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.
