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Aging, The Molecular Concepts


Aging appears to affect several pathways in multiple processes in humans, resulting in the occurrence of various senescent phenotypes. At least some of the pathways appear to be unique to humans. In this context, segmental progeroid syndromes are potentially relevant to aging in humans. These syndromes should therefore be useful to investigate pathways generating age-related phenotypes specific to humans. Among these syndromes, the seven disorders, including several high-ranked segmental progeroid syndromes in particular, were caused by mutations in helicase genes. This implies some contribution of aberrant helicases to phenotypes in ordinary aging. Indeed, there are a few findings consistent with this implication. An example is that frameshift mutation in a polyadenine repeat is found in the coding region of theBLMgene in genetically unstable sporadic gastrointestinal tumors (101). Another example is that a case control study suggested that homozygotes, but not heterozygotes, for a polymorphic missense variant at amino acid 1367 in theWRNprotein have a higher risk for myocardial infarction (102), although this study did not use family-based controls. This result suggests that the missense change itself may affect some function of the WRN protein, because the protein with certain missense change may be inhibited from interacting with specific molecules, possibly causing some of the WS phenotypes. Alternatively, this result could reflect that variation in some locus other than the WRN gene or of some other gene in linkage disequilibrium with the missense change is associated with myocardial infarction. The finding that heterozygotes for the missense variant fail to show an association with myocardial infarction is also reasonable because a relatively small amount of the WRN protein functions adequately (103). Do the helicase disorders share any causative pathways for their age-related phenotypes, and if so, are these pathways also involved in ordinary aging? Each of the helicase disorders appears to have, with a few exceptions, unique pathways generating phenotypes. Nevertheless, overall, these disorders have pathway defects involved in the same specific processes corresponding to the phenotypes (table 8.II). Cancer predisposition appears to be caused by either a spontaneous or UV-induced elevated mutation rate due mainly to defects inDNArepair and:or recombination; neurologic abnormalities appear to be caused by apoptotic neuronal cell death due to defects in DNA repair and:or aberrations in transcription; and various other phenotypes in the disorders are most likely caused by aberrations in transcription. Thus, the various phenotypes of helicase disorders appear to be caused by aberrations in multiple processes, especially in transcription. If such phenotypes include age-related alterations to some extent, helicase disorders may well have some phenotypic similarities to aging. However, of the helicase disorders, WS has the most similarities to aging (table 8.II). For example, at least some of the genes overexpressed in WS fibroblasts are also overexpressed in senescent normal fibroblasts. This finding leads to the idea that WS and senescent fibroblasts enter a similar final pathway where multiple gene overexpressions generate various age-related phenotypes (81). Senescent phenotypes may then derive, at least in part, from altered gene expression in senescent fibroblasts (104). According to this concept, altered gene expression in relatively few senescent fibroblasts would affect other cells and tissues through an altered, especially increased, amount of secreted functional molecules, resulting in some senescent phenotypes. Moreover, senescent fibroblasts are resistant to apoptotic death due to failure to suppress Bcl-2, and are therefore slow to clear (105). Thus, if senescent fibroblasts lack the functions of the WRN protein, this lack could explain some senescent phenotypes in ordinary aging. Consistent with this concept, WRN gene expression is downregulated during fibroblast aging (106) and fibroblasts lacking functional WRN protein have decreased WRN promoter activity (107), although relatively low expression of the WRN gene is sufficient to prevent the onset of WS (103). Furthermore, WS lymphoid cells (108), like senescent T cells (109), have increased susceptibility to Fas-induced apoptosis, with increased Fas and decreased Bcl-2 expression. This similarity suggests the presence of a common primary or secondary transcriptional pathway alteration in lymphocytes of WS and ordinary aging. This alteration might cause susceptibility to apoptosis, resulting in immunodeficiency in ordinary aging.

Table 8.II
Selected possible age-related phenotypes in helicase disorders and ordinary aging.
Table 8.II
* Details in text.
† Abbreviations are as in Table 1.

However, the apparent absence of immunodeficiency in WS counters this simple explanation. Instead, the common alteration in the apoptotic pathway could have some association with increased autoantibody production in WS andordinary aging (110). Other similarities between WS and ordinary aging include the partially dominant phenotype of WS and senescent cells with respect to DNA synthesis on the basis of cell hybridization studies. The cytoplasmic and nuclear environments are responsible for the retarded DNA synthesis in WS fibroblasts, suggesting that the retardation is a secondary consequence (93). Similarly, the partial dominant phenotype of senescent cells could derive from a secondary effect onDNAsynthesis. In fact, expression of several cyclin-dependent kinase inhibitors including p21 and p16 increases transcriptionally during aging, contributing to decreased DNA synthesis. Taken together, a possible decline in function of the WRN protein in senescent cells could explain some phenotypes in ordinary aging. In other words, aberrantWRNprotein could play a role in pathways generating senescent phenotypes in ordinary aging. Alternatively, WS and ordinary aging may merely have similar pathways generating age-related phenotypes. Whatever the case, the many and various common features between WS and ordinary aging are unlikely to occur independently. Helicase disorders other than WS are less easy to relate to ordinary aging. Nevertheless because helicase activity is important for various aspects of DNA metabolism including transcriptional regulation which could be involved in the expression of many genes, at least pleiotropy resulting from aberrations in multiple systems due to helicase defects appears to be related to the apparent relationship between helicase disorders and ordinary aging (table 8.II). Among the putative helicases, the XPB, XPD, BLM, and WRN proteins have helicase activity. The CSB protein lacks helicase activity but functions in pathways in which helicases are involved. Whether the XH2 protein has helicase activity and whether it functions in pathways in which helicases are involved remain to be established, but it appears to be involved in the regulation of gene expression. Moreover, in this context, the ATM protein, which is a kinase not a helicase, encoded by the gene responsible for ataxia telangiectasia, a high-ranked segmental progeroid syndrome, also has a pleiotropic fundamental function involved in cell cycle checkpoints, DNA repair, and apoptosis, although the involvement of the protein in transcription is unknown. Why do some helicases including CSB protein and yeast SNF2: SWI2 protein lack helicase activity despite having the seven-helicase motifs? A possible explanation is that the motifs have functions other than helicase activity. A candidate is some function requiring nucleic-acid-dependent NTPase activity, because the CSB protein (19) and the SNF2: SWI2 protein (111) has DNA-stimulated ATPase activity. The helicase-like region of the SNF2: SWI2 protein is found to be necessary for transcriptional activation (111). Other candidate functions of the motifs include interaction with some molecules such as p53 (112). Finally, alterations in telomere metabolism (113) and in chromatin structure are known to cause altered gene expression. The probable relationships of the WRN protein to telomere metabolism (74, 114) and to chromatin structure (92), and of the XH2 protein to chromatin structure (98) therefore raise the possibility that altered transcriptional regulation in the two disorders is a secondary consequence and that the two disorders and ordinary aging have similar mechanisms for this altered transcriptional regulation (table 8.II).

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