Genome maintenance is considered a prime longevity assurance mechanism as apparent from many progeroid human syndromes that are caused by genome maintenance defects. The ERCC1 protein is involved in three genome maintenance systems: nucleotide excision repair, interstrand cross-link repair, and homologous recombination. Here we describe in-life and post-mortem observations for a hypomorphic Ercc1 variant, Ercc1−/Δ7, which is hemizygous for a single truncated Ercc1 allele, encoding a protein lacking the last seven amino acids. Ercc1−/Δ7 mice were much smaller and median life span was markedly reduced compared to wild-type siblings: 20 and 118 weeks, respectively. Multiple signs and symptoms of aging were found to occur at an accelerated rate in the Ercc1−/Δ7 mice as compared to wild-type controls, including a decline in weight of both whole body and various organs, numerous histopathological lesions, and immune parameters. Together they define a segmental progeroid phenotype of the Ercc1−/Δ7 mouse model.

Summary Aging and age-related pathology is a result of a still incompletely-understood intricate web of molecular and cellular processes. We present a C57BL/6J female mice in vivo aging study of five organs (liver, kidney, spleen, lung and brain), in which we compare genome-wide gene expression profiles during chronological aging with pathological changes throughout the entire murine lifespan (13, 26, 52, 78, 104 and 130 weeks). Relating gene expression changes to chronological aging revealed many differentially expressed genes (DEGs) and altered gene-sets (AGSs) were found in most organs, indicative of intra-organ generic aging processes. However, only ≤ 1% of these DEGs are found in all organs. For each organ, at least one of 18 tested pathological parameters showed a good age-predictive value, albeit with much inter- and intra-individual (organ) variation. Relating gene expression changes to pathology-related aging revealed correlated genes and gene-sets, which made it possible to characterize the difference between biological and chronological aging. In liver, kidney and brain, a limited number of overlapping pathology-related AGSs were found. Immune responses appeared to be common, yet the changes were specific in most organs. Furthermore, changes were observed in energy homeostasis, reactive oxygen species, cell cycle, cell motility and DNA damage. Comparison of chronological and pathology-related AGSs revealed substantial overlap and interesting differences. For example, the presence of immune processes in liver pathology-related AGSs which were not detected in chronological aging. The many cellular processes that are only found employing aging–related pathology could provide important new insights into the progress of aging.

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XPC is one of the key DNA damage recognition proteins in the global genome repair route of the nucleotide excision repair (NER) pathway. Previously, we demonstrated that NER-deficient mouse models Xpa−/− and Xpc−/− exhibit a divergent spontaneous tumor spectrum and proposed that XPC might be functionally involved in the defense against oxidative DNA damage. Others have mechanistically dissected several functionalities of XPC to oxidative DNA damage sensitivity using in vitro studies. XPC has been linked to regulation of base excision repair (BER) activity, redox homeostasis and recruitment of ATM and ATR to damage sites, thereby possibly regulating cell cycle checkpoints and apoptosis. XPC has additionally been implicated in recognition of bulky (e.g. cyclopurines) and non-bulky DNA damage (8-oxodG). However, the ultimate contribution of the XPC functionality in vivo in the oxidative DNA damage response and subsequent mutagenesis process remains unclear. Our study indicates that Xpc−/− mice, in contrary to Xpa−/− and wild type mice, have an increased mutational load upon induction of oxidative stress and that mutations arise in a slowly accumulative fashion. The effect of non-functional XPC in vivo upon oxidative stress exposure appears to have implications in mutagenesis, which can contribute to the carcinogenesis process. The levels and rate of mutagenesis upon oxidative stress correlate with previous findings that lung tumors in Xpc−/− mice overall arise late in the lifespan and that the incidence of internal tumors in XP-C patients is relatively low in comparison to skin cancer incidence.

The encapsulation of Trichinella spiralis larvae in host striated muscle was studied.Capsule formation starts at 13 days post-infection. Between days 20–50 p.i. the largest increase in capsule formation was observed. The capsule is exclusively, or almost exclusively, formed from and by the infected muscle fibre, as might be concluded from the presence of the sarcolemmal basal lamina surrounding the capsule substance during the initial stages of capsule formation. A collagen nature of the capsule cannot be excluded.