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

development appears to be transient and this is also observed for other family members”(Gascoyne et al., 2015, p.13), considered potential connections between FOXP2 and p53 pathways. “Normal osteoblast development is compromised in bone metastases of solid tumours and in bone malignancies such as multiple myeloma, and this characterisation of FOXP2 growth arrest function in a disease context may identify novel malignant pathways. Furthermore, FOXP2 status in osteosarcoma may provide information regarding the stage of developmental block, with potential clinical significance. Direct connection of FOXP2 to the mutated p53 pathway in osteosarcoma, via a common target p21/CDKN1A, is also likely to have implications for understanding osteosarcoma biology.” (Gascoyne et al., 2015, p.14)

      

      Also the review of Wohlgemuth et al., 2014 showed that FOXP2 also provided the NMDAR-mediated neuronal plasticity affecting MAPKK and tyrosine phosphatase. The MARK is a RAS Downstream Effector. RAS is a GTPase that indirectly interacts with oncological relevant p21 and p53 indirectly. So FOXP2 can act alone or in combination with other members of its or other gene families. Its own expression can be influenced both by the cooperation partners and by the feedback loops or by other interactions. These innumerable tissue-specific regulation possibilities allow a fine-tuning and a rapid adaptation to ever-changing environmental conditions which need to be studied more closely.

       Influence of other members of Fox-family on aging processes

      According to Ni et al. 2012, Ribarič 2012 Foxo plays an important epigenetic role in aging and Hansen et al, 2013 describe DAF/FOXO effect on longevity. Steroid hormone dehydrogenases, cytochrome P450s and others aging relevant steroid hormone signalling pathways are influenced not only by LIPL-4 and TOR regulated autophagy but also by daf-16/FOXO (Lapierre et al., 2011).In C. Elegans daf-16/FOXO affects aging and tumor growth. (Pinkston-Gosse and Kenyon, 2007) Experiments with germline-less C. Elegans showed that FOXO3A effects NAD-dependent protein deacetylases and ADP-ribosyl transferases activity of aging relevant sirtuin (Oberdoerffer et al., 2008; Wang et al., 2008) e.g. with the help of histone H3K9 deacetylation, glucose homeostasis, genomic stability and via subunit RelA NF-κB regulating SIRT6 (Kanfi et al., 2010; Kawahara et al., 2009; Zhong et al., 2010). SIRT6 also effects telomers. (Michishita et al., 2008; Mostoslavsky et al., 2006; Tennen & Chua, 2011) AMPK and SIRT1 also directly influence PGC-1α via deacetylation and phosphorylation). Aging is associated with upregulation of chaperones and proteases level via misfolded proteins also appeared by Alzheimer’s and Parkinson’s disease,(Bernales et al., 2012) and UPRmt. UPRmt as well as FOXO signalling can be activated by NAD+ and increase longevity (Mouchiroud et al., 2013) Lon protease is another important for degradation of oxidized proteins within the mitochondrial matrix aging factor (Ngo et al., 2013, 2009; Bota et al, 2002)

      FOXO3 (like mTOR and AMPK) effects aging relevant mitophagy (Rodriguez-Hernandez et al., 2009). Kim et al.,2014 describe how phosphorylation, acetylation, or ubiquitination of FoxO-genes effect histones and chromatin and change this way ROS-level. Therefore FoxO4 shows negativ effect on PI3K/Akt pathways (Karger et al. 2009) as well as on MAFbx and MURF1 in muscle aging (Clavel et al. 2006). Oxidative stress leads to FoxO phosphorylation via Akt and its transport from the nucleus to the cytoplasm. FoxO3 and FoxO4 deacetylation by Sirt1 (Jian et al. 2011) and its upregulation via catalase (Fukuoka et al. 2003; Brunet et al. 1999) play an important role in aging. FoxO1 also regulates apoptosis, DNA repair and cell cycle arrest (Yamaza et al.2010; McLoughlin, 2009; Ma et al., 2016), but also plays a key role in stem cell pluripotency. (Zhang et al., 2011). FoxO6 effects gastric carcinoma (Kim et al. 2011) and together with PGC-1a influences oxidative metabolism in skeletal muscle. Chung et al.,2013 reported that FoxO6 and PGC-1a form a regulatory loop to regulate oxidative metabolism in skeletal muscle. In addition, Foxoa2 plays a potential role in sepsis (Berg et al., 2006) and in asthmatic mucus secretion (Park et al., 2009).

      An interesting aging approach (connected with adjacent to Paneth cells and crypts) are stem cells and their regulation e.g. via cancer relevant Lrig1, Wnt, Olfm4, Hopx, p57, Sox9, Tert, Bmi1, β-catenin, Ascl2, Lgr5, Myc, Ephb2, CD44, PPAR and SMAD signalling (Nalapareddy et al., 2017; Akunuru, and Geiger, 2016) Deficiencies in DNA damage repair limits the function of haematopoietic stem cells with age. (Rossi et al., 2007) Low ISC and increased ROS levels relate to Foxo1, Foxo3a and Foxo4 activity. (Tothova et al., 2007; Miyamoto et al., 2007)

      But FOXO like CoQ and PGC-1α also influences electron transport changes contribute to aging effects such as cardiac failure. (Rosca et al., 2008; Frenzel et al., 2010; López-Lluch et al.,2010; Houtkooper et al., 2010) Shijin et al. mentioned 2016 in „An Update on inflammaging: Mechanisms, Prevention, and Treatment“ the influence of inflammatory cytokines on lymphocytes. Type I and type II cytokines effect CD4+ T lymphocytes (Alberti et al., 2006) and CD8+ and CD4+ T lymphocytes (Franceschi et al., 2000). Especially role on imflamaging play IL-1, IL-6, TNF-α and PGE2 (Bruunsgaard et al., 2003; Cesari et al., 2004). Aging is associated with IGF-1 down- and IL-6- and TNF-α- upregulation (Lio et al., 2003) IL-1, IL-6, and IL-8 are activated via NF-κB signalling pathway (Bartek et al., 2008).

      Different publications mentioned that FOX genes are an important factor in the development of tumors (Nishimura et al.,1998; Wang et al., 2015; Tian et al., 2015; Lo et al., 2016,2018; Lu et al., 2017; Nik et al., 2013; Shi et al., 2016; Yu et al., 2017; Dou et al., 2017; Milewski et al., 2017; Cai et al., 2015; Xian et al., 2018; Herrero and Gitton, 2018; Toma et al., 2011; Zhang et al., 2012; Rousso et al., 2012; Howarth et al., 2008; Teufel et al., 2003; Li and Tucker, 1993; Ji et al., 2016; Myatt et al., 2007) The FOXO family and the transcription factor NF-kB influence the upstream protein kinase B e.g. in connection with the receptors of the Trk family (e.g. the Neurotrophin). Inhibition of NF-κB signalling, NLRP3 inflammasome and other pro-inflammatory pathways or hormonal treatments eventually can restore aging relevant Progerin level, elevated by telomeres disfunction. (Osorio et al., 2010; Cao et al., 2011) In the same time senescence is accompanied by increased IL-1ß level and activated tumor necrosis factor and interferons production. (Review López-Otín, 2013; Green et al., 2011; Salminen et al., 2012, 2019; Adler et al.,2007). The Hsp90 and the IκB-Kinase (IKK) inactivate the NF-κB pathway and inhibit autophagy via induction a cell signalling switch from autophagy to apoptosis in tumor cells downregulation and of Beclin 1 expression. (Jiang et al, 2011) NF-κB also reduces GnRH production (Zhang et al., 2013) and affects this way muscle weakness, reduced neurogenesis, bone fragility and skin atrophy. Further NF-κB decreases H3K27me3 level via H3K27me3 demethylase (Lauren et al., 2016; De Santa et al., 2007). BCL2, transcriptionally regulated by nuclear factor-kappa B, affects cell shrinkage (Chakraborty et al., 2015; Lambie1 and Conradt, 2016) and acts directly on apoptosis-activating BH3. Reqmi et al. discovered that BCL2-related proteins also regulate mitochondrial dynamics using dynamin-related GTPases. (Lüpertz, 2008; Hornstein et al., 2013)

      Hsp90 protects 20S proteasome from oxidative damage inactivation (Höhn et al., 2017; Conconi et al., 1998) and helps to fold oncogenic proteins e.g. of p53 (Saibi et al., 2013). Aging relevant Hsp70 is activated with the help of HSF-1deacetylation by SIRT1 (Westerheide et al., 2009). Aging dependent changes in the amount of sensitive to diet and exercise NAD+ (Cantó et al., 2015) can affect the activity of sirtuins. SIRT1 activity can be decreased via NAD+ level, which also increases activity of the HIF-1α transcription factor resulting in changed in oxidative phosphorylation and mitochondrial dysfunction. (Gomes et al., 2012, 2013; Greer et al., 2007) SIRT1, p53 and HIF-1α in turn effect NAD+ level. Also, AMPK, which inhibits insulin/IGF-1/mTOR, cooperate with SIRT1 to create new mitochondria with the help of PGC-1 and p53. In the same time mitochondria influences TCA cycle. (Salminen et al., 2014) Tollefsbol described 2014 the connection between caloric restriction and longevity. Schultz and Sinclair described 2016 that intestinal stem cells can renewal via BST1 (converts NAD+ cADPR) (Yilmaz et al., 2012 These cells express Notch ligand delta Dl and ESG.

      Low protein-high carbohydrate diet influences energy level via enhancing FGF21 expression and in the same time reduction of mTOR activity. This increases Brain-derived neurotrophic factor expression (Zaptan et al., 2015) and influences neural precursor cells (Marosi and Mattson, 2014; Vivar and van Praag, 2013) Neural progenitor cells are also positively influenced by nutrient-sensing