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SFN and NAC upregulate T(H)1 immunity in aging through a restoration of redox equilibrium.

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Aging is associated with a functional decline and change in the phenotypic distribution of T cell subsets. The free radical theory of aging is widely promoted as the mechanistic basis for cellular senescence, including the immune system. Although the exact molecular explanation for the role of oxidative stress in cellular senescence is unclear, there is a connection to altered mitochondrial function, both as a contributor and as a target of oxidative stress. In this study we demonstrate that splenic T lymphocytes from old C57BL/6 mice exhibit a significant decline in mitochondrial membrane potential (Δψm). However, despite this change, there is a lower rate of withdrawal apoptosis in the memory CD4+ and CD8+ T cells. To explain the survival of these long-lived cells against a background of increased oxidative stress, we demonstrate increased glutathione production and phase II enzyme expression, which combine to protect memory T cells against oxidative stress, mitochondrial dysfunction, and cell death. The accumulation of memory T cells with aging explains higher phase II enzyme expression in CD4+ and CD8+ T cells from old mice. Compared with wild-type mice, mice lacking the expression of NF-E2-related factor-2, the transcription factor that regulates phase II enzyme expression, had a significantly enhanced rate of apoptosis in the presence of an oxidative stress stimulus. NF-E2-related factor-2-deficient T cells exhibit a bigger decline in Δψm and increased reactive oxygen species production than cells from wild-type animals. Taken together, we suggest that phase II enzyme expression and the accompanying increase in intracellular thiol levels protect memory T cells from mitochondrial dysfunction and spontaneous apoptosis.

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One of characteristic signs of aging is the accumulation of proteins in the cells and tissues. Changes in the protein pattern may be related to the functional decline and pathology of the aging tissue or organs. Because calorie restriction (CR) is the only effective experimental manipulation known to retard aging in rodents, we attempted to document the effect of CR on age-related alteration in protein accumulation. In the study, we quantified the changes in the age-dependent protein pattern and the effect of CR in rat kidney homogenate. Specific pathogen-free male Fischer 344 rats of 6, 12, 18, and 24 months of age were fed ad libitum (AL), and CR was used. It is important to note that no evidence of nephrotic lesions were detected in these soyprotein fed rats even at 24 months of age as revealed by histopathological examination. Results showed that the electrophoretic analysis of the protein yielded a major band of albumin with molecular weight of 66.2 kDa that was markedly increased with age in AL rats, whereas CR kept it at low levels throughout at all ages studied. N-terminal amino acid sequencing following eluting confirmed the protein as albumin. Analysis by Western blotting produced additional evidence on the gradual accumulation of albumin with age in AL rats, and its suppression by CR. To test whether renal albumin correlates with serum albumin, we analyzed the age-related changes in serum albumin. The ratio of serum albumin to total serum protein was markedly lower in AL rats than that in CR rats. Decreased serum albumin with age was often taken as a sign of renal dysfunction. However, in view of the absence of nephropathic lesions in these rats, data on the decreased serum protein in AL rats are difficult to explain at present. However, for CR, it may be possible that the antioxidative CR may reduce protein accumulation by reducing glycated proteins. It is known that glycated proteins elicit expression of various proinflammatory genes, which are responsive in changes in renal permeability. The present data suggest that age-related renal protein accumulation needs further clarification as to cause, because oxidatively modified accumulated albumin during aging may be a significant factor contributing to the pathogenic process including inflammation of renal tubules.

The oxidative stress hypothesis of aging proposes that age-dependent progressive deteriorations are elicited by various reactive species (RS). RS are produced by various metabolic processes under normal and pathologic conditions. A less-documented source of RS generation is the cyclooxygenase (COX)-catalyzed prostaglandin pathway. Recent evidence indicates that COX may be one of the major metabolic sources of superoxide and hydroperoxides through the arachidonic acid cascade pathway. COX is the rate-limiting enzyme in this process generating prostaglandin E 2 (PGE 2 ), prostacyclin (PGI 2 ), and thromboxane A 2 (TXA 2 ). COX exists in two distinct isoforms: COX-1, a constitutive isoform that is detected in most tissues and contributes to the production of physiological levels of prostanoid, and inducible COX-2, produced in response to many proinflammatory stimuli, including several cytokines. In the present study, we attempted to assess the contribution of RS generation of the COX pathway contributing to overall oxidative status. Fischer 344 rats of 6, 12, 18, and 24 months of age were used in this study. We quantified RS generation, the activities and gene expression of COX in aged kidney. Results show that COX-derived RS generation was markedly increased with age in parallel to total RS. This increased RS generation was accompanied by increased COX activity. Data on gene expression of COX-2 corroborated with the changes in the protein and mRNA level of COX-2. It was concluded that a substantial amount of total RS was contributed by the age-related COX-dependent process, which was accompanied by the increased gene expression of COX-2 mRNA and protein levels with age. These results suggest that the upregulation of COX-2 during aging can be a major contributor to oxidative status in the aging process. The significance of our finding is that increased COX activity during aging may be the major cause underlying the inflammation process under oxidative stress.