Fight Aging!

Defenestration is apparently a word with two meanings. The second, a scientific term, is the removal or loss of fenestrations. Let it never be said that this is not a place of learning. What, one might ask, are fenestrations? This is another word adopted by the scientific community and given an additional meaning: it refers to a collection of small openings or pores in our biology. The particular small openings or pores that concern us today are those found in the blood vessels of the liver, one of the organs involved in the development and progression of type 2 diabetes.

While we might tend to think of type 2 diabetes as a disease caused by excess fat tissue, and for more than 90% of patients in our modern era of cheap calories this is entirely true, it is also the case that the damage of aging ultimately leads to a similar dysfunction in insulin metabolism. The path to the same end is quite different, however. While even the comparatively late stages of visceral-fat-induced diabetes can be reversed through a sustained low-calorie diet and loss of that fat, there is nothing much that can yet be done to effectively deal with purely age-related diabetes. This is just one of the many age-related conditions we'd like to reverse through rejuvenation therapies based on the SENS research programs.

The short open access commentary below summarizes some of the mechanisms involved in loss of insulin sensitivity in the old, distinct from those losses caused by fat tissue. This is where the fenestrations of blood vessels in the liver enter the picture. The authors present evidence to suggest the loss of fenestrations - defenestration - increasingly blocks the passage of insulin to where it is needed, producing what is in effect insulin resistance and all of its secondary consequences. To me the interesting questions attend the cause of this change: is it a form of dysfunction in tissue maintenance of the sort that arises due to growing inflammation in aging tissues? Is it some other secondary effect, a change in signaling that disrupts whatever cellular coordination is needed to form fenestrations? Further research is needed.

It's the holes that matter

Before circulating insulin can interact with membrane bound insulin receptors and trigger downstream signalling it must first cross the endothelium of the blood vessels in the target tissue. This transfer across the endothelium from the blood is recognised as a rate limiting step in insulin action in muscle and fat in humans, but the role of the liver endothelium in insulin uptake has not been examined previously. Recent research explores the contribution of insulin transfer from the blood, across the liver sinusoidal endothelium and to the insulin receptors on the hepatocytes as a mechanism for the development of hyperinsulineamia and insulin resistance, as identified as a major risk factor for the development of age-related disease in humans.

The sinusoids, or blood vessels of the liver are lined by specialized endothelial cells that are very thin and perforated with transcellular holes or pores that traverse the entire cell. These pores, known as fenestrations, have no diaphragm and are patent passages through the cell. The fenestrations provide efficient ultrafiltration of small material from the blood into the liver. Coupled with very little extracellular matrix and a highly adapted hepatocyte membrane, uptake of substrates, such as nutrients, toxins, and insulin into the liver for metabolism, detoxification, and signalling is rapid and regularly overlooked. However, in older age, the morphology of the liver sinusoids and the endothelium changes significantly. The cells become thicker, and the diameter and number of fenestrations is reduced by up to 50% (known as defenestration), there is extracellular matrix deposition and evidence of loss of hepatocyte microvilli. Collectively, these changes have been called pseudocapillarization. It has previously been shown that these changes reduce hepatocyte uptake of lipoproteins and some drugs.

In the current work, the hepatic and systemic disposition of insulin was explored in young and old animals and insulin resistance was confirmed to be present in the older animals. Critically, using multiple indicator techniques insulin transfer across the liver endothelium was shown to be significantly impaired. The 20% reduction in insulin's volume of distribution in the liver was consistent with limited transfer across the sinusoidal endothelium and retention of insulin in the sinusoid. In concordance with these changes, there were very high circulating insulin levels indicative of both increased secretion and impaired clearance. Despite normal glucose tolerance tests in the older animals, insulin resistance was present. Of key importance, insulin and glucose uptake into muscle and fat was shown to be unchanged with age, suggesting age related insulin resistance was most likely being driven by impaired hepatic uptake and clearance.

This work suggests that defenestration and pseudocapillarization of the liver sinusoidal endothelium seen in aging prevents the access of insulin to the insulin receptor on the hepatocyte membrane through impaired transfer across the endothelium. This results in hyperinsulinemia, impaired hepatic insulin signalling and insulin resistance. Further the work demonstrates that the liver endothelium does not provide a barrier for the uptake of insulin under normal conditions. In summary, patent fenestrations are required for hepatic insulin uptake, clearance, and signalling and loss of fenestrations is a probable causative mechanism for insulin resistance and diabetes seen with aging. This work provides evidence that maintaining the integrity of the liver sinusoidal endothelium into old age may prevent age-related insulin resistance and excitingly, introduces a novel therapeutic target.