Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Rapamycin extends life span, but has limited effects on aging in mice

ABSTRACT: Rapamycin extends life span in mice, but it remains unclear if this compound also delays mammalian aging. Here, we present results from a comprehensive large-scale assessment of a wide rage of structural and functional aging phenotypes in mice. Rapamycin extended life span but showed few effects on a large number of systemic aging phenotypes, suggesting that rapamycin's effects on aging are largely limited to the regulation of age-related mortality and carcinogenesis. Total RNA obtained from 2-4 male mice of each analysed group (25 weeks old controls, 25 month old controls, 25 month old rapamycin treated)

ORGANISM(S): Mus musculus

SUBMITTER: Marion Horsch

PROVIDER: E-GEOD-41018 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Rapamycin extends murine lifespan but has limited effects on aging.

Neff Frauke F Flores-Dominguez Diana D Ryan Devon P DP Horsch Marion M Schröder Susanne S Adler Thure T Afonso Luciana Caminha LC Aguilar-Pimentel Juan Antonio JA Becker Lore L Garrett Lillian L Hans Wolfgang W Hettich Moritz M MM Holtmeier Richard R Hölter Sabine M SM Moreth Kristin K Prehn Cornelia C Puk Oliver O Rácz Ildikó I Rathkolb Birgit B Rozman Jan J Naton Beatrix B Ordemann Rainer R Adamski Jerzy J Beckers Johannes J Bekeredjian Raffi R Busch Dirk H DH Ehninger Gerhard G Graw Jochen J Höfler Heinz H Klingenspor Martin M Klopstock Thomas T Ollert Markus M Stypmann Jörg J Wolf Eckhard E Wurst Wolfgang W Zimmer Andreas A Fuchs Helmut H Gailus-Durner Valérie V Hrabe de Angelis Martin M Ehninger Dan D

The Journal of clinical investigation 20130725 8

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, ...[more]

PMID: 23863708

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Project description:Background: Skin aging is associated with intrinsic processes that compromise structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain. Results: We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B-cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age. Conclusions: Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific. We used Affymetrix microarrays to evaluate genome-wide expression in tail skin from young (5 month) and old (30 month) CB6F1 mice (males and females). Genome-wide expression was evaluated in tail skin from young (5 months) and old (30 months) CB6F1 mice of both sexes. Samples were collected simultaneously but RNA samples were processed in two separate batches.

Project description:Extracellular senile plaques of amyloid beta (Abeta) are a pathological hallmark in brain of patients with Alzheimer`s Disease (AD). Abeta is generated by the amyloidogenic processing of the amyloid precursor protein (APP). Concomitant to Abeta load, AD brain is characterized by an increase in protein level and activity of the angiotensin-converting enzyme (ACE). ACE inhibitors are a widely used class of drugs with established benefits for patients with cardiovascular disease. However, the role of ACE and ACE inhibition in the development of Abeta plaques and the process of AD-related neurodegeneration is not clear since ACE was reported to degrade Abeta. To investigate the effect of ACE inhibition on AD-related pathomechanisms, we used Tg2576 mice with neuron-specific expression of APPSwe as AD model. From 12 months of age, substantial Abeta plaque load accumulates in the hippocampus of Tg2576 mice as a brain region, which is highly vulnerable to AD-related neurodegeneration. The effect of central ACE inhibition was studied by treatment of 12 month-old Tg2576 mice for six months with the brain penetrating ACE inhibitor captopril. At an age of 18 months, hippocampal gene expression profiling was performed of captopril-treated Tg2576 mice relative to untreated 18 month-old Tg2576 controls with high Abeta plaque load. As an additional control, we used 12 month-old Tg2576 mice with low Abeta plaque load. Whole genome microarray gene expression profiling revealed gene expression changes induced by the brain-penetrating ACE inhibitor captopril, which could reflect the neuro-regenerative potential of central ACE inhibition. Microarray gene expression profiling was performed of hippocampi isolated from aged, 18 month-old Tg2576 (APPSwe-transgenic) AD mice with high Abeta plaque load relative to age-matched Tg2576 mice, which were treated for 6 months with the centrally active ACE inhibitor captopril. Another study group consisted of 12 month-old Tg2576 mice with low Abeta plaque load. In total, three study groups were analyzed, i.e. (i) 18 month-old untreated Tg2576 mice with high Abeta plaque load, (ii) age-matched Tg2576 mice treated for 6 months with the brain-penetrating ACE inhibitor captopril (20 mg/kg body weight/day in drinking water), and (iii) untreated 12 month-old Tg2576 mice with low Abeta plaque load reflecting the time point when captopril treatment was initiated. Two biological replicates were made of each group, and total hippocampal RNA of four mice was pooled for one gene chip.

Dataset Information

Rapamycin extends life span, but has limited effects on aging in mice

Publications

Rapamycin extends murine lifespan but has limited effects on aging.

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