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Ageing is a biological process guided by genetic and environmental factors that ultimately lead to adverse outcomes for organismal lifespan and healthspan. Determination of molecular pathways that are affected with age and increase disease susceptibility is crucial. The gene expression profile of the ideal ageing model, namely the nematode Caenorhabditis elegans mapped with the microarray technology initially led to the identification of age-dependent gene expression alterations that characterize the nematode's ageing process. The list of differentially expressed genes was then utilized to construct a network of molecular interactions with their first neighbors/interactors using the interactions listed in the WormBase database. The subsequent network analysis resulted in the unbiased selection of 110 candidate genes, among which well-known ageing regulators appeared. More importantly, our approach revealed candidates that have never been linked to ageing before, thus suggesting promising potential targets/ageing regulators.

Aging is a natural process determined by both genetic and environmental factors. Aging is accompanied by the imbalance of the function of several cellular homeostatic mechanisms, which results, among others, in the accumulation of abnormal (i.e. oxidized, cross-linked, unfolded) proteins. It has been proposed that the increased failure of homeostasis during aging is due to the impaired function of the major cellular proteolytic mechanisms mediated by the lysosome, the calpains and the proteasome. This article will address the issue of the function of these cellular proteolytic systems during aging.

Senescent human fibroblasts exhibit several genetic and biochemical differences as compared to their young counterparts including abnormalities of the main proteolytic mechanism, namely the proteasome. Specifically, we and others have shown that there is an impaired function of the proteasome, as senescent cells have reduced proteolytic activities and less proteasome content. In a complementary work we have recently shown that inhibition of the proteasome by a specific inhibitor induces a senescence-like phenotype in young WI38 fibroblasts [Chondrogianni et al. (2003) J Biol Chem 278: 28026-28037]. In this study we tested whether the induction of a senescence-like phenotype following treatment with proteasome inhibitors is a common feature of primary human fibroblasts. A comparative biochemical analysis, after employing three different human fibroblasts cell lines (IMR90, MRC5 and WI38 cells), as well as two proteasome inhibitors (epoxomicin and MG132), has shown that proteasome inhibition results in the appearance of a senescence-like phenotype in all cell lines used. Proteasome inhibitors treated cells were irreversibly stopped dividing, exhibited positive staining to beta-galactosidase as well as reduced CT-L and PGPH activities. In summary, these data reveal the fundamental role of the proteasome in the progression of replicative senescence and open new dimensions towards a better understanding of protein degradation.

Aging is a natural process determined by both genetic and environmental factors. Aging is accompanied by the imbalance of the function of several cellular homeostatic mechanisms, which results, among others, in the accumulation of abnormal (i.e. oxidized, cross-linked, unfolded) proteins. It has been proposed that the increased failure of homeostasis during aging is due to the impaired function of the major cellular proteolytic mechanisms mediated by the lysosome, the calpains and the proteasome. This article will address the issue of the function of these cellular proteolytic systems during aging.