Evidence for Pyrophosphate to be the Primary Inhibitor of Vascular Calcification

This open access commentary notes the evidence to suggest that therapies based on raised levels of pyrophosphate in blood vessel walls to reduce age-related calcification. The mineralization of blood vessel walls through deposition of calcium, calcification, is one of the mechanisms that contributes to vascular stiffness with age. It impairs the ability of blood vessels to contract and relax as they should. This is a serious issue, as it breaks the feedback mechanisms that control blood pressure, leading to hypertension, vascular disease, and heart failure as heart muscle grows and weakens.

From my point of view, the work here is an excellent example of the wrong way to go about addressing the issues of aging. Researchers note that a process runs awry with aging, so they analyze the dysfunctional and normal operation of the process to find the proteins that regulate it. Then treatment involves finding ways to safely adjust levels of those proteins, overriding their state in older individuals to try to force the process to deliver better outcomes. As the last half century has demonstrated, it is possible to produce marginal, incremental gains at great expense and a high rate of failure via this strategy. The most impressive results involve methods of overriding our biology to reduce blood cholesterol, blood pressure, and inflammation.

But incremental results are all that can be achieved this way. It is a strategy that completely ignores the cause of the issue. Aging results from forms of cell and tissue damage, and then spirals out through a long and complex and poorly understood chain of consequences. Senescent cells - and the chronic, systemic inflammation that they produce - appear to bias cells in blood vessel walls towards deposition of calcium, for example. But senescent cells cause a wide range of other issues. Trying to override cell behavior in the narrow case of calcification while failing to remove senescent cells leaves those errant cells free to contribute to all of the other issues of aging. You can't force a damaged machine to function as though it were undamaged. There is no future in that approach to aging. The research community must look to causes and repair of damage rather than continuing this expensive, marginal, ultimately futile business of trying to override cell behavior, one tiny fraction of aging at a time.

Vascular calcification is associated with physiological aging and is characterized by the deposition of calcium-phosphate crystals in the aortic media and/or intima, usually as hydroxyapatite, the main component of bone. Vascular calcification reduces aortic and arterial compliance and elastance, hampering cardiovascular system function. It is linked to poor clinical outcomes and contributes to cardiovascular morbidity and mortality. Because tissue mineralization may occur at normal concentrations of calcium and phosphate, regulatory mechanisms exist to limit this process to bone and cartilage. Several endogenous inhibitors of vascular calcification have been identified, including the matrix Gla protein, fetuin A, osteopontin, and pyrophosphate.

Pyrophosphate is a potent inhibitor of calcium-phosphate crystal formation and growth. Vascular tissue mineralization occurs when the synthesis of vascular calcification inhibitors is impaired or when the formation of calcium-phosphate crystals is enhanced, for example, by hyperphosphatemia, the main risk factor for vascular calcification. Despite findings showing that hyperphosphatemia triggers vascular calcification, the effects of hyperphosphatemia on extracellular pyrophosphate metabolism remain unclear. A recent study investigated pyrophosphate metabolism in the context of phosphate-induced vascular calcification. It was found that calcification is a passive process that can be actively prevented by pyrophosphate.

The main conclusion of this new study was that high phosphate concentrations resulted in the increased synthesis of pyrophosphate over time. Moreover, the hydrolysis of pyrophosphate was found to decrease during early stages, but increase during later stages, of hyperphosphatemia. Although overall pyrophosphate production is higher during hyperphosphatemia, it was not sufficient to block calcium-phosphate deposition. A growing body of evidence suggests that pyrophosphate is the predominant endogenous inhibitor of vascular calcification. The results of this study, along with previous findings, suggest that induction of pyrophosphate synthesis may be an easy and effective therapeutic strategy to inhibit vascular calcification associated with aging and other pathological conditions.

Link: https://doi.org/10.18632/aging.101703

Comments

" You can't force a damaged machine to function as though it were undamaged. There is no future in that approach to aging." Here Here! There couldn't be a more concise statement of the purpose of this great web site! But there are more certainly future profits for big pharma.

Posted by: Tom Schaefer at December 12th, 2018 9:33 AM

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