Is cell death and replacement a factor in aging?
ABSTRACT The central theme of the 3rd International Conference on Functional Genomics of Ageing was tissue regeneration as a remedial strategy to address age-related cellular damage and the pathology that ensues. The conference included sessions on maintaining genome integrity and the potential of stem cells to restore function to damaged tissues. In addition to several human syndromes that appear to reflect accelerated ageing, there are now a number of mouse models that prematurely display phenotypes associated with ageing. The intent of this summary presented at the end of the conference was to: (1) discuss various human syndromes and mouse models of accelerated ageing; (2) evaluate whether the phenotypes displayed might result from an elevated rate of cell death coupled with an inability to adequately maintain cell number in various tissues with increasing age; and (3) discuss whether similar events may be occurring during normal ageing, albeit much more slowly.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2010; 65(6):580-9. DOI:10.1093/gerona/glp212 · 4.98 Impact Factor
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ABSTRACT: T cell dysfunction is the primary immunologic abnormality associated with aging. Many age-related defects stem from a decline in CD4(+) T cell function. Resistance of aged CD4(+) T cells to apoptosis is associated with autoimmune and infectious diseases. Previous studies suggest that IκB kinase (IKK) may be a key player in cell survival via its inhibition of c-Jun N-terminal protein kinase (JNK) activation. However, the role of IKK-mediated JNK inactivation in the age-related apoptosis of T cells is unclear. Here, we report that splenic CD4(+) T cells in aged mice are resistant to activation-induced cell death (AICD) induced by anti-CD3 plus IL-2 stimulation. Furthermore, aged CD4(+) T cells display increased IKKβ activity that is associated with attenuated JNK activation. The IKKβ-mediated JNK inactivation in aged CD4(+) T cells reduces the degradation of c-FLIP(L) and the interaction of Bad with Bcl-X(L), but it increases the affinity of Bad for 14-3-3. Pretreatment of aged CD4(+) T cells with a specific IKK inhibitor, PS1145, increases the JNK activity blocked by IKKβ and consequently sensitizes the aged CD4(+) T cells to AICD. Our study thus demonstrates that IKK antagonizes the AICD of CD4(+) T cells in aged mice via inhibition of JNK activation.Molecular Immunology 11/2010; 48(1-3):287-93. DOI:10.1016/j.molimm.2010.07.015 · 3.00 Impact Factor
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ABSTRACT: Cell death is as important as cell proliferation for cell turn-over, and susceptibility to cell death is affected by a number of parameters that change with time. A time-dependent derangement of such a crucial process, or even the simple cell loss mediated by cell death impinges upon aging and longevity. In this review we will discuss how cell death phenomena are modulated during aging and what is their possible role in the aging process. We will focus on apoptosis and autophagy, which affect mostly proliferating and post-mitotic cells, respectively, and on mitochondrial degradation in long living cells. Since the “decisional process” that leads the cell to death is very complex, we will also discuss the possibility to address this topic with a systems biology approach.Current Pharmaceutical Design 12/2007; 14(3):226-236. DOI:10.2174/138161208783413266 · 3.29 Impact Factor