. "Appendix B: Homeostatic Processes in Brain Aging: The Role of Apoptosis, Inflammation, and Oxidative Stress in Regulating Healthy Neural Circuitry in the Aging Brain." The Aging Mind: Opportunities in Cognitive Research. Washington, DC: The National Academies Press, 2000.
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The Aging Mind: Opportunities in Cognitive Research
in young individuals. Coinciding with the changes in the TNFRs was an increase in TNFR-associated death domain protein (TRADD) and a decrease in TNFR-associated factor 2 (TRAF-2). These changes mirror those previously reported by Ware et al. (1991) following T-cell activation. However, in the case of lymphocytes from aged individuals, there was no increase in the expression of activation antigens, thus indicating that the T-cells were not in an activated state but rather reflect changes associated with an aging immune system. The potential importance of the change in the ratio of the two TNF receptors becomes obvious when one considers that the TNFRI contains a death domain and, when oligomerized by TNFα binding, recruits TRADD and FADD, resulting in the activation one of the initiator caspases, caspase-8. The TNFRII and TRAF-2 are involved in activation of NFkB and JNK, which are believed to mediate the anti-apoptotic effects of TNFα (Baker and Reddy, 1996, 1998). Based on these observations, Gupta and colleagues have proposed that the cellular and subcellular basis of this age-related immuno-senescence appears to at least partially involve increases in receptors linked with apoptosis and decreases in related compensatory receptors (Aggarwal and Gupta, 1998, 1999; Aggarwal et al., 1999).
Age-related changes may extend to other organs and may be displayed in the ratio of gene expression patterns. The recent introduction of gene chip technology into the field may have particular application to the field of aging. Thus, for example, the gene expression profile of aging in muscle tissue and the influence of caloric restriction have been described (Lee et al., 1999). In essence, using high-density oligonucleotide arrays representing 6,347 genes, it was shown that aging resulted in a differential gene expression pattern that reflected increased cellular stress and lower expression of metabolic and bio-synthetic genes. Some of these, such as DNA repair enzymes, are the same as those induced in the nervous system with age and degeneration. An example of an up-regulated gene found in the muscle is GADD45, which as discussed above, we have found is also induced in Alzheimer's disease.
Importantly, caloric restriction, which is the only really true intervention known to retard aging in mammals, almost completely prevented the gene expression pattern changes that occur with aging. This is a technology that should find particular use in the study of brain aging and cognition but will probably be difficult to get funded through peer review panels because it will be considered just a ''fishing expedition." These gene patterns summarize in one experiment the literature for the past 10 years of individual gene expression patterns. These expression patterns can be envisioned in essence as a fingerprint of homeostasis versus dyshomeostasis. In fact, this pattern of gene expression can be looked at as a view of the cells to engage homeostasis and plasticity mechanisms to compensate for age-related change.