Meeting Reports

The meeting in question was the American Aging Association's 36^th Annual Meeting and 21^st Annual Meeting of the American College of Clinical gerontology: Current Directions in Studying Mechanisms of Aging held in San Antonio, Texas on June 1-4 2007.

The meeting was preceded by a symposium, on Therapeutic Intervention in the Aging Process. This session was quite rich in diversity, and the various papers presented focused on wide-ranging strategies to determine potential targets for intervention and the use of various model systems.

Brian Kennedy (Washington University) proposed a grandiose approach to study evolutionary conserved pathways in various model organisms, yeast, worms and mice. These, included genome-wide screens for gene deletions in yeast resulting in extension of replicative or chronologic lifespan, followed by knockdown of target genes by iRNA in C.elegans and finally generation of mouse knock-out models.

Arlan Richardson (University of Texas) reminded us that there may be more to the "free radical theory of aging" than simple, increased oxidative stress affects on lifespan, despite all the correlative evidence present in the literature. He showed the lifespan effect of various knock-out/transgenic mice models affecting the antioxidant system. The results showed that Sod2^-/+, Gpx1^-/- and Gpx1^-/-Sod2^-/+ mice have the same lifespan as wild-type mice despite increased sensitivity to oxidative stress and increased oxidative damage. Surprisingly, overexpression of thioredoxin 1 did increase mean lifespan.

Following the role of antioxidant defence on mice lifespan, Gordon Lithgow from the Buck Institute presented his approach to high-throughput screen of compounds with antioxidant properties on C.elegans lifespan, similar approaches were presented by Kerry Kornfeld (Universityof Washington) in the same model organism and Sige Zou (University of Texas) in the Mexican fruit fly Anasthepha ludens.

We also had the opportunity to hear three presentations on the studies conducted by the National Institute on Aging (NIA) Interventions Testing Program (ITP), which aims at testing the effects of different candidate drugs on mice lifespan. One important feature of this study was that the data was being generated independently by three independent laboratories, with genetically heterogeneous mice.

The next day, when the actual meeting began, we were already filled with food for thought from the previous day, but ready for more. Despite the jet lag, (it does take a few days to attenuate its effects), despite the welcome reception which involved alcohol consumption, (it does not work in making you go to sleep and might result in even earlier awaken), the meeting did start at 8am with opening remarks by the meeting organiser Holly van Remmen.

Here are some highlights from the first day:

Andrew Dillin from the Salk Institute, presented his groundbreaking work showing the role of PHA-4 in the regulation of diet-restriction-mediated longevity in C. elegans. John Phillips (University of Guelph) showed evidence in Drosophila for an important role of oxygen metabolism in regulation of fly lifespan. He showed that in normoxic conditions (20% oxygen) SOD1 and SOD2 mutants show early onset of mortality, however, chronic hypoxia is able to suppress this phenotype. This presentation generated discussion on the fact that the effects of antioxidants on lifespan seem to work differently in evolutionarily remote model organisms.

A session on the role of IGF-1 in various mouse models followed. We learnt about the mechanisms mediating extension of lifespan by overexpression of hormone Klotho, which is thought to be due to its ability to inhibit IGF-1 signalling and to reduce oxidative stress, as presented by Makoto Kuro-o (University of Texas). He also presented data suggesting a role of fibroblast growth factor on regulation of lifespan, since mice defective on fibroblast growth factor-23 exhibited similar phenotypes to the Klotho deficient mouse. Interesting was the fact that other mouse models questioned the effects of IGF-1 in regulation of lifespan. In work presented by Christian Sell (Drexel University), IGF-1 hypomorphic female mice revealed a 18% increase in lifespan, but this was exclusive to females, since males showed no different to wild-type mice. Surprisingly, independent work by Martin Adamo (University of Texas), showed that mice deficient in liver IGF-1 showed a slight increase (not statistically significant) in median lifespan in females and a decrease in median lifespan in males. This led to discussion and speculation on the role of hormones testosterone/estrogen composition in modulation of the effects of IGF-1 on lifespan.

Lunch was followed by a debate moderated by Steve Austad on the subject "Is Aging programmed?". The inclusion of such a debate in the meeting proved to be a successful gamble by the organisers, since it led to active participation by the audience and the emergence of interesting questions and discussion. The discussion featured two panellists: Daniel Promislow from the University of Georgia and Valter Longo from the University of Southern California. Daniel Promislow, argued eloquently that aging is not programmed and a non adaptive-process, oblivious to the force of natural selection and supported his arguments with substantial evidence. Valter Longo presented his own data on the model of S. cerevisiae, which he believed supported the existence of a programme of altruistic ageing and death.

One of the highlights of the first day of the meeting was the trans-atlantic awareness and collaboration symposium on aging research. One of the purposes of this session was for the American scientific community working on ageing to be aware of some of the research carried out in the United Kingdom. And if diversity was what was expected, diversity was what was offered. In only one hour and a half, the audience was exposed to such disparate subjects as Werner Syndrome, the effects of aging on the immune system, the circadian clock, age-related changes in a pond snail, age-dependent changes in elastic fibres, mitochondria and ROS generation in fibroblasts and contracting muscle cells.

Sunday opened with a session on nutrient sensing. Jim Jefferson and George Thomas from the universities of Pennsylvania State and Cincinnati respectively, presented data on mTOR signalling and Pere Puigserver, from Washington University on his ground breaking work on PGC-1 a and its regulation by SIRT-1.

David Nicholls from the Buck Institute presented some interesting work on bioenergetics of cultured neurons exposed to pathological concentrations of glutamate. He showed evidence that opposed the model of calcium entering mitochondria being responsible for increased oxidative stress, by showing that glutamate activation of NMDA receptors uses the full respiratory capacity of the in situ mitochondria. He concluded that limited ATP generation capacity could be responsible for excitotoxicity, which is a feature of many age-related neuronal diseases.

Rochelle Buffenstein (City College of New York) presented her quite intriguing work on the naked mole-rat. We learnt how this exceptional longed-lived species defies the belief of a causal role for oxidative stress in the ageing process. Despite their longevity (more than 28.3 years), these rodents showed higher levels of all the markers of oxidative stress when compared to age-matched mice. These results suggested that naked mole-rats aged and died due to other mechanisms apart from oxidative stress.

This very stimulating meeting finished with the attribution of the distinguished Achievement Award to Edward Masoro from the University of Texas, for his vast contributions to the field of ageing.

Programme highlights:

The programme started off with an icon of ageing research - George Martin who is a pathologist from Washington University and greatly contributed over the years to the development and increasing quality of ageing research worldwide. He spoke about clonal attenuation as a gradual depletion of replicative potential of mammalian somatic cells that occurs continuously throughout the life of primates in vivo.

He was followed by Jerry Shay from Texas who is well known and respected for his long term achievements in the field of telomeres, as well in basic research, as in finding the biological significance of processes such as telomere shortening, DNA damage and telomerase expression for human diseases such as cancer and others. He reported new data on telomere position effect using telomere microarray for 1523 genes from single copy subtelomeres, where his lab identified potential candidate genes that might be regulated by short or dysfunctional telomeres. He also reported new findings about mutations in genes coding for telomerase in families and patients with idiopathic pulmonary fibrosis. These mutations result in decreased telomerase levels and short telomeres. This is one of the rarely described cases where telomere shortening can be directly connected to pathologies.

Next was Joao Passos, a young talented member of the Lab of Thomas von Zglinicki, Newcastle. He talked about the connection between mitochondrial dysfunction, telomeres and cellular senescence. His work identifies mitochondrial production of reactive oxygen species (ROS) as one important cause of senescence but at the same time it is as well a consequence of senescence. This secondary ROS generation is downstream of p53/p21 and depends on signals from growth factors and TGF-beta/ p38 pathways. This secondary ROS generation seems to contribute to a long-term DNA damage signal and the maintenance of the senescent phenotype.

Tom Kirkwood from the same Institute for Ageing and Health in Newcastle, UK reported about the Systems Biology approach in which his Institute combines mathematical modelling with experiments joining together mitochondrial and telomeric defects in the context of oxidative stress and cell-to cell heterogeneity. Rudy Westendorp from the Leiden University Medical Centre underlined the necessity to better understand healthy ageing in an advanced age in order to postpone diseases and disability in old age. His interest is to use large population studies to find out whether described longevity pathways and genetic factors do indeed play a role in the genetic variation in natural human populations. He believes that basic and clinical research in genomic projects can be used to analyse and exploit common signalling pathways in order to eventually slow down ageing. He is examining the big influence of the environment; for example, pro-and anti-inflammatory immunotypes that can favour and select different genetic setups in evolutionary extreme short periods due to better health systems and social care in the first world.

The guest of honour was Tony Linnane from Australia who gave an overview about the role of the metabolome by cellular redox modulation and pro-oxidant signalling systems. He favoured a view that is recently becoming more popular,that reactive oxygen species do not have exclusively deleterious and damaging influence upon the ageing process, but could also function at lower concentrations as a well regulated redox dependent second messenger system. Therefore there should be a balanced view and approach regarding these molecules.

Jan Hoeijmakers from the Erasmus University in Rotterdam spoke about mouse models of human progeroid DNA repair disorders and their impact on ageing and lifespan extension. His lab created mouse models for mutated helicases involved in nucleotide excision repair (NER). Many of these mice models show premature ageing phenotypes, but there are specific differences due to various mutated sites that can have slightly modified phenotypes, such as decreased spontaneous cancer frequency. Double mutants show a dramatically aggravated premature ageing phenotype coupled to a very pronounced neurodegeneration. His studies show a good correlation between the severity of the repair defect and the onset of the ageing phenotype, ranging from 1 to 15 month. That, in his opinion, provides a strong argument for the DNA damage theory of ageing. Genomic and functional studies demonstrate that DNA damage can trigger a downregulation of the IGF1 axis causing a shift towards energy storage rather than energy production.

Norbert Dencher from Darmstadt technical University (Germany) described his proteomic approach on characterising mitochondria with special account of protein modifications and protein interactions. He drew the attention to the fact that many age-related post-translational modifications could directly interfere with components of the respiratory apparatus and, consequently, with the efficacy of respiration and energy production.

The theme of protein modifications and their role for the ageing process were also the themes of Tilman Grune (Germany) and Bertrand Friguet (France). T. Grune described the role of the proteasome in the degradation of oxidation-induced protein unfolding and their subcellular localisation. B. Friguet continued the topic of oxidatively modified proteins occurring during ageing. He has data showing that both degradation and repair of proteins are compromised during ageing.

Monica Driscoll from New Jersey addressed the role of age-associated decline, genetics and chance in C. elegans. She presented intriguing data on the role of micro-RNAs for the ageing process. Some of these micro RNAs change expression during adulthood and target genes previously identified to affect longevity, such as those for coding of insulin-like ligands. Some microRNAs specifically regulate muscle ageing and the high conservation of these mechanisms make nematodes a good model to explore this fascinating new field for human ageing as well.

Muscle ageing was also a focus of Thomas Rondos's (Stanford) talk. His work aims to understand age-related changes in tissue regenerative potential and uses adult muscle stem cells (satellite cells) as his model. His group identified Notch signalling as a major player for the activation of these stem cells. The main observation of his experiments was that the decline of stem cell potential during ageing is caused by an "ageing environment" as ligands for the Notch signalling are produced from neighbouring cells. If he stimulates "aged" stem cells with "young" signals they function completely normal as young ones do. Therefore, once again, the niche has been proven to be an important player for the functioning of adult stem cells during ageing. He also showed that by inhibiting the Wnt signalling he can improve muscle regeneration in a mouse system.

More interesting data on the interaction of stem cells and the environment were presented by Zhenyu Ju from Lenhard Rudolph's group in Germany. His interests are the consequences of telomere shortening on stem cell function and uses the telomerase knockout models. The study demonstrated that dysfunctional telomeres trigger an intrinsic checkpoint in stem and progenitor cells of the intestine and hematopoietic system. Deletion of p21, however, rescues stem cell function and extends lifespan without effecting upstream signalling. Exonuclease-1 deletions, on the other hand, prevented the induction of DNA damage signals at dysfunctional telomeres. Lenhard's lab also found a profound influence of the cell environment on stem cell function. Telomere dysfunction induces a secretory phenotype with a changed cytokine profile that changes the properties of stem cells, limits engraftment properties and is responsible for skewed hematopoiesis during ageing.

Renu Wadhwa from Japan reported about CARF, a collaborator of ARF that seems to influence the control of the senescence and apoptotic pathway. CARF works via the p53 pathway and its expression is upregulated during cellular senescence, whereas its repression induces apoptosis in cancer cells.

John Sedivy from Browns University reviewed his results on the differential roles of p16 and p21 for replicative senescence and the underlying DNA damage response.

Heinz Osiewacz from Germany uses the ascomycete, Podospora anserine, as a model for his studies. He presented intriguing data on changes of mitochondrial morphology and its dynamics on functional parameters such as mtDNA repair, protein quality control and cell death. When he disrupts the pathway using mutated Dnm1 that increases fusion of mitochondria he could improve stability of mtDNA and get a dramatic increase in lifespan.

There were many more interesting talks that cannot be mentioned due to restricted space, many great posters and very fruitful and helpful discussions. I think that I speak in the name of all participants, if I state that this was an extremely successful meeting and hope for many more to come.

If you are involved in any area of policy-making, research and its funding, industry, patient and public engagement, or the media, and have an interest in how Europe can and must address our changing expectations of life, the reports from this conference will provide essential information to help you enhance and extend your work.

Professor Tom Kirkwood, (director of the Institute for Ageing and Health) summarises the purpose of the meeting and the key challenges in each of the five key areas of ageing research.

The participants were:

• Professor Arne Akbar (University College London)
• Professor Cyrus Cooper (Southampton General Hospital)
• Professor Tom Kirkwood (University of Newcastle)
• Professor Janet Lord (University of Birmingham)
• Professor William Marslen-Wilson (Cambridge University)
• Dr Alan M. Palmer (Pharmidex)
• Professor Linda Partridge (University College London)
• Dr. Frans van der Ouderaa (Unilever)

The meeting began with a discussion of current demographic trends and whether the increases in life expectancy currently being experienced in the UK and Europe showed any signs of slowing and thus was there an upper limit to human life-span. Scientists were in agreement that the current trend of 2 years extra per decade (5 hours per day!) was not showing any signs of slowing and when asked to give their best estimate of the age at which life expectancy might plateau, these varied from 90-100. One caveat was that current trends for reduced physical activity and increased obesity in the younger generation could begin to impact upon life expectancy and Professor Kirkwood reported that in the US life expectancy had already been steady for the last two years.

Each of the scientists was then asked to explain the effect of ageing on the organ system that their research focussed upon and how this contributed to age-related disease and frailty. Time was spent discussing age-related changes that might affect several organ systems, such as the increase in inflammatory cytokines that might influence cardiovascular function, sarcopaenia and cognitive decline. The minister was interested in hearing of approaches that might be used to improve the health of older adults. There was discussion of studies across species showing that single genes (e.g. in the IGF-1 pathway) could influence life-span and health span and that this information may now begin to shape strategies for developing interventions to increase healthy life-span. Caloric restriction had shown that life-span extension could be achieved in species from flies to rodents, but the jury was still out for humans and primates. The question here was whether a more pallatable alternative to CR could be developed. Regular exercise both mental and physical were also put forward as having a sound evidence base for maintaining a healthy phenotype into old age.

This briefing was the second held by the minister, the first being on Stem Cells, he also plans similar events on alternative energy and global warming. It remains to be seen whether his new found understanding on human ageing will influence political policy regarding older adults or ageing research in the UK!

Professor Janet Lord

Chair BSRA

The 5^th European Congress of Biogerontology was held in Istanbul between the 16^th and 20^th September 2006 - my first international conference in 24 years (I've been busy) and my first lesson was: next time travel the day before. After missed connections, lost luggage, visa delays and no taxi to meet me, I had already missed the conference opening ceremony and the Leonard Hayflick keynote lecture by the time I arrived. This was a real regret. Hayflick is a legend, and his work fascinated me as a medical student. His theme - ‘Aging and Longevity are No Longer Unsolved Problems in Biology' correctly asserts his place alongside Medawar, but also troubled me with its ‘all over bar the shouting' implication. Ageing feels as if it still holds plenty of surprises to me, otherwise why be here? It is the allure of uncertainty that makes science worthwhile; the unanswered questions, not the answered ones - or the possibility that those answers are wrong. And it is that appeal that hooked me back to academia after half a career in the NHS.

Post-lecture cocktails were in progress by the time I reached the conference. Drinks were being served on a terrace behind the auditorium while chamber musicians played, surrounded by trees and, somewhat alarmingly, adolescents with automatic rifles. The latter were a novel feature of the venue, the Harbiye Military Museum and Cultural Centre. They mostly appeared after dark, emerging suddenly from behind bushes, and lived in the army base next to the Museum.

Breakfast next morning was full of delegates. This became clear once they all reappeared at reception with purple conference badges and embossed black plastic shoulder bags.

I had struck lucky with the timing of my talk. The first morning of a conference is par for the course if you are a big name, but a lottery for us unknowns. Nerves, which dog even experienced speakers, can be dispensed with quickly. The number of talks for which your attention is on your own slides rather than the speaker's is minimised, and your tongue is loosened by having to take questions from the front. I spoke about post-menopausal acceleration of mortality curves and how the timing of that acceleration has shifted in women from an age that could plausibly be recognised as the end of menopause to one in the late 60s in low mortality countries. A curious change and one that deserves an explanation.

Most of the schedule ran as advertised, though a few of the advertised American contingent didn't show. Gossip put this down to the threat of Islamic terror following recent bombs in the city, but that could be scurrilous. And, frankly, I feel more at risk in London.

Sunday, Monday and Tuesday featured twelve formal sessions, some broken over coffee or lunch, in a programme that ran from 9.00 am to 8.00 pm each day, demanding considerable stamina. Particularly for the type of presentation that leaves me thinking ‘now just run that by me two or three more times, really, really slowly' - like Ebru Erbay's work on adaptive stress responses, inflammation and systemic regulation of adiposity and insulin action. But others just zipped by, compelling attention, even in the siesta session after lunch, such as Jan Vijg's discussion of genomic instability and ageing and Thomas Johnson's curious work showing apparently heritable differences of HSP-16::GFP expression in ‘isogenic worms', which he presented under the title ‘Stochastic Variation in Life Span; Is it Really Stochastic?' - a lovely, big, juicy question. And I was fascinated by Jan Hoejmakers discussion of DNA damage and its connection with ageing and IGF signalling.

There were, in total, 44 lectures, 28 oral presentations and 37 posters. I won't try to summarise them, but they were divided into 13 sessions that toured through longitudinal and genetic studies, evolutionary biology, caloric restriction, premature ageing syndromes, obesity, nutrition and immunology, before ploughing deeper into genome instability, epigenetics, telomeres and proteomics. I was fascinated by the sessions on mitochondria, free radicals and oxidative stress - so manifestly significant but tantalisingly incomplete - and enjoyed greatly the closing session on systems biology.

The proceedings are to appear in a future issue of the Annals of the New York Academy of Sciences.

Overall, and with my admittedly naïve frame of reference, I thought the standard was high. Only a few of the presentations struck me as being obviously flawed. But I find it useful to keep in mind the advice attributed to a one-time Dean of Harvard that ‘half of everything we know is wrong - we just don't know which half'.

Nothing persuaded me that the problems are ‘no longer unsolved'. On reviewing my notebook I find that almost all of my comments are, appropriately, unanswered questions or topics for future work.

For me it was a good conference. I came away with four or five good ideas, and that feels like a big success. On the downside, the days were over-filled. You need a heroic level of concentration to absorb that much for that long. And some of the social and domestic organisation was less than ideal - there were not enough places for all the delegates who would have wished to join the Bosphorus cruise, and the closing tour of Istanbul didn't happen at all. My hotel booking (although more than acceptable) was not at the place I had requested. And the organising company seemed to use an email system that would send but not receive. It is, perhaps, a tribute to the rest of the conference and to the kindness, good humour and enthusiasm of the organisers and hosts that these things mattered so little in my generally positive feelings about the whole event.

The biogerontology community is not a big one, though it seems to be growing -a glance at the most read articles in major journals suggests an increasingly large interest in progress on ageing. There is terrific value in having, in the same room, everyone from the most specialised of laboratory scientist to practising clinicians, theoreticians, epidemiologists and biodemographers. New angles on questions strike you at unexpected times.

I shared a taxi to the airport with Professor Rudi Westendorp who worried about the danger of losing that link from molecule to patient. Earlier in the week he had raged to me about lack of progress in reducing mortality among the over-90s in the Netherlands (in England and Wales it is falling). It was a useful context for considering Aubrey de Grey's final morning lecture. He had arrived from America the previous day, trailing journals, the usual controversy and a cheque made out to SENS for $3.5 million from the founder of PayPal (not without strings - the money has to be matched before the cheque is cashable). Not everyone agrees with SENS or Aubrey's views but you have to admire his drive and his intent that what happens in the lab should stay connected to delivering benefit to people.

And this is why, to my mind, the bold assertion of Professor Hayflick's keynote theme feels premature. Ageing and longevity may no longer be unsolvable, but that doesn't mean they are solved. The bigger issue is what we can do about them. And I returned from Istanbul feeling just a little bit closer to that.

Focus is probably the problem facing every scientist who is ever “lucky” enough to organise a meeting. This problem becomes particularly acute when the subject is ageing and the meeting only lasts one day. Spread the speakers too thin across the topics and most of the audience will be interested for an hour. They will then spend the remaining time doodling cruel caricatures of the speakers, scribbling down half baked ideas that they hope to turn into fundable grants and offering stupefyingly misinformed comments on subjects they really didn’t understand as undergraduates (yours truly has scribbled and stupefied with the best of them). The alternative approach, of tight focus, is also not without its problems. Five of the audience will listen, enraptured, for the day; their pleasure only broken by the gentle snoring of the rest of the scientific community for whom the meeting proceedings are about as worthwhile as an update on the perf o rmance of the Tiblisi women’s second eleven.

It follows that, try as one might, every single ageing meeting is something of a curate’s egg. Mechanisms of ageing & longevity (an Anatomical Society Symposium with additional support from AgeNet, Research Into Ageing and the BBSRC) was no exception. Like the curate I will concentrate on a couple of the areas of this particular egg which I found excellent. Suffice it to say there were also
parts of it I wouldn’t have personally missed if they had stayed in the hen.

I have to confess a personal prejudice in favour of simple model systems and theories with strong testable hypotheses. The opening session, Genetics & Longevity, provided both. Gordon Lithgow (Manchester) gave a workmanlike treatment of mutations which extend lifespan in C.elegans. The majority of the mutants characterised so far (i) upregulate the ability of worms to resist stress and (ii) form part of the daf16-forkhead pathway [1]. The Lithgow lab has recently come up with the idea of using the cosegregation of the stress resistance phenotype and long-life to hunt out new age-style mutants (increased theromotolerance or ITT mutants ). This approach involves mutagenising unsuspecting worms and then subjecting their progeny to a severe thermal shock. This “shake and bake” approach to the genetics of ageing has met with considerable success and is a rather neat piece of lateral thinking. The most interesting observation from my perspective was the presentation of data showing greatly increased lifespans in populations of C.elegans exposed to the catalytic antioxidants Euk-8 and Euk-134. This has to rate as the best news in gerontology since telomerase.

That lifespans vary substantially across the animal kingdom is something every gerontologist picks up fairly early in his or her career. David Gems (UCL) pointed out that there is a 600 fold variation in lifespan just within the phylum Nematoda (lifespans of 8 days to 14 years). David suggested that rather than expressing a single genetic pattern throughout adulthood, the possibility exists for nematodes to express a series of developmental genetic “identities” as they age (a bit like playing a series of tracks from a CD). This concept is developed in some detail in a new ageing hypothesis. David’s tripartite theory of ageing links together evolution, oxidative damage and non-adaptive programmed ageing. Right or wrong the theory leads to testable predictions that are borne out by work with nematode lifespan mutants [2]. As a light aside I was interested to learn that Hydra vulgaris apparently shows negligible senescence [3]. David pointed out that this was in line with his theory, which predicted that organismal senescence should not occur in species where all the cells in the body are turned over. A personal question for me is whether hydra shows a true germline/soma distinction. Answers to the Editor on a postcard please.

Cell turnover is at the heart of the cell hypothesis of ageing. The idea that the senescence (replicative failure) of those classes of somatic cells which divide during life may contribute to whole body ageing. Jose Remacle (Belgium) showed that repeated sublethal oxidative stress can accelerate the onset of senescence in human fibroblasts (measured using a range of markers including telomere shortening). This work supports other observations which show that telomeres are susceptible to oxidative damage and links a major form of exogenous damage with an internal, programmed, counter [4,5]. In vivo veritas? We shall have to wait and see.

A presentation by Emil Toescu (Brimingham) updated the calcium hypothesis of neuronal ageing (essentially the suggestion that small shifts in cellular calcium over long periods of time are functionally equivalent to large neurotoxic shifts in exprescalcium over short periods of time). Emil pointed out that there are a couple of problems with the theory as it currently stands of which the most important is the observation that there does not appear to be any significant evidence of neuronal cell death in the normal ageing brain. That having been said the cytotoxic role of calcium should not be discounted. Normal aged neurones show elongated calcium signals which may act to remove the most active neuronal synapses and contribute to the decrease in connectivity seen in normal brain ageing [6]. The normal neurobiology of ageing is obviously an area to watch and much of the meeting dealt with various aspects of the molecular signalling pathways involved. Local organiser Tim Cohen is to be praised for his networking skills in putting together a meeting of this quality and thanked in advance for his article on the daf16-forkhead pathway which will appear in the next issue of Lifespan.

University College Cork was the setting or the recent 670th meeting of the Biochemical Society this year, a meeting at which the Biochemical Immunology Group Colloquium hosted a one-day session on Ageing and the Immune system. The session was chaired in the morning by Dr David Kipling (Cardiff) and in the afternoon by Dr Janet Lord (Birmingham) and was successful in providing both an overview of current work and a snapshot of recent advances.

The session started with a presentation by Dr Richard Faragher (Brighton). Dr Faragher presented data on the cell turnover rates in different tissues and spoke of the linkage between cells senescence and human ageing. He cited evidence suggesting that senescence was an anti-cancer mechanism and made a strong case for the role of the telomere shortening in the induction of senescence in human tissue.

The role of senescence as a barrier to cancer was taken up by the next speaker, Dr E.K. Parkinson (CRC Beatson labs Glasgow) who was addressing questions as to the mechanisms of senescence in normal human keratinocytes and how this is overcome to produce immortal variants. He presented data from human cell lines which showed that immortal keratinocytes usually showed cor rupted p53 and p16 function and have high levels of telomerase.

This was followed by Dr Simon Cook (Babraham Institute Cambridge) who has been studying the role of different Ras-dependent signalling pathways in regulating cell cycle re-entry and proliferation. Dr Cook presented work on analysing the stress-activated protein kinases in cell cycle arrest, senescence and apoptosis using a series of *MEKK-ER* fusions.

The next speaker, Professor R. Miller (Michigan USA) gave an overview of changes in the immune system with age. He put forward the view that because mice have very long telomeres the decline in the immune function in the mouse could not be adequately explained by telomere shortening alone. He then went on to present data on defects in the ability of the theta isoenzyme of PK-C to move to the region of the T cell/Antigen Presenting Cell interface. Finally he discussed differences in a number of immunological parameters of mice derived from ecological niches of low hazard compared with a normal laboratory adapted strain.

This was then followed by an excellent presentation of work by Dr U.M. Martens (Freiburg) on telomere measurements in haemopoeitic cells. Dr Martens revealed an elegant study on the telomere length in single cells in which measurement was carried out using quantitative fluorescent in situ hybridisation (Q-FISH) and an extension of this method to enable flow cytometric analysis (Flow FISH).

The next presentation from Dr R. Aspinall (Imperial, London) who explained that the thymus atrophied with age and as a consequence its output declined but despite this the number of T cells in the peripheral T cell pool was maintained. This could be achieved by the proliferation of T cells in the peripheral T cell pool but would eventually lead to many of these cells reaching their replicative limit and hence to immune senescence. This problem may be overcome by reversing thymic atrophy, increasing thymic output providing new T cells to refresh the peripheral T cell pool. He then presented data on the causes of thymic atrophy and the use of IL-7 to induce thymopoiesis in ageing mice.

The final speaker in the session was Dr Arne Akbar who discussed homeostatic mechanisms to maintain T cell numbers within defined limits especially after infections with Epstein Barr virus. After infection the massive increase in CD8 cells is reduced by apoptosis but some persist as memory cells. The telomeres in these cells are not as reduced as expected indicating that there may be some telomerase activity which enables these cells to persist for prolonged periods as memory cells.

After a warm welcome by Professor Chadwick (Head of The School of Clinical Sciences at The University of Liverpool) and Anne McArdle (co-organiser), including the now customary mention of the Successful bid for the 2008 European Capital of Culture and Liverpool's success in the Champions League football final, Malcolm Jackson (Liverpool, UK) opened the meeting with an overview of the importance of ROS generation by muscle during exercise and ageing.

Two excellent presentations were than given by Professor Archie Young (Edinburgh, UK) and Professor John Faulkner (Michigan, USA). One most impressive aspect of these presentations was that with a combined age approaching 150 these two eminent scientists are clearly advocates of excellent research into ageing! Professor Young clearly demonstrated that despite the age-associated loss of muscle strength, regular physical training has the potential to gain strengths that are equivocal to 10-20 years rejuvenation. Professor Faulkner followed this with the example of a 74 year old person who ran a sub- 3 hour marathon before presenting his very latest research using single muscle fibre preparations.

The conference organisers and attendees where delighted that Professor James Tidball (UCLA, USA) and Professor Michael Reid (University of Kentucky, USA) made the trip across the Atlantic. Both presentations gave an exciting insight into the cellular mechanisms responsible for muscle catabolism during ageing in rodents.

Closer to home, Professor David Goldspink (Liverpool John Moores University, UK) moved the session back to a human model, discussing the age-related deterioration in cardiac muscle and the functional reserve capacity of the heart in healthy men and women.

Following a well earned coffee break, Dr Holly van Remmen (University of Texas at San Antonio, USA) described altered mitochondrial function in skeletal muscle of ageing mice lacking specific antioxidant enzymes and Dr Sue Brooks (University of Michigan, USA) followed this with an engaging discussion on the mechanisms of contraction-induced muscle damage in young and old animals.

The first day of presentations were concluded by one of the conference organisers, Anne McArdle, (Liverpool, UK) who discussed the functional effects of failure of adaptive responses in skeletal muscle during ageing.

The oral presentations were followed by a poster session and wine reception kindly sponsored by Unilever. The posters (and wine) were of exceptional quality and prizes were awarded to Miss Anna Kayani (Liverpool) and Dr Tapi Magwere (UCL).

Most of the delegates were then ‘shipped' to the spectacular setting of the Maritime Museum at The Albert Dock for the conference dinner. With the wine flowing, the delegates had a tremendous time and many new friends were made. One or two of the delegates were led a little astray after the dinner with the bars of Liverpool reported enhanced profit on Thursday night!

Day 2 was opened with a fascinating presentation by Professor Marie Csete (Emory University, Atlanta, USA) on muscle stem cell proliferation and differentiation from antioxidant deficient mice. Marie clearly demonstrated that changes in antioxidant gene expression results in the defective regeneration of myoblasts suggesting a key role for ROS in muscle regeneration.

The next speaker was Professor Gillian Butler-Browne (Paris, France) who discussed the effects of ageing on human muscle satellite cells. During ageing there is a decrease in the total number of satellite cells. Dr Butler-Browne proposed moderate training may be beneficial in maintaining the pool of muscle stem or satellite cells. However, caution must be exerted since Dr Butler-Browne also demonstrated that prolonged endurance training may have the reverse effect and deplete the satellite cell pool. Dr Jonathan Beauchamp (Imperial College London, UK) expanded on the biochemistry of muscle satellite cells, suggesting that satellite cell pool can be maintained by a process of self-renewal.

There then followed four free communications from Dr Adrian Lambert (Cambridge, UK), Dr Mari-Carmen Gomez-Cabrera (Valencia, Spain) Dr Tapi Magwere (UCL) Jill Saffrey (Open University). The prize was presented to Adrian Lambert who presented on mechanisms of low mitochondrial free radical production by long lived organisms although all 4 presenters where very worthy of this recognition.

After coffee and re-hydration for those who had been led astray, Brian Merry (Liverpool) put us all off our lunches by explaining that one of the only ways known to extend lifespan is though dietary restriction. Brian discussed the mechanisms responsible for the extension in lifespan by calorie restriction in a rodent model in particular focusing on cellular signalling and gene expression.

The session continued with Thomas von Zglinicki (Newcastle) presenting on ROS telomeres and senescence. Alan Morgan (Liverpool) could well have used the phrase ‘and now for something completely different' as he presented a proteomic approach to ageing research in yeast. The session was concluded by Arlan Richardson (Texas). Arlan has been using transgenic and knock out mice to test the oxidative stress theory of ageing and concluded that alteration of certain antioxidant defence enzymes, despite resulting in increased oxidative stress had no significant effects on lifespan.

The conference organisers would like to thank BBSRC, Physiological Society, Research into Ageing, Unilever, British Heart Foundation, Biochemical Society, The Institute of Human Ageing and DSM for sponsoring this meeting. All attendees agreed that the meeting was a complete success both intellectually and socially!