DNA DAMAGE RESPONSE IS ESSENTIAL FOR THE MAINTENANCE OF INTESTINAL HOMEOSTASIS WITH AGE

P. JoungSun, J. Pyo, H. Jeon, Y. Kim, M. Yoo
2017 Innovation in aging  
Calorie restriction (CR) extends lifespan and delays the onset of a number of age-related diseases in multiple laboratory organisms. These anti-aging effects of CR may be mediated by increased lipid metabolism and oxidative stress resistance. Taurine (2-aminoethylphosphonic acid) is an amino acid that has been suggested to function as a regulator of both osmosis and lipid metabolism, and as an antioxidant. In this study, we aimed to evaluate the potential of taurine as a CR mimetic using rats
more » ... d mice. Sprague Dawley (SD) rats were fed a diet supplemented with 0% (control), 0.5%, 1.0%, 3.0% or 5.0% (w/w) taurine for 2 weeks. SD rats fed a 5% taurine diet displayed a significant reduction in white adipose tissue mass compared with rats fed control diet (p < 0.05). Plasma and liver cholesterol and triglycerides were also significantly decreased in taurine-fed rats compared with controls (p < 0.05). Liver gene expression analysis showed decreased mRNA expression of fatty acid synthase and increased mRNA expression of carnitine palmitoyltransferase 1A, a key mediator of beta-oxidation (p < 0.05). Furthermore, C57BL/6 mice fed a 5% taurine diet for 16 weeks showed increased survival under the oxidative stress induced by injection of 3-nitropropionic acid versus mice fed control diet (p < 0.05). These results suggest that taurine might have CR-mimetic effects through modulation of lipid metabolism and induction of oxidative stress resistance. Introduction: Osteoporosis is characterized by loss of bone tissue while age is considered as the common risk factor. There is an impaired osteoblastic bone formation in comparison with osteoclastic bone resorption during aging. One of the possible cellular mechanisms of age-related bone loss is osteoblast senescence. MicroRNAs (miRNAs) regulate the expression of mRNA/protein targets and play an important part in cellular senescence. The purpose of this study was to investigate alternations in the miRNAs that are expressed in replicative senescence of human osteoblast cells. Methods: Osteoblasts were grown in vitro and cultivated to the eighth generation cells. We then employed immunohistochemical techniques to identify the expression of senescence markers of senescence-associated β-galactosidase (SA-β-gal) activity. RNA isolation, small RNA library construction and deep sequencing were performed. The generated next-generation sequencing (NGS) data were analyzed using the miRSeq software package. Results: In vitro aging model showed the positive cell number of SA-β-gal stained osteoblasts were enhanced in the eighth generation senescent cells. Morphological changes of large, flat and multinucleated than earlier young cells (first generation cell as the control group) were observed. In the NGS profiles, 168 miRNAs demonstrated over 2-fold changes. For those read counts over 10 reads per million (RPM), 29 of these miRNAs (including 10 upregulated and 19 downregulated miRNAs) were detected in the senescent group. Conclusions: We demonstrated differentially expressed miRNAs detected between senescent and young human osteoblast cells. Further studies to identify candidate miRNAregulated genes regulating pathways of replicative senescence are required. Aging is a complex phenomenon with the number of contributing biological factors. Recently, important links have been reported between microRNAs (miRNA) and aging. miRNAs are short, non-coding RNAs that induce mRNA degradation or repression post-transcriptionally and thus affect a number of biological processes including stem cell maintenance, proliferation and metabolism. It is well established that for cell-cell and cell-tissue interaction, miRNAs are transported as cargo in exosomes. To identify specific differences between miRNA from young-adult (6 week C57BL/6 mice) and aged (78 week) mesenchymal stem cells (MSCs), we performed microarray analysis of exosomal miRNAs and found that a number of biologically relevant miRNAs were differentially expressed. miR-370 was overexpressed (4.49 fold) in exosomes from the older animals. miR-370 has been implicated in cholesterol homeostasis, fatty acid metabolism and lipogenesis. miR-214 was overexpressed (2.7 fold) in exosomes of old MSCs. miR-214 represses Wnt signaling which regulates adipogenesis. This may explain the possible shift of MSCs differentiation tendency from the osteoblast to the adipocyte lineage; such a shift is also reported in agingrelated diseases. In addition, we investigated the effect of aging on the function of exosomes. MSCs from young-adult and aged animals were exposed to hypoxic (2% oxygen) conditions and exosomes isolated. Under hypoxic conditions, tubule formation induced by exosomes from young-adult animals was greater than that from the older group (p=1e -7 ). Thus, ageassociated differences in miRNA expression may account, in part, for age associated differences in fatty acid metabolism, body composition, and the ability to respond to a hypoxic stress. The stem cell genomic stability forms the basis for robust tissue homeostasis, particularly in high-turnover tissues. For the genomic stability, DNA damage response (DDR) is
doi:10.1093/geroni/igx004.551 fatcat:jpsosylqpbdmnhamw3nqfkamcy