Aubrey de Grey

SENS Foundation · n/a

The early days of biogerontology were blessed with an undiluted forthrightness concerning the field's ultimate goals, epitomized 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...

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 entrenc...

All the major neurodegenerative diseases are characterised by the accumulation of proteinaceous aggregates within neurons. The commonest of such conditions, Alzheimer’s disease, also features extracellular proteinaceous aggregates (amyloid). The role of these aggregates in the aetiology and progression of cognitive impairment is still unclear, but...

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. How...

Elsewhere in this issue, Huber Warner writes a critique of my Strategies for Engineered Negligible Senescence (SENS) proposal for the dramatic postponement of age-related functional decline. His commentary advances the debate on SENS to a proper level of measured discourse, something that has been regrettably lacking hitherto, and for this I applau...

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 d...

Recent studies have demonstrated that transgenic mice with an increased rate of somatic point mutations in mitochondrial DNA (mtDNA mutator mice) display a premature aging phenotype reminiscent of human aging. These results are widely interpreted as implying that mtDNA mutations may be a central mechanism in mammalian aging. However, the levels of...

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...

 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...

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...

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 time frame of decades, leading to four-digit lifespans of m...

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 comin...

On the ethics of extending human life: healthy people have a right to carry on living Humanity has long demonstrated a paradoxical ambivalence concerning the extension of a healthy human lifespan. Modest health extension has been universally sought, whereas extreme (even indefinite) health extension has been regarded as a snare and delusion—a drea...

The intrinsic genetic instability of cancer cells makes age-related cancers more difficult to postpone or treat than any other age-related disease. 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 patter...

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 universa...

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 inco...

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, s...

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...

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 i...

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 patte...

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 mtDN...

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 spon...

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 th...

Following a highly stimulating series of talks on the social and ethical implications of greatly extended life spans, a discussion of the issues was held, in which a series of straw polls was conducted. An alarming conclusion from these polls was that most participants thought it either probable or "not improbable" that comprehensive functional rej...

Should we be considering the social and economic ramifications of a society where life-span could be limitless?

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 o...

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 th...

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 spon...

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...

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....

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 a...

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...

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 describ...

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 cour...

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 describ...

FlyBase (http://ybase.bio.indiana.edu/) provides an integrated view of the fundamental genomic and genetic data on the major genetic model Drosophila melanogaster and related species. FlyBase has primary responsibility for the continual reannotation of the D. melanogaster genome. The ultimate goal of the reannotation effort is to decorate the euchr...

Supplementary tables

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 invol...

FlyBase (http://flybase.bio.indiana.edu/) provides an integrated view of the fundamental genomic and genetic data on the major genetic model Drosophila melanogaster and related species. FlyBase has primary responsibility for the continual reannotation of the D.melanogaster genome. The ultimate goal of the reannotation effort is to decorate the euch...

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...

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 publi...

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 a...

Constance Holden accurately describes the range of opinions in the field of aging research concerning the possible efficacy of future life-extension technologies and the lack of any antiaging medicines today (Bodybuilding: The Bionic Human, “The quest to reverse time's toll,” 8 Feb., p. [1032][1

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 degeneratio...

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 a...

The recent completion of the Drosophila melanogaster genomic sequence to high quality and the availability of a greatly expanded set of Drosophila cDNA sequences, aligning to 78% of the predicted euchromatic genes, afforded FlyBase the opportunity to significantly improve genomic annotations. We made the annotation process more rigorous by inspecti...

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 sin...

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 un...

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 confir...

A series of studies over many years has conclusively disproved the hypothesis that longevity in warm-blooded animals (homeotherms) correlates with high levels of antioxidant enzymes: in fact, these variables generally exhibit a strong negative cross-species correlation. In flies and nematodes, however, substantial extension of maximum life span has...