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Following the first presentation of our
Annual Meeting Session Spotlight (see
our September issue on
Sarcopenia: Cause, Effect
and Treatment), we are continuing our
series with Immunity and Infection
(session scheduled for the morning
of June 4). Dr. Laura Haynes, who
will be chairing this session, provides
us with a background (below). As
always,
we encourage your comments and questions.
Immunity and Infection
CHAIR:
Laura Haynes, PhD, Trudeau Institute, USA
Age and the Adaptive Immune System
-
Jörg
J. Goronzy,
MD, Emory University
The Effect of Age on the Cognate Function of CD4 T- Cells
-
Laura Haynes, PhD,
Trudeau Institute
Influenza Vaccination: T-Cell
Responses Translate to Health
Outcomes in Older Adults
-
Janet McElhaney, MD,
University of Connecticut Health
Center
(Background provided by Dr. Laura Haynes, Session Chair)
This session will address how
age-related changes influence
the function of the immune
system. As individuals age,
morbidity and mortality
resulting from infectious
disease increases. This is
especially evident for new
emerging diseases such as West
Nile virus, severe acute
respiratory syndrome (SARS) and
possibly for new strains of
influenza virus such as bird
flu. Importantly, the ability of
aged individuals to respond to
vaccinations against infectious
diseases also declines. For
example, the yearly influenza
vaccine exhibits only 40-60%
efficacy in elderly populations,
leaving them much more
susceptible to infection
compared to younger populations.
Studies in humans have focused
on antibody production in
response to vaccination and have
shown significant reduction in
antibody production in response
to vaccinations including
influenza, tetanus and hepatitis
in the elderly. In addition to
reduced antibody production,
current vaccines induce less
vigorous cell mediated immune
responses, including reduced T
cell proliferation and IFN-g
production in the aged. Clearly,
this is problematic since the
elderly are often targeted for
vaccination.
In
this session, presentations will
address several aspects of how
aging influences immune
function. I will present basic
studies on which specific cell
types are involved in this
age-related decline in immune
function, especially with regard
to response to vaccinations. Dr.
Goronzy will present a talk on
other age-related changes in
immune function as well as
proposed mechanisms for why
these defects occur. Additionally, Dr.
McElhaney will present her
studies examining better
approaches for studying vaccine
efficacy for elderly
populations.
CHAIR:
 Laura Haynes, PhD,
Trudeau Institute -
Dr. Haynes is an Associate
Member at Trudeau Institute
in Saranac Lake, NY. She has
been working in the field of
aging and immunity since
1994. Her work is focused on
how aging influences the
function of CD4 T cells and
how this impacts the
efficacy of vaccines in the
elderly. She and her
collaborator, Dr. Susan
Swain, pioneered the use of
T cell receptor transgenic
mice in the study of the
effects of aging on immune
function. The model that
they developed allowed for
the direct examination of
antigen-specific naive CD4 T
cells from young and aged
animals both in vitro and in
vivo. Dr. Haynes found that
even in a young environment,
CD4 T cells from aged donors
exhibit poor cognate
function leading to reduced
humoral responses. In
contrast, CD4 T cells from
young donors exhibit potent
cognate function in aged
hosts. Thus, aging has a
dramatic impact on the
cognate function of naive
CD4 T cells which can
influence the response to
both new pathogens and new
vaccinations in aged
individuals.
 Jörg
J. Goronzy, MD, Emory
University -
Dr. Goronzy, MD, PhD, is the
Mason I. Lowance, M.D.
Professor of Medicine and
Director of the Kathleen B.
and Mason I. Lowance Center
for Human Immunology in the
Department of Medicine at
Emory University. From 1990
to 2003, Dr. Goronzy was on
the faculty of the Mayo
Medical and Graduate School,
where he was Professor of
Medicine and Immunology and
Director of the Clinical
Immunology and
Immunotherapeutics Program
in the Department of
Medicine. He received his
medical degree from the
University of Aachen, a
doctoral degree in medicine
from the University of Bonn
in 1979, and a doctoral
degree in medical sciences
from the University of
Heidelberg in 1988. He did
a residency in internal
medicine at Hannover Medical
School in Germany and a
fellowship in clinical
immunology and rheumatology
at Stanford University.
Dr. Goronzy is a leading
researcher in the field of
human immunology. His
research has focused on
molecular pathways
regulating the function of T
lymphocytes in protective
and pathologic immune
responses. Dr. Goronzy’s
work on how humans generate,
select and maintain
immunocompetent cells over
the course of a lifetime has
led to insights into
mechanisms of immune aging,
the effect of aging on
autoimmunity, and the
ability to generate
protective immune responses.
He is author or coauthor of
over two hundred
publications. Among his
awards are the Henry Kunkel
Young Investigator Award
from the American College of
Rheumatology and the
Department of Medicine
Outstanding Investigator
Award from the Mayo
Foundation. He is an
elected member of the
American Association of
Physicians and the American
Society for Clinical
Investigation.
 Janet McElhaney, MD,
University of Connecticut
Health Center - Dr.
McElhaney, MD is an
Associate Professor of
Medicine at the University
of Connecticut (UConn)
School of Medicine and is
Board Certified in both
Internal Medicine and
Geriatric Medicine. Her
research has focused on the
development of assays that
measure T-cell responses to
influenza vaccination and
correlate with protection
against influenza in older
adults. Ultimately, these
assays may be applied to
screen new vaccines for
improved efficacy and
identifying other vaccine
preventable diseases in
older adults. This research
program has been funded by
the National Institute on
Aging (R01AG20634) and
currently by the National
Institute of Allergy and
Infectious Diseases
(R01AI68265).
Read more at:
http://immunotherapy.uchc.edu/labs_mcelhaney.htm
Wish to contact any of the speakers or
comment? Click here.
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Aubrey D.N.J. de Grey, PhD
 Dr.
de Grey holds a B.A., an M.A. and a
Ph.D. from the University of
Cambridge, Cambridge, UK.
Since 1992, Dr. de Grey has been part
of the Department of Genetics,
University of Cambridge. The central goal of his work is to
expedite the development of a true
cure for human aging. Dr. de Grey is the Editor of
"Rejuvenation Research", the world's only peer-reviewed
journal focused on intervention in aging. His
research interests encompass the etiology of all the
accumulating and eventually pathogenic molecular and
cellular side-effects of metabolism that constitute
mammalian aging and the design of interventions to
reverse and/or obviate this accumulation.
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SENS:
an overview for biogerontologists -
Possibly unaware of what he may be
unleashing,
Norm Wolf has asked me to
outline in the AGE newsletter the
approach to postponing aging that I have
been developing for the past five years
[1-3]. It goes by the acronym SENS,
standing for “Strategies for
Engineered Negligible Senescence”,
and I have given it this provocative
name without hyperbole: I claim that it
genuinely has the potential to convert a
species that ages (namely humans) into
one that, at least within the limits of
statistical detectability, does not.
This claim so vastly exceeds that made
for any other future anti-aging strategy
advocated by mainstream
biogerontologists that the reaction of
many in our field has been initially to
look the other way and, more recently,
to dissociate themselves publicly from
something so radical [4]. Much of the
established biology on which SENS builds
is not traditionally considered relevant
to gerontology; doubtless largely
because of this, the reasons recently
stated [4] for skepticism about SENS
have revealed considerable
misunderstanding both of what SENS
proposes and of how close we already are
to implementing its components [5].
Thus, now is an appropriate time to
describe the SENS approach in a forum
such as this. In the interests of
brevity I will not go into the details
of the SENS components where I have
published those details extensively
elsewhere (cited below and available as
preprints at http://www.gen.cam.ac.uk/sens/AdGpubs.htm;
instead I shall focus on SENS’s overall
structure, motivation and justification,
which I perceive are the main points of
contention regarding its credibility.
SENS departs from conventional
biogerontological strategies for
delaying aging in two main ways, both of
which run sharply counter to
conventional wisdom regarding what
approaches to postponing aging might be
effective. Firstly, it is a piecemeal
approach, consisting of a panel of
interventions each focused on one aspect
of aging: this might initially seem
doomed by the ubiquitous phenomenon of
antagonistic pleiotropy, whereby
retardation of one aspect of aging
(e.g., raising p53 levels to prevent
cancer) is prone to accelerate other
aspects (e.g., loss of stem cells
through overly hair-trigger apoptosis).
Second, these interventions are not
pre-emptive measures to "clean up"
metabolism and prevent it from
initiating the cascade of events that
eventually lead to age-related
pathology: rather, the SENS components
are aimed either at repairing the
eventually deleterious side-effects of
metabolism before they spiral out of
control, or else at obviating
them, i.e. interrupting the mechanism by
which they lead to pathology. This would
seem to disregard the even more
ubiquitous rule that prevention is
better than cure. I will therefore begin
by justifying why these two features are
not reasons to reject SENS out of hand.
Figure 1. The bipartite nature of aging
and three paradigms for intervention.
Figure 1 summarises the differences
between three conceptual approaches to
delaying age-related pathology. The
functional decline of aging, for brevity
denoted “pathology” in Figure 1 and
hereafter, is ultimately a side-effect
of metabolism, linked to it by an
immensely complex and interwoven chain
of events. However, that chain can be
dissected into two steps, linked by a
set of phenomena that I will group under
the term "damage." The point of this
dissection is that there is a key
distinction between the (composite)
process by which metabolism causes
damage and that by which damage causes
pathology: the former is an ongoing
process throughout life, whereas the
latter is an eventual process
that occurs at a meaningful rate only
after damage has risen to a threshold
level of abundance. Phenomena that
qualify as damage thus include, for
example, mutations; processes that link
metabolism to mutations include the
creation of oxidative damage by free
radicals generated as a side-effect of
respiration; and processes that link
mutations to pathology include the
failure of cell cycle control due to the
loss of expression of mutated genes,
leading to cancer. In terms of the
postponement of age-related pathology,
the geriatrician focuses on the stage
when pathology has already emerged,
attempting to slow its progression,
while the gerontologist aspires to
“clean up” metabolism and thereby slow
the rate at which damage is laid down in
the first place. The engineering
approach, epitomised by SENS, allows
damage to occur but periodically (a)
repairs the damage, so preventing it
from reaching pathogenic levels, and/or
(b) prevents the chain of events
downstream of the damage from operating.
One further property is required for a
phenomenon to qualify as "damage" in the
sense I am using the word: it must not
be subject to natural repair. Many
molecular and cellular changes that
occur throughout life and are eventually
bad for us are excluded from the set of
intermediaries between metabolism and
pathology because the change is in the
equilibrium between creation and
removal, so is necessarily secondary to
other changes that alter the rates of
creation and removal. An example is the
shift in plasma redox poise to a more
oxidised state.
The validity of this separation of aging
into ongoing processes and eventual
processes can be seen by considering the
time course of age-related pathology:
namely, that it is essentially absent
for the first half of life and then
accelerates. Forty-year-olds who have
paid attention to their health function
virtually as well (both mentally and
physically) as 20-year-olds, but they
have a considerably shorter remaining
life expectancy: this can only be
because, while changes have been
accumulating at the molecular and
cellular level, these have not yet
become sufficiently abundant to impair
function. In other words, all
age-related pathology must arise via
accumulating intermediates of some kind
– in other words, damage as defined in
Figure 1.
Even if it is valid, is this insight
useful? My reason for claiming that it
is will also provide my answers to the
two challenges to the plausibility of
SENS mentioned earlier.
|
Aspects of metabolism |
|
Types of damage |
|
Age-related pathologies |
|
Respiration
(via oxidation)
Carbohydrate metabolism
(via glycation)
Cell turnover (via
mutations,
telomere shortening, stem
cell depletion, etc)
Etc, etc, etc |
|
Cell depletion
Extracellular crosslinks
Extracellular aggregates
Death-resistant cells
Mitochondrial mutations
Lysosomal aggregates
Nuclear [epi]mutations
Er.... that’s it! |
|
Neurodegeneration
Atherosclerosis
Cancer
Diabetes
Hormonal imbalance
Blindness
Immune decline
Etc, etc, etc |
Table 1. Damage is complex, but much
less so than metabolism or pathology.
Table 1 encapsulates the main reason why
I claim that the engineering approach is
so much more feasible than the
gerontology and geriatrics approaches to
postponing age-related functional
decline. The geriatrics approach is
futile in any more than the short term
because age-related pathology is so
complex: the items listed in the
right-hand column above are palpably a
very incomplete list of what goes wrong
in older people. The gerontology
approach is also futile for the
foreseeable future, for essentially the
same reason: however much we may have
learned about metabolism in recent
decades, we all know full well that we
have hardly scratched its surface, and
it seems clear that we will need to
understand it really very well indeed in
order to clean it up substantially
without unacceptable side-effects. The
left-hand column lists a few of the
aspects of metabolism that tend to get a
lot of the blame for aging, but it would
be biologically naïve to absolve any
aspect of metabolism from involvement in
aging, since metabolism is an
interlocking network of processes.
Contemporary efforts to slow the
accumulation of damage are therefore
mostly restricted to eliciting pathways
that the organism already encodes,
notably for survivability of famines;
this clearly has only limited potential,
and for humans it may be very limited
indeed [6].
The SENS approach is founded on the
assertion declared in the middle column
of Table 1 – that unlike metabolism or
pathology, damage can adequately
thoroughly (note that I elaborate on
this qualification below) be classified
into just seven categories, each of
which is potentially remediable by
foreseeable interventions that either
repair it (remove the damage) or obviate
it (render it unable to contribute to
pathology). The objection from
antagonistic pleiotropy is met because
the proposal is to address all
types of damage – thus, the possibility
that an unaddressed one will be
exacerbated by the treatments for the
others does not arise. The objection
that prevention is always better than
cure is met too: SENS acts early enough
in the chain of events to make
comprehensiveness feasible, just not so
early that our ignorance of metabolism
will foil us. Putting it another way,
acting on the damage itself allows us to
sidestep our ignorance of
metabolism: we let metabolism create
damage at the natural rate, so we need
not understand metabolism nearly so well
as we would for comparable efficacy via
the gerontology approach. (Consider how
little one need know of the chemistry of
rusting in order to maintain a car.) In
particular, we do not need to determine
the pecking order for the contribution
of different aspects of metabolism to a
given type of damage, nor of different
types of damage to a particular
pathology: whatever their relative
importance, fixing all the types of
damage will suffice.
An obvious challenge to the above is
that even if all categories of damage
could be adequately repaired
individually, the relevant therapies
might interact in undesirable ways when
simultaneously applied to the same
individual. But this is in fact a
further advantage of SENS: since damage
is defined as side-effects of metabolism
that accumulate due to the absence of
repair, it consists only of molecular or
cellular changes that are metabolically
inert (until they become too abundant),
so whose elimination might have
side-effects if performed
inappropriately (e.g., dissolving
amyloid might be a bad idea if the
resulting rise in concentration of
soluble amyloidogenic protein is toxic)
but would be most unlikely to have
side-effects in combination with other
SENS therapies if it had none on its
own.
Before briefly mentioning the classes of
damage and corresponding interventions,
I will consider two further general
challenges to SENS: first, how can I be
confident that the seven classes of
damage listed above are really all there
are, and second, how can I claim that
these classes will be treatable so
thoroughly that aging can be postponed
indefinitely?
The claim of adequate approximation to
completeness (I define and explain
“adequate” below) of the seven SENS "deadly things" becomes less startling
when we note that damage can only
accumulate in structures that are
long-lived or are constructed by copying
pre-existing ones. Within cells this
means damage to DNA (nuclear and
mitochondrial) and accumulation of
degradation-resistant material within
the lysosome (including material that
actively interferes with lysosomal
function). Outside the cell it means
accumulation of degradation-resistant
material (e.g. amyloid) and
biomechanical changes to structures that
are not turned over (such as the lens or
the artery wall). To these must be added
changes in number of a given cell type –
both depletion, due to death not matched
by replacement, and accumulation, due to
generation not matched by cell death. It
is certainly possible to extend this
list with additional side-effects of
metabolism – aspartate racemisation in
long-lived proteins, for example – but I
contend that there is currently no
strong evidence that any of these (a)
contributes to pathology [within a
currently normal human lifetime – see
below] and (b) is resistant to natural
repair other things being equal, i.e.
would not revert to youthful levels
spontaneously if the seven categories
listed in Table 1 were restored to
youthful levels.
The repair/obviation strategies outlined
below are clearly able to address their
respective category of damage only
partially. ALT-711 only breaks one type
of protein-protein cross-link; anti-Ab
vaccines eliminate only one type of
amyloid; genetic therapies such as
allotopic expression of the mtDNA-encoded
proteins require delivery to the
relevant cells, which is of finite and
variable efficiency depending on
delivery method and cell type; and so
on. Moreover, at ages greatly exceeding
a currently normal human lifespan
(though, I claim, not before [7]) it is
very likely that nuclear mutations and
epimutations not leading to cancer will
reach pathogenic levels, requiring cell
replacement therapies of much greater
sophistication than are within reach
today. However, this does not contradict
my assertion that we will probably be
able to achieve engineered negligible
senescence within a few decades. This is
for a simple reason: we do not have to
repair all the damage in each
category in order to prevent pathology,
only enough of it to reduce the level
below that tolerable by metabolism.
Thus, maintenance of youthful physiology
(and thus a youthful mortality rate) can
be achieved soon and sustained
indefinitely if we repair each category
adequately.
How thoroughly is "adequately"? Perfect
repair will never be necessary, but
increasingly thorough repair will be
needed as people attain ever-greater
ages. For example, if each species of extracellular protein-protein cross-link
accumulates at its own rate and
contributes proportionately to loss of
elasticity in structures such as the
lens, and supposing for simplicity that
one species contributes 50% of the
links, even the most thorough and
repeated cleavage of that species but no
other will still leave a 160-year-old
with lenses as stiff as those of today’s
80-year-olds, so the second (and
subsequent) most abundant species must
eventually be addressed in turn. But the
good news is that once the initial
breakthrough has occurred (eliminating
the first major subclass within a
category of damage), the rate at which
these subsequent, incremental advances
must be made in order to keep the total
level of damage down to reasonably
youthful levels is quite modest by the
standards of technological progress
generally (as illustrated by, for
example, the history of powered flight
since 1903, computers since 1950 or
combating of infectious diseases since
the mid-1800s). This is why I have
claimed [3] that the cusp we need to
reach in order to attain “longevity
escape velocity” (where those receiving
state-of-the-art medical care at all
times are not becoming “biologically
older” as measured by function or
mortality rate) is the addition of only
30 healthy years to the lifespans of
those who are in their mid-50s when the
therapies arrive. (Interestingly,
achieving escape velocity for
shorter-lived species is thus harder –
indeed, maybe never possible for species
whose natural lifespan is under a
decade.)
It remains only to enumerate the
proposed repair/obviation strategies
that I claim will, with 50% cumulative
probability subject to funding, be
implementable within 25 years from now
sufficiently thoroughly to achieve the
30-year, late-onset, healthy life
extension goal just mentioned. I have
derived this estimated timeframe, after
detailed consultation with the
experimentalists who have performed the
most relevant work (and who are mostly
not biogerontologists), from
consideration of:
- the
difficulty of demonstrating the
various interventions in mice (which
has already occurred in a limited
way for some categories, and which I
claim is achievable, subject to
funding, within 10 years with 90%
probability in all seven
categories);
- the
technical difficulty of translating
them to humans once demonstrated in
unison in mice;
- the
social context within which the
translation to humans will be
attempted, bearing in mind that
successful implementation in mice
should at least treble the remaining
lifespan of naturally long-lived
strains (life expectancy raised from
3 years to 5 years) if initiated at
age 2 years and this will imply the
potential malleability of human
aging in an unprecedentedly dramatic
way.
The therapies are listed, with
references to my publications (in which
the relevant experimental work is, of
course, fully cited), in Table 2. (I
have not published on stem cells or
growth factors, but the pace of progress
in replenishing all cell types subject
to age-related depletion is rapid, as I
am confident readers are aware.) All my
publications are available in preprint
form at my website, on this page:
http://www.gen.cam.ac.uk/sens/AdGpubs.htm.
|
Type of damage |
Proposed repair (or
obviation) |
|
Cell depletion |
Stem cells, growth factors,
exercise |
|
Extracellular cross-links |
AGE-breaking molecules, e.g.
ALT-711 [8] |
|
Extracellular aggregates |
Immune-mediated phagocytosis
[8] |
|
Death-resistant cells |
Ablation of unwanted cells
[8] |
|
Mitochondrial mutations |
Allotopic expression of 13
proteins [9] |
|
Lysosomal aggregates |
Microbial hydrolases [10,11] |
|
Oncogenic nuclear mutations/epimutations |
"WILT" (Whole-body
Interdiction of Lengthening
of Telomeres) [12,13] |
Table 2. First-generation strategies for
repairing or obviating the SENS “seven
deadly things”.
In closing, I feel impelled to stress
that the merits of the SENS program do
not strongly rely on the accuracy of the
timeframe estimates above. A key
question that biogerontologists always
have a duty to address is which research
and biomedical directions to follow in
order to extend people’s healthy lives
as much as possible, as soon as
possible. If an intervention is capable
of postponing aging indefinitely once
implemented to a given standard, as I
have here claimed is the case for SENS,
there is a strong case for pursuing it
(though certainly not to the exclusion
of less ambitious alternatives that can
probably be achieved sooner) even if the
timeframe for its implementation is
thought to be several decades and/or if
the chance of achieving it within a few
decades is thought to be modest (say
10%). A proposed intervention with that
sort of potential can only be
justifiably deprioritised if it is so
incompletely specified that continuing
an exclusive focus on improving our
understanding of aging is perceived
still to be the most time-efficient way
forward even though that "basic science"
approach is, by definition, not
goal-directed. I claim that, while by no
means complete in every detail, SENS is
sufficiently detailed to merit its
pursuit at this time.
I look forward to colleagues' comments.
References
1.
de
Grey ADNJ, Ames BN, Andersen JK, Bartke
A, Campisi J, Heward CB, McCarter RJM,
Stock G. Time to talk SENS: critiquing
the immutability of human aging. Annals
NY Acad Sci 2002; 959:452-462.
2.
de
Grey ADNJ. An engineer's approach to the
development of real anti-aging medicine.
Science's SAGE KE 2003; http://sageke.sciencemag.org/cgi/content/full/sageke;2003/1/vp1.
3.
de
Grey ADNJ. Escape velocity: why the
prospect of extreme human life extension
matters now. PLoS Biol 2004;
2(6):723-726.
4.
Warner HR, Andersen JK, Austad SN,
Bergamini E, Bredesen D, Butler RN,
Carnes BA, Clark BFC, Cristofalo VJ,
Faulkner JA, Guarente L, Harrison DE,
Kirkwood TBL, Lithgow GJ, Martin GM,
Masoro EJ, Melov S, Miller RA, Olshansky
SJ, Partridge L, Pereira-Smith O, Perls
TT, Richardson A, Smith JR, von
Zglinicki T, Wang E, Wei JY, Williams TF.
Science fact and the SENS agenda: What
can we reasonably expect from ageing
research? EMBO Reports 2005, in press
(November issue).
5.
de
Grey ADNJ.
Like it or
not, life-extension research extends
beyond biogerontology.
EMBO Reports 2005, in press (November
issue).
6.
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.
7.
de
Grey ADNJ. Are nuclear mutations or
epimutations relevant to other aspects
of mammalian aging than cancer?
Manuscript in preparation.
8.
de
Grey ADNJ. Foreseeable pharmaceutical
repair of age-related extracellular
damage. Curr Drug Targets 2005, in
press.
9.
de
Grey ADNJ. Mitochondrial gene therapy:
an arena for the biomedical use of
inteins. Trends Biotechnol 2000;
18(9):394-399.
10. de
Grey ADNJ. Bioremediation meets
biomedicine: therapeutic translation of
microbial catabolism to the lysosome.
Trends Biotechnol 2002; 20(11):452-455.
11.
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; 4(3):315-338.
12.
de Grey ADNJ, Campbell FC, Dokal I,
Fairbairn LJ, Graham GJ, Jahoda CAB,
Porter ACG. Total deletion of in vivo
telomere elongation capacity: an
ambitious but possibly ultimate cure for
all age-related human cancers. Annals
NY Acad Sci 2004; 1019:147-170.
13.
de Grey ADNJ.
Whole-body
interdiction of lengthening of
telomeres: a proposal for cancer
prevention. Front Biosci 2005;
10:2420-2429.
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