The Aging Heart | ScienceGate

BACKGROUND: Aging per se is a risk factor for reduced cardiac function and heart diseases, even when adjusted for aging-associated cardiovascular risk factors. Accordingly, aging-related biochemical and cell-biological changes lead to pathophysiological conditions, especially reduced heart function and heart disease.CONTENT: Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and PGC-1b in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging.SUMMARY: The aging myocardium with telomere shortening and accumulation of senescent cells restricts the tissue regenerative ability, which contributes to systolic or diastolic heart failure. Moreover, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments.KEYWORDS: aging, telomere, telomerase, aging heart, mitochondria, cardiac stem cell

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Questions and Answers About Myostatin, GDF11, and the Aging Heart

Circulation Research ◽

10.1161/circresaha.115.307861 ◽

2016 ◽

Vol 118 (1) ◽

pp. 6-8 ◽

Cited By ~ 14

Author(s):

Elizabeth M. McNally

Keyword(s):

Aging Heart ◽

Questions And Answers

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3-Nitrotyrosine Modification of SERCA2a in the Aging Heart: A Distinct Signature of the Cellular Redox Environment†

Biochemistry ◽

10.1021/bi051226n ◽

2005 ◽

Vol 44 (39) ◽

pp. 13071-13081 ◽

Cited By ~ 89

Author(s):

Tatyana V. Knyushko ◽

Victor S. Sharov ◽

Todd D. Williams ◽

Christian Schöneich ◽

Diana J. Bigelow

Keyword(s):

Cellular Redox ◽

Aging Heart ◽

Redox Environment ◽

Cellular Redox Environment

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Disturbances of the Cardiac Mechanism and the Aging Heart: Arrhythmias and Conduction Defects and Their Treatment

Medical Clinics of North America ◽

10.1016/s0025-7125(16)34616-8 ◽

1956 ◽

Vol 40 (1) ◽

pp. 153-175

Author(s):

Fred W. Fitz ◽

John R. Laadt

Keyword(s):

Aging Heart ◽

Heart Arrhythmias

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Abstract 30: Endurance Exercise Induces Cardiac Hypertrophy in Aged Nrf2-/- Mice

Circulation Research ◽

10.1161/res.111.suppl_1.a30 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Rajasekaran Namakkal Soorappan ◽

Dinesh Devdoss ◽

Snkaranarayanan Kannan ◽

Curtis Olsen ◽

Sellamuthu Subbanna Gounder ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Hypertrophy ◽

Endurance Exercise ◽

Weight Ratio ◽

The Elderly ◽

Exercise Stress ◽

Aging Heart ◽

Protein Levels ◽

Nuclear Levels ◽

Endurance Stress

Background: Radical forms of oxygen and nitrogen species (ROS/RNS) are highly reactive with nucleic acids, proteins and lipids and promote their oxidation. Normally, cellular ROS/RNS concentrations are tightly controlled by the inducible antioxidant system, which is predominantly regulated by the transcription factor Nrf2 (nuclear erythroid-2 like factor-2) and its cytosolic repressor protein, Keap1. We hypothesized that a decrease or an abrogation of Nrf2 impairs cardiac function and induce hypertrophy upon endurance stress in aging heart. Methods: Age-matched wild-type (WT) and Nrf2-/- (KO) mice (n=12/gp) at 2 and >20 months were subjected to endurance exercise stress (EES; 20 meter/min, 12% grade) and assessed the activation of Nrf2/ARE-dependent transcriptional mechanisms in the heart. Cardiac hypertrophy was determined by echocardiography, heart/body weight ratio and biochemical/molecular marker analyses. Results: Interestingly, both old-WT and Nrf2-/- mice exhibited oxidative stress on EES due to significant decrease or abrogation of Nrf2 nuclear levels, respectively, suggesting that aged-WT is equally susceptible to stress as Nrf2-/- mice. Age-dependent loss of Nrf2 decreased the transcription of Nrf2-dependent antioxidants and thereby elevated ROS levels to cause a more oxidized intracellular environment. Importantly, the loss of Nrf2 induced cardiac hypertrophy upon endurance stress in the aged (>20 mon) mice. At the end of 2-weeks of endurance stress, both the old-WT and Nrf2-/- mice had developed cardiac hypertrophy. Also, qPCR analysis showed significant (p<0.05) upregulation of hypertrophy markers (ANF and BNF) in the old-WT or Nrf2-/- when compared to sedentary WT mice confirmed cardiac hypertrophy due to loss of Nrf2. These results indicate that either a decrease or an abrogation of Nrf2 can increase susceptibility to stress induced hypertrophy in an aging heart. Conclusions: We conclude that enhancing protein levels and stability of nuclear Nrf2 could activate the transcription of major antioxidant enzymes and biosynthesis of key antioxidants. Enhancing protective mechanisms against oxidative stress in the elderly is expected to prevent or delay the onset of age-associated cardiac hypertrophy and cardiomyopathy.

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Abstract 279: A Defective Mechanosensing Promotes Impaired Fibroblast-to-myofibroblast Maturation in the Aging Mouse Heart

Circulation Research ◽

10.1161/res.127.suppl_1.279 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Aude Angelini ◽

JoAnn Trial ◽

Katarzyna A Cieslik

Keyword(s):

Mass Spectrometry ◽

Cardiac Fibroblasts ◽

Fold Increase ◽

Negative Regulator ◽

Mouse Heart ◽

Aging Heart ◽

Aging Mouse ◽

Student’S T ◽

Scar Contraction ◽

Student’S T Test

In the aging heart, fibroblasts have a reduced ability to mature into myofibroblasts (expressing contractile actin a-SMA), which is necessary for scar contraction in wound healing. The mechanosensing pathway bridges the extracellular matrix (ECM) with the actin cytoskeleton and is altered during aging. We emphasize that changes in this pathway may affect myofibroblast activation. Using various methods (mass spectrometry, qPCR, flow, IF staining, and western), we found several abnormalities in the fibroblasts derived from old mouse hearts: 1) ECM deposited was altered with an increased quantity of collagens and the presence of fibronectin variant Anastellin that opposes myofibroblast maturation; 2) there was a 50% reduction of Kindlin-2, a protein that promotes integrin activation; 3) Polymerized (F-) to monomeric (G-) actin ratio was decreased by 65%, possibly due to a 5-fold increase in pERKs1/2 level, a negative regulator of F-actin; and pERKs inhibition (by 2.5μM, PD-0325901) increased by 2-fold F/G actin ratio; 4) we found an increased cytoplasmic retention of MRTF-A (by 44%), an actin-sensitive co-transcription factor (necessary for a-SMA) that shuttles into the nucleus in response to F-actin formation; 5) pERKs inhibition increased a-SMA transcription by 78%. Thus, the disrupted mechanosensing pathway contributes to the impaired myofibroblast maturation in the aging heart. All experiments were performed in young (3-4 month-old) and old (24-30 month-old) hearts or primary cardiac fibroblasts isolated from male C57BL/6J mice. Unpaired Student’s t-test was used for statistical analysis, n=2 for mass spectrometry and n=4-10 for all other biological repeats.

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