Posts in Category: Epidemiology, Lifestyle, & Aging

Atrial Fibrillation Epidemiology, Pathophysiology, and Clinical Outcomes

Atrial Fibrillation: Epidemiology, Pathophysiology, and Clinical Outcomes

Laila Staerk, Jason A. Sherer, Darae Ko, Emelia J. Benjamin, Robert H. Helm

Atrial fibrillation (AF) risk factors (RFs) induce structural and histopathologic changes to the atrium that are characterized by fibrosis, inflammation, and cellular and molecular changes. Such changes increase susceptibility to AF. Persistent AF further induces electric and structural remodeling that promotes perpetuation of AF. AF also may lead to the development of additional AF risk factors that further alters the atrial substrate. Finally, AF is associated with several clinical outcomes. *There are limited data supporting the association. BMI, body mass index; ERP, effective refractory period; HF, heart failure; IL, interleukin; MI, myocardial infarction; OSA, obstructive sleep apnea; SEE, systemic embolism event; TNF, tumor necrosis factor; and VTE, venous thromboembolism. [Powerpoint File]

Mechanical Regulation of Cardiac Aging in Model Systems

Mechanical Regulation of Cardiac Aging in Model Systems

Ayla O. Sessions, Adam J. Engler

Physiological vs pathological age–related changes of the sarcomere and intercalated disc (ID). Schematic representation of sarcomere and ID components in the cardiomyocyte implicated in physiological aging (red, upregulated; green, downregulated), pathological aging (yellow, upregulated; blue, downregulated), or yet undetermined (black). Arrows to nucleus indicate translocation of protein into the nucleus with age. α-CAT indicates α-catenin; ACTN1, α-actinin-1; α-MHC, α-myosin heavy chain; β-CAT, β-catenin; c-TnT4, cardiac troponin T-4; F-actin, filamentous actin; MLP, muscle-binding limb protein; N-CAD, N-cadherin; P-MLC-2, phosphorylated myosin light chain-2; and Vinc, vinculin. [Powerpoint File]

Mechanical Regulation of Cardiac Aging in Model Systems

Mechanical Regulation of Cardiac Aging in Model Systems

Ayla O. Sessions, Adam J. Engler

Physiological vs pathological age–related changes of costamere and extracellular matrix (ECM). Schematic representation of Costamere and ECM of the cardiomyocyte implicated in physiological aging (red, upregulated; green, downregulated), pathological aging (yellow, upregulated; blue, downregulated), or yet undetermined (black). Stripes of 2 colors indicate lack of consensus on expression levels across species or involvement in physiological vs pathological aging. α7 indicates α7-integrin; β1, β1-integrin; ACTN1, α-actinin-1; AGE’s, advanced glycosylation endproducts; Col I, collagen type 1; Col IV, collagen type IV; F-actin, filamentous actin; ID, intercalated disc; ILK, integrin-linked kinase; MMP2, matrix mettaloproteinase-2; MMP9, matrix metalloproteinase-9; MMP14, matrix metalloproteinase-14; and Vinc, vinculin. [Powerpoint File]

Macromolecular Degradation Systems and Cardiovascular Aging

Macromolecular Degradation Systems and Cardiovascular Aging

Hiroyuki Nakayama, Kazuhiko Nishida, Kinya Otsu

Fundamental pathway of ubiquitin (Ub)/proteasome system. Ub conjugation is an ATP-dependent process and is mediated by a series of enzymes. UPS consists of the Ub-activating enzyme E1 that transfers Ub to the active site of the E2 Ub-conjugating enzymes. The E3 Ub-ligases ligate Ub to an internal lysine in the target protein. The ubiquitinated protein will be targeted to the 26S proteasome for degradation or spared form degradation by the action of cytosolic deubiquitinating enzymes. The 26S proteasome consists of the 20S core complex and of 1 or 2 19S regulatory complexes that bind one or both ends of the 20S. The 20S proteasome consists of 28 subunits divided into 4 rings including 2 flanking α and 2 central β rings and contains proteolytic activities. The 3 peptidase activities of the proteasome are localized in the β1, β2, and β5 subunits of β rings. 19S complex is comprised of 20 subunits and contains ATPase activity and function as a polyubiquitin receptor. The immunoproteasome is an alternative form of the standard 20S proteasome in which the proteolytically active subunits β1, β2, and β5 are replaced by alternative subunits β1i (proteasome subunit [PSMB] 9), β2i (PSMB10), and β5i (PSMB8), respectively. The immunoproteasome is induced by interferon (IFN)-γ or tumor necrosis factor (TNF) α and plays an important role in the degradation of oxidized proteins. All 3 immunoproteasome-specific subunits are also upregulated under acute exposure to oxidative stress in cultured cells. On the contrary, 20S proteasome degrades oxidized proteins without prior targeting by ubiquitination. Oxidized proteasome subunits or aggregated proteins induced by extensive oxidation inhibit proteasomal activity that may contribute to proteasomal functional insufficiency observed in advanced aging. ROS indicates reactive oxygen species. [Powerpoint File]

Macromolecular Degradation Systems and Cardiovascular Aging

Macromolecular Degradation Systems and Cardiovascular Aging

Hiroyuki Nakayama, Kazuhiko Nishida, Kinya Otsu

Degradation of DNA and inflammation. Degradation of superfluous DNA by three DNase (DNase I, II, and III) prevents sterile inflammation. The secreted extracellular DNase I degrades inflammogenic genomic DNA released by necrotic cells, what is called a damage-associated molecular patterns, to prevent inflammasome activation. The lysosomal DNase II degrades mitochondrial-DNA during autophagic process thereby hamper toll-like receptor 9–dependent immune responses. Intrinsic self-DNA is degraded by DNase III/3′ repair exonuclease 1 in cytosol, whereby hinder stimulator of interferon gene (STING)–dependent induction of cytokine production caused by cytosolic DNA. [Powerpoint File]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

Schematic of the interfibrillar mitochondrial defects in the aged heart. ETC indicates electron transport chain; IMM, mitochondrial inner membrane; NADH, nicotinamide adenine dinucleotide; PPL, phospholipid, proposed defect affecting subunit VIIa in complex IV; and Q, ubiquinone; Qo site, ubiquinol-binding site on cytochrome bl with proposed defect in Y132. Illustration credit, Ben Smith. [Powerpoint File]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

A schematic of a cardiomyocyte to highlight the location of subsarcolemmal (SSM) and interfibrillar mitochondria (IFM). Illustration credit: Ben Smith. [Powerpoint File]

Mitochondrial Metabolism in Aging Heart

Mitochondrial Metabolism in Aging Heart

Edward J. Lesnefsky, Qun Chen, Charles L. Hoppel

A schematic of a cardiomyocyte to show defects present in global and mitochondrial metabolism with age in concert with mechanisms of mitochondria-driven cellular injury. The aged heart exhibits impaired fatty acid oxidation (FAO) and preserved oxidation of glucose. Aging leads to defects in the electron transport chain that involve complexes III (CIII) and IV (CIV). Monoamine oxidase (MAO) and p66shc are significant sources of oxidants. There is a decrease in cardiolipin (CL). Antioxidant contents are relatively unchanged although a decrease in matrix antioxidant capacity leads to mitochondrial damage. Age-related damage enhances the production of reactive oxygen species (ROS) that lead to mitochondrial and cell damage. In addition, effector mechanisms of age-induced mitochondrial damage discussed include an increased susceptibility to mitochondrial permeability transition pore opening (MPTP; MPTP Opening in the Aged Heart: Relationship With ROS Production section), impaired mitochondrial dynamics favoring fusion over fission (Mitochondrial Fission and Fusion section), likely impaired mitophagy (Mitochondrial Biogenesis, Dynamics, and Removal section), and enhanced oxidant-derived signaling to activate cell death programs (Mitochondrial Metabolism–Based Signaling in Response to ROS Production section). Illustration credit: Ben Smith. ETC indicates electron transport chain. [Powerpoint File]

Dietary Interventions, Cardiovascular Aging, and Disease: Animal Models and Human Studies

Dietary Interventions, Cardiovascular Aging, and Disease: Animal Models and Human Studies

Hamed Mirzaei, Stefano Di Biase, Valter D. Longo

Effects of diets on cardiac health and aging. A, An overview of some of the major signaling pathways that are affected by high-fat diets and dietary restrictions discussed in this review. B, Molecular signaling pathways affected by dietary interventions and their effect on cardiovascular health and aging. AMPK indicates AMP-activated protein kinase; CETP, cholesteryl ester transfer protein; CR, caloric restriction; DR, dietary restriction; FMD, fasting mimicking diet; FOXO, forkhead box O transcription factors; HDL, high-density lipoprotein; IGF-1, insulin-like growth factor 1; LDL, low-density lipoprotein; mTOR, mammalian target of rapamycin; NEFA, nonesterified fatty acids; PKA, protein kinase A; S6K, S6 kinase; ROS, reactive oxygen species; and VLDL, very low-density lipoprotein. [Powerpoint File]

Pharmacological Strategies to Retard Cardiovascular Aging

Pharmacological Strategies to Retard Cardiovascular Aging

Irene Alfaras*, Clara Di Germanio*, Michel Bernier, Anna Csiszar, Zoltan Ungvari, Edward G. Lakatta, Rafael de Cabo

Pharmacological strategies to combat cardiovascular (CV) aging. Age-associated changes in cardiac and vascular properties (depicted in the inner red circle) can be delayed by targeting the related pathways (in the middle yellow circle) with small molecules (represented in the outer blue circle). Some of the pharmacological strategies highlighted in the diagram (bold and underlined) have been shown to improve longevity in healthy mammals. AMPK indicates 5’ adenosine monophosphate–activated protein kinase; Ang-II, angiotensin II; AT1, angiotensin II receptor, type 1; Chol, cholesterol; GH, growth hormone; iACE, inhibitors of angiotensin-converting enzyme; IGF-1, insulin-like growth factor-1; mTOR, mechanistic target of rapamycin; NO, nitric oxide; NOS, nitric oxide synthase; Nrf2, NF-E2-related factor 2; PARP-1, poly(ADP-ribose) polymerase 1; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; and SIRT-1, sirtuin (silent mating type information regulation 2 homolog) 1. [Powerpoint File]

Pharmacological Strategies to Retard Cardiovascular Aging

Pharmacological Strategies to Retard Cardiovascular Aging

Irene Alfaras*, Clara Di Germanio*, Michel Bernier, Anna Csiszar, Zoltan Ungvari, Edward G. Lakatta, Rafael de Cabo

Antiaging effects of caloric restriction in the cardiovascular system. The up arrow notation indicates an improvement or increase, whereas the down arrow shows decrease or impairment of cardiovascular functions and pathologies. NO indicates nitric oxide. [Powerpoint FIle]

The Role of Exercise in Cardiac Aging: From Physiology to Molecular Mechanisms

The Role of Exercise in Cardiac Aging: From Physiology to Molecular Mechanisms

Jason Roh, James Rhee, Vinita Chaudhari, Anthony Rosenzweig

Multiple mechanisms have been proposed for impaired cardiomyocyte function observed in aging, and how exercise partially reverses their effects. (1) Diminished cardiac performance in the pathological hypertrophy of aging is linked to decreased insulin-like growth factor-I (IGF-I)–phosphatidylinositol 3-kinase (PI3K)–AKT and β-adrenergic receptor (β-AR)–cAMP–protein kinase A (PKA) signaling, decreased sarcoplasmic reticulum Ca2+–ATPase2a (SERCA2a) expression and activity and inefficient calcium handling, and mitochondrial dysfunction secondary to excessive reactive oxygen species (ROS). (2) Exercise confers physiological hypertrophy and cardioprotection in the form of enhanced β-adrenergic and IGF-1 signaling, SERCA2a activity and calcium handling, and mitochondrial dynamics, the latter mediated largely through peroxisome proliferator-activated receptor γ coactivator (PGC)-1α. (3) These benefits of exercise potentially mitigate the effects of aging (Illustration Credit: Ben Smith). [Powerpoint File]

Untangling Autophagy Measurements: All Fluxed Up

Untangling Autophagy Measurements: All Fluxed Up

Roberta A. Gottlieb, Allen M. Andres, Jon Sin, David P.J. Taylor

Autophagic puncta in hearts of mCherry-light chain 3 mice on chow or high-fat diet (HFD). A, Representative heart sections of mice from the Mentzer study after 15 weeks of chow or Teklad D12492 HFD. Cardiac sections (5–6 μm) were made using a cryostat, mounted on glass slides, and nuclei stained with Hoechst 33342. Images were acquired with a Nikon TE300 fluorescence microscope equipped with a ×60 Plan Apo objective with excitation/emission wavelengths of 560/630 nm (unpublished images generously provided by Dr Bruce Ito and Dr Robert Mentzer). B, Representative heart sections of mice from the Abel study after 12 weeks of chow or Western diet. Images were taken with Zeiss LSM 510 confocal microscope using ×63 immersion oil objective with excitation/emission wavelengths of 543/613 nm (unpublished images generously provided by Dr Bharat Jaishy and Dr E. Dale Abel). [Powerpoint File]

The GSK-3 Family as Therapeutic Target for Myocardial Diseases

The GSK-3 Family as Therapeutic Target for Myocardial Diseases

Hind Lal, Firdos Ahmad, James Woodgett, Thomas Force

Signaling cascades regulated by glycogen synthase kinase-3 (GSK-3) in heart. In response to growth factor binding to their receptors, the phosphoinositide 3 kinase/AKT8 virus oncogene cellular homolog (PI3K/Akt) pathway is activated, leading to inhibition of GSK-3. GSK-3 negatively regulates a host of factors downstream of growth factor signaling, so the consequences of GSK-3 inhibition are activation of these factors including (1) NF-AT-hypertrophy regulator, (2) glycogen synthase-glycogen synthesis regulator, (3) mammalian target of rapamycin (mTORC1) autophagy and metabolism regulator, (4) D- and E-type cyclin cell cycle regulator, and (5) Myc-metabolism and proliferation regulator. An alternative mechanism to inhibit GSK-3 is mediated by p38. GSK-3β directly binds with contraction of Sma and Mad (mothers against decapentaplegic) (SMAD-3) to negatively regulate the profibrotic transforming growth factor β1 (TGF-β1) signaling. GSK-3 is well known to regulate the canonical Wnt signaling. Phosphorylation of β-catenin by GSK-3 leads to the ubiquitination and degradation of β-catenin by the proteasome, preventing gene expression. In the absence of GSK-3, β-catenin is stabilized, and then translocates to the nucleus leading to gene expression. β-catenin regulates a host of processes from fibrosis to cardiac hypertrophy. GSK-3α regulates AMP-activated protein kinase (AMPK) and mTOR, the master regulators of autophagy and metabolism. In the absence of GSK-3α, mTOR is dysregulated leading to impaired autophagy, which accelerates the progression of aging. GSK-3α also regulates the β-adrenergic receptor responsiveness and cAMP production via unknown mechanisms. GSK-3α directly interacts and phosphorylates cyclin E1 in cardiomyocytes and its deletion promotes E2F-1 and cyclin E1 recruitment and induces the re-entry of adult cardiomyocytes into the cell cycle. 4EBP1 indicates eIF4E binding protein; APC, adenomatous polyposis coli; Dvl, disheveled; ECM, extracellular matrix; eIF, eukaryotic initiation factor; EMT, epithelial-to-mesenchymal transition; FAK, focal adhesion kinase; GPCR, G-protein coupled receptor; GS, glycogen synthase; ILK, integrin-linked kinase; IRS, insulin receptor substrate; MPTP, mitochondrial permeability transition pore; NFAT, nuclear factor of activated T cells; PDK1, 3-phosphoinositide-dependent protein kinase 1; PLB, phospholamban; RhoA, Ras homolog gene family, member A; RTK, receptor tyrosine kinase; and TβR, TGF-β1 receptor (Illustration credit: Ben Smith). [Powerpoint File]

Heart Failure With Preserved Ejection Fraction: Molecular Pathways of the Aging Myocardium

Heart Failure With Preserved Ejection Fraction: Molecular Pathways of the Aging Myocardium

Francesco S. Loffredo, Andriana P. Nikolova, James R. Pancoast, Richard T. Lee

Aging itself leads to molecular changes that contribute to diastolic impairment. Age is associated with systemic changes and myocardial molecular dysfunction that translate into structural changes thought to contribute to heart failure accompanied by preserved ejection fraction (HFpEF). ANGII indicates angiotensin II; ECM, extracellular matrix; ET1, endothelin-1; MCP-1, monocyte chemoattractant protein; ROS, reactive oxygen species; and TNFα, tumor necrosis factor-α. [Powerpoint File]