Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease

Dai, Dao Fu; Chen, Tony; Johnson, Simon C.; Szeto, Hazel H.; Rabinovitch, Peter S.

doi:10.1089/ars.2011.4179

Cited by 278 publications

(251 citation statements)

References 358 publications

(421 reference statements)

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“…Cardiomyopathy, splenomegaly, thymus atrophy, and increased extramedullary hematopoiesis are commonly seen in aging humans and rodents. 2,32,33 As cellular senescence has been implicated in generating age-related phenotypes, 34 we also stained adipose tissues from control and rescued mnd2 mice with the senescenceassociated-b-galactosidase (SA-b-Gal) biomarker. Adipose tissues from aged rescued mnd2 mice, but not from agematched controls or young (3-month-old) rescued mnd2 mice, stained strongly for SA-b-Gal (Figure 3g).…”

Section: Resultsmentioning

confidence: 99%

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals. Cell Death and Differentiation (2013) 20, 259-269; doi:10.1038/cdd.2012 published online 14 September 2012 Mitochondria are dynamic organelles primarily involved in the production of adenosine triphosphate (ATP) through oxidative phosphorylation. They also play important roles in diverse cellular processes such as cell death, autophagy and innate immunity. 1 As a consequence of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS), which damages mitochondrial proteins, lipids and nucleic acids, because of their proximity to the source of ROS production. Accumulation over time of mutations and deletions in mitochondrial DNA (mtDNA) together with increased protein misfolding, as a result of ROS damage, leads to ageassociated decline in mitochondrial function, which is believed to be responsible for organismal aging and age-associated diseases. [2][3][4] To maintain optimal mitochondrial function over time, a number of quality control mechanisms exist that monitor and regulate all aspects of mitochondrial physiology. Damaged and unfolded mitochondrial proteins are removed by mitochondrial quality control proteases, which recognize these proteins and degrade them. 5,6 The ATP-dependent AAA (ATPase-Associated with diverse cellular Activities) proteases, are among the best-characterized proteases implicated in mitochondrial protein quality control. 7 The AAA proteases, ClpXP and Lon, located in the matrix are involved in quality control of matrix proteins. Although no specific mitochondrial substrate has been identified for the ClpXP protease, in vitro studies showed that Lon protease preferentially targets oxidatively damaged matrix aconitase. 8 Two additional AAA proteases, Paraplegin (encoded by the SPG7 gene) and YME1L, are associated with the inner membrane with their catalytic sites facing the matrix and intermembrane space, respectively. 7 These proteases are believed to be primarily involved in the degradation of damaged and unfolded membrane proteins of the electron transport chain. In addition, Paraplegin has been shown to process the mitochondrial ribosomal protein MrpL32, 9 suggesting that it might also function in mitochondrial ribosome assembly. Loss-of-functi...

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Section: Resultsmentioning

confidence: 99%

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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“…This explains the reduced β-adrenergic responsivity observed with age, defined as β-adrenergic desensitization (Ferrara et al 2014). In addition, chronic β-adrenergic stimulation may induce ROS production leading to heart damage (Dai et al 2012). In human heart failure, a similar situation occurs.…”

Section: Neurohormonal Signalingmentioning

confidence: 99%

“…These similarities consisted of the development of cardiac hypertrophy, fibrosis and diastolic dysfunction. In addition, ROS increases after chronic exposure to angiotensin II (Dai et al 2012). In human heart failure, the activity of RAAS is increased and its maladaptive mechanisms may lead to adverse effects such as cardiac remodeling and sympathetic activation (Unger and Li 2004).…”

Section: Neurohormonal Signalingmentioning

confidence: 99%

Cardiac aging and heart disease in humans

2017

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The world population continues to grow older rapidly, mostly because of declining fertility and increasing longevity. Since age represents the largest risk factor for cardiovascular disease, the prevalence of these pathologies increases dramatically with increasing age. In order to improve patient care and prevention for age-related cardiac diseases, insight should be gained from the analysis of processes involved in and leading to cardiac aging. It is from this perspective that we provide here an overview of changes associated with age in the heart on four levels: functional, structural, cellular and molecular. We highlight those changes that are in common with the development of the two major age-associated cardiac pathologies: heart failure and atrial fibrillation. These commonly affected processes in aging and cardiac pathophysiology may provide an explanation for the age risk factor in cardiac disease.

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“…Beyond the gain of skin wrinkles due to loss of matrix elasticity, enhanced matrix deposition and altered matrix composition have been reported for the ageing heart, kidney, skeletal muscle, and, most importantly, for the lung in humans and animal models [284][285][286][287][288][289]. With respect to lung cancer, HANAHAN and WEINBERG [163] emphasised the influence of the tumour microenvironment, i.e.…”

Section: Ecm Dysregulation As a New Hallmark Of Lung Ageingmentioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease

Cited by 278 publications

References 358 publications

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Cardiac aging and heart disease in humans

Hallmarks of the ageing lung

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