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.

Lipodystrophies represent a group of heterogeneous disorders characterized by loss of fat tissue. However, the underlying mechanisms remain poorly understood. Using mice carrying an ERCC1-XPF DNA repair defect systematically or in adipocytes, we show that DNA damage signaling triggers a chronic auto-inflammatory response leading to fat depletion. Ercc1−/− and aP2-Ercc1f/− fat depots show extensive gene expression similarities to lipodystrophic Pparγldi/+ animals along with focal areas of ruptured basement membrane, the reappearance of primary cilia, necrosis, fibrosis and a marked decrease in adiposity. We find that persistent DNA damage in aP2-Ercc1f/− fat depots and in adipocytes ex vivo trigger the induction of pro-inflammatory factors by promoting transcriptionally active histone marks and the dissociation of nuclear receptor co-repressor complexes from promoters; the response is cell-autonomous and requires ATM. Thus, persistent DNA damage-driven auto-inflammation plays a causative role in adipose tissue degeneration with important ramifications for progressive lipodystrophies and natural aging.

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