Transcriptional response to aging and caloric restriction in heart and adipose tissue

Department of Pathology, University of Washington, Seattle, WA 98195, USA.
Aging Cell (Impact Factor: 6.34). 11/2007; 6(5):673-88. DOI: 10.1111/j.1474-9726.2007.00319.x
Source: PubMed


Sustained caloric restriction (CR) extends lifespan in animal models but the mechanism and primary tissue target(s) have not been identified. Gene expression changes with aging and CR were examined in both heart and white adipose tissue (WAT) of Fischer 344 (F344) male rats using Affymetrix RAE 230 arrays and validated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on 18 genes. As expected, age had a substantial effect on transcription on both tissues, although only 21% of cardiac age-associated genes were also altered in WAT. Gene set enrichment analysis revealed coordinated small magnitude changes in ribosomal, proteasomal, and mitochondrial genes with similarities in aging between heart and WAT. CR had very different effects on these two tissues at the transcriptional level. In heart, very few age-associated expression changes were affected by CR, while in WAT, CR suppressed a substantial subset of the age-associated changes. Genes unaltered by aging but altered by CR were identified in WAT but not heart. Most interestingly, we identified a gene expression signature associated with mammalian target of rapamycin (mTOR) activity that was down-regulated with age but preserved by CR in both WAT and heart. In addition, lipid metabolism genes, particularly those associated with peroxisome proliferator-activated receptor gamma (PPARgamma)-mediated adipogenesis were reduced with age but preserved with CR in WAT. These results highlight tissue-specific differences in the gene expression response to CR and support a role for CR-mediated preservation of mTOR activity and adipogenesis in aging WAT.

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Available from: Virginia L Malloy, Nov 21, 2014
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    • "The genes selected to be further investigated in the current study, were selected according to their proved role in ageing in other tissues or species, their effect on proliferation and differentiation of skin cells as well as influence on tumour physiology, chronic inflammation and age related diseases such as atherosclerosis, Alzheimer's and Parkinson's disease [9], [16], [17], [18], [19], [20]. Examination of expression levels of TGFβ, AXIN2, WIF1, SIRT6, MIB1, B3GALT3, APP, TAU, PSEN1, PARK2, ATXN1, and NLGN2 (Figure 3) was performed. "
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    ABSTRACT: The goal of our work has been to investigate the mechanisms of gender-independent human skin ageing and examine the hypothesis of skin being an adequate model of global ageing. For this purpose, whole genome gene profiling was employed in sun-protected skin obtained from European Caucasian young and elderly females (mean age 26.7±4 years [n1 = 7] and 70.75±3.3 years [n2 = 4], respectively) and males (mean age 25.8±5.2 years [n3 = 6] and 76±3.8 years [n4 = 7], respectively) using the Illumina array platform. Confirmation of gene regulation was performed by real-time RT-PCR and immunohistochemistry. 523 genes were significantly regulated in female skin and 401 genes in male skin for the chosen criteria. Of these, 183 genes exhibited increased and 340 decreased expression in females whereas 210 genes showed increased and 191 decreased expression in males with age. In total, 39 genes were common in the target lists of significant regulated genes in males and females. 35 of these genes showed increased (16) or decreased (19) expression independent of gender. Only 4 overlapping genes (OR52N2, F6FR1OP2, TUBAL3 and STK40) showed differential regulation with age. Interestingly, Wnt signalling pathway showed to be significantly downregulated in aged skin with decreased gene and protein expression for males and females, accordingly. In addition, several genes involved in central nervous system (CNS) ageing (f.i. APP, TAU) showed to be expressed in human skin and were significanlty regulated with age. In conclusion, our study provides biomarkers of endogenous human skin ageing in both genders and highlight the role of Wnt signalling in this process. Furthermore, our data give evidence that skin could be used as a good alternative to understand ageing of different tissues such as CNS.
    PLoS ONE 11/2012; 7(11):e50393. DOI:10.1371/journal.pone.0050393 · 3.23 Impact Factor
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    • "A reduction of mitochondrial biogenesis has also been associated with ''healthy'' aging. Indeed, gene expression analysis (whole transcriptome analyses) of skeletal muscle, white adipose tissue, kidney, brain, and heart consistently show a decrease in the expression of nuclear genes encoding mitochondrial proteins with age (Lu et al., 2004; Zahn et al., 2006; Linford et al., 2007; Melov et al., 2007). Alternatively, mitochondrial turnover may also be reduced with age, resulting in an age-related accumulation of old, damaged, or non-functional mitochondria (Terman, 2006). "
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    ABSTRACT: A controlled regulation of mitochondrial mass through either the production (biogenesis) or the degradation (mitochondrial quality control) of the organelle represents a crucial step for proper mitochondrial and cell function. Key steps of mitochondrial biogenesis and quality control are overviewed, with an emphasis on the role of mitochondrial chaperones and proteases that keep mitochondria fully functional, provided the mitochondrial activity impairment is not excessive. In this case, the whole organelle is degraded by mitochondrial autophagy or "mitophagy." Beside the maintenance of adequate mitochondrial abundance and functions for cell homeostasis, mitochondrial biogenesis might be enhanced, through discussed signaling pathways, in response to various physiological stimuli, like contractile activity, exposure to low temperatures, caloric restriction, and stem cells differentiation. In addition, mitochondrial dysfunction might also initiate a retrograde response, enabling cell adaptation through increased mitochondrial biogenesis.
    Journal of Cellular Physiology 06/2012; 227(6):2297-310. DOI:10.1002/jcp.23021 · 3.84 Impact Factor
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    • "Despite the evidences for a role of mTORC1–S6K1 signaling in agonist or pressure-induced cardiac hypertrophy, only little information is available about the signaling of mTORC1–S6K1 in physiological process of aging heart. An early study using microarray analyses reported that gene expression pattern associated with mTOR is suppressed in aging heart of Fischer 344 rats (Linford et al., 2007), while a recent study shows no difference in mTORC1–S6K1 activity (measured by phosphorylated mTOR and S6K1 levels) in the heart between 8 and 30 month old rats of the same strain (Shinmura et al., 2011). There are two points that should be considered for interpretation of the inconsistent results. "
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    ABSTRACT: The global population aging is accelerating and age-associated diseases including cardiovascular diseases become more challenging. The underlying mechanisms of aging and age-associated cardiovascular dysfunction remain elusive. There are substantial evidences demonstrating a pivotal role of the mammalian target of rapamycin complex 1 (mTORC1) and its down-stream effector S6K1 signaling in mammalian lifespan regulation and age-related diseases such as type II diabetes mellitus and cancer. The role of mTORC1-S6K1 in age-related cardiovascular diseases is, however, largely unknown and the available experimental results are controversial. This review article primarily summarizes the most recent advances toward understanding the role of mTORC1-S6K1 in cardiovascular aging and discusses the future perspectives of targeting mTORC1-S6K1 signaling as a healthy lifespan extension modality in anti-aging and anti-cardiovascular aging.
    Frontiers in Physiology 01/2012; 3:5. DOI:10.3389/fphys.2012.00005 · 3.53 Impact Factor
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