EMBO Reports 6, S1, S49â€"S53 2005
A perennial complaint in
biogerontology, and one whose legitimacy I would be the last
to dispute, is that public funding for ageing research is
far lower than it should be. Such funding has roughly kept
pace with biomedical research spending as a whole, but much
more is warranted because postponement of ageing would have
a far greater impact on public health and healthcare
spending than postponement of any or all of the major
age-related diseases. Here, I discuss whether our
obstinately modest funding is due, as most of my
biogerontologist colleagues evidently feel, to a failure on
our part to communicate the scientific and biomedical
realities to our political paymasters, and is therefore best
rectified by continuing to repeat the arguments we have used
for decades until they sink in. I argue that it is instead
because those arguments are genuinely weak. I then discuss
whether our neglect of more effective justifications for
greater investment in biogerontology research is because we
overlook key components of the trade-offs that determine
funding policy, or whether the problem is the failure of
most biogerontologists to maintain an open mind concerning
the scientific options. I conclude that it is for both those
reasons. Thus, our field is passing up the opportunity to
elevate itself to its rightful level of public appreciation
and investment, with the result that much longer healthy
lives are being denied those who will die before 'real
anti-ageing medicine' arrives unless we start working harder
towards it now.
This essay covers controversial and
sensitive issues, so I start with the safest one. Most
biogerontologists believe, or at least claim, that a
legitimate and plausible long-term goal of their research is
to extend the healthy human lifespan by intervening in the
ageing process. Even that seemingly anodyne description of
what biogerontologists seek is replete with land mines, so I
prepare the ground by clarifying what biogerontologists, by
and large, do and do not mean by it.
First, what is 'the ageing process'?
In the context of discussing interventions, ageing can be
defined as the lifelong accumulation of various intrinsic
side effects of normal metabolic processes, which ultimately
reach an abundance that disrupts metabolism and causes
severe dysfunction of tissues and the whole organism. Some
aspects of this dysfunction are classified as age-related
diseases, and some less specifically as 'frailty', but their
common cause is the accumulation of damaging metabolic side
effects. Accordingly, treatments that either slow the rate
of that accumulation or actually reverse it will, if
sufficiently comprehensive, postpone the recipient's decline
into age-related ill health.
Second, biogerontologists generally
focus strongly on healthy lifespan as opposed to total
lifespan. There is general agreement that it is not a
worthwhile goal to improve our ability to keep severely ill
people alive for a long time if, as is the case today, there
is no prospect of ever restoring them to better health. But
this 'expansion of morbidity'â€"extension of the average time
that people are frail at the end of their livesâ€"is not what
most biogerontologists seek. Instead, their goal is
'compression of morbidity'â€"postponement of the onset of ill
health caused by ageing, but with only a shorter
postponement, if any, of death.
The merits of this goal seem
unassailable. Not only is frailty unenviable, it is also
extremely expensive: diverse statistics show that the amount
of healthcare resources that people consume during their
last year of life, whatever their age at death, is typically
more than in the rest of their life in total (Himsworth
& Goldacre, 1999). Compression of morbidity would thus
not only relieve suffering on a huge scale but also be
staggeringly beneficial economically. I do not claim
originality for this logic. Indeed, it has been the mantra
of gerontology since time immemorial. On the cover of the
first issue of the Journal of Gerontology in 1946, it
appeared in the form of the phrase "to add life to years,
not just years to life". The merits of intervening in ageing
itself, rather than concentrating on its late-life
consequences, are also trumpeted in the equally age-old
aphorism that "ageing is not a disease".
One may thus wonder why progress in
attracting funds to pursue these goals has been so slow (Perry,
2004). It was not until 1975 that the US National
Institutes of Health (NIH; Bethesda, MD, USA) opened the
National Institute on Aging (NIA); the NIA still receives
only about 3% of the NIH's total budget, no more than it did
a decade ago. Moreover, even within the NIA only 10% of
funds are directed at the basic biology of ageing per se,
with the remainder being ring-fenced for research on
Alzheimer's disease and behavioural, social or clinical
gerontology.
The ultimate power to determine how
much public money is spent on ageing research lies,
inevitably, with politicians (Mackey,
2004); evidently, therefore, biogerontology's rhetoric
is rather ineffective at swaying them. For illustration, I
focus here on the USA, whose biomedical research expenditure
is the highest in the world, but what I write applies
worldwide. The head of each institute of the NIH gives a
presentation to the US Congress each year. At these
hearings, the NIA's Director consistently delivers the
message "adding life to years, not just years to life" to
Representatives and Senators. And with the same regularity,
the NIA's budget remains in lockstep with those institutes
that focus on specific age-related diseases, even though the
postponement of the latter would do much less for public
health than the achievement of the NIA's goals. Why?
I feel that there are two main
reasons for politicians' resistance to the blandishments of
gerontologists, one of which many biogerontologists
consistently overlook. The one that they wholly appreciate
was perhaps best expressed by Rich Miller in his mostly
outstanding essay "Extending Life: Scientific Prospects and
Political Obstacles" (Miller,
2002): "Senators' and voters' parents died of specific
diseases." (That article has been widely acknowledged as the
definitive account of the issues it addresses, so I shall
return to it repeatedly here, to highlight both the
qualities and the shortcomings of its arguments.) Ageing
therefore does not ignite politicians' emotions when
resources are limited and noble causes are seemingly
unlimited. This, biogerontologists mostly believe, is a
major mental block that impedes politicians' ability to
accept what any objective observer shouldâ€"in the
biogerontologist's viewâ€"consider obvious.
Before moving on to discuss the
second, widely overlooked, source of political resistance to
funding ageing research, we can already note how the
traditional gerontological rhetoric has become an
albatrossâ€"and perhaps always was. "Ageing is not a disease",
as I noted earlier, has long been a slogan of gerontology.
Politicians may be inclined to feel that, well, if ageing is
not a disease, it is probably not something we ought to be
spending much effort combating, then, is it? When we reflect
that this is a gut feeling that most people, and thus most
politicians, probably have at the outsetâ€"what Miller (2002)
termed "gerontologiphobia"â€"and also that when money is tight
its allocators seek excuses to narrow the list of candidate
recipients, we see clearly that describing ageing as "not a
disease" has severe rhetorical drawbacks, regardless of the
value it may once have had in distinguishing biogerontology
from other biomedical research.
This problem is in my view dwarfed,
however, by the second difficulty that politicians may have
in embracing biogerontologists' arguments: the merit of
spending money in pursuit of a given goal depends not only
on that goal's desirability but also on its feasibility.
Those of us who do not suffer from gerontologiphobia are
persistently awed by the logical contortions that
gerontologiphobes perform when asked to justify their
pro-ageing stance. Similar aweâ€"although that might not be
the word they would useâ€"may be felt by politicians who
encounter the efforts of gerontologists to extract from
available data an argument that their work will probably
cause substantial compression of morbidity in the
foreseeable future.
Although the concept is much older,
the term 'compression of morbidity' was introduced by James
Fries in a paper published in 1980: "Present data allow
calculation of the ideal average life span, approximately 85
years. Chronic illness may presumably be postponed by
changes in life style [...] Thus, the average age at first
infirmity can be raised, thereby making the morbidity curve
more rectangular. Extension of adult vigor far into a fixed
life span compresses the period of senescence near the end
of life" (Fries,
1980). Even ignoring the questionable assumption of a
fixed lifespan, we immediately see that Fries is not
predicting that combating ageing will compress morbidity.
Instead, he stresses "changes in life style"â€"not a noted
sphere of biogerontological influence. Fries's hope that US
morbidity would be compressed has been realized in the
meantime, and the details of that change duly support the
theory that lifestyle, rather than biomedical progress, is
responsible. All the compression observed is in mild to
moderate disability, which is substantially achievable by
lifestyle changes, whereas absolutely no compression of
severe morbidity has occurred (Fries,
2003).
One must also doubt the biological
plausibility that postponing frailty will not similarly
postpone death. For this to occur, there must be some aspect
of ageing that contributes more to death than to frailty:
compression of morbidity might then be achieved by
postponing only the other aspects of ageing. But if we have
learned anything about ageing over the past decades, it is
that ageing consists of multiple interacting processes that
are mutually regulated. Altering the rate of some such
processes but not others is thus a highly implausible goal.
Fries's assumption of a fixed lifespan is certainly wrong,
and indeed he may only have been speaking about the time
until means of truly postponing ageing are developed.
However, whether before that advance or beyond it,
compressing morbidity by postponing ageing is a pipe dream.
You would not guess this had you
attended, to take just one conspicuous example, an April
2001 presentation to Congress by Richard Hodes, Director of
the NIA (Hodes,
2001). As a major plank of his presentation, Hodes cited
a report that documents compression of morbidity (Manton
et al, 1997). He did not state explicitly that
biogerontology was substantially responsible for this, but
he certainly implied it. I feel he did so in the sincere
belief that progress was being made in combating ageing and
that this was compressing morbidity, although, as noted
above, that is a gross misinterpretation of Manton et al's
data. If this were a successful policy that brought
gerontology an ever-increasing share of public research
spending, it could perhaps be forgivenâ€"but it has not done
that.
I suspect that, in their heart of
hearts, many of my colleagues in biogerontology secretly
realize or at least fear the futility of compressing
morbidity by manipulating ageing. These people face an
unenviable problem: they are scientists trapped in a
biomedical discipline, so their path of least resistance may
be to submit to the gerontologiphobia of society and not
rock the boat. I should explain what I mean by this. When
many of today's senior biogerontologists entered the field,
serious postponement of ageing was not realistic, and they
therefore became biogerontologists partlyâ€"and in most cases,
I believe, mainlyâ€"with the curiosity-driven motivations of a
basic scientist rather than the goal-directed ones of an
engineer or clinician. They find discovery fulfilling, and
seek only the resources to carry on discovering more. Any
talk of actually doing something about ageing is then a Fig
leafâ€"the sort of camouflage that all scientists use to make
society value their work without fretting that there is no
guarantee that it will ever be useful. Perhaps this is why
those who propound the most blatantly invalid reasons why
our hitherto minimal rate of progress in postponing ageing
cannot be acceleratedâ€"reasons transparently based on misuse
of logic (Hayflick,
2004) or of extrapolation (Olshansky
et al, 2001)â€"are often allowed to carry on
espousing their views without challenge. There may be a
tacit hope that the blinding unjustifiability of their
pessimism will distract the attention of the funding bodies
from the subtler contradictions in what mainstream
gerontology is saying to justify its existence.
If I thought that serious
postponement of ageing was still an indefinitely distant
prospect, I would thus feel that the honest way forward for
biogerontology would be to reinvent itself as a basic
science, with no pretensions to biomedical relevance other
than what may arise from serendipitous discoveries along the
way. In reality, however, I contend that we now know enough
about ageing and how we might postpone it that it is time to
try. Our appropriate course should therefore be in the
opposite direction: to declare that our goal is to postpone
ageing as much as possible, as soon as possible, to describe
how we intend to do this, and to respond to the inchoate
gerontologiphobic mutterings of the pro-ageing masses with
the systematic dismantling of their logic (de
Grey, 2003b) that we biogerontologists all know that we
can deliver but are too often tempted to keep to ourselves
in the interests of a quiet life.
Let me, therefore, leave the reader
in no doubt about what I mean by postponing ageing as much
as possible, as soon as possible. I mean developing ways to
stop people from getting frailer and more prone to
life-threatening diseases as they get older, and moreover to
restore the already frail to youthful vitality (de
Grey et al, 2002;
de Grey, 2003a). I mean doing this indefinitely, so that
people's vigour and risk of death are not influenced by
their age, even at ages many times what we reach today (de
Grey, 2004a). Just as the purpose of oncology is to
defeat cancer, the purpose of biogerontology is, and should
be declared to be, to defeat ageing. Vintage cars do not
age, because their owners have the dedication and expertise
to give them the necessary maintenance. We will in due
course have the expertise to maintain ourselves with similar
fidelity, and few can doubt that we will then also have the
dedication. Hastening that advance, therefore, is a
legitimate and honourable goal of which we have been ashamed
for too long.
Until a few years ago, the only
reproducible way to make a mammal live longer was to reduce
its caloric intake (Masoro,
2003). No one knows quite how this works, so in view of
the popularity of eating in most human populations there was
little biogerontologists could offer in the way of
acceptable life-extension therapies. In recent years,
however, some of the main genetic components of the caloric
restriction (CR) response have been identified, and
lifespans have been extended by genetic manipulationâ€"not
only in short-lived species such as flies, but also in
rodents (Liang
et al, 2003). Pharmacological emulation of these
results is eminently plausible and several researchers have
created start-up companies to accelerate the development of
such drugs (Stuart,
2003).
An alternative approach, which I
have spearheaded for the past 4−5 years, is termed SENS:
Strategies for Engineered Negligible Senescence (de
Grey et al, 2002;
Arking, 2004). It does not consist of a search for
'magic bullets' that will elicit a latent CR-like response
and coordinatedly retard all the processes that contribute
to age-related degeneration, but rather a collection of
piecemeal interventions to repair specific categories of
molecular and cellular damage. As such, it could not be more
different from the CR-emulation approach. At first glance it
seems unlikely to be feasible, but on closer inspection this
is less clear, because SENS consists of interventions that
target the initially inert by-products of metabolism, rather
than metabolism itself, and thus may be much freer of side
effects. Also, because SENS entails repair rather than
retardation, its potential to postpone frailty even in those
who first receive it in middle age is far greater than with
the holistic CR-emulation approach, as is its potential to
do this indefinitely. Reversing a process may seem
intuitively far more difficult than just slowing it down,
but this is not necessarily so: preventing a leaking dinghy
from sinking by bailing water over the side requires no
greater technological sophistication than doing so by
plugging the hole with a rag.
This brings me back to Miller's 2002
commentary. Miller is optimistic about the medium-term
prospects for postponing ageing dramatically by emulating CR
(Miller,
2002): "CR typically produces in rodents an increase in
mean and maximal longevity of about 30−40%. Similarly, the
dwarf mutations of mice lead to an increase in both their
mean and maximal lifespan of about 25−70%, and the
longest-lived small dog breeds typically outlive
average-sized dogs by a similar amount. Restriction of the
amino acid methionine, which, like the restriction of
calories, also retards growth and extends lifespan,
lengthens life by about 30−42%, and a mutation that alters
cellular resistance to irradiation seems to produce mice
that live 28% longer. Thus one can, with some confidence,
expect that an effective antiaging intervention might
increase the mean and maximal human lifespan by about 40%,
which is a mean age at death of about 112 years for
Caucasian American or Japanese women, with an occasional
winner topping out at about 140 years."
This is not a passage of which, in
my view, Miller should be proud. Elsewhere in the essay he
lists several reasons why biogerontology is hard to sell to
politicians, students and the public, the first of which is
that "Most gerontologists who are widely known to the public
are unscrupulous purveyors of useless nostrums." Although he
does not name anyone, others have singled out the American
Academy of Anti-Aging Medicine (A4M;
http://www.worldhealth.net) as the archetype of this
group. Here, for illustrative purposes, is an excerpt from A4M's
mission statement: "A4M believes that the
disabilities associated with normal aging are caused by
physiological dysfunction which in many cases are amenable
to medical treatment, such that the human life span can be
increased, and the quality of one's life improved as one
grows chronologically older." One needs little experience of
promotional literature to spot the selective omissions
hereâ€"there is no mention of whether this medical treatment
is already available, or whether its effect will be on the
lifespan of all, most or only a few people. But that degree
of rose-tinting is typical of those who want to make
moneyâ€"which A4M's leaders do not conceal,
although A4M itself is a non-profit entity;
society considers this acceptable and lays the blame for any
disappointment with non-performance of products at the door
of the over-gullible consumer.
Let us now similarly analyse
Miller's prediction quoted above. "Thus" is a strong word
among scientistsâ€"one that should be avoided unless it can be
robustly defended with data. However, Miller finds it
possible to extrapolate "with some confidence" from
mammalian interventions begun at either conception or
weaning to implicitly foreseeable anti-ageing interventions
for humans. The long-lived mammals that Miller describes are
much smaller than normal members of the same speciesâ€"not
something most people would impose on their children even if
long life resultedâ€"and Miller ignores the complete failure
of CR to extend lifespan when initiated in rats in late life
(Lipman
et al, 1995,
1998). The more encouraging results of Stephen
Spindler's group (Dhahbi
et al, 2004;
Rae, 2004) greatly post-date Miller's essay so do not
excuse this. There is a modest effect if CR is begun earlier
in adulthood (Weindruch
& Walford, 1982), but again, when mentioning this,
Miller fails to acknowledge that taking any CR-mimetic pill
throughout one's adult life is unwise when one weighs the
necessarily unknowable risk of long-term side effects
against the rather large chance of something coming along in
the subsequent decades whose greater efficacy outweighs its
later initiation. Miller also mentions one mouse mutant that
has shown life extension without growth retardation (Migliaccio
et al, 1999), but omits that this was in a strain
so short-lived that most gerontologists considered the
result highly preliminary (Lithgow
& Andersen, 2000). Finally, in common with most
gerontologists, he neglects the clear inverse correlation
across the animal kingdom between the normal lifespan of a
species and the proportion by which that lifespan can be
increased by nutrient deprivation, even though this was
noted in independent publications a decade earlier (Harrison
& Archer, 1989;
Holliday, 1989).
This departure from the critical
incisiveness that earned Miller the influence he now wields
in biogerontology is made worse by the fact that he is not
in this business for the money. Several gerontologists who
share Miller's view have started biotech companies, so
observers are suitably careful in analysing what they say on
these matters. Miller has not, and is thus in a position of
greater authority than everâ€"authority that is abused by
selectivity such as the above.
I have recently published (de
Grey, 2005) a detailed critique of the biological
underpinnings of the CR-emulation approach, extending the
arguments just cited (Harrison
& Archer, 1989;
Holliday, 1989), in which I conclude, on the basis of a
wide variety of data and evolutionary theory, that even
bona fide CR initiated in early adulthood, let alone
pharmacological CR emulation initiated later in life, will
probably confer a maximum addition of 2−3 years of healthy
and total life in humans. My pessimism concerning this
approach to human life extension is therefore available for
open discussionâ€"whether in the academic literature, at the
conference bar or in the wider media.
Many biogerontologists are similarly
pessimistic about the prospects for SENS. Some of their
criticisms are easily dismissed (de
Grey, 2003b). The fact that SENS originates from someone
without experimental training is irrelevantâ€"I indeed know
less than most biogerontologists about how to run a gel, but
I certainly know more than they about the hitherto non-biogerontological
fields that I have brought to bear on the ageing problem, as
I have thoroughly researched the experimental literature in
these areas and discussed my proposals with the researchers
who published that literature, which most biogerontologists
have not done. The absence of modest life-extension results
from existing precursor technologies to SENS means nothing
for the efficacy of the complete SENS panel, any more than
the failure of windscreens, steering wheels and carburettors
to move slowly along the ground when petrol is poured on
them implies anything about their combination. The intuition
that repairing age-related damage must be far harder than
preventing it was rebutted above in general terms and fares
no better when the specifics are examined, because the
hardest parts of both approachesâ€"if one wishes to go further
than what pharmacological CR emulation can promiseâ€"are in
the delivery of genes and cells to somatic tissues,
technologies that will work as well for SENS as for any
other medical purpose.
This does not, of course, suffice to
show that SENS is promising: what is needed is public
scrutiny of its feasibility by researchers who may be better
placed than its author to identify its flaws. In contrast to
my critique of the CR-emulation model, this scrutiny has not
been forthcoming. Is this because my colleagues are
otherwise engaged? Doubtless it largely is. But not
entirely, as shown by the following sentence from an
anonymous review of the first manuscript describing SENS (de
Grey et al, 2002): "I think it would be
irresponsible to publish the work as it stands, because it
could engender quite unwarranted optimism in readers." Even
more blatantly, an anonymous review of a recent manuscript (Rae,
2005) in which Michael Rae, a newcomer to biogerontology,
bemoans the lack of such discussion, stated: "Rae laments
that he 'has yet to hear a cogent rejoinder...' from the
anti-aging skeptics; in my view it's because we skeptics
have yet to see [anything] even remotely convincing from de
Grey and his ilk, and don't wish to draw further public
attention to this fringe movement." While in a certain
respect it is cheering to note that those scientists who
would rather suppress debate than engage in it at least
acknowledge that I have an ilk, most biogerontologists would
have some difficulty in regarding the co-authors of my SENS
papers (see
de Grey et al, 2002) as a 'fringe movement'. One
might thus question whether the author of these comments
entirely lives up to the scientific ideal of open debate.
It virtually goes without saying
that the above state of affairs may be costing lives.
Perhaps the CR-emulation approach is more promising than I
believe at present, in which case the flaws in my arguments
will be identified; my publication of those arguments will
hasten that event and stimulate the development of CR
mimetics. Conversely, perhaps the SENS approach is the more
promising, and if so it will eventually attract the funding
necessary to realize it. That funding will not be readily
forthcoming, however, until SENS has withstood detailed
scrutiny by the biogerontology and other relevant
communities. Delaying such a test by the above stratagems
thus risks a corresponding delay in the development of the
first 'real anti-ageing medicines'. As the risk of death
from accidents and infections as well as 'intrinsic' causes
rises steeply with age (Carnes
& Olshansky, 1997), it is safe to say that fewer people
die of truly age-independent causes above the age of 65 than
of age-related causes below 65: in other words, the death
rate from ageing exceeds the death rate of those over 65.
Thus, ageing claims on the order of 100,000 lives per day (de
Grey, 2004b). Those lives should be in biogerontologists'
minds when we exercise our influence on research directions.
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