The accumulation of cellular damage, including DNA damage, is thought to contribute to aging-related degenerative changes, but how damage drives aging is unknown. XFE progeroid syndrome is a disease of accelerated aging caused by a defect in DNA repair. NF-κB, a transcription factor activated by cellular damage and stress, has increased activity with aging and aging-related chronic diseases. To determine whether NF-κB drives aging in response to the accumulation of spontaneous, endogenous DNA damage, we measured the activation of NF-κB in WT and progeroid model mice. As both WT and progeroid mice aged, NF-κB was activated stochastically in a variety of cell types. Genetic depletion of one allele of the p65 subunit of NF-κB or treatment with a pharmacological inhibitor of the NF-κB–activating kinase, IKK, delayed the age-related symptoms and pathologies of progeroid mice. Additionally, inhibition of NF-κB reduced oxidative DNA damage and stress and delayed cellular senescence. These results indicate that the mechanism by which DNA damage drives aging is due in part to NF-κB activation. IKK/NF-κB inhibitors are sufficient to attenuate this damage and could provide clinical benefit for degenerative changes associated with accelerated aging disorders and normal aging.

Mutant dwarf and calorie-restricted mice benefit from healthy aging and unusually long lifespan. In contrast, mouse models for DNA repair-deficient progeroid syndromes age and die prematurely. To identify mechanisms that regulate mammalian longevity, we quantified the parallels between the genome-wide liver expression profiles of mice with those two extremes of lifespan. Contrary to expectation, we find significant, genome-wide expression associations between the progeroid and long-lived mice. Subsequent analysis of significantly over-represented biological processes revealed suppression of the endocrine and energy pathways with increased stress responses in both delayed and premature aging. To test the relevance of these processes in natural aging, we compared the transcriptomes of liver, lung, kidney, and spleen over the entire murine adult lifespan and subsequently confirmed these findings on an independent aging cohort. The majority of genes showed similar expression changes in all four organs, indicating a systemic transcriptional response with aging. This systemic response included the same biological processes that are triggered in progeroid and long-lived mice. However, on a genome-wide scale, transcriptomes of naturally aged mice showed a strong association to progeroid but not to long-lived mice. Thus, endocrine and metabolic changes are indicative of “survival” responses to genotoxic stress or starvation, whereas genome-wide associations in gene expression with natural aging are indicative of biological age, which may thus delineate pro- and anti-aging effects of treatments aimed at health-span extension. To identify mechanisms that regulate mammalian longevity, we have quantified the expression parallels of a number of long-lived mice that show delayed aging and DNA repair mutants that age and die prematurely. Unexpectedly, we found significant, genome-wide similarities and a widespread overlap of over-represented biological processes in the transcriptomes of these disparate mouse strains. Subsequent analysis revealed that similar responses are triggered constitutively in a number of organs in aged mice. Thus, both intrinsic and environmental stressors (e.g., aging, genome instability, or food shortage) induce survival responses aimed at overcoming crisis and extending lifespan. Such survival responses are likely to allow assessment of biological age as well as provide valuable targets for therapies aimed at health-span extension.

Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb^m/m/Xpa^−/− mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb^m/m/Xpa^−/− mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb^m/m/Xpa^−/− and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair–deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis. Normal metabolism routinely produces reactive oxygen species that damage DNA and other cellular components and is thought to contribute to the ageing process. Although DNA damage is typically kept in check by a variety of enzymes, several premature ageing disorders result from failure to remove damage from active genes. Patients with Cockayne syndrome (CS), a genetic mutation affecting one class of DNA repair enzymes, display severe growth retardation, neurological symptoms, and signs of premature ageing followed by an early death. Whereas mouse models for CS exhibit relatively mild deficits, we show that concomitant inactivation of a second DNA repair gene elicits severe CS pathology and ageing. Moreover, a few days after birth, these mice undergo systemic suppression of genes controlling growth, an unexpected decrease in oxidative metabolism, and an increased antioxidant response. Similar physiological changes are also triggered in normal mice by chronic exposure to DNA-damaging oxidative stress. From these findings, we conclude that DNA damage triggers a response aimed at limiting oxidative DNA damage levels (and associated tissue degeneration) to extend lifespan and promote healthy ageing. Better understanding of the ageing process will help to delineate intervention strategies to combat age-associated pathology.