Arterial Stiffening is Enough to Explain Hypertension
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Many and varied are the harmful medical conditions that emerge with increasing age. The consensus position in the research community is that tracing back the biochemical chains of cause and effect to root causes, something that is not yet possible for many common medical conditions, will show that all age-related conditions and their complexities are the consequences of a comparatively small number of types of cellular and molecular damage. That damage accumulates with age to cause secondary effects, which in turn cause further issues, and by the time the process of dysfunction rises to the level of being called a disease it has become a huge mess of broken mechanisms, confusion, and dead ends. With that as the starting point for research into treating age-related disease it is no wonder that all too many conditions are not yet fully understood in terms of a clear chain of consequences from top to bottom.

Hypertension, you might think, is such a simple medical condition that it couldn't possibly be stuck in this situation. It is quite simply high blood pressure, something that places all sorts of physical, mechanical stress on important parts of the circulatory system. Pretty much every fatal thing that can go wrong with your heart and blood vessels is aggravated by hypertension. Yet the root causes and middle region of the chain of cause and effect for the rising incidence of hypertension with age are not nailed down at this point: it is all very much up for debate.

Here researchers take a different strategy to the normal approach of painstakingly tracing relationships between proteins in cells, starting at the end point of full blown disease and working backwards one step at a time. They are instead using computer modeling to try to constrain the bounds of the possible, to narrow down the region of study for those who will come afterwards to piece together mechanisms and interactions. Their argument, in short, is that you don't need anything more than the process of arterial stiffening that occurs with aging to explain the observed effects of hypertension:

Arterial Stiffening Provides Sufficient Explanation for Primary Hypertension

Hypertension is highly age-related and affects more than 1 billion people worldwide. It is a major source of morbidity and mortality as it makes us more prone to experience heart failure, stroke, and kidney disease. Despite intense research efforts over several decades, there is still no consensus on what are the primary causes of this disorder.

Here we present a computational physiology model which shows that the increase in arterial stiffness that follows with age is sufficient to account for an overwhelming amount of experimental and clinical data on hypertension. We demonstrate quantitatively that the stiffening causes the baroreceptors, the blood-pressure sensors located in the arterial wall, to misinform the highly complex machinery responsible for blood pressure regulation. This misinformation occurs because the baroreceptors are strain sensitive, not pressure sensitive, and with stiffening the aortic wall strain ceases to be a good proxy for aortic blood pressure.

Contrary to wide-held conceptions, the blood pressure regulation may thus become compromised without any other detrimental physiological change of the regulatory machinery. Our results therefore suggest that arterial stiffness represents a major therapeutic target by which an otherwise intact physiological machinery may be exploited for blood pressure regulation.

Aha, you might say, but assuming this research pans out it just swaps one unknown chain of cause and effect for another that is only one item shorter. Instead of working to figure out what is going on in hypertension, scientists are instead figuring out what is going on in arterial stiffening. As it happens this is actually a good swap, as much more is known of the causes of blood vessel stiffening with age.

For example, the formation of advanced glycation end product (AGE) cross-links shackles layered proteins in tissues and is one well-researched direct cause of age-related stiffness in blood vessel walls and loss of elasticity in skin. In humans just one type of cross-linking compound called glucosepane accounts for almost all such cross-links in the most studied tissues. Getting rid of glucosepane and removing its contribution to degenerative aging requires only a single successful drug development program to produce a safe means of breaking down the compound. Unfortunately this has yet to see much interest from pharmaceutical companies, despite the great size of the market for an effective AGE-breaker drug.

If you spend much time watching the research and development community, you'll see many areas like this, in which obvious near term goals of great potential benefit are little pursued. Progress, sad to say, isn't always ruthless and rational, and gaping holes of this nature can last for decades. Thus in the field of glucosepane research the only initiatives of note at the present time are set in motion by philanthropic funding, such as the programs coordinated by the SENS Research Foundation.


"If you spend much time watching the research and development community, you'll see many areas like this, in which obvious near term goals of great potential benefit are little pursued"

Can you name some of the other areas that could be pushed forward by a single successful drug development program? The only other one that comes to mind is the SENS foundation's development of an enzyme for removing oxidized cholesterol from foam cells.

Posted by: Jim at May 27, 2014 10:30 PM

Something that breaks glucosepane cross links in a significant amount of tissue or something that removes most senescent cells from an organism.

Posted by: Michael at May 27, 2014 11:31 PM

@Jim: At the time I was thinking of mitochondrial DNA repair. That has been frustratingly slow. It has more attention than AGE-breakers, but is essentially a backwater of a few small research groups. Despite the tremendous potential, next to no-one is working on it. This is very strange given that mitochondria are widely acknowledged to be important in all sorts of diseases as well as aging, and many, many researchers are involved in working with them as a primary focus.

Posted by: Reason at May 28, 2014 6:14 AM

Doesn't mitochondrial DNA repair require a vector that can transfect every cell in the body? Or some kind of targeted vector that can transfect muscle tissue or some other tissue type alone?

To my knowledge that genetic engineering technology does not yet exist. So although SENS are trying to solve the mitochondrial import problem, no one will try to develop a treatment until the technology has been created.

Posted by: Jim at May 28, 2014 8:52 AM

"Something that breaks glucosepane cross links in a significant amount of tissue or something that removes most senescent cells from an organism. "

While it is questionable whether it would increase cancer, one way to get rid of senescent cells would be a substance that restores telomeres(as telomere restoration has restored senescent cells to a more youthful behavior in the lab.).

It was seen that at least for some cells vegetarian diets with moderate exercise could restore telomeres. If telomere restoration is all over the whole body, we'd need to verify, this too could get rid of senescent cells.

Posted by: Darian S at May 29, 2014 12:39 AM
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