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Role of mitochondria in conserved mechanisms of ageing

Final Report Summary - MIMAGE (Role of mitochondria in conserved mechanisms of ageing)

The ultimate aim of the MIMAGE project was to elaborate the role of mitochondrial function in ageing and lifespan control in biological systems. Of special interest was the discovery and experimental manipulation of evolutionarily conserved mechanisms shared between invertebrate and mammalian model systems. A range of experimental organisms and cell culture systems were studied.

'Candidate' (hypotheses driven) as well as 'unbiased' (non-candidate) approaches were utilised. In the 'candidate' approach pathways (signalling pathways) which were known to affect lifespan and ageing in certain systems but which were not linked or only loosely linked to mitochondrial functions, were investigated. In the 'non-candidate' or 'unbiased' approach, available random lifespan mutants or differential gene expressions (young versus old; wild-type versus longevity mutant) at the level of transcriptomes or proteomes were investigated. The data obtained from these investigations provided information leading to known or novel traits (genes, pathways) which subsequently were validated in order to obtain robust information about the involved ageing mechanisms.

Some general key conclusions towards a better understanding of the interacting molecular pathways governing ageing and lifespan were obtained. These can be grouped within the two following categories:
- identification and definition of common signatures of ageing (e.g. changes in protein abundances and post-translational modification). From several independent studies it became clear that, instead of an age-related modification (i.e. carbonylation) of the bulk of all cellular proteins, rather the modification and / or damage of specific proteins appears to be of special relevance for ageing;
- a hierarchical system with conserved modules involved in the control of functional mitochondria was identified in the different systems studied to be effective and of relevance for biological ageing, lifespan and healthspan control. These pathways were effective at the (i) molecular level and (ii) at the organellar level, as well as at the cellular level programmed cell death. Although these mechanisms may differ in detail amongst species it emerged that the more general molecular modules (molecular damage, different maintenance pathways) were conserved amongst organisms.

Apart from the large set of elaborated data (from proteome analyses) that remains a rich source of information for future in-depth analyses the major overall outcome of the project was the shaping of a more holistic view of events, pathways and interactions governing the ageing process. Furthermore, especially the overall evaluation and critical analyses of the work performed during the lifespan of MIMAGE revealed that an integration of available and new, complementing data in a broader approach than the usual reductionistic approaches taken in biology was of prime importance. This conclusion urgently calls for real interdisciplinaric work in which different disciplines including experimental biologists, bioinformaticians and mathematical modellers work together using the huge amount of data generated during the last decade in different collaborative project and critically evaluate and integrate them to generate valuable experimentally testable predictions and views. These conclusions urgently call for subsequent programmes and provide solid ground for perspectives towards the investigation of mechanisms of human ageing utilising a systems biology approach.

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