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  • de Grey ADNJ. Foreseeable and more distant rejuvenation therapies. In: Aging Interventions and Therapies (S.I.S. Rattan, ed.), World Scientific, 2005, pp. 379-395.

    Foreseeable and more distant rejuvenation therapies.

    In: Aging Interventions and Therapies (S.I.S. Rattan, ed.), World Scientific, 2005, pp. 379-395.

    Foreseeable and more distant rejuvenation therapies.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • 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. When and where to publish important findings: a casualty of biogerontology's rise to respectability. Rejuvenation Res. 2005 Spring;8(1):1-2. PubMed: 15798366. Categories: Beyond the Bench

    When and where to publish important findings: a casualty of biogerontology's rise to respectability.

    Rejuvenation Res. 2005 Spring;8(1):1-2.

    When and where to publish important findings: a casualty of biogerontology's rise to respectability.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Aging, childlessness or overpopulation: the future's right to choose. Rejuvenation Res. 2004 Winter;7(4):237-8. PubMed: 15671724. Categories: Beyond the Bench

    Aging, childlessness or overpopulation: the future's right to choose.

    Rejuvenation Res. 2004 Winter;7(4):237-8.

    Aging, childlessness or overpopulation: the future's right to choose.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Mitochondrial mutations in mammalian aging: an over-hasty about-turn? Rejuvenation Res. 2004 Fall;7(3):171-4. PubMed: 15588517. Categories: MitoSENS

    Mitochondrial mutations in mammalian aging: an over-hasty about-turn?

    Rejuvenation Res. 2004 Fall;7(3):171-4.

    Mitochondrial mutations in mammalian aging: an over-hasty about-turn?

    de Grey ADNJ.

    Abstract

    Abstract:

    The very low abundance of mitochondrial DNA (mtDNA) mutations in nearly all mammalian tissues even in old age has led most mitochondriologists to reject the idea that such mutations might have a causal role in aging, despite (1) the strong circumstantial (e. g., interspecies) evidence that they do have such a role, (2) the promulgation since 1998 of two detailed mechanisms whereby low levels of mtDNA mutations could be harmful, and (3) the report of a transgenic mouse with cardiomyopathy apparently caused by artificially high levels of mtDNA mutations in the heart. A recent report of a mouse with ubiquitously accelerated accumulation of mtDNA mutations and an array of phenotypes reminiscent of aging has abruptly overturned this consensus, with not only the authors but also many other expert commentators suggesting that the mtDNA mutation theory of aging has risen from the ashes. However, there are compelling reasons to doubt the relevance of this mouse to normal mammalian aging, and thus to seek further testing of specific mechanistic hypotheses for how mtDNA mutations could cause age-related dysfunction.

  • de Grey ADNJ. Three self-evident life-extension truths. Rejuvenation Res. 2004 Fall;7(3):165-7. PubMed: 15588515. Categories: Beyond the Bench

    Three self-evident life-extension truths.

    Rejuvenation Res. 2004 Fall;7(3):165-7.

    Three self-evident life-extension truths.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Inter-species therapeutic cloning: the looming problem of mitochondrial DNA and two possible solutions. Rejuvenation Res 2004;7(2):95-98. PubMed: 15312296. Categories: MitoSENS, RepleniSENS

    Inter-species therapeutic cloning: the looming problem of mitochondrial DNA and two possible solutions.

    Rejuvenation Res 2004;7(2):95-98.

    Inter-species therapeutic cloning: the looming problem of mitochondrial DNA and two possible solutions.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Biogerontologists' duty to discuss timescales publicly. Ann N Y Acad Sci. 2004 Jun;1019:542-5. PubMed: 15247082. Categories: Beyond the Bench

    Biogerontologists' duty to discuss timescales publicly.

    Ann N Y Acad Sci. 2004 Jun;1019:542-5.

    Biogerontologists' duty to discuss timescales publicly.

    de Grey ADNJ.

    Abstract

    Abstract:

    Aging is unpopular with the general public-but, it would seem, only up to a point. Treatments that claim (sometimes justifiably) to extend the total and/or healthy life span of elderly people, or even just make them look younger, are welcomed with open wallets throughout the world. If, however, one suggests to the typical nonbiologist-or even to the typical nongerontologist biologist-that we should therefore aim, in due course, to take this desire to its logical conclusion and bring aging under the same degree of control that we currently have over most infectious diseases, one is nearly always met with strong and sometimes strident opposition. I argue here that the prevalence of this outright irrationality is largely the fault of gerontologists themselves. Most people harbor a deep-seated fear of profound change in their lives and embrace it only after extensive soul-searching to convince themselves of its benefit. It cannot and should not be denied that a postaging world would be as profoundly different from today's as we can imagine. Hence, when given the opportunity to postpone sober consideration of its pros and cons, most people leap at that opportunity. It is provided to them by the nearly universal refusal of gerontologists to speculate about the timescales within which truly effective rejuvenation therapies may be developed. I suggest that this reticence, while appropriate in purely scientific fields, is hugely irresponsible in a biomedical discipline, because of its potential to delay the development of such therapies by denying them the funding that would be forthcoming if society had greater optimism concerning their foreseeability. Arguments that such funding, and/or the public's trust in scientists, would be short-lived if timescale predictions were not borne out are too flimsy to outweigh this. A further danger is the avoidable loss of life following the development of rejuvenation therapies that would result from inadequate ability to provide them universally; here again, scientists today can minimize this loss of life by agitating for forward planning by government, which will only occur when policymakers' minds are concentrating on timescale predictions.

  • 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. Leon Kass: quite substantially right. Rejuvenation Res. 2004 Summer;7(2):89-91. PubMed: 15312294. Categories: Beyond the Bench

    Leon Kass: quite substantially right.

    Rejuvenation Res. 2004 Summer;7(2):89-91.

    Leon Kass: quite substantially right.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Welcome to Rejuvenation Research. Rejuvenation Res. 2004 May;7(1): 1-2. Read on external site.

    Welcome to Rejuvenation Research.

    Rejuvenation Res. 2004 May;7(1): 1-2.

    Welcome to Rejuvenation Research.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Mitochondria in homeotherm aging: will detailed mechanisms consistent with the evidence now receive attention? Aging Cell. 2004 Apr;3(2):77 PubMed: 15038822. Categories: MitoSENS

    Mitochondria in homeotherm aging: will detailed mechanisms consistent with the evidence now receive attention?

    Aging Cell. 2004 Apr;3(2):77

    Mitochondria in homeotherm aging: will detailed mechanisms consistent with the evidence now receive attention?

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Models on trial: falsifying overstated claims of generality does not falsify correctly-stated ones. Exp Gerontol 2004 Mar;39(3):453.

    Models on trial: falsifying overstated claims of generality does not falsify correctly-stated ones.

    Exp Gerontol 2004 Mar;39(3):453.

    Models on trial: falsifying overstated claims of generality does not falsify correctly-stated ones.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Escape velocity: why the prospect of extreme human life extension matters now. PLoS Biology 2004;2(6):e187. Categories: Beyond the Bench

    Escape velocity: why the prospect of extreme human life extension matters now.

    PLoS Biology 2004;2(6):e187.

    Escape velocity: why the prospect of extreme human life extension matters now.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The war on aging. In: The Scientific Conquest of Death (B.J. Klein et al., eds.), Libros en Red, 2004, pp. 17-29. Categories: Beyond the Bench

    The war on aging.

    In: The Scientific Conquest of Death (B.J. Klein et al., eds.), Libros en Red, 2004, pp. 17-29.

    The war on aging.

    de Grey ADNJ.

    Abstract

    Abstract:

    Possibly the most absurd argument opposing the effort to cure human aging is that to extend our lives indefinitely would be unnatural: would render us in some sense no longer human. The feature that, in my view, places this argument above all others in the absurdity stakes is the enormity of what it overlooks within its own scope. To stand back and (by one’s inaction) cause someone to die soon, when one could act to let them live in good health for a lot longer at no (or even at some modest) cost to oneself or anyone else, is arguably the second most unnatural thing a human can do, second only (and by a very small margin) to causing someone’s death by an explicit action. To ask humanity to accept the “naturalness” argument against life extension, and on that basis to delay the development of a cure for aging, is thus to ask it to transform itself into something as un-human as can be imagined. In this essay I explore the opposite scenario: that, far from following such advice, once we begin to make fairly rapid progress in increasing life expectancy we will never return to the fatalistic acquiescence that we exhibit so predominantly today. In this scenario, however rare human death becomes, we will never again consider it quite rare enough. Starting from this assumption, I consider the successive biomedical challenges that we seem likely to face as the most frequent remaining potential causes of death and how we may successively overcome them.

  • de Grey ADNJ. Falsifying falsifications: the most critical task of theoreticians in biology. Med Hypotheses 2004;62(6):1012-1020. PubMed: 15142666.

    Falsifying falsifications: the most critical task of theoreticians in biology.

    Med Hypotheses 2004;62(6):1012-1020.

    Falsifying falsifications: the most critical task of theoreticians in biology.

    de Grey ADNJ.

    Abstract

    Abstract:

    Occasionally, experimental biologists obtain results which mystify them so deeply that the paradoxical nature of their finding is acknowledged in the paper reporting it. This constitutes a more-or-less explicit invitation to those who did not perform the experiments - and even those who do not perform experiments at all - to propose explanations that eluded the experimenter. A much more frequent scenario, however, is that the experimenter asserts confidently that his or her data can be explained by a particular model but are at odds with some other model. In such circumstances, it is often overlooked that the stated falsification of the latter model is error-prone: just as the mystified experimenter saw no explanation when in fact there is one, the other experimenter may see only one explanation of the data when there are two. The main reason this phenomenon is neglected is, of course, the fact that here the theoretician (or other experimenter) must take the initiative in critiquing a conclusion that, far from troubling the experimenter, may by the time of its publication be a cornerstone of his or her research program, so whose refutation may be decidedly unwelcome. For precisely this reason, such critiques - especially, perhaps, when they come from those who do not do bench work at all and thus have a complementary approach to the analysis of data - are fundamental to maximising the rate of progress in fields of biology that otherwise risk languishing in ever-better-studied cul-de-sacs for many years. Computational biology, including simulation, plays an especially important role in this, whereas its ability to contribute to biology in other ways is often less than its proponents claim. Here I discuss some representative examples of falsification-falsification, including a previously unpublished analysis of mitochondrial DNA population dynamics in cell culture, in the hope of stimulating more theoreticians - and perhaps also more experimentalists - to engage in it.

  • de Grey ADNJ. The foreseeability of real anti-aging medicine: focusing the debate. Exp Gerontol. 2003 Sep;38(9):927-34. PubMed: 12954478. Categories: Beyond the Bench

    The foreseeability of real anti-aging medicine: focusing the debate.

    Exp Gerontol. 2003 Sep;38(9):927-34.

    The foreseeability of real anti-aging medicine: focusing the debate.

    de Grey ADNJ.

    Abstract

    Abstract:

    There has recently been a sharp and very welcome increase in the rate of appearance of articles discussing the concept of medical interventions that would greatly increase the maximum healthy human lifespan. Much of this literature has emphasised the current non-existence of any such therapies, and has done so with laudable accuracy and authority. Regrettably, however, such articles have frequently extended their ambit to include the issues of how soon such interventions could be developed and of how advisable such an effort would be anyway, and have addressed these much more weakly, thereby diminishing the force of their main message. Here a survey is made of the more conspicuously flawed arguments suggesting tremendous difficulties or dangers in developing such interventions, with the aim thereby to tow those arguments firmly out into the ocean and give them the decent but unambiguous public burial that they so richly deserve. It is hoped that, by clearing the debate on future anti-aging advances of these obfuscations, the many aspects of this topic that have hitherto received much less attention than they warrant will be brought to the fore.

  • de Grey ADNJ. Overzealous maximum-likelihood fitting falsely convicts the slope heterogeneity hypothesis. Exp Gerontol. 2003 Aug;38(8):921-3. PubMed: 12915214.

    Overzealous maximum-likelihood fitting falsely convicts the slope heterogeneity hypothesis.

    Exp Gerontol. 2003 Aug;38(8):921-3.

    Overzealous maximum-likelihood fitting falsely convicts the slope heterogeneity hypothesis.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. A hypothesis for the minimal overall structure of the mammalian plasma membrane redox system. Protoplasma. 2003 May;221(1-2):3-9. PubMed: 12768336.

    A hypothesis for the minimal overall structure of the mammalian plasma membrane redox system.

    Protoplasma. 2003 May;221(1-2):3-9.

    A hypothesis for the minimal overall structure of the mammalian plasma membrane redox system.

    de Grey ADNJ.

    Abstract

    Abstract:

    After a long period of frustration, many components of the mammalian plasma membrane redox system are now being identified at the molecular level. Some are apparently ubiquitous but are necessary only for a subset of electron donors or acceptors; some are present only in certain cell types; some appear to be associated with proton extrusion; some appear to be capable of superoxide production. The volume and variety of data now available have begun to allow the formulation of tentative models for the overall network of interactions of enzymes and substrates that together make up the plasma membrane redox system. Such a model is presented here. The structure discussed here is of the mammalian system, though parts of it may apply more or less accurately to fungal and plant cells too. Judging from the history of mitochondrial oxidative phosphorylation, it may be hoped that the development of models of the whole system - even if they undergo substantial revision thereafter - will markedly accelerate the pace of research in plasma membrane redox, by providing a coherent basis for the design of future experiments.

  • de Grey ADNJ. Critique of the demographic evidence for "late-life non-senescence". Biochem Soc Trans. 2003 Apr;31(2):452-4. PubMed: 12653660.

    Critique of the demographic evidence for "late-life non-senescence".

    Biochem Soc Trans. 2003 Apr;31(2):452-4.

    Critique of the demographic evidence for "late-life non-senescence".

    de Grey ADNJ.

    Abstract

    Abstract:

    Although the Gompertz formula accurately describes observed mortality distributions over most of their extent, their 'tail' is much longer than that of a Gompertz curve fitted to the whole data set. A simple candidate explanation is that the longest-lived subset of any population will necessarily be enriched in individuals that age more slowly than the average of that population. However, some investigators have suggested that, instead, individuals actually cease to senesce after a certain age. Here, using a new approach to determining the best-fit degree of heterogeneity in the Gompertz slope parameter, it is shown that observed distributions can in fact be fit quite accurately by purely 'heterogeneous Gompertz' curves. Either explanation may therefore be correct.

  • 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. Mechanisms underlying the age-related accumulation of mutant mitochondrial DNA. In: Genetics of mitochondrial diseases (I.J. Holt, ed.), Oxford University Press, 2003, pp. 247-275. Categories: MitoSENS

    Mechanisms underlying the age-related accumulation of mutant mitochondrial DNA.

    In: Genetics of mitochondrial diseases (I.J. Holt, ed.), Oxford University Press, 2003, pp. 247-275.

    Mechanisms underlying the age-related accumulation of mutant mitochondrial DNA.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. UK research on the biology of aging -- the next ten years. Lifespan 2003; 11(1):1-4. Categories: Beyond the Bench

    UK research on the biology of aging -- the next ten years.

    Lifespan 2003; 11(1):1-4.

    UK research on the biology of aging -- the next ten years.

    de Grey ADNJ.

    Abstract

    Abstract:

    We are, at least in my opinion, the leading nation in Europe as regards biogerontology research. Will we remain so? For reasons best known to himself, Richard has asked me to offer my views on how we can best capitalise on our present position in the coming decade. It has been said that my habit of making suggestions to my experimentalist colleagues, when I myself have no clue how to run a gel, amounts to treating the world’s PIs as my graduate students; perhaps that is fair. This time, however, at least I have the defence that I am not doing so at my own initiative. Like it or not, biogerontology is a biomedical field. Whether aging is or is not a disease (a question which is, in my view, purely semantic), it is rather widely perceived as undesirable—and, quite correctly, as potentially combatable by future medical technology. Biogerontologists cannot, therefore, consider themselves as no different than students of areas less directly related to human suffering, such as development. For present purposes, this means that maintaining our pre-eminence entails doing the most useful basic research, applying its findings in the most effective therapeutic ways, and maximising the quantity as well as quality of both these types of output by obtaining as much funding as possible. I will therefore divide my comments into three groups: how to understand aging better, how to expedite the alleviation of suffering associated with aging, and how to convey our knowledge and aspirations to policy-makers and the public so as best to increase financial support for our work.

  • de Grey ADNJ, Baynes JW, Berd D, Heward CB, Pawelec G, Stock G. Fear of misrepresentation cannot justify silence about foreseeable life-extension biotechnology. BioEssays 2003;25(1):94-95. Categories: Beyond the Bench

    Fear of misrepresentation cannot justify silence about foreseeable life-extension biotechnology.

    BioEssays 2003;25(1):94-95.

    Fear of misrepresentation cannot justify silence about foreseeable life-extension biotechnology.

    de Grey ADNJ, Baynes JW, Berd D, Heward CB, Pawelec G, Stock G.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ, Gavrilov L, Olshansky SJ, Coles LS, Cutler RG, Fossel M, Harman SM. Antiaging technology and pseudoscience. Science. 2002 Apr 26;296(5568):656. PubMed: 11985356. Categories: Beyond the Bench

    Antiaging technology and pseudoscience.

    Science. 2002 Apr 26;296(5568):656.

    Antiaging technology and pseudoscience.

    de Grey ADNJ, Gavrilov L, Olshansky SJ, Coles LS, Cutler RG, Fossel M, Harman SM.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. HO2*: the forgotten radical. DNA Cell Biol. 2002 Apr;21(4):251-7. PubMed: 12042065.

    HO2*: the forgotten radical.

    DNA Cell Biol. 2002 Apr;21(4):251-7.

    HO2*: the forgotten radical.

    de Grey ADNJ.

    Abstract

    Abstract:

    HO2*, usually termed either hydroperoxyl radical or perhydroxyl radical, is the protonated form of superoxide; the protonation/deprotonation equilibrium exhibits a pK(a) of around 4.8. Consequently, about 0.3% of any superoxide present in the cytosol of a typical cell is in the protonated form. This ratio is rather accurately reflected by the published literature on the two species, as identified by a PubMed search; at the time of writing only 28 articles mention "HO2," "hydroperoxyl" or "perhydroxyl" in their titles, as against 9228 mentioning superoxide. Here it is argued that this correlation is not justifiable: that HO2*'s biological and biomedical importance far exceeds the attention it has received. Several key observations of recent years are reviewed that can be explained much more economically when the participation of HO2* is postulated. It is suggested that a more widespread appreciation of the possible role of HO2* in biological systems would be of considerable benefit to biomedical research.

  • de Grey ADNJ. Mitochondrial mutations in vertebrate aging. In: Oxidative stress and aging: advances in basic science, diagnostics, and intervention (R.G. Cutler and H. Rodriguez, eds.), World Scientific Publishing, 2002, pp. 437-451. Categories: MitoSENS

    Mitochondrial mutations in vertebrate aging.

    In: Oxidative stress and aging: advances in basic science, diagnostics, and intervention (R.G. Cutler and H. Rodriguez, eds.), World Scientific Publishing, 2002, pp. 437-451.

    Mitochondrial mutations in vertebrate aging.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • 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.

  • de Grey ADNJ. Bioremediation meets biomedicine: therapeutic translation of microbial catabolism to the lysosome. Trends Biotechnol 2002;20(11):452-455. PubMed: 12413818. Categories: LysoSENS

    Bioremediation meets biomedicine: therapeutic translation of microbial catabolism to the lysosome.

    Trends Biotechnol 2002;20(11):452-455.

    Bioremediation meets biomedicine: therapeutic translation of microbial catabolism to the lysosome.

    de Grey ADNJ.

    Abstract

    Abstract:

    Lysosomal degradation of damaged macromolecules is imperfect: many cell types accumulate lysosomal aggregates with age. Some such deposits are known, or are strongly suspected, to cause age-related disorders such as atherosclerosis and neurodegeration. It is possible that they also influence the rate of aging in general. Lysosomal degradation involves extensive cooperation between the participating enzymes: each generates a substrate for others until breakdown of the target material to recyclable units (such as amino acids) is complete. Hence, the age-related accumulation of lysosomal aggregates might be markedly retarded, or even reversed, by introducing just a few bacterial or fungal enzymes -'xenohydrolases' - that can degrade molecules that our natural machinery cannot. This article examines the feasibility and biomedical potential of such lysosomal enhancement as an approach to retarding or treating age-related physiological decline and disease.

  • de Grey ADNJ. The reductive hotspot hypothesis of mammalian aging: membrane metabolism magnifies mutant mitochondrial mischief. Eur J Biochem 2002; 269(8):2003-2009. PubMed: 11985576. Categories: MitoSENS

    The reductive hotspot hypothesis of mammalian aging: membrane metabolism magnifies mutant mitochondrial mischief.

    Eur J Biochem 2002; 269(8):2003-2009.

    The reductive hotspot hypothesis of mammalian aging: membrane metabolism magnifies mutant mitochondrial mischief.

    de Grey ADNJ.

    Abstract

    Abstract:

    A severe challenge to the idea that mitochondrial DNA mutations play a major role in the aging process in mammals is that clear loss-of-function mutations accumulate only to very low levels (under 1% of total) in almost any tissue, even by very old age. Their accumulation is punctate: some cells become nearly devoid of wild-type mitochondrial DNA and exhibit no activity for the partly mitochondrially encoded enzyme cytochrome c oxidase. Such cells accumulate in number with aging, suggesting that they survive indefinitely, which is itself paradoxical. The reductive hotspot hypothesis suggests that these cells adjust their metabolism to use plasma membrane electron transport as a substitute for the mitochondrial electron transport chain in the reoxidation of reduced dinucleotides, and that, like mitochondrial electron transport, this process is imperfect and generates superoxide as a side-effect. This superoxide, generated on the outside of the cell, can potentially initiate classical free radical chemistry including lipid peroxidation chain reactions in circulating material such as lipoproteins. These, in turn, can be toxic to mitochondrially nonmutant cells that import them to satisfy their cholesterol requirements. Thus, the relatively few cells that have lost oxidative phosphorylation capacity may be toxic to the rest of the body. In this minireview, recent results relevant to this hypothesis are surveyed and approaches to intervening in the proposed process are discussed.

  • de Grey ADNJ, Baynes JW, Berd D, Heward CB, Pawelec G, Stock G. Is human aging still mysterious enough to be left only to scientists? BioEssays 2002;24(7):667-676. PubMed: 12111727. Categories: SENS Overviews

    Is human aging still mysterious enough to be left only to scientists?

    BioEssays 2002;24(7):667-676.

    Is human aging still mysterious enough to be left only to scientists?

    de Grey ADNJ, Baynes JW, Berd D, Heward CB, Pawelec G, Stock G.

    Abstract

    Abstract:

    The feasibility of reversing human aging within a matter of decades has traditionally been dismissed by all professional biogerontologists, on the grounds that not only is aging still poorly understood, but also many of those aspects that we do understand are not reversible by any current or foreseeable therapeutic regimen. This broad consensus has recently been challenged by the publication, by five respected experimentalists in diverse subfields of biogerontology together with three of the present authors, of an article (Ann NY Acad Sci 959, 452-462) whose conclusion was that all the key components of mammalian aging are indeed amenable to substantial reversal (not merely retardation) in mice, with technology that has a reasonable prospect of being developed within about a decade. Translation of that panel of interventions to humans who are already alive, within a few decades thereafter, was deemed potentially feasible (though it was not claimed to be likely). If the prospect of controlling human aging within the foreseeable future cannot be categorically rejected, then it becomes a matter of personal significance to most people presently alive. Consequently, we suggest that serious public debate on this subject is now warranted, and we survey here several of the biological, social and political issues relating to it.

  • de Grey ADNJ. UK research on the biology of aging. Exp Gerontol. 2001 Dec;37(1):1-7. PubMed: 11738141.

    UK research on the biology of aging.

    Exp Gerontol. 2001 Dec;37(1):1-7.

    UK research on the biology of aging.

    de Grey ADNJ.

    Abstract

    Abstract:

    Only a few years ago, it could fairly be said that biogerontology research in the UK was in a sorry state. With the exception of the evolutionary biology of aging, which was revolutionized by Britons in the 1950s and in which the UK has remained paramount ever since, the number of research groups whose main focus was biogerontology had waned to single digits, and even those groups were generally very small. This situation has been transformed during the past decade, with the result that the UK arguably leads Europe in this field, in terms of both the quality and the quantity of its output. Moreover, the health of UK biogerontology research seems secure for the foreseeable future. Its one potential Achilles heel is the overemphasis on compression of morbidity as a goal, since further compression is highly unlikely to occur and is anyway inconsistent with the public's demonstrated desires.

  • de Grey ADNJ. Response to "approaches and limitations to gene therapy for mitochondrial diseases," Antioxid. Redox Signal. 2001;3:451-460. Antioxid Redox Signal. 2001 Dec;3(6):1153-5. PubMed: 11813989. Categories: MitoSENS

    Response to "approaches and limitations to gene therapy for mitochondrial diseases," Antioxid. Redox Signal. 2001;3:451-460.

    Antioxid Redox Signal. 2001 Dec;3(6):1153-5.

    Response to "approaches and limitations to gene therapy for mitochondrial diseases," Antioxid. Redox Signal. 2001;3:451-460.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. A proposed mechanism for the lowering of mitochondrial electron leak by caloric restriction. Mitochondrion. 2001 Aug;1(2):129-39. PubMed: 16120273.

    A proposed mechanism for the lowering of mitochondrial electron leak by caloric restriction.

    Mitochondrion. 2001 Aug;1(2):129-39.

    A proposed mechanism for the lowering of mitochondrial electron leak by caloric restriction.

    de Grey ADNJ.

    Abstract

    Abstract:

    Caloric restriction (CR) of laboratory rodents, which extends their maximum lifespan, only transiently reduces the specific metabolic rate of highly oxidative tissues. However, superoxide production by mitochondria of those tissues is greatly reduced by CR. This is probably a major contributor to the slowed aging seen in CR, but its mechanism is unknown. Here it is proposed that the major metabolic shift enabling reduced superoxide production is a diversion of much of the electron flux generated by glycolysis and the TCA cycle away from its usual destination, Complex I, and to the plasma membrane redox system. The cell's ATP synthesis capacity is thereby diminished, but so is its ATP demand, due to reduced turnover of the Na+/K+-ATPase. Direct tests of this hypothesis are proposed.

  • de Grey ADNJ. Response to "telomere shortening with aging in human liver". J Gerontol A Biol Sci Med Sci. 2001 Jun;56(6):B237-8. PubMed: 11407362.

    Response to "telomere shortening with aging in human liver".

    J Gerontol A Biol Sci Med Sci. 2001 Jun;56(6):B237-8.

    Response to "telomere shortening with aging in human liver".

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Biologists abandon Popper at their peril. Bioessays. 2000 Feb;22(2):206-7. PubMed: 10655042.

    Biologists abandon Popper at their peril.

    Bioessays. 2000 Feb;22(2):206-7.

    Biologists abandon Popper at their peril.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Mitochondrial gene therapy: an arena for the biomedical use of inteins. Trends Biotechnol 2000;18(9):394-399. PubMed: 10942964. Categories: MitoSENS

    Mitochondrial gene therapy: an arena for the biomedical use of inteins.

    Trends Biotechnol 2000;18(9):394-399.

    Mitochondrial gene therapy: an arena for the biomedical use of inteins.

    de Grey ADNJ.

    Abstract

    Abstract:

    Mitochondrial DNA (mtDNA) mutations underlie many rare diseases and might also contribute to human ageing. Gene therapy is a tempting future possibility for intervening in mitochondriopathies. Expression of the 13 mtDNA-encoded proteins from nuclear transgenes (allotopic expression) might be the most effective gene-therapy strategy. Its only confirmed difficulty is the extreme hydrophobicity of these proteins, which prevents their import into mitochondria from the cytosol. Inteins (self-splicing 'protein introns') might offer a solution to this problem: their insertion into such transgenes could greatly reduce the encoded proteins' hydrophobicity, enabling import, with post-import excision restoring the natural amino acid sequence.

  • de Grey ADNJ. Gerontologists and the media: the dangers of over-pessimism. Biogerontology. 2000;1(4):369-70. PubMed: 11708218. Categories: Beyond the Bench

    Gerontologists and the media: the dangers of over-pessimism.

    Biogerontology. 2000;1(4):369-70.

    Gerontologists and the media: the dangers of over-pessimism.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The non-correlation between maximum longevity and enzymatic antioxidant levels among homeotherms; implications for retarding human aging. J Anti-Aging Med 2000; 3(1):25-36. Categories: MitoSENS

    The non-correlation between maximum longevity and enzymatic antioxidant levels among homeotherms; implications for retarding human aging.

    J Anti-Aging Med 2000; 3(1):25-36.

    The non-correlation between maximum longevity and enzymatic antioxidant levels among homeotherms; implications for retarding human aging.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The reductive hotspot hypothesis: an update. Arch Biochem Biophys 2000; 373(1):295-301. PubMed: 10620352. Categories: MitoSENS

    The reductive hotspot hypothesis: an update.

    Arch Biochem Biophys 2000; 373(1):295-301.

    The reductive hotspot hypothesis: an update.

    de Grey ADNJ.

    Abstract

    Abstract:

    The mitochondrial free radical theory of aging is seriously challenged by the finding that mutant mtDNA never becomes abundant in vivo, a result disputed only in experiments using novel PCR variants whose quantitative accuracy is widely doubted. However, evidence continues to mount that mitochondria are the crucial site of free radical damage in vivo, most notably that mice lacking the nonmitochondrial isoforms of superoxide dismutase are healthy. It is thus important to determine whether a low level of mutant mtDNA could have serious systemic effects. This possibility exists because of the observed mosaic distribution of mutant mtDNA: some cells (or muscle fiber segments) lack any aerobic respiration. Such cells are presumed to satisfy their ATP needs by glycolysis. In vitro, however, NADH recycling by transmembrane pyruvate/lactate exchange does not suffice: cells only survive if they can up-regulate the plasma membrane oxidoreductase (PMOR). The PMOR's physiological electron acceptor is unknown. It was proposed recently (de Grey, A. D. N. J. (1998) J. Anti-Aging Med. 1(1), 53-66) that a prominent in vivo acceptor from these mitochondrially mutant cells may be oxygen, forming extracellular superoxide. The mosaic ("hotspot") distribution of this superoxide would limit its dismutation by extracellular superoxide dismutase; it may thus reduce transition metals leading to oxidation of circulating material, such as LDL. This would raise systemic oxidative stress, greatly amplifying the damage done by the originating mitochondrially mutant cells. This model, now known as the "reductive hotspot hypothesis," has recently gained much indirect experimental support; several direct tests of it are also feasible.

  • de Grey ADNJ. Incorporation of transmembrane hydroxide transport into the chemiosmotic theory. Bioelectrochem Bioenerg. 1999 Oct;49(1):43-50. PubMed: 10619447.

    Incorporation of transmembrane hydroxide transport into the chemiosmotic theory.

    Bioelectrochem Bioenerg. 1999 Oct;49(1):43-50.

    Incorporation of transmembrane hydroxide transport into the chemiosmotic theory.

    de Grey ADNJ.

    Abstract

    Abstract:

    A cornerstone of textbook bioenergetics is that oxidative ATP synthesis in mitochondria requires, in normal conditions of internal and external pH, a potential difference (delta psi) of well over 100 mV between the aqueous compartments that the energy-transducing membrane separates. Measurements of delta psi inferred from diffusion of membrane-permeant ions confirm this, but those using microelectrodes consistently find no such delta psi--a result ostensibly irreconcilable with the chemiosmotic theory. Transmembrane hydroxide transport necessarily accompanies mitochondrial ATP synthesis, due to the action of several carrier proteins; this nullifies some of the proton transport by the respiratory chain. Here, it is proposed that these carriers' structure causes the path of this "lost" proton flow to include a component perpendicular to the membrane but within the aqueous phases, so maintaining a steady-state proton-motive force between the water at each membrane surface and in the adjacent bulk medium. The conflicting measurements of delta psi are shown to be consistent with the response of this system to its chemical environment.

  • de Grey ADNJ. Are those 13 proteins really unimportable? In: From Symbiosis to Eukaryotism - Endocytobiology VII (E. Wagner et al., eds.), Geneva University Press, 1999, pp. 489-502. Categories: MitoSENS

    Are those 13 proteins really unimportable?

    In: From Symbiosis to Eukaryotism - Endocytobiology VII (E. Wagner et al., eds.), Geneva University Press, 1999, pp. 489-502.

    Are those 13 proteins really unimportable?

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The mitochondrial free radical theory of aging. Austin, TX: Landes Bioscience, 1999, 212pp, hardcover (ISBN 1-57059-564-X). Read on external site. Categories: MitoSENS

    The mitochondrial free radical theory of aging.

    Austin, TX: Landes Bioscience, 1999, 212pp, hardcover (ISBN 1-57059-564-X).

    The mitochondrial free radical theory of aging.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. A Mechanism Proposed to Explain the Rise in Oxidative Stress During Aging. J Anti-Aging Med. 1998 Spring. 1(1): 53-66. doi:10.1089/rej.1.1998.1.53. Read on external site. Categories: MitoSENS

    A Mechanism Proposed to Explain the Rise in Oxidative Stress During Aging.

    J Anti-Aging Med. 1998 Spring. 1(1): 53-66. doi:10.1089/rej.1.1998.1.53.

    A Mechanism Proposed to Explain the Rise in Oxidative Stress During Aging.

    de Grey ADNJ.

    Abstract

    Abstract:

    Most phenotypes of aging in vertebrates may be caused by a progressive decline in the ability of antioxidant defences to maintain cellular and systemic homeostasis. This is due both to a diminished efficacy of those defences and to an enhanced level of pro-oxidant toxicity; the imbalance between the two has been termed oxidative stress. However, the cause of this increasing imbalance remains obscure. This article proposes a mechanism by which spontaneously mutant mitochondrial DNA (mtDNA), despite being present only in very small quantities in the body, may be the main generator of oxidative stress. Mutant mtDNA is distributed very unevenly within a tissue: some cells apparently contain no wild-type mtDNA whatever. Those cells must rely on glycolysis for ATP production; furthermore, they require a system to stabilize their NAD+/NADH ratio. This can only be achieved by an efflux of electrons from the cell, most probably mediated by the plasma membrane oxidoreductase (PMOR). It is proposed that the required rate of electron efflux from these anaerobic cells exceeds the local electron-accepting capacity of "safe" acceptors in plasma such as dehydroascorbate, with the result that reactive species, such as Superoxide, are formed. This leads to increased oxidation of lipids in the plasma, notably of low-density lipoprotein (LDL) particles, which are subsequently imported into mitochondrially healthy cells. This oxidized lipoprotein must be destroyed by the recipient cells' antioxidant defences. That task diverts the cell from the degradation of pro-oxidants that it is itself generating; thus, it imposes oxidative stress on the cell. As the number of anaerobic cells in the body rises, so does oxidative stress in all cells. The consistency of this hypothesis with known facts is discussed, and technically feasible tests are suggested both of the proposed mechanism and of its overall contribution to mammalian aging, including plausible interventions to retard the process.

  • de Grey ADNJ. A proposed refinement of the mitochondrial free radical theory of aging. BioEssays 1997; 19(2):161-166. PubMed: 9046246. Categories: MitoSENS

    A proposed refinement of the mitochondrial free radical theory of aging.

    BioEssays 1997; 19(2):161-166.

    A proposed refinement of the mitochondrial free radical theory of aging.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. More on mitochondria and senescence: Response to Gershon. BioEssays 1997; 19(6):534-534.

    More on mitochondria and senescence: Response to Gershon.

    BioEssays 1997; 19(6):534-534.

    More on mitochondria and senescence: Response to Gershon.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

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