Delayed and Accelerated Aging Share Common Longevity Assurance Mechanisms

Björn Schumacher,Stephen R Spindler,Ingrid Van Der Pluijm,George A Garinis,Jan H J Hoeijmakers,Timo M Breit,Andrzej Bartke,Michael J Moorhouse,Laura J Niedernhofer,Wilfred Van Ijcken,Yousin Suh,Gijsbertus T J Van Der Horst,Theodore Kosteas,Andria Rasile Robinson,Harry Van Steeg

doi:10.1371/journal.pgen.1000161

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.

Highlights

The complexity of the aging process, as well as the conspicuous lack of tools to study it, has hindered hypothesis-driven reductionist approaches to identifying the molecular mechanism of aging in mammals
Prime examples are Cockayne syndrome (CS; affected proteins: CSB, CSA), XPF-ERCC1 syndrome (XFE; affected proteins: XPF, ERCC1) or trichothiodystrophy (TTD; affected proteins: XPB, XPD, TTDA) that are caused by defects in the transcription-coupled subpathway of nucleotide excision repair (TC-NER) [6,7]
Both intrinsic and environmental stressors induce survival responses aimed at overcoming crisis and extending lifespan

Summary

Introduction

The complexity of the aging process, as well as the conspicuous lack of tools to study it, has hindered hypothesis-driven reductionist approaches to identifying the molecular mechanism of aging in mammals. Recent progress has revealed that several aspects of aging could be accelerated or delayed by single gene mutations. Mouse models for progeroid syndromes are invaluable for studying accelerated aging [1]. Defects in the genome maintenance mechanisms can lead to a variety of progeroid disorders [2] suggesting a causative role of DNA damage in aging [3,4,5]. NER removes a wide range of helix-distorting DNA damage such as UV lesions, and is divided into global genome (GG-NER) that recognizes helical distortions throughout the genome and TC-NER that removes transcription-blocking lesions on the transcribed strand of active genes [2,8]. We applied genome-wide expression profiling to characterize the severe progeroid Csbm/m;Xpa2/2 and Ercc12/2

Methods

Results

Discussion

Conclusion