Table 4.

Age-related diseases that entail an increased risk of cancer development.

NF-κB Gene	Genetic Modification	Recapitulated Disease and Proposed Mechanisms
		Type 2 Diabetes Mellitus/Obesity/Insulin Resistance
Ikkβ [147]	Ikkβ+/− mice. Ikkβ+/+Lepob/ob obtained by crossing Ikkβ+/− mice with ob/ob mice (Lepob/ob), a mouse model for type 2 diabetes, obesity and insulin-resistance.	Ikkβ+/− mice are protected against the development of insulin resistance during high-fat feeding; they show lower concentrations of glucose and insulin in blood. Ikkβ heterozygosity also diminishes levels of blood glucose concentrations and improves insulin sensitivity in Lepob/ob mice. Eight-week-old mice were analyzed.
Ikkβ [149]	Transgenic mice with conditional inhibition of Ikkβ in hepatocytes (Ikbkb∆hep) or myeloid cells (Ikbkb∆mye).	The inhibition of NF-κB pathway in myeloid cells improved insulin sensitivity in all tissues, while the inhibition of this pathway in hepatocytes maintained insulin sensitivity only in the liver: IKKβ acts locally in the liver, inducing proinflammatory mediators, which act only in a paracrine manner to downregulate insulin sensitivity in the liver, and systematically in myeloid cells. 3- to 14-month-old mice were studied.
Ikkβ, Iκbα [148]	Constitutive activation of Ikkβ in hepatocytes (LIKK mice). Expression of Iκbα supper-repressor in the liver of mice (LISK mice).	LKK mice show a type 2 diabetes phenotype, with hyperglycemia, and hepatic and systemic diet-induced insulin resistance, through mechanisms involving hepatocellular activation of NF-κB; increased levels of cytokines in liver and muscle and activation of resident Kupffer cells. LISR mice reversed the phenotype of LIKK mice. Mice between 4 and 16 weeks of age were analyzed.
Ikkβ [144]	Ikkβ deficiency in smooth muscle cells (SMCs) driven by a SM22Cre-Ikkβ-flox system.	Ikkβ-deficient mice were resistant to diet-induced obesity and metabolic disorders: lower glucose and insulin concentration in blood; reduced hepatic triglycerides and cholesterol. Mechanisms involved: inhibition of NF-κB; increased levels of the uncoupling protein-1 (UCP-1) and increased thermogenesis; lower expression of both hepatic lipogenic genes (SREBP1c, SCD-1, and PPARγ), and inflammatory cytokines. Mice from 8- to 28-week-old were analyzed.
Rela [150]	Mice L-p65-KO with a deletion of Rela gene in the liver (p65+/− mice) were generated by crossing floxed-Rela and Alb-cre mice.	L-p65-KO exhibited improvement hepatic insulin sensitivity, and a decrease gene expression in hepatic gluconeogenesis (feed with a high fat diet). The inhibition of the NF-κB pathway decreased the expression levels of cAMP and the phosphorylation of CREB in the liver of L-p65-KO mice. The low levels of cAMP results from increased expression of PDE3B, a cAMP-degrading enzyme. Mice between 8 and 32 weeks of age were studied.
Iκbα [151]	Mice expressing the Iκbα superrepressor under the Tie2 enhancer (E-DNIκB mice). Crossing of E-DNIκB mice (a genetic model for obesity-diabetes syndrome), generates the E-DNIkB; Ay/+ mice.	Functionally inhibition of NF-κB specifically in endothelial cells prevents obesity-related metabolic deteriorations, with a decrease both in the macrophage infiltration into adipose tissue, and plasma oxidative stress markers induced by obesity; it also prevents age-related insulin resistance and vascular senescence at the time that extents the life span. Mice aged 8 to 50 weeks were analyzed.
Nfkb1 [153]	Nfkb1-KO mice.	Nfkb1-deficient mice have improved insulin sensitivity. They exhibit lower expression levels of the p70 ribosomal protein S6 kinase (p70s6k or S6K1) in the liver, and reduced activity of IKKβ and IKKγ. Mice from 6- to 26-week-old were analyzed.
Nfkb1 [154]	Nfkb1-KO mice.	Nfkb1-KO mice had both higher fatty acid utilization and oxidation in the liver, and, when feeding with a high-fat diet, they are resistant to fat accumulation and adipose tissue inflammation. Mice between 1 and 23 weeks of age were studied.
Nfkb1[155]	Nfkb1-KO mice.	Nfkb1-KO mice exhibits reduced body weight gain on a high-fat diet, reduced plasma triglyceride levels and adiposity. The reduced susceptibility to diet-induced obesity and dyslipidemia in p50-deficient mice results from an increase in metabolic rate, associated with elevated skeletal muscle oxidative metabolism and decreased DGAT2 expression. Mice between 10 and 34 weeks of age were analyzed.
		Liver Diseases
Nfkb1 [160]	Nfkb1-deficient mice. Nfkb11S340A/S340A mice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes.	Chronic liver disease Loss of Nfkb1 promotes ageing associated chronic liver disease (CLD) (steatosis, neutrophilia, fibrosis, hepatocyte telomere damage, dysplasia) and HCC development. Hepatic lesions in aged Nfkb1-/- mice were associated with highly elevated numbers of hepatic neutrophils, which stimulates hepatocellular ROS and telomere DNA damage. Mice between 4 weeks and 20 months of age were studied.
Nfkb1, Rela [156]	Nfkb1-KO and Rela-KO mice.	Hepatic steatosis Hepatic steatosis was decreased in Nfkb1-KO mice; also, they showed reduction of both lipogenic genes (scd1, Fas and Cd36) and lipogenic proteins (SREBP1c and SCD1). Implication of a signaling pathway of Nfkb1-/HDAC1/SCREBP1c in hepatocytes in the control of hepatic steatosis. Inactivation of NF-κB p65 did not alter the hepatic steatosis. Mice between 8 and 28 weeks of age were studied.
Cyld [66]	K5-CyldC/S mice. Expression of a mutant Cyld gene carrying a point mutation C/S that acts as a dominant negative in keratin 5 expressing cells.	Chronic hepatitis K5-CyldC/S exhibit signs of premature aged liver, generalized inflammation, with multifocal chronic hepatitis; develop spontaneous HCC and hepatocellular adenomas. Chronic NF-κBp65 activation. Tumors likely develop as a consequence both of the premature aging and the systemic inflammation of the transgenic mice. Young (1- to 9-month-old) and old (20- to 24-month-old) mice were analyzed.
Nik, Ikkα [165]	Hepatocyte-specific Nik (NikDhep) and Ikkα (ikkαDhep) knockout mice.	Progression of liver disease Pathological activation of hepatic NIK or IKKα likely blocks hepatocyte replication, contributing to liver disease progression in PHx mouse models. The NIK/IKKα pathway suppresses reparative hepatocyte proliferation at least in part by inhibiting the JAK2/STAT3 pathway. Mice 8 and 18 weeks of age were studied.