**5. Future directions**

Prevention of metabolic syndrome and its health consequences is primordial. A healthy diet that is balanced not only in calories but also in its components, specially fats and carbohydrates would avoid fat storage spillage from a saturated fat body compartment. In addition, a substantial use of lean mass through directed exercise will decrease further cell, organ and body aging. In the brain, the melacortin forms a network of neural food sensing connecting signals of metabolic rate with neurological sites that regulates food intake behaviors and energy expenditure homeostasis. Central administration of α-MSH reduces food intake and may also increase energy expenditure resulting in weight loss [92]. Metabolic disturbances in the liver renders liver cell changes that progress from NAFLD to NASH to cirrhosis and malignancy. A non-invasive plasma based monitoring of such changes on disease progression and treatment response as well as for tumor screening may be possible by metabolomic liver prints in the near future [30].

There have been a myriad or reports on compounds that not only prevent but reverse cell aging and some even malignant development in the animal model [25, 93–102]. Curcumin, the major bioactive compound of turmeric spice, through its antioxidant and anti-inflammatory properties has been claimed to retard tumorigenesis and diabetes and to modulate lipid metabolism [103]. Furthermore, curcumin prevents the development of atherosclerosis and NASH, perhaps by the upregulation of a fatty acid binding protein present in adipocytes (aP2) but also found in macrophages (FABP-4). This protein is a cytosolic protein present in adipocytes and macrophages which modulates the trafficking of lipids/cholesterol processes and activation of inflammatory mechanisms through CD36 upregulation and reduced expression of NF-kß thus, decreasing cytokine secretion [103]. Prior studies showed that high fat diet and obesity promoted liver tumorigenesis by inducing chronic inflammation through the IL6/STAT3 pathway and, STAT3 activated tumors has been showed to be more aggressive in humans. Lycopene attenuated HCC occurrences in the animal model through downregulation of the STAT3 signaling [95]. The aqueous extract of *Ligustrum lucidum* fruit induced apoptosis through the activation of the caspase cascade and cellular senescence by upregulation of p21 and downregulation of RB phosphorylation [102].

Other molecules with promising cell aging and tumor repression properties included the COX-2 and a Na/K/ATP signaling mechanisms. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice [43]. During a chemical screen, a low molecular compound was identified capable of selectively inhibiting 15-PGDH with the subsequent increase of PGE2 levels in bone marrow and other organs, accelerating hematopoietic recovery in mice receiving bone marrow transplant and tissue regeneration in the colon and liver. It also promoted tissue regeneration in mouse models of colon and liver injury. Selective COX-2 products may have rescued telomere dysfunction, cell senescence and tissue regenerative potential [74]. However, its mechanism and signal transduction remains to be determined. pNaKtide is a synthetic peptide that conserves the active sequence for the ligand-binding capacity to the ß-subunit of the transmembrane Na/K-ATPase. Although the Na/K-ATPase mainly exercise its function as an ion exchanger pump vital for cell survival, recently it was shown to elicit nuclear signaling that regulates mitochondrial function and cell energy production through a Src/ERK pathway [104–112]. Furthermore, pNaKtide prevents the development of atherosclerosis and fatty liver disease in the HFD mice model with significant amelioration of ROS. In addition, it downregulates collagen synthesis and inhibit growth of human cancer cells in vitro. Translation of promising compounds to the treatment of patients with NAFLD/NASH is expected in the near future to further prevent the consequences of advanced liver fibrosis and HCC development.
