Newcastle Symposium on the Goals of Ageing Research
24th-25th April 2001 International Centre for Life Times Square, Newcastle
Session 1. The Challenge of Ageing Science
Session 1.1
Session 1.2 Discussion Points
Contents of Session 1
Chair: Professor Jim Edwardson
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Paper 1.1: A Science Comes of Age - Gordon J. Lithgow
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Paper 1.2: Biological ageing research: Problems of maturation - Thomas von Zglinicki
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Points from Discussions
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Session 1. The Challenge of Ageing Science
Paper 1.1
A Science Comes of Age
Gordon J. Lithgow
Biologists feel a genuine sense of privilege at this time when the accrual of knowledge about life
is so rapid. This is particularly true for those of us involved in studying the basic biology of
ageing. We are in the transition phase from a state, 10 years ago, of profound ignorance to a state
in the near future, when we will have developed a rudimentary knowledge of what determines
lifespan. From the biologist’s point of view, here is the chance to solve one of the last major
questions in basic biology – what makes animals age? Ageing is puzzling, paradoxical, complex,
but we now feel solvable.
What is the utility of this rudimentary knowledge? We are optimistic that some solutions to the
challenges of demographic change might be apparent when the basic biology of the process is
understood. These solutions may in part be interventions in the major age-related diseases that
reduce health span and bring with them a heavy social and economic burden. In addition, we
might better be able to predict the requirements of an ageing population by understanding the
biological changes a person experiences when growing old. However, there are no technological
quick fixes being promised, but instead a new culture of the Science of Aging based less on
speculation and theory and more on hard facts and experience.
How is all this coming about? From my viewpoint, as an experimental biologist, the driving
force has been a few critical experiments performed in a handful of laboratories working with
either human cells or microscopic organisms such as nematodes roundworms or fruit flies. The
discoveries in themselves do not provide all the answers to the questions of ageing but have
completely turned the field on its head. Collectively, these experiments clearly demonstrate that
lifespan is not a fixed quantity, that ageing is not unavoidable and most importantly, that we have
the tools to proceed rapidly to the new knowledge. Ageing has been a darkened room - we may
not yet have found the light switch, we have certainly found a torch.
What are these discoveries that provide me with such confidence? Different species have quite
characteristic lifespan and it is genes that determine these differences in lifespan. Over 100 genes
that determine the lifespan of simple animals have been discovered in the last eight years. These
genes have been uncovered by looking for rare genetic variants of that have prolonged life. For
example, some genetic mutations increase the lifespan of the roundworm C. elegans by up to
300%. The analysis of what those genes do is ongoing in approximately a dozen laboratories
around the world. That work is the beginnings of a complete description of the molecular genetic
influences on ageing and lifespan. It will eventually lead to an understanding of the physiological
determinates of ageing in these simple animal systems.
In a separate line of enquiry, investigations into the causes of the ageing of human cells in
culture have been highly successful. Human cells, when cultured in the laboratory, undergo a
"replicative senescence" in which cell growth and division arrests after a certain number of cell
divisions. While the relevance of this phenomenon to whole animal ageing is still contentious,
the critical cause of replicative senescence in most cells has been discovered. By reversing the
attrition of the ends of chromosomes associated with cell division, human cells can be made
immortal in the culture. If a similar trick can be performed to senescent cells in, for example
human skin, some age-related changes may be prevented.
The benchmark of understanding an ageing process is the ability to make a change in an animal’s
genetic makeup and correctly predict that the change will extend lifespan. Such experiments
have been performed successfully in both flies and roundworms and drugs have been developed
that mimic these genetic changes, making it possible to extend lifespan with a pharmacological
agent.
To summarise, the essence of the new biology of ageing, it is trivial to engineer longevity into a
simple animal strongly suggesting we are on the brink of learning a great deal about makes these
simple animals age.
But are the causes of aging the same in different animals and do the simple animals tell us
anything about our own ageing processes? The signs are encouraging. For example, a cellular
signalling pathway has been discovered that greatly influences the lifespan of the roundworm.
The same pathway also influences the lifespan of the very distantly related fruit fly and a similar
pathway even determines the lifespan of the single celled yeast. That pathway is the same one
that responds to the hormone insulin in mammals raising the possibility that information derived
from simple "model" systems will lead to important discoveries in humans.
Another area for optimism arises from the some of the characteristics of long-lived genetic
variants. Many if not all of the genetic and pharmacological interventions that prolong lifespan,
also are associated with enhanced resistance to stress. By engineering stress resistance in
roundworms we have been able to significantly extend life, suggesting that the molecular
mechanisms of stress resistance counteract the ageing process and that ageing may be the result
of intrinsic stress. The most widely studies intrinsic stress is the production of toxic by-products
from normal cellular metabolic processes. These by-products are free radicals and production
and removal of free radicals is shaping up to be a central theme in ageing across a diverse range
of species including mammals.
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Session 1. The Challenge of Ageing Science
Paper 1.2
Biological ageing research: Problems of maturation
Thomas von Zglinicki
Research into the biological basis of ageing has lagged behind most other areas of bio-medical
research for the better part of the second half of the last century. A major problem was that of
practicable definitions: What is ageing? Being not a disease, where are the unaffected controls?
What are the goals of ageing research? Should a serious biologist really risk the odour of
wizardry by promising long and happy life? Moreover, ageing is enormously complex, and more
easily rewarding fields were around aplenty to test and exploit the tools of modern biology. As a
result, influx of creativity into basic research in ageing was a trickle at best for a long time,
output was low and the field as a whole was terribly underdeveloped in terms of methodology.
Interestingly, increased social and political demands and, with it, improved funding possibilities
have changed this picture dramatically. Today, we do have extremely well characterised and
deeply understood biological models of ageing at both the cellular and organismal level. We are
on the way towards a molecular biology and a molecular genetics of ageing and longevity. So, all
is well? Well….Let me give you few examples.
Recent research has shown that a very limited number of genes in one single pathway controls
ageing in three different model organisms: yeast, worms and flies (for review, see 1). Control in
this respect means that certain mutations in these genes prolong lifespan by as much as 100%. At
least in some cases another advantage, namely increased resistance to a variety of stresses, goes
with it. Of course, there is a price to pay, and that is sterility. There are homologous genes in
humans, and the huge biological diversity between this three model organisms alone suggests
that these genes might also play an important role in controlling longevity in humans. This of
course translates into the search for polymorphisms and their linkage to human longevity. At this
stage, ageing research finally and irretrievably loses its innocence.
We know the setting from cancer research: Understanding of the mechanisms allows prediction
of a lifetime risk but does not improve the cure. What do we do with this knowledge, and what
does the (potential) patient with it? At least in the short term, insurance companies would benefit
much more from knowing that someone is genetically destined to be a slow or a fast "ager" than
this person himself.
In reality, life in ageing is a bit more complicated. For instance, whether a certain set of genetic
markers (a mitochondrial haplotype for instance, see 2) might predict longevity or not, depends
not only on your sex, but also, if you are Italian, on whether you have lived in the north or in the
south of the country. Such results clearly show the low penetrance and the great interdependence of possible genetic markers analysed so far. However, one should expect that the
establishment of ageing control genes in model organisms will lead to the identification of more
closely linked ageing genotypes in humans as well.
The search for biomarkers of ageing is another not quite unproblematic story. Unlike a genetic
marker, a biomarker of ageing is a parameter which changes with time in a manner that mirrors
more closely the (or better a) "real ageing process" than calendaric time does. If we were to find
such a reasonable ageing marker, it could be used to monitor the efficiency of pharmaceutical,
nutritional or even social measures to slow down the ageing process. In an ideal world, this
should be possible at the level of the single person, allowing custom tailored suggestions for a
healthy life. Again, there are precedents in modern cancer research: Using chip technology to
measure nearly exhaustive gene expression pattern, one tries to establish an individual diagnosis
of one person’s malignancy with the goal to apply an unique therapeutic combination, which
takes into account all the specific strengths and weaknesses of this singular tumour. Whether and
how far this approach will work in oncology is still an open question. I am rather pessimistic
whether a similar approach to establish exhaustive gene expression pattern as a marker of
biological age would work out. At present, a person’s physical and mental impression seems still
the best biomarker of ageing, and this is not really something to be content with from a scientific
point of view. There might be other possibilities, however.
Tom Kirkwood’s group has shown a positive correlation between mammalian life span and
cellular resistance to stress (3). Alexander Buerkle in our Department has demonstrated a
correlation between life span and activity of one specific enzyme involved in repair of stressinduced DNA damage, poly(ADP-ribose)polymerase (4). In my group, we are interested in the
interplay between stress, specifically oxidative stress, and telomeres and its role in the ageing of
human cells and, eventually, human beings. Telomeres are specific DNA-protein structures that
define the ends of chromosomes, and they shorten in most human cells with each cell division as
well as with age in human tissues. There is good evidence that it is this shortening, which
ultimately signals cellular senescence. We have shown that the rate of telomere shortening
depends to a large extend on oxidative DNA damage, in fact that telomeres are sentinels for
DNA damage, comparable to a canary in a mine who by dying signals high time to leave to the
miners (5). Under constant external stress conditions, telomeres shorten faster in cells with a less
effective protection system. This seems to translate from cells into human ageing: We found
significantly shorter telomeres in the blood of humans suffering from probable or possible
vascular dementia, a disease with a strong oxidative component in its pathogenesis (6). At the
moment, this is just a correlation. It is not known whether telomere shortening actually precedes
the onset of dementia. In fact, nothing is known about longitudinal differences in telomere
shortening rate between individuals at all, but we are presently working on it. In the end,
telomere length might become one possible marker of some aspects of biological age.
Again, it is to be hoped that such a parameter could be used to monitor the influence of lifestyle
factors on the rate of ageing. This might be very positive, allowing the installation of a feedback
loop to encourage healthy lifestyle. It is very clear however that this prospect has its frightening
aspects as well. On the one hand, the experience with smoking clearly shows that compliance
with a long-term health programme, even if scientifically extremely well founded, is
distressingly low. On the other hand, there would be still a big commercial potential, and huge
international companies can easily be envisaged as Healthy Big Brother watching us as we age,
telling us the rights and wrongs. This vision is not quite realistic yet and it might well turn out
that humans, and especially human ageing, are too complicated to predict so easily. However, it
is also no longer in the realm of fairy tales.
References
1. Strauss E, Science 292 (2001) 41-43.
2. De Benedictis G et al. FASEB J 13 (1999) 1532-1536.
3. Kapahi P et al. Free Radic Biol Med. 26 (1999) 495-500.
4. Muiras ML et al. J Mol Med. 76 (1998) 346-354.
5. Petersen S et al. Exp Cell Res 239 (1998) 152-160.
6. von Zglinicki T et al. Lab Invest 80 (2000) 1739-1747.
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Session 1. The Challenge of Ageing Science
Discussion Points from Session 1
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In research it is difficult to see where the decisions are made which determine the
direction of research and the ethical decisions need to be made wherever those directiondetermining decisions are made.
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The aim of research into ageing is to understand the biological mechanisms that underpin
ageing. It is not in itself to extend the lifespan, which occurs as a by-product.
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An alternative view is that there would be more benefits from encouraging people to stop
smoking, in terms of quality of life, than there might be from ageing research. In
addition, there might be gains from considering the effects of nutrition in both the very
young and in the old, which might also improve the quality of life for older people.

Small perturbations in complex systems might lead to major changes in direction later.
This raises the question whether affecting the genes for ageing might lead to unforeseen
problems in the longer term, even if they produce short-term advantages. This is linked to
the point that there is a difference between knowledge and wisdom; we cannot be sure
that benefits will accrue from the new knowledge that comes from ageing research. For
instance, oxygen-free radicals, which are implicated in ageing, are also involved in
perfectly ordinary biological processes and it may be that, at a distance, interfering with
oxygen radicals will have an effect on the biological system as a whole. As a further
example of this, given that there are no ageing genes, that all genes have some other
function, it is clear that interference with any genes will have some effect other than the
effect on ageing.

There are some striking geographical differences in terms of both disease and ageing and
it seems likely that these will be both genetically and environmentally determined.
Biological, or genetic, determinism is suggested by differences in mortality seen at an
early age, but later differences between the sexes might reflect sociological factors.
However, even in later age, there is still evidence of biological differences, for instance,
between the sexes. An example of this is the risk of Alzheimer’s and the association
between certain alleles of the apolipoprotein and gender. Nevertheless, it remains true
that there is bound to be a complex interaction between both genetic and environmental
factors.

From other areas of medicine, such as the research into Huntington’s disease, we already
know that there are mixed reactions to genetic knowledge. We should bear in mind that
certain genetic effects are no greater and no less than some social effects. We can
compare, for instance, the likelihood of a particular gene leading to an illness and the
likelihood of a particular social or environmental event leading to the same illness. There
will be different emotional responses to interventions that affect genes or gene products
and interventions that are social.

How can the fruits of the breathtaking research, which has been discussed, be made
equally available? There is the danger that the pharmaceutical interventions will only be
afforded by a gerontocracy, who might well be wealthy, middle-class Americans! The
lack of equity is already manifest with 90% of expenditure on health promotion research
being spent on diseases which cause 10% of the global burden of disease. In addition,
60% of all pharmaceutical products come from the U.S.A. Since ageing research will
continue, with possible benefits for the pharmaceutical industry, there is some urgency
behind the discussion of ethical issues relating to this sort of medical research.
Academics are relatively lacking in the influence in comparison to the pharmaceutical
companies, yet we know that there is very likely to be a huge market in the affluent parts
of the world for anti-ageing medicaments.

There is the possibility of a vaccine to cure Alzheimer’s. However, apart from the fact
that the vaccine may not be as effective as the vaccines against infections, there is some
doubt as to whether there would be a mechanism available to encourage the worldwide
use of such a vaccine.

Scientific research might lead to inequalities in health care. There is a concern that basic
scientists might be blamed for the results of their research. However, on the one hand, the
lack of equity is already present in other fields and may reflect broader societal
influences; whilst on the other hand, basic scientists must continue to have some social
responsibilities. There is certainly a feeling that some transparency is needed in research.
It is questionable whether there is any lack of transparency in ageing research itself as
opposed to other types of research, such as research into biochemical warfare. It might
still be, however, that scientists are naïve even if not bad.

There are three motivations behind people engaging in ageing research: first, there is
simply a love of the study of life, which is regarded as a privilege; secondly, the ravages
of ageing, as seen in psychogeriatrics, suggest that there is some work worth doing;
thirdly, there may be a small element of personal interest at stake, given that some people
simply wish to avoid ageing! Most people are influenced by the first two motivations
rather than the third.
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Scientists are also citizens and they take part in and are influenced by the broader
political agendas. They can contribute to rational political decisions that may, after all,
affect them themselves. Bodies such as the Medical Research Council and Welcome
Trust place a heavy emphasise on the public understanding of science and people
engaged in this sort of scientific research spend a considerable amount of time educating
the public and see this as important. However, individual scientists are aware that they
may do themselves harm by making public, media appearances.
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Ageing pages constructed by Andrew J. Palmer Jan 2002