Elucidating the regulatory mechanisms of human cardiac aging remains a great challenge. Here, using human heart tissues from 74 individuals ranging from young (<= 35 years) to old (>= 65 years), we provide an overview of the histological, cellular and molecular alterations underpinning the aging of human hearts. We decoded aging-related gene expression changes at single-cell resolution and identified increased inflammation as the key event, driven by upregulation of ARID5A, an RNA-binding protein. ARID5A epi-transcriptionally regulated Mitochondrial Antiviral Signaling Protein (MAVS) mRNA stability, leading to NF-kappa B and TBK1 activation, amplifying aging and inflammation phenotypes. The application of gene therapy using lentiviral vectors encoding shRNA targeting ARID5A into the myocardium not only mitigated the inflammatory and aging phenotypes but also bolstered cardiac function in aged mice. Altogether, our study provides a valuable resource and advances our understanding of cardiac aging mechanisms by deciphering the ARID5A-MAVS axis in post-transcriptional regulation.
基金：
This work was supported by
the National Key Research and Development Program of China
(2022YFA1103700 to W.Z.), the National Natural Science Foundation
of China (32341001 to G.-H.L., 82125011 to J.Q., 81921006 to
G.-H.L., 32121001 to W.Z., 92149301 to G.-H.L., 92168201 to G.-H.L.,
82361148131 to W.Z., 82322025 to S.M., 82241205 to W.J., 82170487
to W.J.), the Strategic Priority Research Program of the Chinese
Academy of Sciences (XDA0460403 to W.Z.), Beijing Natural
Science Foundation (JQ24044 to W.Z.), Shenzhen Medical Research
Fund (D2401003 to Y. Fan), CAS Youth Interdisciplinary Team to
W.Z., the National Key Research and Development Program of
China (2020YFA0804000 to G.-H.L., 2021YFF1201000 to W.Z., the
STI2030-Major Projects-2021ZD0202400 to S.W.), the National Natural
Science Foundation of China (82330044 to G.-H.L., 92049304,
82192863 to W.Z., 82122024 to S.W., 82071588 to S.W., 82271600
to S.M., 82070332 to Y. Yao, 82370315 to Y. Yao, 82270691 to G.X.,
82070674 to G.X, 82361148130 to G.-H.L.), CAS Project for Young
Scientists in Basic Research (YSBR-076 to G.-H.L., YSBR-012 to W.Z.,YSBR-073 to Y. Yang), the Program of the Beijing Natural Science
Foundation (5242024 to Y. Fan, JQ24039 to W.J.), Beijing Municipal
Public Welfare Development and Reform Pilot Project for Medical
Research Institutes (JYY2023-13 to W.Z.), Youth Innovation Promotion
Association of CAS (2022083 to S.M.), the Informatization Plan of
Chinese Academy of Sciences (CAS-WX2022SDC-XK14 to G.-H.L.),
New Cornerstone Science Foundation through the XPLORER
PRIZE (2021-1045 to G.-H.L.), Excellent Young Talents Program
of Capital Medical University (12300927 to S.W.), The Project for
Technology Development of Beijing-affiliated Medical Research
Institutes (11000023T000002036310 to S.W.), Excellent Young
Talents Training Program for the Construction of Beijing Municipal
University Teacher Team (BPHR202203105 to S.W.), Initiative Scientific
Research Program, Institute of Zoology, Chinese Academy of
Sciences (2023IOZ0102 to S.M.), Scientific Research Key Program of
Beijing Municipal Commission of Education (KZ202110025033 to Y.
Yao), the Fundamental Research Funds for the Central Universities
(number 2023SCU12055 to G.X.), the Beijing Nova Program
(Z201100006820104 to Y. Yang), the China Postdoctoral Science
Foundation (number 2022M712262 to G.X.) and Beijing Anzhen
Hospital Major Science and Technology Innovation Fund (number
KCZD202203 to W.J., KCQY202201 to W.J.).
医学