Posts Tagged: aging

Elixir of Life: Thwarting Aging With Regenerative Reprogramming

Elixir of Life: Thwarting Aging With Regenerative Reprogramming

Ergin Beyret, Paloma Martinez Redondo, Aida Platero Luengo, Juan Carlos Izpisua Belmonte

Regenerative reprogramming approaches. In vivo induction of transdifferentiation can be used to repopulate the cells lost during aging as an alternative to transplantation, complementing the intrinsic regenerative capacity. For instance, neurons lost to neurodegenerative diseases can be replaced by transdifferentiating resident glia or astrocytes; cardiac fibroblasts can be the cell source for induced cardiomyocytes; α, ductal, and acinar cells can be used for β cells. Alternatively, transient 4F (OCT4, KLF4, SOX2, and c-Myc) expression can be used to rejuvenate cells. This in turn can decelerate degeneration of biological units that have low regeneration capacity (eg, aorta) or augment regeneration capacity by counteracting stem cell exhaustion (eg, muscle) or by enhancing the plasticity of organs that intrinsically undergo cell conversions during regeneration (eg, transdifferentiation in the pancreas and dedifferentiation in the kidney). MuSC indicates muscle stem cell. [Powerpoint File]

Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease

Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease

José J. Fuster, Kenneth Walsh

Somatic mutations in blood cells as a shared mechanism of hematologic cancer and cardiovascular disease. A, The accumulation of somatic mutations in hematopoietic progenitor and stem cells is an inevitable consequence of the process of aging. Some of these random mutations confer a competitive advantage to the mutant cells, leading to its clonal expansion. This phenomenon can be defined as somatic mutation-driven clonal hematopoiesis. B, Most individuals exhibiting somatic mutation-driven clonal hematopoiesis only carry 1 driver mutation (eg, in DNMT3A, TET2, ASXL1, or JAK2). Although this situation greatly increases the risk of acquiring additional driver mutations and eventually developing a hematologic cancer, this condition is infrequent, even in individuals with clonal hematopoiesis. The main cause of death in individuals exhibiting somatic mutation-driven clonal hematopoiesis is atherosclerotic cardiovascular disease. Grey shade in the figure indicates decreasing frequency. HSPC indicates hematopoietic stem/progenitor cell. [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]

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]

The Role of Autophagy in Vascular Biology

The Role of Autophagy in Vascular Biology

Samuel C. Nussenzweig, Subodh Verma, Toren Finkel

Stimulation of autophagy occurs through mechanistic target of rapamycin (MTOR)–dependent and MTOR-independent pathways within vascular cells. Complex I of MTOR (mTORC1) is a well characterized, negative regulator of autophagosome formation. The classical autophagic stimulus of nutrient withdrawal is thought to be largely transduced through this pathway, whereas the pharmacological agent, rapamycin, works as an inhibitor of MTOR, thereby relieving the tonic autophagic-inhibition of MTORC1. Other agents, such as endoplasmic reticulum (ER) stress, reactive oxygen species (ROS), and oxidized lipids seem to largely work through a mix of both MTOR-dependent and MTOR-independent pathways, although the precise mechanism of action for these stimuli is largely unknown (illustration credit: Ben Smith). [Powerpoint File]

The Role of Autophagy in Vascular Biology

The Role of Autophagy in Vascular Biology

Samuel C. Nussenzweig, Subodh Verma, Toren Finkel

Endothelial disruption of autophagic flux impairs Weibel–Palade Body (WPB) formation. Graphical illustration of the normal maturation and secretion of von Willebrand factor (vWF) within endothelial cells (top). After deletion of Atg7 or Atg5 within the endothelium (bottom), there is no change in the level of vWF, but more is found in the endoplasmic reticulum (ER) and Golgi and less within the mature WPB. Moreover, perhaps, because of impaired ER and Golgi homeostasis, the pH of the WPB is altered in the absence of autophagy, leading to a shorter and more rounded morphology. Electron micrographs of these different WPB morphologies are shown (Reprinted from Torisu et al64 with permission). [Powerpoint File]

The Role of Autophagy in Vascular Biology

The Role of Autophagy in Vascular Biology

Samuel C. Nussenzweig, Subodh Verma, Toren Finkel

The convergence of autophagic flux and vascular aging. A variety of intrinsic and extrinsic factors (age, glucose, lipids, etc.) can regulate vascular autophagy. The induction of autophagy may be important in minimizing the damage that these factors can induce. With increasing age, vascular autophagic flux seems to decline and this decline may contribute to the impairment in endothelial function (with decreased nitric oxide [NO] signaling) and to the increase in vascular stiffness. Efforts to maintain and augment vascular autophagy may prove to be therapeutically beneficial. eNOS indicates endothelial nitric oxide synthase; and ox-LDL, oxidized low-density lipoprotein. [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

New molecular pathways in aging biology could lead to new treatments of age-related diastolic heart failure. Existing therapies for systolic heart failure have been unsuccessful at treating heart failure accompanied by preserved ejection fraction (HFpEF). Novel therapeutic pathways including microRNAs (miRNAs), metabolic factors, and age-dependent circulating hormones offer the new opportunities for developing successful treatments. GDF11 indicates growth differentiation factor 11; and miR-34a, miRNA-34a. [Powerpoint File]

Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis

Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis

Sarajo Kumar Mohanta*, Changjun Yin*, Li Peng, Prasad Srikakulapu, Vineela Bontha, Desheng Hu, Falk Weih, Christian Weber, Norbert Gerdes*, Andreas J.R. Habenicht*

Hypothetical choreography of balanced T and B lymphocyte-mediated, autoantigen-specific autoimmune reactions in artery tertiary lymphoid organs (ATLOs). The structural and cellular organization of ATLOs and our unpublished data about recruitment, priming, and generation of T-cell effectors, as well as the identification of various B-cell subtypes, indicate both primary autoantigen-specific T- and B-cell responses. After recruitment of blood monocytes through vasa vasora and their subsequent differentiation into monocyte-derived dendritic cells (mDCs), of naïve T and B cells through high endothelial venules (HEVs), and of conventional DCs (cDCs) through lymph vessels, autoantigen(s) is (are) presented by cDCs and mDCs to T cells and by follicular DCs to B cells, respectively. Priming of cognate naïve T cells may then result in activation,26 functional avidity maturation,24,25 imprinting,27 and clonal expansion of antigen-specific T-cell clones, which differentiate into effector T cells, effector memory T cells, and central memory T cells28,31; other T cells that do not interact with DCs may return into the circulation; some DC-activated T cells may undergo either death by neglect or activation-induced cell death caused by overwhelming antigen exposure. Central memory T cells may leave ATLOs to home to secondary lymphoid organs (SLOs). Priming of cognate naïve B cells, with the help of either conventional helper T cells or T follicular helper cells, undergo activation and subsequently multiple rounds of proliferation during which multiple events of somatic hypermutation during affinity maturation of their variable immunoglobulin light chain genes occurs in germinal center reactions resulting in the generation of memory B cells or plasma cells. Some plasma cells may emigrate from ATLOs and home into the bone marrow, whereas memory B cells may home into SLOs and the bone marrow. The regulatory immune cell subsets are not depicted for ease of reading (Figure 5). FDC indicates follicular DC; and TFH, T follicular helper cells (functional effect on atherosclerosis controversial). [Powerpoint File]

Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis

Artery Tertiary Lymphoid Organs Contribute to Innate and Adaptive Immune Responses in Advanced Mouse Atherosclerosis

Sarajo Kumar Mohanta*, Changjun Yin*, Li Peng, Prasad Srikakulapu, Vineela Bontha, Desheng Hu, Falk Weih, Christian Weber, Norbert Gerdes*, Andreas J.R. Habenicht*

Atherosclerotic arteries harbor distinct immune cell infiltrates in plaques and adventitia. The adventitia of the normal arterial wall constitutively contains vasa vasora, lymph vessels, tissue macrophages, few T cells, mast cells, conventional dendritic cell (cDCs), and myofibroblasts. In response to transmural arterial wall inflammation in early stages of atherosclerosis, single T cells begin to infiltrate the adventitia. During disease progression, extensive reorganization of adventitia segments adjacent to atherosclerotic plaques can be observed in the abdominal aorta of Apoe−/− mice resulting in several forms of ATLOs (artery tertiary lymphoid organs). Reorganization of the adventitia includes both the connective tissue–derived cells, such as myofibroblasts and neogenesis of lymph vessels, angiogenesis, conduit formation, and high endothelial venule (HEV) formation. Concomitantly, monocytes are recruited through blood vessels, cDCs are recruited through lymph vessels, and naϊve T and B cells are recruited through newly formed HEVs. Moreover, survival niches are populated by plasma cells. In contrast to the adventitia, advanced atherosclerotic plaques are comparably acellular and show a limited set of adaptive immune cells. mDC indicates monocyte-derived DC. [Powerpoint File]

Regulation of Akt Signaling by Sirtuins: Its Implication in Cardiac Hypertrophy and Aging

Regulation of Akt Signaling by Sirtuins: Its Implication in Cardiac Hypertrophy and Aging

Vinodkumar B. Pillai, Nagalingam R. Sundaresan, Mahesh P. Gupta

A model illustrating the role of silent information regulator (SIRT) 1 and SIRT3 in regulating Akt activation. Under basal conditions, the pleckstrin homology (PH) domains of Akt and 3-phosphoinositide–dependent protein kinase 1 (PDK1) are acetylated, leading to inhibition of their binding to phosphatidylinositol 3,4,5 triphosphate (PIP3) and, hence, inactivation. During growth factor stimulation of cells, SIRT1 binds to and deacetylates Akt and PDK1 PH domains. This change enables them to bind to PIP3, which is generated from PIP2 by the activation of phosphatidylinositide 3-kinase (PI3K) during growth factor stimulation of cells. PH domain deacetylation is likely to make lysine residues available for tumor necrosis factor receptor–associated factor 6 (TRAF6)–mediated ubiquitination, thereby facilitating ubiquitination-mediated transport of the protein to the plasma membrane (ubiquitination of PDK1 has not been described; but based on PH domain acetylation studies, it seems also subject to ubiquitination similar to Akt). At the level of plasma membrane, PDK1 phosphorylates and activates Akt, leading to cellular response (for details, see Sundaresan et al9). Under oxidative stress, Akt can be hyperactivated by reactive oxygen species (ROS)–mediated rat sarcoma (Ras) activation, which activates PI3K. In this condition, SIRT3 blocks Akt activation by suppressing ROS production from mitochondria (for details, see Sundaresan et al9,33). [Powerpoint File]

Regulation of Akt Signaling by Sirtuins: Its Implication in Cardiac Hypertrophy and Aging

Regulation of Akt Signaling by Sirtuins: Its Implication in Cardiac Hypertrophy and Aging

Vinodkumar B. Pillai, Nagalingam R. Sundaresan, Mahesh P. Gupta

Reversible lysine acetylation in the pleckstrin homology (PH) domain regulates Akt activation. Crystal structure of the PH domain of Akt (top). Acetylated lysine residues (Lys14 and Lys20) are shown in purple and phosphatidylinositol 3,4,5 triphosphate (PIP3) in green. Both lysines are in close proximity to the binding pocket for PIP3. Schematic activation of Akt by silent information regulator (SIRT) 1 (bottom). Lysine acetylation of the PH domain makes Akt incapable to bind to PIP3, leading to inactivation of the kinase. SIRT1-dependent deacetylation promotes Akt–PIP3 binding and hence phosphorylation and activation of Akt by the upstream kinases (for details, see Sundaresan et al9). [Powerpoint File]