Today, I'll point out an open access commentary in which the authors survey a number of lines of research into age-related dysfunction in the liver, all of which lead back to elevated levels of cyclin-dependent kinase 4 (CDK4). Some of this work involves investigation of the mechanisms of fatty liver disease, more properly known as hepatic steatosis. This is most commonly caused by being overweight in this age of cheap calories, but, setting aside the morbidly obese, the condition nonetheless tends to emerge later rather than earlier in life. Other research programs look at more directly age-associated measures of liver function, such as senescent cell burden, changes in gene expression, and proteins and lipids in the bloodstream. Inhibition of CDK4 in late life to some degree reverses many of these declines.
Manipulation of specific proteins and genes is an intervention with widely varying expectations of ease and safety. The ideal gene and its protein product has little influence over anything other than the one disease-associated mechanism of interest. Or at the least, it only has that one relationship in the organ suffering from the disease state, even if it has other roles elsewhere in the body. Unfortunately that can be said for all too few genes. CDK4 is a dangerous-looking target, showing up in considerations of cancer via its close relationship to retinoblastoma proteins, and because it is involved in cell replication. Growth and replication genes tend to be hard to safely target as downstream effects of change are unpredictable, and their influence on cancer risk is one of those unpredictable items. This is the challenge for any gene involved in vital low-level cellular processes, and is one of the reasons why adjusting gene expression to form new metabolic states is an expensive, slow process.
The question remains as to why CDK4 levels rise with age in the liver. This is a reaction to which of the root causes of aging, mediated by which intermediary mechanisms? Just because chronic inflammation is important in liver aging, and the inflammation-producing accumulation of senescent cells is measured here doesn't mean that cellular senescence is the most important of underlying causes. As is usually the case, the approach of fixing root causes and observing the results is likely to be a faster path to answers than working backwards through pathways and relationships in the cell.
The earliest stage of Non-Alcoholic Fatty Liver Disease (NAFLD), hepatic steatosis (or non-alcoholic fatty liver, NAFL) has no evidence of liver injury, but is characterized by an accumulation of triglycerides in hepatocytes. In some patients, NAFL can progress in age-dependent manner to fibrosis and then to non-alcoholic steatohepatitis (NASH) and cirrhosis. Mechanisms of development of hepatic steatosis are not well understood and approaches to treat hepatic steatosis are not developed.
Researchers have investigated the role of the endogenous ligand of growth hormone Ghrelin in development of age-associated hepatic steatosis. The authors clearly demonstrated the deletion of ghrelin prevents development of hepatic steatosis. This prevention is mediated by down-regulation of C/EBPα-p300 axis suggesting that the inhibition of ghrelin activities or C/EBPα-p300 pathway might be considered as a therapeutic approach. In agreement with these findings, other scientists have recently reported that blocking cdk4, a direct activator of C/EBPα-p300 complex, eliminates age-associated hepatic steatosis as well as several age-associated disorders of the liver.
Researchers have investigated age-associated development of hepatic steatosis in mice with deletion of ghrelin. At young age, no significant differences were observed. However, while wild type (WT) mice developed severe steatosis, Ghrelin knockout (KO) mice showed significant inhibition of steatosis. Further studies revealed that the enzyme of the last step of synthesis of triglycerides, DGAT1, is not elevated in livers of Ghrelin KO mice, while it is elevated with age in livers of old mice. Activation of DGAT1 promoter does not occur in ghrelin KO mice due to a lack of C/EBPα-p300 complexes. The lack of these complexes is associated with failure of Ghrelin KO mice to phosphorylate C/EBPα, the event that is required for the formation of C/EBPα-p300 complexes. This phosphorylation is typically under control of cdk4 and it is likely that the deletion of ghrelin leads to the inhibition of cdk4, suggesting that cdk4 is a key mediator of ghrelin-dependent hepatic steatosis.
Researchers examined the role of cdk4 in age-dependent hepatic steatosis using three settings: liver biopsies from old patients with NAFLD, cdk4-resistant C/EBPα-S193A mice, and inhibition of cdk4 in old WT mice. These three experimental settings showed that cdk4 is elevated in old patients and degree of elevation correlates with severity of NAFLD. Work with S193A mice and the inhibition of cdk4, revealed that cdk4 is a key driver of the age-associated hepatic steatosis. Surprisingly, the authors found that inhibition of cdk4 not only eliminates hepatic steatosis, but also corrects several other age-dependent liver disorders including cellular senescence, heterochromatin structures, E2F1 and RB-dependent pathways of proliferation, liver/body weight ratio, and several blood parameters.