An Interesting Study on Aggregates in Aged Tissues

The paper here provides an interesting perspective on the formation of solid aggregates of misfolded or damaged proteins with age, one of the distinguishing features of old tissues. There are numerous types of such aggregate, varying by tissue, and a mix of evidence for their contribution to specific aspects of aging or specific age-related diseases. In some cases it is hard to draw a direct line between a form of aggregate and its consequences. In others the chain of cause and effect is comparatively well understood, as is the case for Alzheimer's disease, amyloid-β, and tau, for example. It seems clear that the fastest way to proceed in each case is build a method to remove the aggregate and then observe the outcomes, both for the goal of increased understanding, and the arguably more important goal of removing causes of aging in order to produce rejuvenation therapies.

Deaths from atherosclerotic cardiovascular disease (CVD) comprise 31% of all mortality worldwide. Age and hypertension are the major risk factors for atherosclerotic CVD, and both are associated with increased stiffness of the heart. This rigidity, resulting in diastolic dysfunction, is largely attributed to myofibroblast growth and collagen deposition between cardiomyocytes. Most proteins adopt, either spontaneously or with the help of other proteins, specific folded structures with limited degrees of freedom. Chemically altered or misfolded structures, when they occur, are vulnerable to aggregation with other unstructured proteins. Although protein damage and misfolding are inevitable, multiple proteostasis systems are devoted to the repair or clearance of damaged proteins. The heart, in particular, is subject to continuous mechanical and metabolic stress; as a result, the cardiac proteome may be especially reliant on multi-level quality control to ensure proper folding and integrity of proteins.

Although protein aggregation has been studied extensively in neurodegenerative diseases, aggregates that form during normal cardiac aging or sporadic CVD have not previously been characterized. In this study, we isolated and quantified compact aggregates from the hearts of young-adult and aged mice and identified their protein constituents. To ask whether the hypertensive state itself disrupts proteostasis and thus mimics aging, we compared protein aggregates from hearts of young mice that were either hypertensive or normotensive. We also examined protein aggregation in early- and late-passage cardiac myofibroblasts, to assess whether their proteostasis is impaired during in vitro senescence and thus may contribute to cardiac senescence in vivo.

Detergent-insoluble protein aggregates were isolated from mouse hearts and characterized on 2-dimensional gels. Their levels increased markedly and significantly with aging and after sustained angiotensin II-induced hypertension. Of the aggregate components identified by high-resolution proteomics, half changed in abundance with age (392/787) or with sustained hypertension (459/824), whereas 30% (273/901) changed concordantly in both. One fifth of these proteins were previously associated with age-progressive neurodegenerative or cardiovascular diseases, or both (eg, ApoE, ApoAIV, clusterin, complement C3, and others involved in stress-response and proteostasis pathways). Because fibrosis is a characteristic of both aged and hypertensive hearts, we posited that aging of fibroblasts may contribute to the aggregates observed in cardiac tissue. Indeed, as cardiac myofibroblasts "senesced" (approached their replicative limit) in vitro, they accrued aggregates with many of the same constituent proteins observed in vivo during natural aging or sustained hypertension.

In summary, we have shown for the first time that compact (detergent-insoluble) protein aggregates accumulate during natural aging, chronic hypertension, and in vitro myofibroblast senescence, sharing many common proteins. Thus, aggregates that arise from disparate causes (aging, hypertension, and replicative senescence) may have common underlying mechanisms of accrual.

Link: https://doi.org/10.1161/HYPERTENSIONAHA.115.06849

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