May 30;134(21):8958-67.

    Exploring post-translational arginine modification using chemically synthesized methylglyoxal hydroimidazolones.

    Wang T, Kartika R, Spiegel DA.

    Abstract

    Abstract:

    The methylglyoxal-derived hydroimidazolones (MG-Hs) comprise the most prevalent class of non-enzymatic, post-translational modifications of protein arginine residues found in nature. These adducts form spontaneously in the human body, and are also present at high levels in the human diet. Despite numerous lines of evidence suggesting that MG-H-arginine adducts play critical roles in both healthy and disease physiology in humans, detailed studies of these molecules have been hindered by a lack of general synthetic strategies for their preparation in chemically homogeneous form, and on scales sufficient to enable detailed biochemical and cellular investigations. To address this limitation, we have developed efficient, multigram-scale syntheses of all MG-H-amino acid building blocks, suitably protected for solid-phase peptide synthesis, in 2-3 steps starting from inexpensive, readily available starting materials. Thus, MG-H derivatives were readily incorporated into oligopeptides site-specifically using standard solid-phase peptide synthesis. Access to synthetic MG-H-peptide adducts has enabled detailed investigations, which have revealed a series of novel and unexpected findings. First, one of the three MG-H isomers, MG-H3, was found to possess potent, pH-dependent antioxidant properties in biochemical and cellular assays intended to replicate redox processes that occur in vivo. Computational and mechanistic studies suggest that MG-H3-containing constructs are capable of participating in mechanistically distinct H-atom-transfer and single-electron-transfer oxidation processes. Notably, the product of MG-H3 oxidation was unexpectedly observed to disassemble into the fully unmodified arginine residue and pyruvate in aqueous solution. We believe these observations provide insight into the role(s) of MG-H-protein adducts in human physiology, and expect the synthetic reagents reported herein to enable investigations into non-enzymatic protein regulation at an unprecedented level of detail.

  • Brindley DA, Davie NL, Sahlman WA, Bonfiglio GA, Culme-Seymour EJ, Reeve BC, Mason C. Promising growth and investment in the cell therapy industry during the first quarter of 2012. Cell Stem Cell. 2012 May 4;10(5):492-6. PubMed: 22560072. Categories: RepleniSENS

    Promising growth and investment in the cell therapy industry during the first quarter of 2012.

    Cell Stem Cell. 2012 May 4;10(5):492-6.

    Promising growth and investment in the cell therapy industry during the first quarter of 2012.

    Brindley DA, Davie NL, Sahlman WA, Bonfiglio GA, Culme-Seymour EJ, Reeve BC, Mason C.

    Abstract

    Abstract:

    In the first quarter of 2012, publicly traded companies in the cell-based therapy industry continued to show promising overall growth. Highlights included $85 million in new capital investment and steady clinical trial progress.

  • Brindley DA, Mason C. The Commercialisation of Cell Therapies. In: Progenitor and stem cell technologies and therapies: Principles and Issues (Vol 1). Woodhead Publishing (2012). Read on external site.

    The Commercialisation of Cell Therapies.

    In: Progenitor and stem cell technologies and therapies: Principles and Issues (Vol 1). Woodhead Publishing (2012).

    The Commercialisation of Cell Therapies.

    Brindley DA, Mason C.

    Abstract

    Abstract:

    No abstract available.

  • Davie ND, Brindley DA, Culme-Seymour EJ, Mason C. Streamlining Cell Therapy Manufacturing: From Clinical to Commercial Scale. BioProcess International. 10(3):24-29. Read on external site.

    Streamlining Cell Therapy Manufacturing: From Clinical to Commercial Scale.

    BioProcess International. 10(3):24-29.

    Streamlining Cell Therapy Manufacturing: From Clinical to Commercial Scale.

    Davie ND, Brindley DA, Culme-Seymour EJ, Mason C.

    Abstract

    Abstract:

    The cell therapy industry (CTI) is no longer a cottage industry; it is a distinct and sustainable component of the global healthcare sector. Today, CTI prospects are strong, with annual revenues exceeding US$1 billion/year, supported by improving investor sentiment and public support. The next phase of CTI growth — toward a multibillion-dollar global industry — will depend on the biomanufacturing community innovating to meet growing market demands and providing products at affordable costs to healthcare payers.

    Currently, the majority of cell therapy clinical trials are in phases 1 or 2. However, as more CTI companies break the phase 3 frontier, clinical trials and regulatory requirements are becoming increasingly more predictable. This enables new companies to start out with a focus firmly on commercialization, using lessons learned from preceding trials to streamline their manufacturing processes and minimize the time to market.

    Here we propose a simple requirements-based framework for approaching three key, interrelated aspects of cell therapy bioprocessing that must be considered as these therapies translate from laboratory development to market launch: characterization, scale-up, and cost of goods (CoGs). In particular, we highlight the critical need to appreciate commercial implications of key bioprocessing decisions to maximize the efficiency and speed of cell therapy translation.

  • Brindley D, Reeve B, Mason C. Pharmaceutical industry: Investors unfazed by drug-patent expiry. Nature. 2012 Jan 18;481(7381):265. PubMed: 22258594.

    Pharmaceutical industry: Investors unfazed by drug-patent expiry.

    Nature. 2012 Jan 18;481(7381):265.

    Pharmaceutical industry: Investors unfazed by drug-patent expiry.

    Brindley D, Reeve B, Mason C.

    Abstract

    Abstract:

    No abstract available.

  • Brindley D, Mason C. Human embryonic stem cell therapy in the post-Geron era. Regen Med. 2012 Jan;7(1):17-8. doi: 10.2217/rme.11.115. PubMed: 22168491.

    Human embryonic stem cell therapy in the post-Geron era.

    Regen Med. 2012 Jan;7(1):17-8. doi: 10.2217/rme.11.115.

    Human embryonic stem cell therapy in the post-Geron era.

    Brindley D, Mason C.

    Abstract

    Abstract:

    (No abstract available.)

  • Brindley DA, Davie NL, Culme-Seymour EJ, Mason C, Smith DW, Rowley JA. Peak serum: implications of serum supply for cell therapy manufacturing. Regen Med. 2012 Jan;7(1):7-13. doi: 10.2217/rme.11.112. PubMed: 22168489.

    Peak serum: implications of serum supply for cell therapy manufacturing.

    Regen Med. 2012 Jan;7(1):7-13. doi: 10.2217/rme.11.112.

    Peak serum: implications of serum supply for cell therapy manufacturing.

    Brindley DA, Davie NL, Culme-Seymour EJ, Mason C, Smith DW, Rowley JA.

    Abstract

    Abstract:

    (No abstract available.)

  • Brindley DA, Reeve BC, Sahlman WA, Bonfiglio GA, Davie NL, Culme-Seymour EJ, Mason C. The impact of market volatility on the cell therapy industry. Cell Stem Cell. 2011 Nov 4;9(5):397-401. PubMed: 22056137.

    The impact of market volatility on the cell therapy industry.

    Cell Stem Cell. 2011 Nov 4;9(5):397-401.

    The impact of market volatility on the cell therapy industry.

    Brindley DA, Reeve BC, Sahlman WA, Bonfiglio GA, Davie NL, Culme-Seymour EJ, Mason C.

    Abstract

    Abstract:

    Stock market volatility in the cell therapy industry has greatly hindered the investment necessary to fund translational therapies. Here, we review the volatility of leading companies and suggest that a distinct industry is maturing to a point at which the volatility should subside, providing a more attractive environment for future growth.

  • Brindley D, Moorthy K, Lee JH, Mason C, Kim HW, Wall I. Bioprocess forces and their impact on cell behavior: implications for bone regeneration therapy. J Tissue Eng. 2011;2011:620247. PubMed: 21904661. Categories: RepleniSENS

    Bioprocess forces and their impact on cell behavior: implications for bone regeneration therapy.

    J Tissue Eng. 2011;2011:620247.

    Bioprocess forces and their impact on cell behavior: implications for bone regeneration therapy.

    Brindley D, Moorthy K, Lee JH, Mason C, Kim HW, Wall I.

    Abstract

    Abstract:

    Bioprocess forces such as shear stress experienced during routine cell culture are considered to be harmful to cells. However, the impact of physical forces on cell behavior is an area of growing interest within the tissue engineering community, and it is widely acknowledged that mechanical stimulation including shear stress can enhance osteogenic differentiation. This paper considers the effects of bioprocess shear stress on cell responses such as survival and proliferation in several contexts, including suspension-adapted cells used for recombinant protein and monoclonal antibody manufacture, adherent cells for therapy in suspension, and adherent cells attached to their growth substrates. The enhanced osteogenic differentiation that fluid flow shear stress is widely found to induce is discussed, along with the tissue engineering of mineralized tissue using perfusion bioreactors. Recent evidence that bioprocess forces produced during capillary transfer or pipetting of cell suspensions can enhance osteogenic responses is also discussed.

  • Mason C, Brindley DA, Culme-Seymour EJ, Davie NL. Cell therapy industry: billion dollar global business with unlimited potential. Regen Med. 2011 May;6(3):265-72. PubMed: 21548728.

    Cell therapy industry: billion dollar global business with unlimited potential.

    Regen Med. 2011 May;6(3):265-72.

    Cell therapy industry: billion dollar global business with unlimited potential.

    Mason C, Brindley DA, Culme-Seymour EJ, Davie NL.

    Abstract

    Abstract:

    No abstract available.

  • Wu Y, Zhou J, Fishkin N, Rittmann BE, Sparrow JR. Enzymatic degradation of A2E, a retinal pigment epithelial lipofuscin bisretinoid. J Am Chem Soc. 2011 Feb 2;133(4):849-57. doi: 10.1021/ja107195u. PubMed: 21166406. Categories: LysoSENS

    Enzymatic degradation of A2E, a retinal pigment epithelial lipofuscin bisretinoid.

    J Am Chem Soc. 2011 Feb 2;133(4):849-57. doi: 10.1021/ja107195u.

    Enzymatic degradation of A2E, a retinal pigment epithelial lipofuscin bisretinoid.

    Wu Y, Zhou J, Fishkin N, Rittmann BE, Sparrow JR.

    Abstract

    Abstract:

    Some forms of blinding macular disease are associated with excessive accumulation of bisretinoid lipofuscin in retinal pigment epithelial (RPE) cells of the eye. This material is refractory to lysosomal enzyme degradation. In addition to gene and drug-based therapies, treatments that reverse the accumulation of bisretinoid would be beneficial. Thus, we have examined the feasibility of degrading the bisretinoids by delivery of exogenous enzyme. As proof of principle we report that horseradish peroxidase (HRP) can cleave the RPE bisretinoid A2E. In both cell-free and cell-based assays, A2E levels were decreased in the presence of HRP. HRP-associated cleavage products were detected by ultraperformance liquid chromatography (UPLC) coupled to electrospray ionization mass spectrometry, and the structures of the aldehyde-bearing cleavage products were elucidated by 18O-labeling and 1H NMR spectroscopy and by recording UV−vis absorbance spectra. These findings indicate that RPE bisretinoids such as A2E can be degraded by appropriate enzyme activities.

  • 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.

  • Rae MJ. SENS Foundation: Accelerating Progress Toward Biomedical Rejuvenation. In: Fahy GM, West M, Coles LS, Harris SB (eds). The Future of Aging: Pathways to Human Life Extension, Chapter: SENS Foundation: Accelerating Progress Toward Biomedical Rejuvenation. 2010; Springer Verlag, New York, pp. 806–826. Read on external site. Categories: Beyond the Bench

    SENS Foundation: Accelerating Progress Toward Biomedical Rejuvenation.

    In: Fahy GM, West M, Coles LS, Harris SB (eds). The Future of Aging: Pathways to Human Life Extension, Chapter: SENS Foundation: Accelerating Progress Toward Biomedical Rejuvenation. 2010; Springer Verlag, New York, pp. 806–826.

    SENS Foundation: Accelerating Progress Toward Biomedical Rejuvenation.

    Rae MJ.

    Abstract

    Abstract:

    An overview of the "damage-repair" heuristic of rejuvenation biotechnology, and the role of SENS Research Foundation in catalyzing the emergence of a comprehensive panel of such therapies.

  • Rae MJ, Butler RN, Campisi J, de Grey ADNJ, Finch CE, Gough M, Martin GM, Vijg J, Perrott KM, Logan BJ. The Demographic and Biomedical Case for Late-Life Interventions in Aging. Sci Transl Med. 2010 Jul 14;2(40):40cm21. PubMed: 20630854. Categories: Beyond the Bench

    The Demographic and Biomedical Case for Late-Life Interventions in Aging.

    Sci Transl Med. 2010 Jul 14;2(40):40cm21.

    The Demographic and Biomedical Case for Late-Life Interventions in Aging.

    Rae MJ, Butler RN, Campisi J, de Grey ADNJ, Finch CE, Gough M, Martin GM, Vijg J, Perrott KM, Logan BJ.

    Abstract

    Abstract:

    The social and medical costs of the biological aging process are high and will rise rapidly in coming decades, creating an enormous challenge to societies worldwide. In recent decades, researchers have expanded their understanding of the underlying deleterious structural and physiological changes (aging damage) that underlie the progressive functional impairments, declining health, and rising mortality of aging humans and other organisms and have been able to intervene in the process in model organisms, even late in life. To preempt a global aging crisis, we advocate an ambitious global initiative to translate these findings into interventions for aging humans, using three complementary approaches to retard, arrest, and even reverse aging damage, extending and even restoring the period of youthful health and functionality of older people.

  • 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.

  • 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: Beyond the Bench

    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:

    No abstract available.

  • 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.

  • Schloendorn J, Webb T, Kemmish K, Hamalainen M, Jackemeyer D, Jiang L, Mathieu J, Rebo J, Sankman J, Sherman L, Tontson L, Qureshi A, Alvarez P, Rittmann B. Medical bioremediation: a concept moving toward reality. Rejuvenation Res. 2009 Dec;12(6):411-9. doi: 10.1089/rej.2009.0917. PubMed: 20041735. Categories: LysoSENS

    Medical bioremediation: a concept moving toward reality.

    Rejuvenation Res. 2009 Dec;12(6):411-9. doi: 10.1089/rej.2009.0917.

    Medical bioremediation: a concept moving toward reality.

    Schloendorn J, Webb T, Kemmish K, Hamalainen M, Jackemeyer D, Jiang L, Mathieu J, Rebo J, Sankman J, Sherman L, Tontson L, Qureshi A, Alvarez P, Rittmann B.

    Abstract

    Abstract:

    A major driver of aging is catabolic insufficiency, the inability of our bodies to break down certain substances that accumulate slowly throughout the life span. Even though substance buildup is harmless while we are young, by old age the accumulations can reach a toxic threshold and cause disease. This includes some of the most prevalent diseases in old age-atherosclerosis and macular degeneration. Atherosclerosis is associated with the buildup of cholesterol and its oxidized derivatives (particularly 7-ketocholesterol) in the artery wall. Age-related macular degeneration is associated with carotenoid lipofuscin, primarily the pyridinium bisretinoid A2E. Medical bioremediation is the concept of reversing the substance accumulations by using enzymes from foreign species to break down the substances into forms that relieve the disease-related effect. We report on an enzyme discovery project to survey the availability of microorganisms and enzymes with these abilities. We found that such microorganisms and enzymes exist. We identified numerous bacteria having the ability to transform cholesterol and 7-ketocholesterol. Most of these species initiate the breakdown by same reaction mechanism as cholesterol oxidase, and we have used this enzyme directly to reduce the toxicity of 7-ketocholesterol, the major toxic oxysterol, to cultured human cells. We also discovered that soil fungi, plants, and some bacteria possess peroxidase and carotenoid cleavage oxygenase enzymes that effectively destroy with varied degrees of efficiency and selectivity the carotenoid lipofuscin found in macular degeneration.

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

    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 DA, 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.

  • 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.

  • Sjöberg JS, Bulterijs S. Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link. Rejuvenation Res 2009;12(2):137-48. PubMed: 19415980. Categories: GlycoSENS

    Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link.

    Rejuvenation Res 2009;12(2):137-48.

    Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link.

    Sjöberg JS, Bulterijs S.

    Abstract

    Abstract:

    Advanced glycation end products are the results of a series of chemical reactions collectively known as the Maillard reaction, or nonenzymatic glycation, and sometimes cross-link proteins, thereby impairing their normal function. Glucosepane is the most abundant protein cross-link found in vivo so far and mainly has been shown to accumulate in the extracellular matrix, where it cross-links collagen. Levels of glucosepane increase with aging. By increasing collagen stiffness, glucosepane cross-links may have significant implications in several age-related diseases, such as cardiovascular disease, diabetes, and osteoporosis. Although the formation pathways for glucosepane are relatively well researched, much is still unknown about the accumulation and pathophysiology of glucosepane.

  • 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.

  • 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.

  • Rittmann BE, Schloendorn J. Engineering away lysosomal junk: medical bioremediation. Rejuvenation Res 2007;10(3):359-365. PubMed: 17708688. Categories: LysoSENS

    Engineering away lysosomal junk: medical bioremediation.

    Rejuvenation Res 2007;10(3):359-365.

    Engineering away lysosomal junk: medical bioremediation.

    Rittmann BE, Schloendorn J.

    Abstract

    Abstract:

    Atherosclerosis, macular degeneration, and neurodegenerative diseases such as Alzheimer's disease, are associated with the intracellular accumulation of substances that impair cellular function and viability. Reversing this accumulation may be a valuable therapy, but the accumulating substances resist normal cellular catabolism. On the other hand, these substances are naturally degraded in the soil and water by microorganisms. Thus, we propose the concept of "medical bioremediation," which derives from the successful field of in situ environmental bioremediation of petroleum hydrocarbons. In environmental bioremediation, communities of microorganisms mineralize hydrophobic organics using a series of enzymes. In medical bioremediation, we hope to utilize one or several microbial enzymes to degrade the intracellular accumulators enough that they can be cleared from the affected cells. Here, we present preliminary, but promising results for the bacterial biodegradation of 7-ketocholesterol, the main accumulator of foam cells associated with atherosclerosis. In particular, we report on the isolation of several Nocardia strains able to biodegrade 7-ketocholesterol and as an ester of 7-ketocholoesterol. We also outline key intermediates in the biodegradation pathway, a key step towards identifying the key enzymes that may lead to a therapy.

  • 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.

  • de Grey AD. Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging. Mech Ageing Dev 2007;128(7-8):456-9. PubMed: 17588643. Categories: OncoSENS

    Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging.

    Mech Ageing Dev 2007;128(7-8):456-9.

    Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging.

    de Grey AD.

    Abstract

    Abstract:

    Since Szilard's seminal 1959 article, the role of accumulating nuclear DNA (nDNA) damage -- whether as mutations, i.e. changes to sequence, or as epimutations, i.e. adventitious but persistent alterations to methylation and other decorations of nDNA and histones -- has been widely touted as likely to contribute substantially to the aging process throughout the animal kingdom. Such damage certainly accumulates with age and is central to one of the most prevalent age-related causes of death in mammals, namely cancer. However, its role in contributing to the rates of other aspects of aging is less clear. Here I argue that, in animals prone to cancer, evolutionary pressure to postpone cancer will drive the fidelity of nDNA maintenance and repair to a level greatly exceeding that needed to prevent nDNA damage from reaching levels during a normal lifetime that are pathogenic other than via cancer or, possibly, apoptosis resistance. I term this the "protagonistic pleiotropy of chromosomal damage" (PPCD) hypothesis, because this interaction of cancer-related and -unrelated damage is the converse of the well-known "antagonistic pleiotropy" phenomenon. I then consider a selection of recent data on the rate of accumulation of nDNA damage in the context of this hypothesis, and conclude that all presently available evidence is consistent with it. If this conclusion is correct, the implications for the feasibility of greatly postponing mammalian (and eventually human) aging and age-related pathology are far-reaching.

  • de Grey ADNJ. Foreseeable pharmaceutical repair of age-related extracellular damage. Curr Drug Targets. 2006 Nov;7(11):1469-77. PubMed: 17100587. Categories: ApoptoSENS, GlycoSENS

    Foreseeable pharmaceutical repair of age-related extracellular damage.

    Curr Drug Targets. 2006 Nov;7(11):1469-77.

    Foreseeable pharmaceutical repair of age-related extracellular damage.

    de Grey ADNJ.

    Abstract

    Abstract:

    Various molecular and cellular alterations to our tissues accumulate throughout life as intrinsic side-effects of metabolism. These alterations are initially harmless, but some, which we may term "damage", are pathogenic when sufficiently abundant. The slowness of their accumulation explains why decline of tissue and organismal function generally does not appear until the age of 40 or older. Aging is thus best viewed as a two-part process in which metabolism causes accumulating damage and sufficiently abundant damage causes pathology. Hence, a promising approach to avoiding age-related pathology is periodically to repair the various types of damage and so maintain them at a sub-pathogenic level. Some examples of such types of damage are intracellular and others extracellular. Several types of intracellular damage are highly challenging--sophisticated cellular and genetic therapies will be needed to combat them, which are surely at least 20 years away and maybe much more. Extracellular damage, by contrast, generally appears more amenable to pharmaceutical repair which may be feasible in a shorter timeframe. In this article, the major types of age-related extracellular damage and promising avenues for their repair are reviewed.

  • de Grey ADNJ, Alvarez PJJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR. Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases. Ageing Res Rev. 2005 Aug;4(3):315-38. PubMed: 16040282. Categories: LysoSENS

    Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases.

    Ageing Res Rev. 2005 Aug;4(3):315-38.

    Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases.

    de Grey ADNJ, Alvarez PJJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR.

    Abstract

    Abstract:

    Several major diseases of old age, including atherosclerosis, macular degeneration and neurodegenerative diseases are associated with the intracellular accumulation of substances that impair cellular function and viability. Moreover, the accumulation of lipofuscin, a substance that may have similarly deleterious effects, is one of the most universal markers of aging in postmitotic cells. Reversing this accumulation may thus be valuable, but has proven challenging, doubtless because substances resistant to cellular catabolism are inherently hard to degrade. We suggest a radically new approach: augmenting humans' natural catabolic machinery with microbial enzymes. Many recalcitrant organic molecules are naturally degraded in the soil. Since the soil in certain environments - graveyards, for example - is enriched in human remains but does not accumulate these substances, it presumably harbours microbes that degrade them. The enzymes responsible could be identified and engineered to metabolise these substances in vivo. Here, we survey a range of such substances, their putative roles in age-related diseases and the possible benefits of their removal. We discuss how microbes capable of degrading them can be isolated, characterised and their relevant enzymes engineered for this purpose and ways to avoid potential side-effects.

  • de Grey ADNJ. Forces maintaining organellar genomes: is any as strong as genetic code disparity or hydrophobicity? BioEssays 2005;27(4):436-446. PubMed: 15770678. Categories: MitoSENS

    Forces maintaining organellar genomes: is any as strong as genetic code disparity or hydrophobicity?

    BioEssays 2005;27(4):436-446.

    Forces maintaining organellar genomes: is any as strong as genetic code disparity or hydrophobicity?

    de Grey ADNJ.

    Abstract

    Abstract:

    It remains controversial why mitochondria and chloroplasts retain the genes encoding a small subset of their constituent proteins, despite the transfer of so many other genes to the nucleus. Two candidate obstacles to gene transfer, suggested long ago, are that the genetic code of some mitochondrial genomes differs from the standard nuclear code, such that a transferred gene would encode an incorrect amino acid sequence, and that the proteins most frequently encoded in mitochondria are generally very hydrophobic, which may impede their import after synthesis in the cytosol. More recently it has been suggested that both these interpretations suffer from serious "false positives" and "false negatives": genes that they predict should be readily transferred but which have never (or seldom) been, and genes whose transfer has occurred often or early, even though this is predicted to be very difficult. Here I consider the full known range of ostensibly problematic such genes, with particular reference to the sequences of events that could have led to their present location. I show that this detailed analysis of these cases reveals that they are in fact wholly consistent with the hypothesis that code disparity and hydrophobicity are much more powerful barriers to functional gene transfer than any other. The popularity of the contrary view has led to the search for other barriers that might retain genes in organelles even more powerfully than code disparity or hydrophobicity; one proposal, concerning the role of proteins in redox processes, has received widespread support. I conclude that this abandonment of the original explanations for the retention of organellar genomes has been premature. Several other, relatively minor, obstacles to gene transfer certainly exist, contributing to the retention of relatively many organellar genes in most lineages compared to animal mtDNA, but there is no evidence for obstacles as severe as code disparity or hydrophobicity. One corollary of this conclusion is that there is currently no reason to suppose that engineering nuclear versions of the remaining mammalian mitochondrial genes, a feat that may have widespread biomedical relevance, should require anything other than sequence alterations obviating code disparity and causing modest reductions in hydrophobicity without loss of enzymatic function.

  • de Grey ADNJ. Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention. Front Biosci 2005;10:2420-2429. PubMed: 15970505. Categories: OncoSENS

    Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention.

    Front Biosci 2005;10:2420-2429.

    Whole-body interdiction of lengthening of telomeres: a proposal for cancer prevention.

    de Grey ADNJ.

    Abstract

    Abstract:

    The intrinsic genetic instability of cancer cells makes age-related cancers more difficult to postpone or treat than any other age-related diseases. Any treatment that a cancer can resist by activating or inactivating specific genes is unlikely to succeed over the long term, because pre-existing cancer cells with the necessary gene expression pattern will withstand the therapy and proliferate. "Whole-body Interdiction of Lengthening of Telomeres" (WILT) is a proposal to pre-empt this problem by deleting from as many of our cells as possible the genes needed for telomere elongation. Cancers lacking these genes can never reach a life-threatening stage by altering gene expression, only by acquiring new genes, which is far more unlikely. Continuously-renewing tissues can be maintained by periodic reseeding with telomere elongation-incompetent stem cells that have had their telomeres lengthened in vitro with exogenous telomerase. Here, I describe why WILT might prove to be an exceptionally powerful anti-cancer modality.

  • de Grey ADNJ. A strategy for postponing aging indefinitely. Stud Health Technol Inform. 2005;118:209-19. PubMed: 16301780. Categories: SENS Overviews

    A strategy for postponing aging indefinitely.

    Stud Health Technol Inform. 2005;118:209-19.

    A strategy for postponing aging indefinitely.

    de Grey ADNJ.

    Abstract

    Abstract:

    It may seem premature to be discussing approaches to the effective elimination of human aging as a cause of death at a time when essentially no progress has yet been made in even postponing it. However, two aspects of human aging combine to undermine this assessment. The first is that aging is happening to us throughout our lives but only results in appreciable functional decline after four or more decades of life: this shows that we can postpone aging arbitrarily well without knowing how to prevent it completely. The second is that the typical rate of refinement of dramatic technological breakthroughs is rather reliable (so long as public enthusiasm for them is abundant) and is fast enough to change such technologies (be they in medicine, transport, or computing) almost beyond recognition within a natural human lifespan. Here I explain, first, why it is reasonable to expect that (presuming adequate funding for the initial preclinical work) therapies that can add 30 healthy years to the remaining lifespan of healthy 55-year-olds will arrive within the next few decades, and, second, why those who benefit from those therapies will very probably continue to benefit from progressively improved therapies indefinitely and thus avoid debilitation or death from age-related causes at any age.

  • de Grey ADNJ. The unfortunate influence of the weather on the rate of aging: why human caloric restriction or its emulation may only extend life expectancy by 2-3 years. Gerontology 2005; 51(2):73-82. PubMed: 15711074.

    The unfortunate influence of the weather on the rate of aging: why human caloric restriction or its emulation may only extend life expectancy by 2-3 years.

    Gerontology 2005; 51(2):73-82.

    The unfortunate influence of the weather on the rate of aging: why human caloric restriction or its emulation may only extend life expectancy by 2-3 years.

    de Grey ADNJ.

    Abstract

    Abstract:

    Much research interest, and recently even commercial interest, has been predicated on the assumption that reasonably closely-related species--humans and mice, for example--should, in principle, respond to ageing-retarding interventions with an increase in maximum lifespan roughly proportional to their control lifespan (that without the intervention). Here, it is argued that the best-studied life-extending manipulations of mice are examples of a category that is highly unlikely to follow this rule, and more likely to exhibit only a similar absolute increase in maximum lifespan from one species to the next, independent of the species' control lifespan. That category--reduction in dietary calories or in the organism's ability to metabolize or sense them--is widely recognized to extend lifespan as an evolutionary adaptation to transient starvation in the wild, a situation which alters the organism's optimal partitioning of resources between maintenance and reproduction. What has been generally overlooked is that the extent of the evolutionary pressure to maintain adaptability to a given duration of starvation varies with the frequency of that duration, something which is--certainly for terrestrial animals and less directly for others--determined principally by the weather. The pattern of starvation that the weather imposes is suggested here to be of a sort that will tend to cause all terrestrial animals, even those as far apart phylogenetically as nematodes and mice, to possess the ability to live a similar maximum absolute (rather than proportional) amount longer when food is short than when it is plentiful. This generalization is strikingly in line with available data, leading (given the increasing implausibility of further extending human mean but not maximum lifespan in the industrialized world) to the biomedically and commercially sobering conclusion that interventions which manipulate caloric intake or its sensing are unlikely ever to confer more than 2 or 3 years' increase in human mean or maximum lifespan at the most.

  • de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG. Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers. Ann N Y Acad Sci. 2004 Jun;1019:147-70. PubMed: 15247008. Categories: OncoSENS

    Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.

    Ann N Y Acad Sci. 2004 Jun;1019:147-70.

    Total deletion of in vivo telomere elongation capacity: an ambitious but possibly ultimate cure for all age-related human cancers.

    de Grey ADNJ, Campbell FC, Dokal I, Fairbairn LJ, Graham GJ, Jahoda CAB, Porter ACG.

    Abstract

    Abstract:

    Despite enormous effort, progress in reducing mortality from cancer remains modest. Can a true cancer "cure" ever be developed, given the vast versatility that tumors derive from their genomic instability? Here we consider the efficacy, feasibility, and safety of a therapy that, unlike any available or in development, could never be escaped by spontaneous changes of gene expression: the total elimination from the body of all genetic potential for telomere elongation, combined with stem cell therapies administered about once a decade to maintain proliferative tissues despite this handicap. We term this therapy WILT, for whole-body interdiction of lengthening of telomeres. We first argue that a whole-body gene-deletion approach, however bizarre it initially seems, is truly the only way to overcome the hypermutation that makes tumors so insidious. We then identify the key obstacles to developing such a therapy and conclude that, while some will probably be insurmountable for at least a decade, none is a clear-cut showstopper. Hence, given the absence of alternatives with comparable anticancer promise, we advocate working toward such a therapy.

  • de Grey ADNJ. Challenging but essential targets for genuine anti-ageing drugs. Expert Opin Ther Targets. 2003 Feb;7(1):1-5. PubMed: 12556198. Categories: ApoptoSENS, GlycoSENS, SENS Overviews

    Challenging but essential targets for genuine anti-ageing drugs.

    Expert Opin Ther Targets. 2003 Feb;7(1):1-5.

    Challenging but essential targets for genuine anti-ageing drugs.

    de Grey ADNJ.

    Abstract

    Abstract:

    Contrary to what one might conclude from the popular press, anti-ageing drugs do not yet exist, in the sense in which the term 'drug' is normally used. Since a drug is assumed to be effective against its target human pathology and since the vast majority of deaths in the developed world are from ageing-related causes, it is inappropriate to describe something as an anti-ageing drug unless one has good reason to believe that it will appreciably extend the life expectancy of those in the developed world who receive it. A drug that rejuvenates aspects of the aged body but does not increase life expectancy is an antifrailty drug, not an anti-ageing one. This distinction is critical for decision makers in the drug discovery sphere because, while the market for antifrailty drugs (even unproven ones) is large, that for genuine anti-ageing drugs - which, as the author explains, are now foreseeable - will certainly be far larger. In this article, the author surveys the main aspects of age-related degeneration that are believed to be essential targets for genuine anti-ageing drugs - that is, without whose amelioration human life expectancy probably cannot be greatly increased - and some promising strategies for the design of such drugs.

  • de Grey ADNJ. An engineer's approach to the development of real anti-aging medicine. Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Also in: The Fountain of Youth: Ethical, Religious, and Existential Perspectives on a Biomedical Goal (S.G. Post and R.H. Binstock, eds.), Oxford University Press, 2003, pp. 249-267. PubMed: 12844502. Categories: SENS Overviews

    An engineer's approach to the development of real anti-aging medicine.

    Sci Aging Knowledge Environ. 2003 Jan 8;2003(1):VP1. Also in: The Fountain of Youth: Ethical, Religious, and Existential Perspectives on a Biomedical Goal (S.G. Post and R.H. Binstock, eds.), Oxford University Press, 2003, pp. 249-267.

    An engineer's approach to the development of real anti-aging medicine.

    de Grey ADNJ.

    Abstract

    Abstract:

    In this Viewpoint, I list the various age-related molecular and cellular changes that are thought to limit mammalian life-span, and I outline a problem-solving approach to reversing these detrimental changes. This approach should help to prevent the development of these age-related changes into life-threatening pathologies and possibly, in due course, allow a large increase in healthy human life expectancy.

  • de Grey ADNJ, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJM, Stock G. Time to talk SENS: critiquing the immutability of human aging. Ann N Y Acad Sci 2002;959:452-462. PubMed: 11976218. Categories: SENS Overviews

    Time to talk SENS: critiquing the immutability of human aging.

    Ann N Y Acad Sci 2002;959:452-462.

    Time to talk SENS: critiquing the immutability of human aging.

    de Grey ADNJ, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJM, Stock G.

    Abstract

    Abstract:

    Aging is a three-stage process: metabolism, damage, and pathology. The biochemical processes that sustain life generate toxins as an intrinsic side effect. These toxins cause damage, of which a small proportion cannot be removed by any endogenous repair process and thus accumulates. This accumulating damage ultimately drives age-related degeneration. Interventions can be designed at all three stages. However, intervention in metabolism can only modestly postpone pathology, because production of toxins is so intrinsic a property of metabolic processes that greatly reducing that production would entail fundamental redesign of those processes. Similarly, intervention in pathology is a "losing battle" if the damage that drives it is accumulating unabated. By contrast, intervention to remove the accumulating damage would sever the link between metabolism and pathology, and so has the potential to postpone aging indefinitely. We survey the major categories of such damage and the ways in which, with current or foreseeable biotechnology, they could be reversed. Such ways exist in all cases, implying that indefinite postponement of aging--which we term "engineered negligible senescence"--may be within sight. Given the major demographic consequences if it came about, this possibility merits urgent debate.

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