A mouse model of accelerated liver aging caused by a defect in DNA repair

Abstract

The liver changes with age leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging-related liver changes. One potential opportunity is murine models of human progerias, or diseases of accelerated aging. Ercc1−/Δ mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine if hepatic changes that occur with normal aging occur prematurely in Ercc1−/Δ mice, we systematically compared liver from 5 month-old, progeroid Ercc1−/Δ mice to old (24–36 month) wild-type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in Ercc1−/Δ mice than in old WT mice. Liver enzymes were significantly elevated in serum of Ercc1−/Δ mice and old WT mice, while albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of Ercc1−/Δ liver following partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in Ercc1−/Δ and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein as well as increased hepatocellular senescence. There was a highly significant correlation in genome-wide transcriptional changes between old WT and 16 but not 5 week-old Ercc1−/Δ mice emphasizing that the Ercc1−/Δ mice acquire an aging profile in early adulthood. Conclusion There are strong functional, regulatory and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging-related hepatic changes.

NF-κB inhibition delays DNA damage–induced senescence and aging in mice

“…Alternatively, activation of conserved stress response pathways may promote aging. Herein, to decipher how damage drives aging, we used a well-defined murine system: mice that spontaneously age rapidly as a consequence of failure to repair endogenous DNA damage (44,49,67).…”

“…Deletion (Ercc1 -/-p65 -/-MEFs) or p65 heterozygosity (Ercc1 -/-p65 +/-MEFs) rescued proliferation and senescence to a large extent ( Figure 5, A and B). Hepatocytes of Ercc1 -/Δ mice show profound cellular senescence (44). Reduced expression of p65 resulted in a significant reduction in the number of senescent hepatocytes in Ercc1 -/Δ mice ( Figure 5C).…”

“…The syndrome is characterized by accelerated aging of virtually all organ systems, all driven by failure to repair stochastic endogenous DNA damage. A murine model of XFE progeroid syndrome, Ercc1 -/Δ mice, have about 10% of the normal amount of ERCC1 protein and spontaneously develop progressive, degenerative changes that correlate strongly with natural aging (43)(44)(45)(46)(47). Thus, Ercc1 -/-mice, which have a complete absence of ERCC1 protein, and Ercc1 -/Δ mice offer a unique opportunity to investigate the mechanism by which one type of cellular damage promotes aging and whether NF-κB plays a pivotal role.…”

Defective transcription initiation causes postnatal growth failure in a mouse model of nucleotide excision repair (NER) progeria

“…5B). Moreover, the NER defect alone could account for the numerous progressive hepatic symptoms associated with aging in Ercc1 -/Δ mice that are healthy into adulthood and live substantially longer than the growth-defective, short-lived Ercc1 −/− and Taf10 −/− animals (26). Mutations in ERCC1, XPF, and XPG represent the only singlegene defects known in NER that are associated with growth attenuation and death before weaning in mice (27).…”

Modeling Alzheimer’s disease in progeria mice. An age-related concept

“…In fact, murine progeria models may mimic human aging to a greater extent than aged wild-type (WT) mice [6,]. Ercc1 −/Δ mice that model XFE progeroid syndrome develop conditions common in elderly humans such as osteoporosis, pulmonary fibrosis, chronic kidney disease, cardiovascular disease, muscle wasting, peripheral neuropathy, hepatic fibrosis, urinary incontinence, intervertebral disc degeneration, cognitive decline, and loss of hearing and vision [6,9–13]. In addition, multiple therapeutic interventions have been demonstrated to extend the health span of Ercc1 −/Δ mice [14,15], including anti-geronic therapeutics and senolytics [16,17].…”