**Abbreviations**

cardiac muscles, liver and kidney are more affected by somatic mtDNA mutations compared to other organs such as the skin and lung [17]. Furthermore, the clonal expansion of mtDNA mutations occurs via a phenomenon called genetic drift, a random propagation and expansion of DNA mutations occurring at each DNA replication. The drift of mutations may be more important in metabolically more active organs that require more energy expenditure and therefore more ATP synthesis. The expansion of mtDNA mutations may be enhanced not only by its duplication and drift but also by a lower state of DNA damage repair mechanisms [17]. The Base Excision Repair (BER) process is impaired in senescence and aging due to a loss of function to BER associated proteins CSA and CSB. Thus, the increase production of ROS creates a vicious loop of mtDNA mutations than in turn favor an increase production of ROS perpetuating and enhanced organelle dysfunction by defective reparative mechanisms. A naturally occurring thymidine to cytidine mutation in the mitochondrial stressors tRNAILE gene is associated with phenotypes of hypertension, hypercholesterolemia and hypomagnesemia [10]. Furthermore, the DNA A3243G mutation causes impaired insulin secretion and polymorphisms in the promoter of the UCP2 protein, alterations associated with increased incidence of obesity, reduced insulin secretion and DMII [10]. Mitochondrial function may be impaired in chronic high fat diet challenge as a result of a decrease in ß-lipid oxidation. Indirect evidence showed an accumulation of diacylglycerol and fatty-Acyl-CoA which in turn activates stress-related serine/threonine kinase activity and inhibit glucose transport [10]. Oxidative stress contributes further to impaired insulin signaling increasing UCP2 activity which in turn enhances "proton leak" with uncoupling of the glucose metabolism pathway and decreased ATP production. A progressive higher lipid peroxidation may favor further oxidative stress with DNA damage and low DNA repair by affecting members of the Bcl-2 family, triggering an influx of Ca2+ with subsequent opening of the mitochondrial permeability transition pore, cytochrome-c leakage to the cytosol and activation of the caspace-3 complex. Cell self-digestion and nuclear DNA fragmentation overcomes with the typical cell fragments morphology [10]. Alternatively, DNA damage and telomerase shortening results in mutations that may affect mitochondrial function to a level of organelle survival but inefficient ATP production assuring the "apoptosis switch" and diverting biochemical reactions to a cytosolic site for ATP production. The later assumption may find some support in the obser-

90 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment

vations that tumor development and early growth is favored in low O<sup>2</sup>

**5. Future directions**

tumor development is associate with increase lactate production, the Warburg effect [30, 69].

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

delivery zones and that


PI3K Phosphatidylinositol 3-kinase

SAH Senescence associated heterochromatic foci SASP Senescence associated secretary phenotype

TIMP Tissue inhibitor of metalloproteinases

, Jacqueline A Sanabria1†

, Amrita Mallick<sup>1</sup>

University, Cleveland, OH, United States

Lancet. 2015;**386**(10010):2287-2323

\*Address all correspondence to: sanabriaj@marshall.edu

, Milad Modarresi<sup>1</sup>

, Henri Brunengraber2

1 Department of Surgery and the Marshall Institute for Interdisciplinary Research, Marshall

2 Department of Nutrition Proteomic & Metabolomic Core Facility at Case Western Reserve

[1] Collaborators GBDRF, Forouzanfar MH, Alexander L, Anderson HR, Bachman VF, Biryukov S, et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013.

University Joan Edwards School of Medicine, Huntington, WV, United States

† Authors contributed equally and should be considered as first authors

, Bryan Gillon<sup>1</sup>

Cellular Senescence and Their Role in Liver Metabolism in Health and Disease...

http://dx.doi.org/10.5772/intechopen.71659

93

and Juan Sanabria1,2\*

, Zach Hunter1

,

PKC Protein kinase C

SA-ß-GAL ß-galactosidase

SMase Neural Smase TAG Triacylglycerol

**Author details**

Matthew Schade1†

Jacqueline Fannin<sup>1</sup>

**References**

TCA Tricarboxylic cycle

TNF-α Tumor necrosis alpha TOR Target of Rapamycin

UPR Unfolded proteins response

ROS Radical oxygen species

SEC Sinusoidal endothelial cells SGK Serum/glucocorticoid kinase


