Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak

( Renault et al., 2009; Devin et al., 2016; Renault et al., 2009) Also grey matter volume of subcortical regions is positively affected this way. (Colman et al., 2009)

       Low caloric intake has also positive effect on SIRT1 activity which leads to dendritic outgrowth and plasticity and low inflammatory cytokine activity. (Maalouf et al., 2009) Ohkura et al., 2010 described how FOXO interacts with the sirtuin, which is relevant to aging and cancer. Sirtuin in turn decreases apoptosis via FOXO or BAX. (Dang et al., 2009; Dang et al., 2009; Martins et al., 2015) According to „CYB5R3: a key player in aerobic metabolism and aging?“ (de Cabo et al. 2010) coenzyme Q (CoQ) helps to reduce NADH-level in mitochondria and regulate this way NAD+-dependent enzymes e.g., sirtuins. So, cytochrome b5 coding reductase CYB5R needs NADH and CoQ for its function.(Villalba et al., 1995) Also low calories intake enhanced aerobic metabolism. This needs cytosolic cooperation of N-myristoylated CYB5R3 (a component of P-450 mediated hydroxylation of drugs and steroid hormones (Passon and Hultquist, 1972), fatty acid elongation (Keyes and Cinti ,1980) and cholesterol biosynthesis (Reddy et al, 1977)) and SIRT1. SIRT1 in turn needs lysine acetylation for this cooperation. It modifies CYB5R3 activity and regulates this way the cytosolic NAD+/NADH level.

      The activity of FOXO/DAF-16 is positively and negatively regulated by different molecular players (e.g., the insulin/IGF signalling pathway and the nutrient sensor AMPK) and stresses (e.g., oxidative and heat stress). (Eijkelenboom and Burgering, 2013; Salih and Brunet, 2008; Dervis and al., 2008) Sirtuins and H2S induced AMPK and IIS (influences FOXO and mTOR (effected by GH)) have opposite actions. (Barzilai et al., 2012; Fontana et al., 2010; Kenyon, 2010, 2005; Blagosklonny, 2006; Kapahi et al., 2010; Stanfelet al., 2009; Polak and Hall, 2015; Moskalevet al., 2014) FOXO also effects detoxification enzymes MnSOD and GADD45. (Kops et al., 2002; Nemoto and Finkel, 2002)

      Apolipoprotein E4 (apoE4) and FOXO are not only associated with quick cell aging (Aksenov et al., 2001; Martins, et al., 2015) but also with Alzheimer’s disease (Sando et al., 2008; DiLoreto & Murphy, 2015).

      Further aging factors are rapamycin target S6K activator and 4EBP1 inhibiter mTORC1 and cytoskeletal relevant TORC2 protein kinases (Zoncu et al., 2011),

      AMP/ATP ratio and metformin activated AMPK, insulin and IGF1 influenced (FOXO) , which in turn activates MnSOD.

       FOX genes and anti-aging agents

      Aging relevant SIRT2 deacetylase can be regulated via Resveratrol. Resveratrol is known for his positive affect on Alzheimer disease, on neuroendocrine tumors, on multiple myeloma, on follicular lymphoma, on colon-ca etc. Like EGCG and alpha-M it inhibits PI3K/PTEN/Akt/mTORC1 and WNT/beta-catenin pathway. Resveratrol effects c-Myc, MMP-7 and SIRT1activity and increases SLUG-, vimentin- and NF-kappa-B level. NF-kappa-B level in turn influences caspase-3, MMP-9- and CXCR4- level as well as EMT-level via TGF-beta/SMAD. TGF-beta/SMAD regulates SNAIL/E-cadherin level. ( Ji et al., 2015)

      Resveratrol also increases PARP-1 and AMPK level (which in turn decreases MDR1 and CREB phosphorylation level (Wang et al., 2015), E-cadherin-level and apoptosis. It decreases cell migration, invasion and proliferation. Resveratrol interacts with type II topoisomerase and causes double strand DNA breaks and also influences TP53 via ATM. (Demoulin et al., 2015) Together with mitomycin it effects C p21it level and shows an anti-proliferative effect. (Ali et al., 2014) Resveratrol increases the expression of miR-34 which resulted in the decreased expression of E2F3 and SIRT1 (Kumazaki et al., 2013) Tumor suppressor Klotho gene have also aging relevant effect. It increases SIRT1 level (Melatonin shows similar effects) and activates FOXO3 phosphorylation via PI3K/PTEN/Akt pathway. Resveratrol has positive effect on liver cancer and macular degeneration (via VEGF-A and VEGF-C negative regulation), on cardiovascular diseases, on endometriosis, on PCOS, on dyslipidaemia, on diabetes, on chronic renal insufficiency, on Friedreich Ataxia, on Huntington disease and on brain ca via TP53 and p21, 1A/1B light chain 3B (LC3-II), Atg5, beclin-1 and NANOG Cip1 etc. Resveratrol inhibits cyclooxygenase activity, CYP A1 metabolism and influences aging relevant TNFRSF6,TNF-alpha, HIF-1alpha, VEGF, NF-kappaB activity, FAS/FAS-ligand, TP53, FAS-L = CD95, IL-17 but also apoptosis of activated T cells interleukin 17. In head and neck cancer Resveratrol decreases ALDH1, CD44 , HNC-TICs, EMT, NANOG, NESTIN and OCT4 level (Hu et al., 2012) In leukaemia it decreases pLKB1level via SIRT1 and STK11 (Peng et al., 2015) Antiaging phytochemicals are Stilbenoid Resveratrol from Veratrum, which among others influences caspase-1 (Yang et al., 2014; Pietrocola et al., 2012) as well as Catechins and EGCG from Green, which also influence Beclin 1 (Yang et al., 2013; Yang, 2008; Fan et al, 2014) and Camellia sinensis. which also positively influences Helicobacter pylori-triggered caspase-1 signalling pathway.

      Not only Resveratrol but also Andrographolide and Parthenolide effect NF-kappaB (Gunn et al., 2011) Further antiaging products are e.g. Iberis amara, which effects apoptosis and ROS ( Weidner et al., 2016) and Beta-carotene, which interact with FOXP2 and piperine, which like Vitamin A kill CSCs. ( Scarpa et al., 2015) Omega-3 polyunsaturated fatty acids negatively influences PI3K/PTEN/Akt/mTORC1 signalling and effects apoptosis (Vasudevan et al., 2014) According to (Rafael de Cabo et al., 2014) caloric restriction influences FGF21, TOR/S6K pathways, insulin, SIRT3, mitochondrial acetyl proteome (Hebert et al., 2013) and metformin - ATP Level in mitochondria, SKN-1/Nrf (Berstein, 2012) (in the same time in worms it lowers ATP levels (Dillin et al., 2002; Lee et al., 2003) possible via mutations in the mitochondrial leucyl-tRNA synthetase gene (Lee et al., 2003),Atg5 (Pyo et al., 2013), TOR signalling, p53 (Jia and Levine, 2007; Tavernarakis et al., 2008).Also acetylproteome, spermidine and sirtuin, which influences autophagy, histone acetyltransferase like resveratrol effects histone deacetylase (sirtuin) (Morselli et al., 2010) and Atg5 (Morselli et al., 2011).SIRT3 is positively affected by dietary restriction via deacetylation of mitochondrial proteins (Someya et al., 2010) and also can be upregulated by Resveratrol. ROS activates hypoxia-inducible factor 1 (HIF-1) and (AMP)-activated protein kinase (AMPK) and affects transcription factors NRF2/SKN-1 and p53/CEP-1 (Chang et al., 2015; Ventura et al., 2009 ). AMPK activates PGC1α , which regulates mitochondrial respiration and detoxification( Liang and Ward, 2006 ). Low PGC1α level effects antioxidant NO (Borniquel et al., 2006 ) which also contribute to proper memory functions. CR also positively influences Hormesis (Calabrese et al., 1987).and anti-stress transcription factors e.g. Gis1, Msn2/Msn4 and Rim15 in yeast and FOXO in mammals.(Wang et al., 2011) In flies it needs help of Complex I and IV (Zid et al., 2009), d4E-BP (Zid et al., 2009) and catalase (Schriner et al., 2005).

      Several reports illustrated that Metformin activates AMP-activated protein kinase (Zhou et al., 2001) and inhibits tyrosine phosphates activity (Holland et al., 2004) . and mTORC1 signalling (Kalender et al., 2010)

      Campisi showed in her review „Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors25 February 2005“ p53 and RB tumor suppressor proteins as aging relevant agents with anticancer effect. Senescence is associated with RAS-RAF-MEK signalling cascade. Different senescence signals can converge (Bringold and Serrano, 2000; Lundberg et al., 2000; Narita and Lowe, 2004), so p53 can be influenced by telomeres (d’Adda di Fagagna et al., 2003, Takai et al., 2003) and RAS (Serrano et al., 1997; Ferbeyre et al., 200;, Pearson et al., 2000), RAS also upregulates pRB (responsible for repressive heterochromatin at loci containing transcription factor E2F) and effects p16 (Beausejour et al., 2003;Wright and Shay, 200;, Collins and Sedivy, 2003; Ben-Porath and Weinberg, 2004; Harvey et al., 1993; Smogorzewska and de Lange, 2002) and plays a role in oxygen toxicity during replicative senescence (Parrinello et al., 2003), p16, p53 pathway, which overlap with oncogenic RAS (Beausejour et al., 2003; Brookes et al., 2002; Huot et al., 2002), but also with ROS (Irani et al., 1997), IGF1 signalling pathway, ARF, MDM2 (Krishnamurthy et al., 2004), p16 transcriptional activator Ets-1 (Ohtani et al., 2001), correlated with p16 expression (Krishnamurthy et al., 2004). It is possibly due to increased sensitivity of the INK4a/ARF locus to transcriptional activation.

      According to Blagosklonny, 2012 sirtuins negatively regulate rDNA recombination (Kaeberlein et al., 1999) and number of extrachromosomal rDNA circles. (Stinclair and Guarente, 1997) Sir.2 improves FOXO ortholog, DAF-16 function in worms possibly via IIS (Tissenbaum et al., 2001) and in flies via Rpd3 deacetylation. (Rogina and Helfand, 2004)

      Rapamycin inhibits mTOR and rejuvenates cardiac and