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Delayed and accelerated aging share common longevity assurance mechanisms.

Schumacher B, van der Pluijm I, Moorhouse MJ, Kosteas T, Robinson AR, Suh Y, Breit TM, van Steeg H, Niedernhofer LJ, van Ijcken W, Bartke A, Spindler SR, Hoeijmakers JH, van der Horst GT, Garinis GA - PLoS Genet. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

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.

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Relative mRNA expression levels of genes associated with significantly over-represented biological processes.(A–D) % of relative mRNA expression levels of genes associated with immune responses (A), apoptosis (B), carbohydrate (Impa12, Gyk, Phkb) and lipid metabolism (Crot, Dhrs8, Akr1d1) (C), and energy derivation and biosynthesis (D) in the liver of an independent aging cohort of 130-week old compared to 13-week old wt male mice. For each gene, expression levels in the 130-week old livers are plotted relative to those of 13-week old tissues (red colored dotted line). Error bars indicate S.E.M between replicates (n≥6).
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pgen-1000161-g004: Relative mRNA expression levels of genes associated with significantly over-represented biological processes.(A–D) % of relative mRNA expression levels of genes associated with immune responses (A), apoptosis (B), carbohydrate (Impa12, Gyk, Phkb) and lipid metabolism (Crot, Dhrs8, Akr1d1) (C), and energy derivation and biosynthesis (D) in the liver of an independent aging cohort of 130-week old compared to 13-week old wt male mice. For each gene, expression levels in the 130-week old livers are plotted relative to those of 13-week old tissues (red colored dotted line). Error bars indicate S.E.M between replicates (n≥6).

Mentions: To independently assess the relevance of these processes to natural aging, we examined the expression levels of several genes relevant to immune responses (Ccr2, Tnfsf13, Saa1, Saa3, Fcgr3, Ccl6, C1qb, C1qc), apoptosis (Cd5l, Siva, Tnfrsf21, Tnfrsf1a, Casp4), carbohydrate and lipid metabolism (Impa1, Gyk, Phkb, Crot, Dhrs8, Akr1d1) and ATP and protein biosynthesis (Atp5k, Harsl, Rsl1d1, Atp5k, Rpl37) in livers derived from an independent aging cohort of male mice (n = 6) by means of quantitative real time PCR (Figure 4A–D). Confirming the gene expression changes of the first aging cohort of female mice (Figure S3), we found that all examined genes associated with immune and apoptotic responses were significantly upregulated in the 130-week mouse livers (compared to 13-week old mouse livers) whereas the expression of those genes associated with energy utilization and metabolism was substantially downregulated.


Delayed and accelerated aging share common longevity assurance mechanisms.

Schumacher B, van der Pluijm I, Moorhouse MJ, Kosteas T, Robinson AR, Suh Y, Breit TM, van Steeg H, Niedernhofer LJ, van Ijcken W, Bartke A, Spindler SR, Hoeijmakers JH, van der Horst GT, Garinis GA - PLoS Genet. (2008)

Relative mRNA expression levels of genes associated with significantly over-represented biological processes.(A–D) % of relative mRNA expression levels of genes associated with immune responses (A), apoptosis (B), carbohydrate (Impa12, Gyk, Phkb) and lipid metabolism (Crot, Dhrs8, Akr1d1) (C), and energy derivation and biosynthesis (D) in the liver of an independent aging cohort of 130-week old compared to 13-week old wt male mice. For each gene, expression levels in the 130-week old livers are plotted relative to those of 13-week old tissues (red colored dotted line). Error bars indicate S.E.M between replicates (n≥6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2493043&req=5

pgen-1000161-g004: Relative mRNA expression levels of genes associated with significantly over-represented biological processes.(A–D) % of relative mRNA expression levels of genes associated with immune responses (A), apoptosis (B), carbohydrate (Impa12, Gyk, Phkb) and lipid metabolism (Crot, Dhrs8, Akr1d1) (C), and energy derivation and biosynthesis (D) in the liver of an independent aging cohort of 130-week old compared to 13-week old wt male mice. For each gene, expression levels in the 130-week old livers are plotted relative to those of 13-week old tissues (red colored dotted line). Error bars indicate S.E.M between replicates (n≥6).
Mentions: To independently assess the relevance of these processes to natural aging, we examined the expression levels of several genes relevant to immune responses (Ccr2, Tnfsf13, Saa1, Saa3, Fcgr3, Ccl6, C1qb, C1qc), apoptosis (Cd5l, Siva, Tnfrsf21, Tnfrsf1a, Casp4), carbohydrate and lipid metabolism (Impa1, Gyk, Phkb, Crot, Dhrs8, Akr1d1) and ATP and protein biosynthesis (Atp5k, Harsl, Rsl1d1, Atp5k, Rpl37) in livers derived from an independent aging cohort of male mice (n = 6) by means of quantitative real time PCR (Figure 4A–D). Confirming the gene expression changes of the first aging cohort of female mice (Figure S3), we found that all examined genes associated with immune and apoptotic responses were significantly upregulated in the 130-week mouse livers (compared to 13-week old mouse livers) whereas the expression of those genes associated with energy utilization and metabolism was substantially downregulated.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus