Comparative transcriptional pathway bioinformatic analysis of dietary restriction, Sir2, p53 and resveratrol life span extension inDrosophila

Institute for Brain and Neural Systems, and Department of Physics, Brown University, Providence, RI, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 03/2011; 10(6):904-11. DOI: 10.4161/cc.10.6.14912
Source: PubMed


A multiple comparison approach using whole genome transcriptional arrays was used to identify genes and pathways involved in calorie restriction/dietary restriction (DR) life span extension in Drosophila. Starting with a gene centric analysis comparing the changes in common between DR and two DR related molecular genetic life span extending manipulations, Sir2 and p53, lead to a molecular confirmation of Sir2 and p53's similarity with DR and the identification of a small set of commonly regulated genes. One of the identified upregulated genes, takeout, known to be involved in feeding and starvation behavior, and to have sequence homology with Juvenile Hormone (JH) binding protein, was shown to directly extend life span when specifically overexpressed. Here we show that a pathway centric approach can be used to identify shared physiological pathways between DR and Sir2, p53 and resveratrol life span extending interventions. The set of physiological pathways in common among these life span extending interventions provides an initial step toward defining molecular genetic and physiological changes important in life span extension. The large overlap in shared pathways between DR, Sir2, p53 and resveratrol provide strong molecular evidence supporting the genetic studies linking these specific life span extending interventions.

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    • "Polyphenols are characterized by hydroxylated phynyl moieties and classified as flavonoid polyphenols, such as catechine and fisetin, or non-flavonoid polyphenols, including resveratrol and curcumin, based on chemical structure. protein kinase (AMPK), p53, and peroxisome proliferator-activated receptor-γ- coactivator-1α (PGC-1α) may instead be associated with the pro-longevity effect of resveratrol (Lagouge et al. 2006; Baur et al. 2006; Pirola and Frojdo 2008; Antosh et al. 2011). "

    Life extension: Lessons from Drosophila, 05/2015: chapter Phytochemicals with lifespan extension effect in Drosophila: pages 229-244; Springer., ISBN: 978-3-319-18325-1
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    • "Mechanistically, nutrient-sensing pathways have been identified as a major class of conserved life span regulators. This group includes caloric restriction, insulin and insulin-like growth factor signaling, and target of rapamycin signaling (Antosh et al., 2011; Kapahi et al., 2004; Rogina and Helfand, 2004; Spindler, 2010; Zid et al., 2009). A central aspect of cellular metabolism and energy homeostasis is the maintenance of adenosine derivatives (e.g., AMP, ADP, and ATP) at relatively constant levels (Hardie, 2003). "
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    ABSTRACT: A common thread among conserved life span regulators lies within intertwined roles in metabolism and energy homeostasis. We show that heterozygous mutations of AMP biosynthetic enzymes extend Drosophila life span. The life span benefit of these mutations depends upon increased AMP:ATP and ADP:ATP ratios and adenosine monophosphate-activated protein kinase (AMPK). Transgenic expression of AMPK in adult fat body or adult muscle, key metabolic tissues, extended life span, while AMPK RNAi reduced life span. Supplementing adenine, a substrate for AMP biosynthesis, to the diet of long-lived AMP biosynthesis mutants reversed life span extension. Remarkably, this simple change in diet also blocked the prolongevity effects of dietary restriction. These data establish AMP biosynthesis, adenosine nucleotide ratios, and AMPK as determinants of adult life span; provide a mechanistic link between cellular anabolism and energy sensing pathways; and indicate that dietary adenine manipulations might alter metabolism to influence animal life span.
    Cell metabolism 01/2013; 17(1):101-12. DOI:10.1016/j.cmet.2012.12.006 · 17.57 Impact Factor
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    • "p53 was demonstrated to inhibit geroconversion (a conversion from quiescence or simple arrest to senescence [76]) and, importantly, it did not cause senescence in quiescent cells [79]. Not surprisingly, the effects of p53 on longevity may vary [33, 172-180]. On the other hand, since p53 is the most frequently mutated tumor suppressor gene, p53 is under further investigations for various cancer therapies to characterize and develop new drugs and approaches for targeting both mutated and WT p53 [181-194]. "
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    ABSTRACT: It is widely believed that aging results from the accumulation of molecular damage, including damage of DNA and mitochondria and accumulation of molecular garbage both inside and outside of the cell. Recently, this paradigm is being replaced by the "hyperfunction theory", which postulates that aging is caused by activation of signal transduction pathways such as TOR (Target of Rapamycin). These pathways consist of different enzymes, mostly kinases, but also phosphatases, deacetylases, GTPases, and some other molecules that cause overactivation of normal cellular functions. Overactivation of these sensory signal transduction pathways can cause cellular senescence, age-related diseases, including cancer, and shorten life span. Here we review some of the numerous very recent publications on the role of signal transduction molecules in aging and age-related diseases. As was emphasized by the author of the "hyperfunction model", many (or actually all) of them also play roles in cancer. So these "participants" in pro-aging signaling pathways are actually very well acquainted to cancer researchers. A cancer-related journal such as Oncotarget is the perfect place for publication of such experimental studies, reviews and perspectives, as it can bridge the gap between cancer and aging researchers.
    Oncotarget 12/2012; 3(12):1522-32. DOI:10.18632/oncotarget.889 · 6.36 Impact Factor
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