Abstract
The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca2+ control; (d) disturbance to mitochondria–lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing
Highlights
Despite the fact that the clinical management of cardiac diseases has improved over the past decades, cardiac disease remains the leading cause of mortality in an ageing population [1]
When the hearts of Mfn2KO mice are examined, the contact lengths of mitochondria-associated membrane (MAM) are reduced by 30%; this is accompanied by an increased level of ROS, and reduced cardiac contractility [48]
The “National Institute on Ageing Interventions Testing Program” has carried out several trials with the aim of finding potential interventions that can extend the lifespan of genetically heterogeneous mice
Summary
Despite the fact that the clinical management of cardiac diseases has improved over the past decades, cardiac disease remains the leading cause of mortality in an ageing population [1]. Age-related mitochondrial alterations include reduced mitochondrial Ca2+ uptake and diminished buffering capacity against reactive oxygen species (ROS); these result in impaired metabolism, which in turn bring about an increased sensitivity of the heart to stress, as well as compromising cardiac functioning. A persistently high level of Cisd, which can be achieved by transgenic overexpression, is able to reverse age-related cardiac dysfunction [19], Alzheimer’s-related neuronal loss [23], nonalcoholic fatty liver disease [18], and sarcopenia [22]. It does the above by maintaining Ca2+ homeostasis, reducing ROS production, and improving metabolic flexibility. Recent genetic evidence highlights Cisd as a promising new target for developing novel therapeutics that are aimed at attenuating cardiac ageing and providing a new avenue to geroprotection
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