Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms

Abstract

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.

Relationship Between DNA Damage and Energy Metabolism: Evidence from DNA Repair Deficiency Syndromes

“…Nonetheless, in select mouse models of severe NER progeria, effects on serum IGF-1 and glycemic index can be transient, occurring prior to weaning but normalizing in animals that survive this apparent developmental bottleneck (van de Ven et al 2006). Global profiling of gene expression in liver confirmed a significant overlap between NER progeria and long-lived dwarfism (Schumacher et al 2008) consistent with the physiologic data. Paradoxically, the core feature of IGF-1 signaling attenuation increases lifespan in several species (Rincon et al 2004;Longo and Finch 2003) but is associated with decreased longevity in NER progeria.…”

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

“…We carried out a series of in vivo chromatin immunoprecipitation (ChIP) assays to study occupancies of the Igf1, GhR, Dio1, and PrlR promoters. These genes are essential for postnatal animal growth (17). Unlike Ercc1 −/− livers, beginning on day 5, the wt livers demonstrated a robust increase in the mRNA levels of these genes ( Fig.…”

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

“…The expression of key genes known to be altered in old WT mice was also evaluated by qRT-PCR (47). The growth hormone/IGF-1 axis is downregulated in aged mice and progeroid ERCC1-deficient mice (45).…”

“…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.…”