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Living to 100 and maybe much longer: the
engineering and biotechnology of life-extension
medicine and when it may arrive
Aubrey D.N.J. de Grey, Ph.D.
Cmairman and Chief Science Officer, Methuselah Foundation
PO Box 1137, Lorton, VA 22099, USA
email: aubrey@sens.org
Abstract
The present high demand for medicines and therapies that retard or reverse the effects of aging on
both one's appearance and one's physical and mental vigour leaves no room for doubt that
progressive advances in the efficacy of such interventions will be immensely valued by society. The
opposition of bioconservatives and the apparent ambivalence inherent in the public's attitude to
extreme life extension, focusing as they do on the sociopolitical challenges that this transition would
cause, should be viewed in this context; they can thus confidently be predicted to evaporate almost
entirely once these therapies arrive, and to a large extent even when they become widely
acknowledged as foreseeable, which will be much sooner. In this article I describe a plan termed
"strategies for engineered negligible senescence" (SENS), which is the approach to extreme life
extension that I consider the most likely to succeed in the foreseeable future. I summarise where we
currently stand in the development of the various biotechnological areas that form components of this
approach, and conclude that we have a good chance of demonstrating proof-of-concept in mice
within just ten years if the necessary funding is forthcoming, with a 50% chance of translating that
result to humans only 15 years thereafter. I also touch on the role that plastic and reconstructive
surgery can be expected to play in these techniques.
Introduction: general principles of the SENS approach
The complexity of aging is real. Though it has been traditional in gerontology to speak of "theories of
aging", with the implication that aging is a unitary process ultimately driven by a single process,
there is now essentially universal agreement that many such proposals have some truth but none has a
monopoly of it. Both evolutionary theory and direct observation demonstrate that, to use Olshansky
et al.’s particularly succinct phrase [1], aging is a product of evolutionary neglect rather than
evolutionary intent. This is manifest as a fundamentally chaotic progression of loss of function with
age, best described not so much as a chain of events but more a tangled "rope of events".
Nonetheless, it is inescapable that age-related pathology is an eventual side-effect of essential
metabolic processes.
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Figure 1. The two traditional approaches to postponing age-related decline. Age-related pathologies
are complex side-effects of metabolism, via intricate and interlinked chains of events. The geriatrics
approach is to intervene late in this sequence, combating the pathology directly. The gerontology
approach is to intervene early, reducing the rate at which metabolism initiates the sequence, thereby
partly pre-empting the cascade of deleterious consequences and thus delaying the point at which they
become pathogenic.
What does this mean for the prospects of postponing that loss of function? A cursory analysis might
lead to a decidedly pessimistic conclusion. On the face of it there are only two available strategies,
which are depicted in Figure 1: one must adopt either the "geriatrics" approach, which is to intervene
late in the sequence of events (when pathology has already begun to emerge) or else the
"gerontology" approach, intervening early and thus pre-empting pathology. The geriatrics approach
cannot pretend to be other than a short-termist one: the intermediate side-effects of metabolism that
are the proximate causes of pathology are not addressed, so continue to accumulate, and thus the
prevention of pathology becomes ever more difficult. The gerontology approach is designed to avoid
that problem, but it faces an equally fundamental obstacle: the still profound inadequacy of our
understanding of metabolism. As things stand – and, most biologists would agree, for the foreseeable
future – we have so incomplete a comprehension of how organisms work, or even how cells work,
that any interventions we design with the aim of substantially retarding the accumulation of a given
type of metabolic side-effect are almost certain to accelerate the accumulation of others, via the
destabilisation of equilibria that evolution has adjusted rather precisely over the millennia. The
paradigmatic example of this is the production of reactive oxygen species, which was for many years
believed to be an unalloyed evil but which is now understood to play numerous valuable roles in
metabolism [2], leading to the conclusion that excessive administration of powerful antioxidants
would generally do more harm than good.
Figure 2. The fact that the sequence of events from metabolism to pathology is complex allows a
third approach to intervention, the engineering approach. The accumulating intermediates
(“damage”) that are the proximate, ongoing side-effects of metabolism are only pathogenic once they
reach a certain level of abundance. Thus, repair of this damage preempts pathology by keeping the
level of damage down to sub-pathogenic levels.
The above argument has indeed persuaded many biogerontologists to abandon, until further notice,
all hope for the meaningful postponement of aging. However, a problem is only as hard as its easiest
solution, and it is thus legitimate to scrutinise the logic just rehearsed with great care, in case the
conclusion that only two types of approach to postponing pathology are available is in fact
premature. In doing this I became aware, in 2000, that a third potential approach indeed exists, which
I like to call the engineering approach (Figure 2) or, more fully, “strategies for engineered negligible
senescence” (SENS) [3,4]. This entails repair of the initial side-effects of metabolism before they
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have reached a level of abundance that triggers loss of tissue or organismal function (i.e., pathology).
The key merits of the SENS approach are threefold. Firstly, it shares with the gerontology approach
the feature that it pre-empts pathology and thus is not a losing battle. Second, it exploits the fact that
metabolism's initial, direct side-effects are necessarily ongoing throughout life whereas its more
indirect side-effects on function are only apparent starting in middle age: this reveals that the initial
side-effects must reach a threshold of abundance before they become harmful, and thus that strategies
which reverse such side-effects can prevent pathology indefinitely even if they are always imperfect,
only removing part of the accumulated damage at each attempt. And third, because SENS does not
attempt to alter the rate at which metabolism drives the accumulation of the initial side-effects, it
sidesteps our ignorance of the details of how those side-effects are laid down (and, most critically, of
how metabolism succeeds in laying them down as slowly as it does).
Is SENS practical? A reason for cautious optimism
It is, clearly, not enough to show that the engineering approach to postponing aging is more practical
than two other, manifestly impractical approaches. In order to show that it is truly practical, we must
examine the biological nuts and bolts.
The first step in doing so is to enumerate, convincingly, the molecular and cellular differences
between middle-aged and young adults that may, plausibly, contribute to the former's shorter
remaining life expectancy. (Hereafter I will refer to this set of changes as "damage", as depicted in
Figure 2, and I shall use the term "damage" to refer specifically to this entire set of changes and to
nothing else.) If we cannot do that, it is hard to see how to proceed. If we can, however, we have
made a key first step, even though we have given no consideration to the elderly: since pathology
arises as a delayed, and thus indirect, consequence of metabolism we can be confident that the repair
of the changes which are already occurring early in life will facilitate – and in some cases entirely
obviate – the need to address directly their delayed consequences. Put simply, frequent and thorough
repair of all types of damage would uncouple metabolism from pathology and thereby postpone
aging indefinitely. (The feasibility and consequences of imperfect, but ever-better, approximations to
this ideal will be discussed in the last part of this review.)
In attempting this enumeration we can be guided by a key principle: damage can only accumulate in
long-lived information. If a protein molecule (for example) suffers oxidative damage and is thereafter
degraded, the damage disappears along with the protein. If a cell dies and is entirely digested by a
macrophage, any damage that it contained is eliminated from the body. We can thus restrict our
consideration to a few general categories of progressive change:
- change (increase or decrease) in the abundance of a given type of cell
- accumulation of intracellular molecules that are not broken down or excreted
- accumulation of mutations and epimutations
- accumulation of extracellular molecules that are not broken down or excreted
- accumulation of changes to extracellular molecules that are not broken down or excreted
How does the above list follow from the restriction to long-lived information? The reasoning goes as
follows. We are composed of cells and stuff between cells. Cells of a given type can increase in
number if there is no adequate system to remove them when they are overabundant; conversely, they
can diminish in number if there is no system to replace ones that have died or developed into a
different type. Both within and outside cells, molecules can be created and will accumulate if there is
no adequate system to remove them once they become overabundant. The depletion of such
molecules need not be included in the list because it cannot be a truly direct side-effect of
metabolism: all molecules present in the body arise by a combination of introduction from the
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environment (breathing, eating) and biosynthesis by cells, and thus are maintained at equilibrium for
as long as the relevant cell types are similarly maintained in both number and function. Within cells,
all molecules except DNA are recycled with a half-life that is a small fraction of the human lifespan,
so damage cannot accumulate in them; in DNA, moreover, changes both to primary sequence and to
epigenetic decorations (such as methylation) are propagated when the molecule is replicated, so can
accumulate as if DNA were never recycled. In extracellular material, by contrast, protein molecules
exist that are never broken down or excreted; these can accumulate chemical changes even if they do
not accumulate in abundance.
The relative brevity of the above list can be considered as a reason for preliminary, cautious
optimism that the engineering approach to postponing aging is worthy of further analysis. Clearly
there is much such analysis to be done before one can conclude that SENS is truly feasible, however.
The partitioning of age-related damage into the categories listed above is not, in fact, the ideal one. A
slight variation is motivated by the principle that the classification which will be of most use is based
on the method whereby the category might be repaired: types of damage that are amenable to broadly
the same intervention should be grouped together, while those requiring fundamentally distinct
approaches are best separated. This has led me to describe damage as consisting of the "seven deadly
things" shown in Table 1 [5]. The main departure here from the description given in the previous
section is that nuclear and mitochondrial mutations are listed separately. Note also that nuclear
mutations and epimutations are grouped together (mitochondrial epimutations are unknown), whereas
increase and decrease in cell number are listed separately.
Type of damage
Cell loss, cell atrophy
Death-resistant cells
Oncogenic nuclear
mutations/epimutations
Mitochondrial mutations
Intracellular aggregates
Extracellular aggregates
Extracellular crosslinks
Proposed repair (or obviation)
Stem cells, growth factors, exercise
Ablation of unwanted cells
“WILT” (Whole-body Interdiction of Lengthening of
Telomeres)
Allotopic expression of 13 proteins
Microbial hydrolases
Immune-mediated phagocytosis
AGE-breaking molecules
Table 1. The “seven deadly things” that accumulate throughout life and contribute to age-related
physical and cognitive decline from middle age. Also given are the currently most promising
approaches to either repairing or obviating these types of damage. For details, see text.
SENS specifics: the components
Of the seven items in Table 1, interventions to reverse three are already in clinical trials in one or
another form. Another is the subject of extensive work in rodents, while the remaining three are still
at the cell culture stage.
The plethora of research on stem cells and growth factors is too broad to review here, so I will restrict
myself to the mention of two particularly encouraging clinical applications recently published: the
alleviation of Alzheimer’s disease symptoms by introducing cells that secrete the growth factor NGF
[6,7] and the restoration of basic motor function to a spine injury victim who had been wheelchairbound for nearly 20 years [8].
Extracellular molecules accumulate in aggregates, collectively termed amyloid, in a variety of
tissues. Of these, by far the best-studied is the senile plaque in Alzheimer’s disease, which is
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composed mainly of the protein amyloid beta (Aβ). Following spectacular preclinical results [9], the
team of Dale Schenk at Elan Pharmaceuticals initiated a phase I clinical trial of a vaccination
procedure in which patients were immunised with Aβ and, to varying extents, mounted an antibody
response. The intention here was that the immune system of the brain – specifically the microglia,
which are the neural equivalent of the macrophage – would internalise the Aβ and degrade it within
the lysosomal compartment. The trial was halted prematurely following the occurrence of severe
side-effects in 6% of patients [10], but the technique is still being vigorously pursued, for two main
reasons: first, there are strong indications of the mechanism that caused these side-effects and
relatively straightforward modifications to the technique that should pre-empt it, and second, those
patients that mounted a robust immune response to the vaccine also exhibited a substantial alleviation
of their cognitive deficit [11].
The third SENS component for which a repair therapy has reached clinical trials is the modification
of long-lived extracellular molecules. Though certain circumstantial evidence has been presented, it
remains unlikely that adducts or rearrangements (such as racemisation) of such molecules are toxic at
levels as low as seen in vivo (even in old age), probably because these long-lived molecules have
structural rather than enzymatic or other chemical roles. For that same reason, however,
intermolecular crosslinks can have increasingly pathogenic effects by diminishing the elasticity of
material such as cartilage or lens [12]. A compound that appears to cleave a common species of
accumulating crosslink, the alpha-dicarbonyl linkage, was identified a decade ago [13] and has been
the subject of a number of phase II clinical trials for hypertension [14]. Results have not reached
statistical significance, precluding progression to phase III trials, but there is reason for optimism that
indications less prone to large placebo effects, such as visual accommodation, may give more
unequivocal results. No corresponding work has yet occurred in respect of other amyloids, such as in
the pancreas in type II diabetes (main component amylin) or in the heart in systemic senile
amyloidosis (main component transthyretin), but there is no obvious reason why it should be any less
effective.
The ablation of cells which have outstayed their welcome in the body is at a preclinical stage, but
progress is still encouraging. (Note that this category specifically excludes cancers, which are
discussed below in the context of nuclear mutations and epimutations.) The most straightforward
example is the visceral adipocyte, which when overabundant promotes non-insulin-dependent
diabetes via its secretion of certain hormones. Surgical removal of visceral fat reverses diabetes in
rats [15]. More challenging is the deletion of clonally-expanded lymphocytes that have become
anergic (incapable of activation by antigen). These cells exhibit resistance to apoptosis and are not
easily distinguished from the active cells reactive to the same antigen (most often an epitope of
cytomegalovirus), whose deletion would risk severe resurgence of the infectious agent. However,
recent progress in identifying truly diagnostic markers of the unwanted cells that could be targets for
selective ablation is encouraging [16]. A third case is cells exhibiting a phenotype reminiscent of
replicative senescence in cell culture; these are rare in all tissues yet studied except articular cartilage
but may be toxic, again because of factors that they secrete, and their ablation is being pursued by a
suicide gene therapy strategy [17] and may also be amenable to an immunotherapy approach.
Considerably further from the preclinical, let alone clinical, stage is the treatment of mitochondrial
mutations. These have the surprising (but perhaps nearing explanation [18]) feature that they clonally
expand in non-dividing cells, eventually rendering affected cells entirely incapable of oxidative
phosphorylation. Here the most promising approach is not to repair these mutations (e.g. by replacing
mutated mitochondrial DNA), but to obviate them by inserting copies of the 13 protein-coding
mitochondrial genes into the nuclear genome after modifying them so that the encoded proteins will
be synthesised correctly in the cytosol and then imported into mitochondria for assembly into the
respiratory chain [19]. Initial success in this approach [20] was followed by over a decade of
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frustration, but in recent years there has been great progress: one of the 13 target genes has been
expressed from the nucleus in mammalian cells and shown to be functional [21,22], while genes
successfully transferred to the nucleus during evolution in other species have been cloned and their
sequences analysed for clues as to the changes needed to their mammalian homologues.
The elimination of intracellular aggregates probably requires only one major enhancement to
mammalian biology: increasing the catabolic arsenal of the cell’s garbage disposal machinery of last
resort, the lysosome, which accumulates such molecules evidently because it does not possess the
enzymatic wherewithal to break them down [23,24]. An approach to this that was proposed some
years ago by the present author [25] is to seek suitable genes in microbes from the soil, specifically
from environments enriched in human remains (such as graveyards), on the basis that this
environment will have imposed selective pressure to evolve genes to degrade substances which we
could not degrade while we were alive. This paradigm, first introduced over 50 years ago under the
title “the microbial infallibility hypothesis” [26], has underpinned the highly successful branch of
environmental decontamination known as bioremediation; its applicability to this biomedical
problem has by now caught the imagination of a number of prominent researchers and is being
aggressively pursued.
Finally we come to nuclear mutations and epimutations (the latter being defined [27] as adventitious
changes to the adducts, such as methyl or phosphate groups, that are attached either to DNA or to the
histones around which it is wrapped and which are propagated when that DNA is replicated). There is
compelling evidence [28], as well as evolutionary theoretical arguments, that in mammals (though
not in model invertebrates) the requirement to avoid dying of cancer before puberty has driven the
fidelity of nuclear DNA maintenance and repair to a level far exceeding what is necessary to prevent
loss of tissue function resulting from non-tumorigenic mutations. No such loss of function can occur
until a fair proportion of the cells in a tissue have become similarly mutated, in contrast to the
situation with cancer where just one cell with the wrong constellation of mutations is enough to cause
death within a few years. My preferred approach to truly eliminating death from cancer – a strategy
that I have termed WILT, Whole-body Interdiction of Lengthening of Telomeres [29,30] – is to
delete, by both ex vivo and somatic gene targeting, the genes encoding both telomerase and the yetuncharacterised ALT mechanism for telomere elongation, and to prevent the resulting failure of
continuously renewing tissues like blood and skin by roughly decadal stem cell replenishment. This
is without doubt the most challenging of the therapies that I perceive as necessary components of
SENS, but even in this case the relevant work is proceeding apace and gives cause for optimism that
it can be implemented in mice within a decade and in humans only a decade or two thereafter.
Implications for lifespans of those alive today
The therapies described above will not deliver a complete elimination of aging, for two reasons:
eighth “sins” will surely emerge at sufficiently extreme ages, and the treatments described for the
seven existing types of damage are inherently impossible to implement perfectly throughout the
body. Thus, my estimate is that in its first incarnation the SENS panel will only about double the
roughly 30-year remaining natural lifespan of those for whom it will be most effective. However, that
does not immediately tell us how long those people will in fact live. Since the SENS panel consists of
bona fide rejuvenation therapies, it will (imperfectly) restore those people to a younger biological
age, possessing less age-related molecular and cellular damage, such that they only return to their
pre-treatment biological age after perhaps 30 years. 30 years is a very long time in technology, so a
reasonable inference from this is that by the time those 30 years have passed, the first-generation
SENS panel will have been improved in comprehensiveness. How much will they have been
improved? A reasonable estimate can be obtained by reference to the rate of advance of other
technologies when they were amenable to incremental progress, rather than requiring fundamental
breakthroughs, which turns out to be rather uniform. The intervals between the achievements of the
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Wright brothers and Lindbergh, between Sanger and Venter, between Pasteur and Fleming and
between Turing and Gates, to name but four examples, vary by a factor of less than two. After 30
years, therefore, therapies that give 55-year-olds 30 years of extra life will very probably have been
refined into ones that give them 80 years of extra life, and that give those who are biologically more
or less 55 but chronologically 85 at least a further 40. This logic can clearly be extended arbitrarily
far into the future, leading to the indefinite avoidability of death from old age, a concept that I call
“life extension escape velocity” (Figure 3) [31]. Four-digit lifespans of many people already alive
today are thus wholly realistic.
Figure 3. Depending on one’s age (indicated by the numbers) and health at the point when therapies
arrive that can extend the healthy lifespan of middle-aged people by 30 years, one’s effective
biological age (defined as, e.g., degree of frailty or vulnerability to death in the coming year) may
increase at a decelerating rate and eventually actually decrease, as a result of the progressive
improvements in comprehensiveness of the available rejuvenation therapies. Longevity escape
velocity is defined as the point when these therapies are being improved faster than their remaining
imperfections are catching up with those who benefit the most from them.
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References
1.
Olshansky, S. J., Hayflick. L., Carnes, B. A. Position statement on human aging. J. Gerontol.
A Biol. Sci. Med. Sci. 57: B292-B297, 2002.
2.
Rhee, S. G., Kang, S. W., Jeong, W., et al. Intracellular messenger function of hydrogen
peroxide and its regulation by peroxiredoxins. Curr. Opin. Cell Biol. 17: 183-189, 2005.
3.
de Grey, A. D. N. J., Ames, B. N., Andersen, J. K., et al. Time to talk SENS: critiquing the
immutability of human aging. Annals N.Y. Acad. Sci. 959: 452-462, 2002.
4.
de Grey, A. D. N. J. An engineer's approach to the development of real anti-aging medicine.
Science's SAGE KE 2003: vp1, 2003.
5.
de Grey, A. D. N. J. The foreseeability of real anti-aging medicine: focusing the debate. Exp.
Gerontol. 38: 927-934, 2003.
6.
Tuszynski, M. H., Thal, L., Pay, M., et al. A phase 1 clinical trial of nerve growth factor gene
therapy for Alzheimer disease. Nat. Med. 11: 551-555, 2005.
7.
Ebert, A. D., Svendsen, C. N. A new tool in the battle against alzheimer’s disease and aging:
ex vivo gene therapy. Rejuvenation Res. 8: 131-134, 2005.
8.
Song, C. H. Clinical application of human umbilical cord blood mesenchymal stem cells.
Rejuvenation Res. 8: S50, 2005.
9.
Schenk, D., Barbour, R., Dunn, W., et al. Immunization with amyloid-beta attenuates
Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173-177, 1999.
10. Schenk, D., Hagen, M., Seubert, P. Current progress in beta-amyloid immunotherapy. Curr.
Opin. Immunol. 16: 599-606, 2004.
11.
Hock, C., Konietzko, U., Streffer, J. R., et al. Antibodies against beta-amyloid slow
cognitive decline in Alzheimer's disease. Neuron 38: 547-554, 2003.
12. de Grey, A. D. N. J. The 8th International Symposium on the Maillard reaction (Charleston,
South Carolina, August 28 to September 1, 2004). Rejuvenation Res. 7: 257-256, 2004.
13. Vasan, S., Zhang, X., Zhang, X., et al. An agent cleaving glucose-derived protein crosslinks
in vitro and in vivo. Nature 382: 275-278, 1996.
14. Kass, D. A., Shapiro, E. P., Kawaguchi, M., et al. Improved arterial compliance by a novel
advanced glycation end-product crosslink breaker. Circulation 104: 1464-1470, 2001.
15. Barzilai, N., She, L., Liu, B. Q., et al. Surgical removal of visceral fat reverses hepatic
insulin resistance. Diabetes 48: 94-98, 1999.
16. Ouyang, Q., Wagner, W. M., Voehringer, D., et al. Age-associated accumulation of CMVspecific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1).
Exp. Gerontol. 38: 911-920, 2003.
17. Campisi, J. Cellular senescence, cancer and aging. Rejuvenation Res. 8: S25, 2005.
18. Lemasters, J. J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense
against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 8: 3-5,
2005.
19. de Grey, A. D. N. J. Mitochondrial gene therapy: an arena for the biomedical use of inteins.
Trends Biotechnol. 18: 394-399, 2000.
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20. Nagley, P., Farrell, L. B., Gearing, D. P., et al. Assembly of functional proton-translocating
ATPase complex in yeast mitochondria with cytoplasmically synthesized subunit 8, a
polypeptide normally encoded within the organelle. Proc. Natl. Acad. Sci. USA 85: 20912095, 1988.
21. Zullo, S. J., Parks, W. T., Chloupkova, M., et al. Stable transformation of CHO Cells and
human NARP cybrids confers oligomycin resistance (olir) following transfer of a
mitochondrial DNA-encoded olir ATPase6 gene to the nuclear genome: a model system for
mtDNA gene therapy. Rejuvenation Res. 8: 18-28, 2005.
22. Khrapko K. Mitochondrial DNA gene therapy: a gene therapy for aging? Rejuvenation Res.
8: 6-8, 2005.
23. de Grey, A. D. N. J, Alvarez, P. J. J, Brady, R. O., et al.. Medical bioremediation: prospects
for the application of microbial catabolic diversity to aging and several major age-related
diseases. Ageing Res. Rev. 4: 315-338, 2005.
24. Jessup, W., Brown, A. J. Novel routes for metabolism of 7-ketocholesterol. Rejuvenation
Res. 8: 9-12, 2005.
25. de Grey, A. D. N. J. Bioremediation meets biomedicine: therapeutic translation of microbial
catabolism to the lysosome. Trends Biotechnol. 20: 452-455, 2002.
26. Gayle, E. F. The Chemical Activities of Bacteria. London: Academic Press, 1952.
27. Holliday, R. Mutations and epimutations in mammalian cells. Mutat Res. 250: 351-363,
1991.
28. Busuttil, R. A., Dolle, M., Campisi, J., et al. Genomic instability, aging, and cellular
senescence. Annals N.Y. Acad. Sci. 1019:245-255, 2004.
29. de Grey, A. D. N. J, Campbell, F. C., Dokal, I., et al. Total deletion of in vivo telomere
elongation capacity: an ambitious but possibly ultimate cure for all age-related human
cancers. Annals N.Y. Acad. Sci. 1019:147-170, 2004.
30. de Grey, A. D. N. J. Whole-body interdiction of lengthening of telomeres: a proposal for
cancer prevention. Front. Biosci. 10: 2420-2429, 2005.
31. de Grey, A. D. N. J. Escape velocity: why the prospect of extreme human life extension
matters now. PLoS Biol. 2: 723-726, 2004.