In today's research materials, scientists demonstrate that the combination of reduced SIRT1 and SIRT3 causes weakness in heart muscle via disruption of mitochondrial function. Mitochondria are the power plants of the cell, a herd of hundreds of bacteria-like organelles that are responsible for producing the chemical energy store molecule adenosine triphosphate (ATP) to power cellular operations. Impairment of mitochondrial function thus results in impaired cell function, a characteristic change observed in old tissues. Mitochondrial dynamics, the balance of fusion and fission of mitochondria, shift with age in ways that impair the processes of mitophagy that are responsible for removing damaged mitochondria. This leads to impaired function as damaged mitochondrial accumulate. A number of lines of evidence suggest that improved mitophagy can help restore mitochondrial function in old individuals.
Of note, the research here only shows that (a) depletion of SIRT1 and SIRT3 in young individuals causes harm, (b) the resulting changes in cells have some similarities to those seen in aging, and (c) that SIRT1 and SIRT3 are depleted in old individuals. This does not prove that boosting SIRT1 and SIRT3 in old individuals will help restore lost function, but it makes the case to fund that experiment. Of note, upregulation of SIRT1 on its own was the focus of considerable effort some years back, with entirely lackluster results when it came to health and life span. SIRT1 just does not seem to be an important part of the mechanisms linking metabolism to aging. One has to make a solid case in order to convince people to revisit that failure.
Mitochondria produce the energy needed to drive nearly all processes in living cells. Cardiac muscle cells contain more mitochondria than any other cells, because the heart needs large amounts of energy to constantly pump blood throughout the body. Stable mitochondrial dynamics maintain a healthy balance between the constant division (fission) and merging (fusion) of mitochondria and help ensure the quality of these specialized structures known as the "powerhouse" of the cell.
Reperfusion, a common treatment following acute heart attack, restores blood flow (and thus oxygen) to a region of the heart damaged by a blood clot blocking the coronary artery. Paradoxically, in some patients this necessary revascularization procedure triggers further injury to heart muscle tissue surrounding the initial heart attack site. No effective therapies currently exist to prevent reperfusion injury.
To help analyze the response of cardiac mitochondria to ischemia-reperfusion stress, researchers deleted SIRT1 or SIRT3 in cardiac muscle cells of mouse hearts, and examined the mitochondrial response to ischemic stress by restricted blood flow. The researchers found that the mitochondria in mouse hearts lacking cardiomyocyte SIRT3 were more vulnerable to reperfusion stress than the mouse hearts with SIRT3 intact. The cardiac mitochondrial dynamics (including shape, size, and structure of mitochondria) in these knockout mice physiologically resembled that of aged wildtype (normal) mice retaining cardiac SIRT3.
Furthermore, the young mice with SIRT1 or SIRT3 removed had measurably weaker cardiomyocyte contractions and exhibited aging-like heart dysfunction when ischemia-reperfusion stress was introduced. In essence, without SIRT1/SIRT3 the hearts of these otherwise healthy young mice looked and behaved like old hearts.
Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis, especially mitochondrial dynamics, to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24-26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4-6 months) mice hearts impair cardiomyocyte contractility and shows aging-like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury.