title: 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.
authors.affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Björn
authors.initials: B
authors.lastname: Schumacher
authors.forename: Ingrid
authors.initials: I
authors.lastname: van der Pluijm
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Moorhouse
authors.forename: Theodore
authors.initials: T
authors.lastname: Kosteas
authors.forename: Andria Rasile
authors.initials: AR
authors.lastname: Robinson
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.forename: Timo M
authors.initials: TM
authors.lastname: Breit
authors.forename: Harry
authors.initials: H
authors.lastname: van Steeg
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.forename: Wilfred
authors.initials: W
authors.lastname: van Ijcken
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Spindler
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
mesh_terms: D019588:Aging, Premature / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D031204:Caloric Restriction; D004392:Dwarfism / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D008136:Longevity / Q000235:genetics*; D008168:Lung / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011371:Progeria / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000503:physiopathology