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  • de Grey ADNJ. Our right to life. J Evol Technol 2008; 17(2):53-57, in press. Categories: Beyond the Bench

    Our right to life.

    J Evol Technol 2008; 17(2):53-57, in press.

    Our right to life.

    de Grey ADNJ.

    Abstract

    Abstract:

    A pervasive reaction to the idea of extreme or indefinite postponement of human aging – one heard from many professional bioethicists and also from a high proportion of the general public – is that aging differs morally from other causes of debilitation and death in a manner that exempts us from the duty to combat it that we perceive as so self-evident in respect of those other causes. Precisely what characteristic of aging underpins this alleged distinction? I argue here that it is in fact a false distinction, perpetuated only by unwarranted psychological forces posing as philosophical arguments. In particular, I note that even an argument based ultimately on the currently unpopular meta-ethical concept of non-cognitivism cannot logically permit one to regard aging as a phenomenon that we can morally desist from combating to the best of our ability. I conclude that a cognitivism-agnostic line of reasoning, based on reflective equilibrium, offers the best chance for influencing hearts and minds on this issue in the near term.

  • de Grey ADNJ. Postponing aging: who are the experts? In: Tomorrow’s People, Proceedings of the 1st James Martin Institute World Forum (P. Healey, ed.), 2008, in press. Categories: Beyond the Bench

    Postponing aging: who are the experts?

    In: Tomorrow’s People, Proceedings of the 1st James Martin Institute World Forum (P. Healey, ed.), 2008, in press.

    Postponing aging: who are the experts?

    de Grey ADNJ.

    Abstract

    Abstract:

    In November 2005, 28 eminent biogerontologists signed a letter published in EMBO Reports that must rank among the most strongly-worded denunciations of a colleague’s work to appear in the scientific literature this millennium. It was triggered by the increasingly successful efforts of that colleague not only in attracting respect for his ideas in many quarters, including the media, but also in drawing attention to what he viewed as the shortcomings, both in scientific priorities and in communication to the wider world, of the established orthodoxy within his field. The field in question is biogerontology; the ideas concern the indefinite postponement of aging; and I am the colleague in question. In this essay I will briefly explain why the transition of the biogerontology establishment’s opposition to my ideas from off-the-record ridicule to on-the-record specifics is a development that I hugely welcome. It allows me to address the flaws in my critics’ reasoning with concrete scientific arguments – arguments whose presence in my various publications has hitherto escaped those critics’ attention – and thus to demonstrate that expertise in the biology of aging does not confer an infallible ability to evaluate novel proposals for postponing aging. I will further argue that this situation is an unusually overt demonstration that biology is just as much in need of theoreticians as physics, which of course has whole departments of them: in botth fields, the narrow focus required for experimentalists to be at the cutting edge should be complemented by the synthesis of disparate subfields that only the theoretician has the time to perform. I will conclude that no specialisation within biology has a monopoly on the development of ways to combat so complex and chaotic a phenomenon as mammalian aging and that a confederation of experimentalists from numerous biological disciplines, harnessed together by those with crossdisciplinary but not necessarily experimental expertise, is our best strategy for hastening the defeat of humanity’s foremost scourge.

  • de Grey ADNJ. Aging, elimination of. Entry for inclusion in the Berkshire Encyclopedia of the 21st Century, 2008, in press.

    Aging, elimination of.

    Entry for inclusion in the Berkshire Encyclopedia of the 21st Century, 2008, in press.

    Aging, elimination of.

    de Grey ADNJ.

    Abstract

    Abstract:

    Aging is a process of decay – the accumulation of various types of molecular and cellular damage that our genetically-programmed metabolism causes but cannot repair. The past century’s progress in biology and biotechnology has opened up the possibility that, within decades, we will be able to augment our in-built repair and maintenance processes with a range of “rejuvenation biotechnologies,” so that people first given these treatments in middle age can remain youthful perhaps 30 years longer than they naturally would. If these technologies are then refined at a rate typically seen with past technologies, this will confer indefinite youth, because residual aspects of aging will be progressively overcome more rapidly than they catch up with us. The consequences for individuals and society would penetrate all aspects of life, but foremost among these consequences will be the alleviation of aging-related suffering and the saving of lives on an unprecedented scale.

  • de Grey ADNJ. Endless Youth. In: Eindeloos, 22ste Almanak der Groningse Farmaceutische Studenten Vereniging "Pharmaciae Sacrum" (I. Dubbelboer et al., eds.), 2008, pp. 22-27.

    Endless Youth.

    In: Eindeloos, 22ste Almanak der Groningse Farmaceutische Studenten Vereniging "Pharmaciae Sacrum" (I. Dubbelboer et al., eds.), 2008, pp. 22-27.

    Endless Youth.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Is the quest to defeat aging ethical? In: Ethical Futures (S. Wint, ed.), 2008, in press. Categories: Beyond the Bench

    Is the quest to defeat aging ethical?

    In: Ethical Futures (S. Wint, ed.), 2008, in press.

    Is the quest to defeat aging ethical?

    de Grey ADNJ.

    Abstract

    Abstract:

    Ethics and psychology are more closely intertwined than might be apparent without detailed scrutiny. I feel that this is particularly so in the case of humanity’s attitude to the combating, and especially the outright defeat, of the process that biogerontologists tend to term “senescence” but most people, despite the attendant ambiguity, term “aging.” Specifically, doubts about the feasibility of defeating aging and about its desirability become seductively linked in a classic case of circular logic: when challenged (as they often are by me!), people tend to use their negativity about each as a basis for refusing to examine the legitimacy of their negativity about the other. It is not unreasonable to say that it doesn’t matter whether aging is a good thing because we can’t do anything about it anyway, and it is equally fair to say that it doesn’t matter whether we can defeat aging because doing so would be a bad idea anyway – but it is very unreasonable indeed to take both these positions at the same time. In this essay I offer some ways out of this trap.

  • de Grey ADNJ. Consciousness in the context of radical life extension. In: Holistic Consciousness: Cognition, Memory, Individuality, Free Will, Zombies, Life, Death, Immortality and the Immune System (N. Bauer, ed.), 2008, in press.

    Consciousness in the context of radical life extension.

    In: Holistic Consciousness: Cognition, Memory, Individuality, Free Will, Zombies, Life, Death, Immortality and the Immune System (N. Bauer, ed.), 2008, in press.

    Consciousness in the context of radical life extension.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Aging: A Foreseeable Target of Stem Cells and Regenerative Medicine. In: World Stem Cell Report 2008, in press.

    Aging: A Foreseeable Target of Stem Cells and Regenerative Medicine.

    In: World Stem Cell Report 2008, in press.

    Aging: A Foreseeable Target of Stem Cells and Regenerative Medicine.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The singularity and the Methuselarity: similarities and differences. In: Strategy for the Future (Bushko R, ed.), 2008, in press. Categories: Beyond the Bench

    The singularity and the Methuselarity: similarities and differences.

    In: Strategy for the Future (Bushko R, ed.), 2008, in press.

    The singularity and the Methuselarity: similarities and differences.

    de Grey ADNJ.

    Abstract

    Abstract:

    Aging, being a composite of innumerable types of molecular and cellular decay, will be defeated incrementally. I have for some time predicted that this succession of advances will feature a threshold, which I here christen the “Methuselarity,” following which there will actually be a progressive decline in the rate of improvement in our anti-aging technology that is required to prevent a rise in our risk of death from age-related causes as we become chronologically older. Various commentators have observed the similarity of this prediction to that made by Good, Vinge, Kurzweil and others concerning technology in general (and, in particular, computer technology), which they have termed the “singularity.” In this essay I compare and contrast these two concepts.

  • de Grey ADNJ. Life span extension research and public debate: societal considerations. Studies in Ethics, Law, and Technology: Vol. 1 : Iss. 1, Article 5. Read on external site. Categories: Beyond the Bench

    Life span extension research and public debate: societal considerations.

    Studies in Ethics, Law, and Technology: Vol. 1 : Iss. 1, Article 5.

    Life span extension research and public debate: societal considerations.

    de Grey ADNJ.

    Abstract

    Abstract:

    The pace of a given strand of scientific research, whether purely curiosity-driven or motivated by a particular technological goal, is strongly influenced by public attitudes towards its value. In the case of research directed to the radical postponement of aging and the consequent extension of healthy and total lifespans, public opinion is entrenched in a "pro-aging trance" - a state of resolute irrationality. This arises from the entirely rational attitude to a grisly, inevitable and relatively far-off fate: putting it out of one's mind allows one to make the most of what time one has, free of preoccupation with one's demise, and it is immaterial how irrational the arguments that one uses to achieve this are, e.g. by persuading oneself that aging is not such a bad thing after all. As biotechnology increasingly nears the point where aging will no longer be inevitable, however, this studied fatalism has become a core part of the problem, making people reluctant to join the crusade to hasten that technology's arrival. An effective way to address this hesitation is to promote debate about the reasons people give for fearing the defeat of aging, most of which are sociological. Such debate exposes people to the glaring flaws in their own logic. Thus, the more the debate is sustained and promoted, the harder it is for those flaws to be ignored.

  • de Grey ADNJ. The need to debalkanize gerontology: a case study. Rejuvenation Res. 2007 Dec;10(4):431-4. PubMed: 18158741.

    The need to debalkanize gerontology: a case study.

    Rejuvenation Res. 2007 Dec;10(4):431-4.

    The need to debalkanize gerontology: a case study.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Understanding and tackling aging: two fields communicating (a little) at last. Rejuvenation Res. 2007 Dec;10(4):637-40. PubMed: 18158742. Categories: Beyond the Bench

    Understanding and tackling aging: two fields communicating (a little) at last.

    Rejuvenation Res. 2007 Dec;10(4):637-40.

    Understanding and tackling aging: two fields communicating (a little) at last.

    de Grey ADNJ.

    Abstract

    Abstract:

    Those who have followed this journal’s, and this author’s, efforts over recent years to stimulate the rational design of interventions to combat aging have good reason for bewilderment that the concerted application of our knowledge of biology to the defeat of humanity’s foremost killer needed to be kick-started by a bearded troublemaker whose formal academic training was not even in biology at all. Elsewhere in this issue I bemoan the persistent balkanisation of traditional gerontology, whereby biologists, clinicians, sociologists and psychologists studying the elderly seem almost studiously to avoid each other even when participating in the same conference. In this commentary, however, I have something more positive to report. A string of recent and forthcoming conferences, organized not only by those at the forefront of life-extension research but also by highly influential mainstream groups, have publicly endorsed the Methuselah Foundation’s goal of defeating aging. The field of biomedical gerontology—the interface between biogerontology and geriatrics, where biological knowledge is focused on developing the geriatrics of tomorrow—is not a traditional component of gerontology, having been poorly appreciated by biogerontologists and geriatricians alike, but these developments show that it is rapidly taking its place at that table.

  • de Grey ADNJ. Alzheimer's, atherosclerosis, and aggregates: a role for bacterial degradation. Nutr Rev. 2007 Dec;65(12 Pt 2):S221-7. PubMed: 18240553. Categories: LysoSENS

    Alzheimer's, atherosclerosis, and aggregates: a role for bacterial degradation.

    Nutr Rev. 2007 Dec;65(12 Pt 2):S221-7.

    Alzheimer's, atherosclerosis, and aggregates: a role for bacterial degradation.

    de Grey ADNJ.

    Abstract

    Abstract:

    Several of the most prevalent and severe age-related diseases, notably Alzheimer's disease and atherosclerosis, feature the accumulation of non-degradable aggregates within the lysosomes of disease-affected cells. At an early point in disease progression, the breakdown of lysosomal contents by the resident catabolic enzymes stops working properly. A return of lysosomal enzymatic activity to pre-disease levels may restore aggregate elimination. In this review, a method of bioremediation-derived lysosomal enzyme enhancement is proposed, featuring the cellular introduction of microbial-isolated enzymes, or xenoenzymes. The benefits and challenges of using xenoenzymes to break down aggregates are discussed. As the size of our elderly population grows, the incidence of age-related diseases will increase, necessitating the exploration of radical, but potentially powerful, therapeutic strategies.

  • de Grey ADNJ. The case for prioritising research on late-onset life-extension interventions in mammals. Rejuvenation Res. 2007 Sep;10(3):257-9. PubMed: 17822351. Categories: Beyond the Bench

    The case for prioritising research on late-onset life-extension interventions in mammals.

    Rejuvenation Res. 2007 Sep;10(3):257-9.

    The case for prioritising research on late-onset life-extension interventions in mammals.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Edmonton: a future center for pioneering biomedical gerontology? Rejuvenation Res. 2007 Sep;10(3):345-7. PubMed: 17822354. Categories: Beyond the Bench

    Edmonton: a future center for pioneering biomedical gerontology?

    Rejuvenation Res. 2007 Sep;10(3):345-7.

    Edmonton: a future center for pioneering biomedical gerontology?

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Calorie restriction, post-reproductive lifespan and programmed aging: a plea for rigor. Ann N Y Acad Sci. 2007 Nov;1119:296-305. Epub 2007 Aug 23. PubMed: 17717100.

    Calorie restriction, post-reproductive lifespan and programmed aging: a plea for rigor.

    Ann N Y Acad Sci. 2007 Nov;1119:296-305. Epub 2007 Aug 23.

    Calorie restriction, post-reproductive lifespan and programmed aging: a plea for rigor.

    de Grey ADNJ.

    Abstract

    Abstract:

    All scientists are acutely aware of the profound challenge that they face when communicating scientific findings to nonscientists, especially when great uncertainty is involved and when the topic is of personal interest to the general public. Simplification of the issues--sometimes extending to a degree of oversimplification--is a sad but generally recognized necessity. It is not, however, a necessity when scientists communicate with each other, and when that happens, the explanation may lie elsewhere: either in the speaker's vested interests or in overconfidence on the speaker's part in the extent to which he or she has grasped the topic under discussion. Both these explanations are serious allegations and must not be made without good reason, not least because an alternative explanation is often the entirely legitimate preference for scientific "shorthand." However, when a general tendency toward oversimplification emerges within an expert community, not only in informal interactions but in learned publications, the field in question can suffer a loss of reputation for rigor, which may especially infect younger scientists joining that field (or contemplating joining it). I feel that this has occurred to a dangerous degree within biogerontology in respect of the way in which the effect of the environment on the rate of aging-whether that of an individual organism or of a lineage-is described. There are still important controversies in that area, but I refer here strictly to issues concerning which a thorough consensus exists. In this essay I highlight some fundamental tenets of biogerontology that are frequently, and to my mind problematically, mis-stated by many in this field in their printed pronouncements. Greater precision on these points will, I believe, benefit biogerontology at many levels, avoiding confusion among biogerontologists, among other biologists, and among the general public.

  • de Grey ADNJ. New Developments at Rejuvenation Research: High Impact Factor, Advance Online Publication, and More. Rejuvenation Res. 2007 Jun;10(2):125-126. Read on external site.

    New Developments at Rejuvenation Research: High Impact Factor, Advance Online Publication, and More.

    Rejuvenation Res. 2007 Jun;10(2):125-126.

    New Developments at Rejuvenation Research: High Impact Factor, Advance Online Publication, and More.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The natural biogerontology portfolio: "defeating aging" as a multi-stage ultra-Grand Challenge. Ann N Y Acad Sci. 2007 Apr;1100:409-23. PubMed: 17460206. Categories: Beyond the Bench

    The natural biogerontology portfolio: "defeating aging" as a multi-stage ultra-Grand Challenge.

    Ann N Y Acad Sci. 2007 Apr;1100:409-23.

    The natural biogerontology portfolio: "defeating aging" as a multi-stage ultra-Grand Challenge.

    de Grey ADNJ.

    Abstract

    Abstract:

    The early days of biogerontology were blessed with an undiluted forthrightness concerning the field’s ultimate goals, epitomised by its leaders. Luminaries from Pearl to Comfort to Strehler declared the desirability of eliminating aging with no more diffidence than that with which today’s oncologists aver that they seek a cure for cancer. The field’s subsequent retreat from this position garnered a modicum of political acceptability and public financial support, but all biogerontologists agree that this fell, and continues to fall, vastly short of the funding that the prospect of even a modest postponement of aging would logically justify. The past 20 years’ discoveries of life-extending genetic manipulations in model organisms have weakened the argument that a policy of appeasement of the public’s ambivalence about defeating aging is our only option; some of the biogerontologists responsible for these advances have espoused views of which our intellectual forefathers would be proud, without noticeably harming their own careers. With the recent emergence of a detailed, ambitious, but practical roadmap for the comprehensive defeat of aging, this process has moved further: our natural and most persuasive public stance is, more than ever, to re-embrace the same unassailable logic that served pioneering biogerontologists perfectly well. In particular, we are in a position to explain that the disparate strands of contemporary biomedical gerontology are not in conflict, but rather that they constitute a portfolio of approaches with a range of potential efficacies and degrees of difficulty of implementation, which can save more lifes together than any can save individually, and all of which thus merit intensive pursuit.

  • de Grey ADNJ. Aging and airborne HIV: a reassuring analogy. Rejuvenation Res. 2007 Mar;10(1):1-3. PubMed: 17378747. Categories: Beyond the Bench

    Aging and airborne HIV: a reassuring analogy.

    Rejuvenation Res. 2007 Mar;10(1):1-3.

    Aging and airborne HIV: a reassuring analogy.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • Phoenix CR, de Grey ADNJ. A model of aging as accumulated damage matches observed mortality patterns and predicts the life-extending effects of prospective interventions. AGE 2007;29(4):133-189. PubMed: 19424837. Categories: Beyond the Bench

    A model of aging as accumulated damage matches observed mortality patterns and predicts the life-extending effects of prospective interventions.

    AGE 2007;29(4):133-189.

    A model of aging as accumulated damage matches observed mortality patterns and predicts the life-extending effects of prospective interventions.

    Phoenix CR, de Grey ADNJ.

    Abstract

    Abstract:

    The relative insensitivity of lifespan to environmental factors constitutes compelling evidence that the physiological decline associated with aging derives primarily from the accumulation of intrinsic molecular and cellular side-effects of metabolism. Here we model that accumulation starting from a biologically based interpretation of the way in which those side-effects interact. We first validate this model by showing that it very accurately reproduces the distribution of ages at death seen in typical populations that are well protected from age-independent causes of death. We then exploit the mechanistic basis of this model to explore the impact on lifespans of interventions that combat aging, with an emphasis on interventions that repair (rather than merely retard) the direct molecular or cellular consequences of metabolism and thus prevent them from accumulating to pathogenic levels. Our results strengthen the case that an indefinite extension of healthy and total life expectancy can be achieved by a plausible rate of progress in the development of such therapies, once a threshold level of efficacy of those therapies has been reached.

  • de Grey ADNJ. Old people are people too: why it is our duty to fight aging to the death. Cato Unbound 2007(12): lead essay. Categories: Beyond the Bench

    Old people are people too: why it is our duty to fight aging to the death.

    Cato Unbound 2007(12): lead essay.

    Old people are people too: why it is our duty to fight aging to the death.

    de Grey ADNJ.

    Abstract

    Abstract:

    It has been obvious to me since my earliest days that the eventually fatal physiological decline associated with getting older is both tragic and potentially preventable by medical intervention. It was, therefore, a matter of some consternation to me to discover in my late twenties that my view on this matter was not universally shared. In this essay I explode various myths and illogicalities that surround the effort to combat (and especially to defeat) aging, with an emphasis on some that are often perpetrated by currently influential commentators.

  • de Grey ADNJ. Rejuvenating neurons and glia with microbial enzymes. In: Interaction Between Neurons and Glia in Aging and Disease (J.O. Malva et al., eds.), Springer, 2007, pp. 503-510. Categories: LysoSENS

    Rejuvenating neurons and glia with microbial enzymes.

    In: Interaction Between Neurons and Glia in Aging and Disease (J.O. Malva et al., eds.), Springer, 2007, pp. 503-510.

    Rejuvenating neurons and glia with microbial enzymes.

    de Grey ADNJ.

    Abstract

    Abstract:

    All the major neurodegenerative diseases are characterised by the accumulation of proteinaceous aggregates within neurons. The commonest such condition, Alzheimer’s disease, also features extracellular proteinaceous aggregates (amyloid). The role of these aggregates in the etiology and progression of cognitive impairment is still unclear, but their absence in young adults suggests that their removal would at any rate not be harmful. However, no method for removing the intracellular aggregates in question has yet been developed. Moreover, the engulfment of amyloid by microglia as a result of immunisation may result in loss of microglial function if the amyloid then resists lysosomal digestion. A novel approach to eliminating intracellular aggregates in the brain (and elsewhere) was proposed by the present author in 2002 and has recently attracted enthusiastic support from all relevant specialities, which are unusually disparate. This approach is to isolate bacterial or fungal strains with the capacity to metabolise the recalcitrant aggregates, following which the genes encoding the enzymes responsible would be identified and modified for expression in mammalian cells and targeting to the appropriate subcellular compartment. Delivery could be either of the genes themselves, using somatic gene therapy, or of the enzymes they encode, which would be injected either directly into the brain or into the circulation in conjunction with agents to deliver them across the blood-brain barrier. Ambitious though this approach undoubtedly is, its potential for both the prevention and the treatment of the entire range of neurodegenerative diseases so far exceeds any alternative presently being explored that the case for pursuing it is strong.

  • 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. Free radicals in aging: causal complexity and its biomedical implications. Free Radic Res. 2006 Dec;40(12):1244-9. PubMed: 17090413. Categories: MitoSENS

    Free radicals in aging: causal complexity and its biomedical implications.

    Free Radic Res. 2006 Dec;40(12):1244-9.

    Free radicals in aging: causal complexity and its biomedical implications.

    de Grey ADNJ.

    Abstract

    Abstract:

    Superoxide generated adventitiously by the mitochondrial respiratory chain can give rise to much more reactive radicals, resulting in random oxidation of all classes of macromolecules. Harman's 1956 suggestion that this process might drive aging has been a leading strand of biogerontological thinking since the discovery of superoxide dismutase. However, it has become apparent that the many downstream consequences of free radical damage can also be caused by processes not involving oxidation. Moreover, free radicals have been put to use by evolution to such an extent that their wholesale elimination would certainly be fatal. This multiplicity of parallel pathways and side-effects illustrates why attempts to postpone aging by "cleaning up" metabolism will surely fail for the foreseeable future: we simply understand metabolism too poorly. This has led me to pursue the alternative, "repair and maintenance" approach that sidesteps our ignorance of metabolism and may be feasible relatively soon.

  • 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. SENS is hard, yes, but not too hard to try: a reply to Warner. Rejuvenation Res 2006;9(4):443-445.

    SENS is hard, yes, but not too hard to try: a reply to Warner.

    Rejuvenation Res 2006;9(4):443-445.

    SENS is hard, yes, but not too hard to try: a reply to Warner.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. SENS survives the Challenge; now let's get to work. Rejuvenation Res. 2006 Winter;9(4):429-30. PubMed: 17105378. Categories: Beyond the Bench

    SENS survives the Challenge; now let's get to work.

    Rejuvenation Res. 2006 Winter;9(4):429-30.

    SENS survives the Challenge; now let's get to work.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Is SENS a farrago? Rejuvenation Res. 2006 Winter;9(4):436-9. PubMed: 17105381. Categories: Beyond the Bench

    Is SENS a farrago?

    Rejuvenation Res. 2006 Winter;9(4):436-9.

    Is SENS a farrago?

    de Grey ADNJ.

    Abstract

    Abstract:

    SENS (Strategies for Engineered Negligible Senescence) is a panel of proposed interventions in mammalian aging that I have suggested may be sufficiently feasible, comprehensive, and amenable to subsequent incremental refinement that it could prevent death from old age (at any age) within a timeframe of decades, leading to four-digit lifespans of many people alive today. This extreme conclusion has drawn sharp criticism from some colleagues, especially because the methodology of SENS departs radically from approaches generally considered the most promising ways to combat aging and because it is perceived as endangering biogerontology’s respectability. Here I briefly respond to these criticisms.

  • de Grey ADNJ. Has Hippocrates had his day? Rejuvenation Res. 2006 Fall;9(3):371-3. PubMed: 16859477. Categories: Beyond the Bench

    Has Hippocrates had his day?

    Rejuvenation Res. 2006 Fall;9(3):371-3.

    Has Hippocrates had his day?

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Extrapolaholics Anonymous: why demographers' rejections of a huge rise in cohort life expectancy in this century are overconfident. Ann N Y Acad Sci. 2006 May;1067:83-93. PubMed: 16803973. Categories: Beyond the Bench

    Extrapolaholics Anonymous: why demographers' rejections of a huge rise in cohort life expectancy in this century are overconfident.

    Ann N Y Acad Sci. 2006 May;1067:83-93.

    Extrapolaholics Anonymous: why demographers' rejections of a huge rise in cohort life expectancy in this century are overconfident.

    de Grey ADNJ.

    Abstract

    Abstract:

    Criticisms of demographers by other demographers have become frequent in scientific literature, generally consisting of accusations that trends observed in the recent past have been extrapolated unjustifiably into the future. Demographers, along with their colleagues in the actuarial profession, are in an invidious position in this regard, knowing full well that extrapolation is almost always only minimally justifiable, but knowing also that their readers, colleagues, and sources of funding tend to be much more interested in the future than in the past. It is unfortunate that, while actuaries typically resolve this dilemma by emphasizing the limitations of their methods and thereby lowering expectations that their predictions will be accurately fulfilled, demographers are more prone to respond combatively, attempting to reinforce the credibility of their extrapolations by recourse to data from areas in which their expertise is less tested, such as biology. This is valuable in that it raises the profile of the debate on the likely rate of scientific progress relevant to mortality rates, but it also runs the risk of lowering the technical quality of that debate, by telling policy makers and the public what they want to hear and thereby entrenching their expectations without recourse to the relevant biological facts. Extrapolations based on plausible sequences of scientific advances and the sociopolitical responses to them, summarized in this article, have led to the prediction of four-digit life expectancies of cohorts born in the 21st century and possibly even in the 20th. This prediction has attracted inevitable ridicule from prominent demographers, but being founded on science and sociology rather than on history it may be much more reliable than the extrapolations that those demographers presently prefer.

  • de Grey ADNJ. Compression of morbidity: the hype and the reality, part 2. Rejuvenation Res. 2006 Summer;9(2):167-8. PubMed: 16706638. Categories: Beyond the Bench

    Compression of morbidity: the hype and the reality, part 2.

    Rejuvenation Res. 2006 Summer;9(2):167-8.

    Compression of morbidity: the hype and the reality, part 2.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Appropriating microbial catabolism: a proposal to treat and prevent neurodegeneration. Neurobiol Aging 2006;27(4):589-595. PubMed: 16207503. Categories: LysoSENS

    Appropriating microbial catabolism: a proposal to treat and prevent neurodegeneration.

    Neurobiol Aging 2006;27(4):589-595.

    Appropriating microbial catabolism: a proposal to treat and prevent neurodegeneration.

    de Grey ADNJ.

    Abstract

    Abstract:

    Intraneuronal, largely proteinaceous aggregates accumulate in all major neurodegenerative disorders. Lysosomal degradation of proteinaceous and other material declines early in such diseases. This suggests that intraneuronal aggregates consist of material which is normally broken down in the lysosome and thus accumulates when lysosomal degradation fails. This is plausible even though those aggregates are generally non-lysosomal, because lysosomal uptake may be affected. Thus, restoring lysosomal function might eliminate them--and without increasing the concentration of the soluble monomers or oligomers of which they are formed. This approach is therefore unlikely to be harmful and may well be beneficial. How might lysosomes be rejuvenated? Since lysosomal dysfunction is likely to be caused by intralysosomal material that is resistant to lysosomal degradation, normal function might be recovered by augmenting that function to cause the toxin to be degraded. Here, I describe how such augmentation might be achieved with microbial enzymes. Soil microbes display astonishing catabolic diversity, something exploited for decades in the bioremediation industry. Environments enriched in human remains impose selective pressure on the microbial population to evolve the ability to degrade any recalcitrant, energy-rich human material. Thus, microbes may exist that can degrade these lysosomal toxins. If so, it should be possible to isolate the genes responsible and modify them for therapeutic activity in the mammalian lysosome.

  • de Grey ADNJ. Compression of morbidity: the hype and the reality, part 1. Rejuvenation Res. 2006 Spring;9(1):1-2. PubMed: 16608388. Categories: Beyond the Bench

    Compression of morbidity: the hype and the reality, part 1.

    Rejuvenation Res. 2006 Spring;9(1):1-2.

    Compression of morbidity: the hype and the reality, part 1.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The urgency dilemma: is life extension research a temptation or a test? Update 2006; 21(1):6-10. Categories: Beyond the Bench

    The urgency dilemma: is life extension research a temptation or a test?

    Update 2006; 21(1):6-10.

    The urgency dilemma: is life extension research a temptation or a test?

    de Grey ADNJ.

    Abstract

    Abstract:

    The prospect of greatly postponing, or even reversing, the aging process has in recent years moved emphatically from the realms of science fiction to being science foreseeable. While many differences of opinion between experts remain concerning likely timeframes, an increasing number of specialists in the biology of aging (including the author) now take the view that we (a) know enough about the molecular and cellular basis of aging, and (b) possess versatile enough tools for modifying cells and molecules, that aging may well come within range of effective medical intervention within the lifetimes of many people alive today. In this essay I will explore some of the issues that this raises for people in general and Christians in particular. I will focus especially on what I feel the Christian ethical framework says about the rights and wrongs of developing life-extension medicine and thereby postponing death.

  • de Grey ADNJ. Strategie per un invecchiamento transcurabile ingegnerizzato. In: Alterando il destino dell'umanità (P. Donghi, ed.), Proceedings of the 2005 Spoletoscienza conference. Rome: Laterza & Figli, 2006, pp. 49-63. Translation by Bruna Tortorella. (PDF in English)

    Strategie per un invecchiamento transcurabile ingegnerizzato.

    In: Alterando il destino dell'umanità (P. Donghi, ed.), Proceedings of the 2005 Spoletoscienza conference. Rome: Laterza & Figli, 2006, pp. 49-63. Translation by Bruna Tortorella. (PDF in English)

    Strategie per un invecchiamento transcurabile ingegnerizzato.

    de Grey ADNJ.

    Abstract

    Abstract:

    In the past few years, it has become possible to enumerate a comprehensive panel of technically feasible interventions which, jointly, would probably reduce the risk of death from current age-related causes to a level similar to our present risk of death from bacterial infections. The timeframe for developing these interventions in laboratory mice may be as little as a decade from now, subject to adequate funding. We don't know how long it would take thereafter to translate them to humans, but it might be only a couple of decades. In the first half of this essay I will describe the main components of this panel of interventions and the reasons why more and more biogerontologists feel that they will be so much more effective than anything we have today. In the remainder, I shall explore the consequences of developing such therapies: consequences that are much more dramatic than they may at first appear. These therapies will be decidedly imperfect, so they can realistically be expected to confer only perhaps 30 additional years of healthy life – a modest extension. If that were all we could expect, there might be a serious argument that the necessary expenditure should be directed instead to extending the lives of those in the developing world who die in such huge numbers from diseases that we already know how to treat. But one feature of these therapies changes all that: they will be genuine rejuvenation therapies, benefiting middle-aged people the most. In all areas that enjoy substantial public interest – and we can be quite sure that this will be one such – technology advances enormously in 30 years following the initial breakthrough. Thus, it is virtually certain that the middle-aged beneficiaries of the first-generation rejuvenation therapies, who are still biologically no more than middle-aged thirty years later, will be able to take advantage of greatly improved therapies that will “re-rejuvenate” them so that they will be biologically less than middle-aged for another few decades. This cycle seems sure to be repeatable indefinitely: we will stay one step ahead of the new problems of aging, with the imperfections in our rejuvenation therapies being eliminated faster than they are catching up with us. I have called this phenomenon "life extension escape velocity". It implies that anyone who lives long enough, in good enough health, to benefit fully from the first-generation rejuvenation therapies (those that will give such people about 30 extra years of healthy life) should in fact never need to die of old age at any age. The average lifespan of such people is likely to exceed 1000 years. This enormous change in people's potential longevity greatly strengthens the moral case for prioritising this research and hastening its success.

  • de Grey ADNJ. Defeat of aging - utopia or foreseeable scientific reality? In: The Future of Life and the Future of our Civilization (V. Burdyuzha, ed.), Springer, 2006, pp. 277-290.

    Defeat of aging - utopia or foreseeable scientific reality?

    In: The Future of Life and the Future of our Civilization (V. Burdyuzha, ed.), Springer, 2006, pp. 277-290.

    Defeat of aging - utopia or foreseeable scientific reality?

    de Grey ADNJ.

    Abstract

    Abstract:

    If we ignore reductions of mortality in infancy and childbirth, life expectancy in the developed world has risen only by between one and two years per decade in the past century. This is an impressive acceleration relative to previous centuries. Curiously, while many demographers consider that the current rate of increase may be maintained in coming decades, none have explored in detail the possibility that the acceleration will continue. This is probably because further acceleration would indeed be highly unlikely in the absence of major technological advances in the postponement not only of age-related diseases but of “aging itself” – the progressively accumulating molecular and cellular changes that underlie those diseases and also underlie the aspects of age-related functional decline that we usually do not call diseases, such as loss of muscle strength and immune response. In this essay I explain why technological advances of that sort are indeed foreseeable – indeed, I estimate a 50% chance that they will arrive within 25 years given adequate funding. I also explain why, even though these therapies will initally confer only perhaps 30 additional years of healthy life, those who benefit from them will very probably also benefit from progressively improved therapies, thereby maintaining “life extension escape velocity” and avoiding death from age-related causes at any age, with the result that (barring global catastrophe) many of them will attain four-digit lifespans.

  • de Grey ADNJ. Gene therapy. In: Encyclopedia of Aging, Fourth Edition (R. Schulz et al., eds.), Springer, 2006, pp. ???-???. Categories: Delivery Mechanisms

    Gene therapy.

    In: Encyclopedia of Aging, Fourth Edition (R. Schulz et al., eds.), Springer, 2006, pp. ???-???.

    Gene therapy.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Like it or not, life extension research extends beyond biogerontology. EMBO Rep. 2005 Nov;6(11):1000. PubMed: 16264420. Categories: Beyond the Bench

    Like it or not, life extension research extends beyond biogerontology.

    EMBO Rep. 2005 Nov;6(11):1000.

    Like it or not, life extension research extends beyond biogerontology.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Life extension, human rights, and the rational refinement of repugnance. J Med Ethics. 2005 Nov;31(11):659-63. PubMed: 16269565. Categories: Beyond the Bench

    Life extension, human rights, and the rational refinement of repugnance.

    J Med Ethics. 2005 Nov;31(11):659-63.

    Life extension, human rights, and the rational refinement of repugnance.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The SENS challenge: $20,000 says the foreseeable defeat of aging is not laughable. Rejuvenation Res. 2005 Winter;8(4):207-10. PubMed: 16313219. Categories: Beyond the Bench

    The SENS challenge: $20,000 says the foreseeable defeat of aging is not laughable.

    Rejuvenation Res. 2005 Winter;8(4):207-10.

    The SENS challenge: $20,000 says the foreseeable defeat of aging is not laughable.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • 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. The ethical status of efforts to postpone aging: a reply to Hurlbut. Rejuvenation Res. 2005 Fall;8(3):129-30. PubMed: 16144465. Categories: Beyond the Bench

    The ethical status of efforts to postpone aging: a reply to Hurlbut.

    Rejuvenation Res. 2005 Fall;8(3):129-30.

    The ethical status of efforts to postpone aging: a reply to Hurlbut.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. Resistance to debate on how to postpone ageing is delaying progress and costing lives. EMBO Rep. 2005 Jul;6 Spec No:S49-53. PubMed: 15995663. Categories: Beyond the Bench

    Resistance to debate on how to postpone ageing is delaying progress and costing lives.

    EMBO Rep. 2005 Jul;6 Spec No:S49-53.

    Resistance to debate on how to postpone ageing is delaying progress and costing lives.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. "The rate of aging": a counterproductively undefinable term. Rejuvenation Res. 2005 Summer;8(2):77-8. PubMed: 15929713. Categories: Beyond the Bench

    "The rate of aging": a counterproductively undefinable term.

    Rejuvenation Res. 2005 Summer;8(2):77-8.

    "The rate of aging": a counterproductively undefinable term.

    de Grey ADNJ.

    Abstract

    Abstract:

    No abstract available.

  • de Grey ADNJ. The foreseeability of real anti-aging medicine. In: Anti-Aging Medical Therapeutics, volume 7 (R. Klatz, ed.), American Academy for Anti-Aging Medicine, 2005, pp. 59-68.

    The foreseeability of real anti-aging medicine.

    In: Anti-Aging Medical Therapeutics, volume 7 (R. Klatz, ed.), American Academy for Anti-Aging Medicine, 2005, pp. 59-68.

    The foreseeability of real anti-aging medicine.

    de Grey ADNJ.

    Abstract

    Abstract:

    Anti-aging medicine does not yet exist, in the sense in which the term “medicine” is generally used. Effective medicine nearly or completely eliminates the risk of death from its target cause; antibiotics, for example, have cut American deaths from bacterial infections by a factor of 20 in the past century. All we have to combat aging, at this point, is interventions that modestly (if at all) delay the onset and progression of age-related frailty. In the past few years, however, it has become possible to enumerate a comprehensive panel of technically feasible interventions, which, jointly, would probably constitute real anti-aging medicine: that is, would probably reduce the risk of death from current age-related causes to a level similar to our present risk of death from bacterial infections. The timeframe for developing these interventions in laboratory mice has recently been authoritatively estimated to be around a decade from now. We don’t know how long it would take thereafter to translate them to humans, but it might only be a couple of decades. As the population aged while in possession of these medicines, new aspects of aging would doubtless emerge that would need progressively more sophisticated medicine, but these might well not be beyond us once aging’s aura of immutability has at last been swept aside. The aim of this paper is to describe (a) the main components of this panel of interventions and the reasons why more and more biogerontologists feel that they will be so much more effective than anything we have today, and (b) the reasons why it is in the interest of anti-aging providers today to maintain a strong interest in this research and to communicate its progress to their patients so as to expedite that research’s success and to profit from it at that time.

  • 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. Lysosomal enhancement with microbial hydrolases: a novel strategy for removing protein aggregates. In: New Trends in Alzheimer and Parkinson Disorders: ADPD 2005 (A. Fisher et al., eds.), Medimond, 2005, pp. 51-54. Categories: LysoSENS

    Lysosomal enhancement with microbial hydrolases: a novel strategy for removing protein aggregates.

    In: New Trends in Alzheimer and Parkinson Disorders: ADPD 2005 (A. Fisher et al., eds.), Medimond, 2005, pp. 51-54.

    Lysosomal enhancement with microbial hydrolases: a novel strategy for removing protein aggregates.

    de Grey ADNJ.

    Abstract

    Abstract:

    All neurodegenerative diseases are associated with the intracellular accumulation of substances that impair cellular function and viability. Reversing this accumulation may thus be valuable, but has proven challenging, doubtless because substances resistant to cellular catabolism are inherently hard to degrade. I suggest a radically new approach: augmenting humans’ natural catabolic machinery with microbial enzymes. Many highly 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.

  • 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. Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation. Rejuvenation Res. 2005 Spring;8(1):13-7. PubMed: 15798370. Categories: MitoSENS

    Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation.

    Rejuvenation Res. 2005 Spring;8(1):13-7.

    Reactive oxygen species production in the mitochondrial matrix: implications for the mechanism of mitochondrial mutation accumulation.

    de Grey ADNJ.

    Abstract

    Abstract:

    The vicious cycle theory postulates that typical mitochondrial DNA (mtDNA) mutations cause their host mitochondria to generate more superoxide and other reactive oxygen species (ROS) than do normal mitochondria, thereby promoting the occurrence of additional mtDNA mutations at an ever-accelerating rate. However, nearly all the loss-of-function mtDNA mutations seen in vivo are large deletions, which (as the original statement of the theory indeed noted, though this has been widely overlooked) should not trigger a vicious cycle because they will prevent the assembly of the potentially superoxide-generating enzyme complexes. Consistent with this is the observation that each cell exhibiting loss of mtDNA-encoded function in vivo contains copies of a single, evidently clonally expanded, mutant mtDNA species, whereas the vicious cycle theory predicts a spectrum of mutant forms in each cell. Two recent papers, however, unveil a way in which mtDNA mutations could indeed promote ROS production of their host mitochondria. MtDNA mutations probably shift the intramitochondrial NAD(+)/NADH redox couple towards NADH, and this is now shown in vitro to cause ROS production by alpha-ketoglutarate dehydrogenase, an essential enzyme of the TCA cycle. This does not revive the vicious cycle theory, but it has complex implications for the two most plausible more recent theories, known as "survival of the slowest" and "crippled mitochondria." It may also prove to explain other recent observations in mitochondrially mutant cells in vivo.

  • de Grey ADNJ. The plasma membrane redox system: a candidate source of aging-related oxidative stress. AGE J Am Aging Assoc 2005; 27(2):129-138. Categories: MitoSENS

    The plasma membrane redox system: a candidate source of aging-related oxidative stress.

    AGE J Am Aging Assoc 2005; 27(2):129-138.

    The plasma membrane redox system: a candidate source of aging-related oxidative stress.

    de Grey ADNJ.

    Abstract

    Abstract:

    The plasma membrane redox system (PMRS) is an electron transport chain in the plasma membrane that transfers electrons from either intra- or extracellular donors to extracellular acceptors. Unlike the superoxide-generating NADPH oxidase of phagocytes and the homologous (but much less active) enzymes found in some other cells, the PMRS is still incompletely characterised at the molecular level. Much is known, however, concerning its function and affinity for both physiological and nonphysiological substrates. A role for it in aging, the “reductive hotspot hypothesis” (RHH), was proposed in 1998 as part of an explanation for the apparently indefinite survival in vivo of cells that have entirely lost mitochondrial respiratory capacity as a result of the accumulation of mitochondrial mutations. Stimulation of the PMRS might allow the cell to maintain redox homeostasis even while continuing to operate the Krebs cycle, which may be advantageous in many ways. However, the PMRS may, like the mitochondrial respiratory chain, be prone to generate superoxide when thus dysregulated—and in this case superoxide would be generated outside the cell, where antioxidant defences are more limited than inside the cell and where much highly oxidisable material is present. Cascades of peroxidation chain reactions initiated by this process may greatly amplify the oxidative stress on the organism that is caused by rare mitochondrially mutant cells. Since such cells increase in abundance with aging (though remaining rare), this is an economical hypothesis to explain the rise in oxidative stress seen in (and generally believed to contribute substantially to) mammalian aging. In an extension of previously published accounts of RHH, I propose here that the lysosomal toxicity of oxidised cholesterol derivatives (oxysterols) may contribute to the toxicity of mitochondrial mutations by affecting lysosomal function in many cell types in the same way as they have been proposed to do in arterial macrophages.

  • 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.

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