The Role of Age-Related Extracellular Matrix Restructuring in Heart Conduction Disorders

The extracellular matrix (ECM) is the complex structure of proteins surrounding and supporting cells. The varied mechanical properties of different tissues derive from the particular arrangement and types of molecules making up this structure: the elasticity of skin and blood vessels, the load bearing resilience of bone and cartilage, and so forth. Some of the fundamental forms of cellular and molecular damage that cause aging produce degenerative effects through changes to the extracellular matrix that degrade its properties. For example, cross-links formed by sugary metabolic waste glue together structural proteins. The most persistent types of cross-link accumulate over the years and their presence contributes to the loss of elasticity in skin and blood vessel walls, as well as to the growing fragility of bones in the elderly.

A different type of problem is caused by senescent cells, which have removed themselves from the cell cycle in response to damage or a potentially damaging local tissue environment. Senescent cells adopt what is known as a senescent-associated secretory phenotype, releasing a mix of compounds that encourage other nearby cells to become senescent, but which also degrade or restructure the surrounding extracellular matrix. Cellular senescence may be a repurposed tool of embryonic development, a mechanism that helps shape growing organs, and its activities in attacking the extracellular matrix are a holdover from that role. Whether or not this is the case, senescent cells are destructive and degrade the structural properties of the extracellular matrix where they gather in numbers.

Both senescent cells and cross-links could be dealt with in the very near future, removing and reversing their contributions to degenerative aging, given sufficient funding for research. Selective destruction of senescent cells has been demonstrated in principle, and a few research groups are working on different approaches to making a therapy of this approach. On the cross-link side of the house, the single most important type of cross-link in humans is formed of a single compound, glucosepane. Thus drug development has a single target to hit: all it takes is for the tools to be produced and for one laboratory to find a good drug candidate. This work is also underway in the early stages, carried out by a few small research groups. Neither of these lines of research is anywhere near well enough funded, or appropriately funded for the size of the potential benefits, however. A sizable chunk of the presently ongoing work is funded by one organization, the SENS Research Foundation, and supported entirely by philanthropic donations. This is the story for much of the potential rejuvenation toolkit that could be built in the years ahead - but which will take much longer to realize than it might, because funding and interest are the limiting factors. This is exactly why advocacy and education for this cause are so very important.

Structural properties of tissue determined by the extracellular matrix go beyond elasticity and strength. There is also the matter of electrical properties, important in the heart and nervous system. Degradation of the extracellular matrix in heart tissues and its impact on the heart's electrical conduction system is probably a contributing factor the increased prevalence of arrhythmias and similar issues with advancing age.

The role of extracellular matrix in age-related conduction disorders: a forgotten player?

Prevalence of cardiac arrhythmias increases over time during aging, carrying significantly higher morbidity and mortality in the elderly. Defective impulse generation and conduction and ECM disarray with augmented intramyocardial fibrosis during aging are considered the main biological processes responsible of these disturbances.

In this context, in spite of the interest addressed by the literature to the "aged cardiomyocyte" as the main pathological responsible of age-related conduction disturbances, there are several lines of evidence pointing at changes in the structure and function of the extracellular matrix (ECM) as an important actor. At the biophysical level, cardiac ECM exhibits a peculiar degree of anisotropy, which is responsible for the elastic and compliant properties of the ventricle and for the structural properties of heart valves. However, ECM components and their arrangement are also the main determinants of the conductive properties of the specialized electrical conduction system. Moreover, cardiac ECM is actively sending biological signals regulating cellular function and tissue homeostasis. Alterations of ECM function in the elderly might additionally exert a detrimental effect on the normal function of the conduction system and on overall ventricular function and cardiac performance. Age-associated alterations of cardiac ECM are therefore able to profoundly affect the function of the conduction system with striking impact on the patient clinical conditions.

The function of the sinoatrial node (SAN) deteriorates with age with an increase in the nodal conduction time and a decrease in the intrinsic heart rate. Collectively, those alterations translate at the clinical side in the so-called sick sinus syndrome, whose manifestations include bradycardia, sinus arrest, and sinus exit block. Additionally, considering the hemodynamic changes occurring with aging, which are basically constituted by a reduction of ventricular compliance and an increased contribution of atrial contraction to ventricular filling, dual chamber pacemakers maintaining synchrony between atria and ventricles are advantageous in older adults. During the aging process, the described structural and functional changes occurring in the left ventricle are interlaced with malfunction of the conduction system, which in turn results in non-efficient and non-synchronous activation of both ventricles, fostering a vicious circle eventually worsening the detrimental effects on cardiac performance.

Conduction disturbances are frequent among the elderly and carry significant morbidity and mortality representing a clinical and economical burden. Complex cellular interplay and paracrine biological signaling underlie this phenomenon and targeting fibrosis generation and its pathological characteristics might be a promising therapeutical approach for age-related arrhythmic disease. Deepening knowledge on ECM age-associated alterations might be important in the development of novel therapeutical approaches in the widespread panorama of age-related disease.

Comments

It would be very interesting to remove senescent cells AND cross links in a rhesus monkey or mouse and see what the combined effect is. Hopefully it improves heart function in old age.

To be honest I was surprised that the Mayo Clinic's removal of senescent cells in a mouse model had an effect on healthspan (although that might be due to the mouse model accumulating senescent cells at a far greater rate than a regular mouse). I kind of expect that you will have to remove between 2-4 types of damage before the needle starts to move on healthspan/lifespan in a regular animal.

Good luck to Dr William Bains and all the others working on removing ECM cross links.

Posted by: Jim at March 1st, 2015 8:15 AM

This is indeed an exciting site to find!

With my Cardiologist's help I have reversed my Heart Failure through blood pressure management, weight loss to Normal Range and exercise. However, either due to aging or as a byproduct of the Heart Failure, I still have Left Bundle Branch Block 1 at a relatively young age! This research looks so much more attractive than, for example, surgical implantation of a pacemaker. This research may not be completed in time to help me, but for so many younger people coming along.

The US President has planned funding for a massive research project into the brain! Hopefully some of that funding can be applied to these Aging issues. However, if not, I wonder how much value a young brain may be without, for example, a heart beating to provide blood!

I intend to follow this site and to contribute a modest amount.

Alex 'Zan Wilson

Posted by: Alex Wilson at March 5th, 2016 7:19 PM

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