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.
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ABSTRACT: Molecular studies in model organisms have identified potent longevity genes which can delay the aging process and extend the lifespan. Longevity factors promote stress resistance and cellular survival. It seems that the aging process itself is not genetically programmed but a random process involving the loss of molecular fidelity and subsequent accumulation of waste products. This age-related increase in cellular entropy is compatible with the disposable soma theory of aging. A large array of host defence systems has been linked to the NF-kappaB system which is an ancient signaling pathway specialized to host defence, e.g. functioning in immune system. Emerging evidence demonstrates that the NF-kappaB system is activated during aging. Oxidative stress and DNA damage increase with aging and elicit a sustained activation of the NF-kappaB system which has negative consequences, e.g. chronic inflammatory response, increase in apoptotic resistance, decline in autophagic cleansing, and tissue atrophy, i.e. processes that enhance the aging process. We will discuss the role of NF-kappaB system in the pro-aging signaling and will emphasize that several longevity factors seem to be inhibitors of NF-kappaB signaling and in that way they can suppress the NF-kappaB-driven entropic host defence catastrophe.Ageing research reviews 11/2009; 9(3):298-314. · 5.62 Impact Factor
- The Journals of Gerontology Series A Biological Sciences and Medical Sciences 06/2010; 65(6):580-9. · 4.31 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 01/2010; 48(1-3):287-93. · 2.65 Impact Factor