• Age-related decline in two sirtuin enzym

    From ScienceDaily@1:317/3 to All on Tue Aug 24 21:30:38 2021
    Age-related decline in two sirtuin enzymes alters mitochondrial
    dynamics, weakens cardiac contractions

    Date:
    August 24, 2021
    Source:
    University of South Florida (USF Health)
    Summary:
    The potential protective effect of sirtuin enzymes in age-related
    diseases, including cardiovascular diseases, remains an area of
    intense investigation. Now, researchers has determined that sirtuin
    1 (SIRT1) and sirtuin 3 (SIRT3) levels decline in aging hearts,
    disrupting the ability of cardiac muscle cells (cardiomyocytes)
    to contract in response to ischemia-reperfusion injury.



    FULL STORY ========================================================================== Sirtuins are a family of anti-aging proteins that help regulate cellular lifespan, metabolism, and resistance to stress. The potential protective
    effect of these sirtuin enzymes in age-related diseases, including cardiovascular diseases, remains an area of intense investigation.


    ==========================================================================
    Now, a new preclinical study led by University of South Florida
    Health (USF Health) researchers has determined that sirtuin 1 (SIRT1)
    and sirtuin 3 (SIRT3) levels decline in aging hearts, disrupting
    the ability of cardiac muscle cells (cardiomyocytes) to contract in
    response to ischemia-reperfusion injury (also known as reperfusion
    injury). Furthermore, age-related SIRT1 and SIRT3 deficiency can impair
    cardiac function by altering mitochondrial dynamics, which play an
    important role in metabolic health and inflammatory response, the
    researchers report.

    The findings were published online July 3 in Aging Cell.

    "We discovered that age-related changes in mitochondrial dynamics are
    caused by SIRT1/SIRT3 deficiency, specifically in the cardiomyocytes,"
    said principal investigator Ji Li, PhD, professor of surgery in the USF
    Health Morsani College of Medicine. "You need a strong presence of SIRT1
    and SIRT3 to keep mitochondrial dynamics healthy in the heart. Otherwise,
    the heart's pumping function becomes weak." Mitochondria produce the
    energy needed to drive nearly all processes in living cells. Cardiac
    muscle cells contain more mitochondria than any other cells, because
    the heart needs large amounts of energy to constantly pump blood
    throughout the body. Stabile mitochondrial dynamics maintain a healthy
    balance between the constant division (fission) and merging (fusion) of mitochondria and help ensure the quality of these specialized structures
    known as the "powerhouse" of the cell.

    Reperfusion, a common treatment following acute heart attack, restores
    blood flow (and thus oxygen) to a region of the heart damaged by a blood
    clot blocking the coronary artery. Paradoxically, in some patients this necessary revascularization procedure triggers further injury to heart
    muscle tissue surrounding the initial heart attack site. No effective
    therapies currently exist to prevent reperfusion injury.

    To help analyze the response of cardiac mitochondria to
    ischemia-reperfusion stress, the USF Health researchers deleted SIRT1
    or SIRT3 in cardiac muscle cells of mouse hearts, and examined the mitochondrial response to ischemic stress by restricted blood flow. The researchers found that the mitochondria in mouse hearts lacking
    cardiomyocyte SIRT3 were more vulnerable to reperfusion stress than
    the mouse hearts with SIRT3 intact. The cardiac mitochondrial dynamics (including shape, size, and structure of mitochondria) in these knockout
    mice physiologically resembled that of aged wildtype (normal) mice
    retaining cardiac SIRT3.

    Furthermore, the young mice with SIRT1 or SIRT3 removed had measurably
    weaker cardiomyocyte contractions and exhibited aging-like heart
    dysfunction when ischemia-reperfusion stress was introduced. In essence, without SIRT1/SIRT3 the hearts of these otherwise healthy young mice
    looked and behaved like old hearts.

    "We started this study trying to understand why older people have higher incidence of heart attacks than younger people, and why they die more
    often even if they receive maximum treatment. Younger people are much
    more likely to recover from heart attacks and less likely to suffer from ischemia-reperfusion injury," said Dr. Li, a member of the USF Health
    Heart Institute. "Our research suggests that one reason could be that
    both SIRT1 and SIRT3 are downregulated with aging. Younger people have
    higher levels of these proteins needed to make mitochondrial dynamics healthier." The study also suggests that, before surgically opening
    blocked coronary arteries to restore blood flow in older patients, administering a treatment to "rescue" (improve) their diminished SIRT1/
    SIRT3 levels may increase tolerance to cardiac muscle reperfusion stress, thereby reducing heart attack complications and deaths, Dr. Li said. Such
    a cardioprotective treatment might apply a genetic approach to increase SIRT1/SIRT3 production, or an agonist (drug) to activate SIRT1/ SIRT3,
    he added.

    If their mouse model findings translate to human hearts, Dr. Li's group
    wants to work with companies interested in developing and testing
    SIRT1/SIRT3 activators to mitigate heart attack-related reperfusion
    injury.

    "Our ultimate goal is to identify ideal targets for the treatment of heart attack, especially in older patients," said Dr. Li, whose research is
    supported by grants from the National Heart, Lung, and Blood Institute,
    the National Institute on Aging, and the National Institute of General
    Medical Sciences.

    ========================================================================== Story Source: Materials provided by
    University_of_South_Florida_(USF_Health). Original written by Anne
    DeLotto Baier. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Jingwen Zhang, Zhibin He, Julia Fedorova, Cole Logan, Lauryn
    Bates, Kayla
    Davitt, Van Le, Jiayuan Murphy, Melissa Li, Mingyi Wang, Edward G.

    Lakatta, Di Ren, Ji Li. Alterations in mitochondrial dynamics with
    age‐related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte
    contractility. Aging Cell, 2021; 20 (7) DOI: 10.1111/acel.13419 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2021/08/210824104133.htm

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