Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging

Abstract

Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.

Biomarkers of aging

“…A variety of important molecular signaling pathways change during heart aging, such as oxidative stress and autophagy. In addition, several recent single-cell transcriptome studies provide important references for revealing the molecular mechanisms of cardiac aging (Choudhury et al, 2022;Emechebe et al, 2021;Ma et al, 2021;Zhang et al, 2022g).…”

“…For instance, single-nucleus transcriptomic sequencing of primate ventricles has revealed that the inflammatory factor IL-7 increases during cardiac aging (Ma et al, 2021). Besides, single-nucleus transcriptomic sequencing analysis of primate hearts of different ages has identified forkhead box protein 1 (FOXP1) and forkhead box protein 2 (FOXP2) as key age-downregulated transcriptional regulators whose target genes are associated with various heart diseases (Ma et al, 2021;Zhang et al, 2022g). Consistently, FOXP1-deficient cardiomyocytes derived from human embryonic stem cells exhibit multiple cardiac aging phenotypes, including cellular hypertrophy and senescence (Zhang et al, 2022g).…”

“…Besides, single-nucleus transcriptomic sequencing analysis of primate hearts of different ages has identified forkhead box protein 1 (FOXP1) and forkhead box protein 2 (FOXP2) as key age-downregulated transcriptional regulators whose target genes are associated with various heart diseases (Ma et al, 2021;Zhang et al, 2022g). Consistently, FOXP1-deficient cardiomyocytes derived from human embryonic stem cells exhibit multiple cardiac aging phenotypes, including cellular hypertrophy and senescence (Zhang et al, 2022g). Furthermore, singlecell transcriptome analysis of endothelial cells sorted from mouse hearts at 3 months and 24 months of age has revealed increased expression of spectrin repeat containing nuclear envelope 2 (Syne2) and decreased expression of nestin (Nes) with age (Emechebe et al, 2021).…”

A single-cell transcriptomic atlas of exercise-induced anti-inflammatory and geroprotective effects across the body

“…Since both aging and exercise involve distinct organs, tissues, and cell types, 4 , 6 , 21 , 22 , 23 , 24 a systemic and integrative study across multiple tissues, dissecting the molecular programs in tissue- and cell type-specific manner, is of critical importance. 25 , 26 , 27 , 28 , 29 In the past few years, high-throughput single-cell transcriptomes have been constructed for aging and its interventions, 30 , 31 , 32 such as caloric restriction and heterochronic parabiosis in mammalian species, 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 providing unprecedented resolution of the cellular and molecular changes in aged animals. However, whether and how exercise rewires the transcriptome at the systemic level, especially in aged animals, remains largely unexplored.…”

Single-cell transcriptomic Atlas of mouse cochlear aging

“…Although the structural and cellular anatomy of the cochlea has been rigorously described, a high-resolution and in-depth molecular analysis of this organ that can help us understand how age-related molecular changes cause hearing loss remains outstanding. In broadly related work, single-cell RNA sequencing (scRNA-seq) approaches have identified transcriptional signatures associated with aging and related diseases within multiple organs and heterogeneous tissues ( Angelidis et al, 2019 ; He et al, 2020 ; Ma et al, 2020 ; Tabula Muris, 2020 ; Wang et al, 2020a , 2021a ; Zhang et al, 2020 , 2022 ; Li et al, 2021 ; Zou et al, 2021 ; Cai et al, 2022 ; Leng and Pawelec, 2022 ; Zhou et al, 2022 ). However, scRNA-seq has not yet been applied to systematically map and molecularly profile the structurally and functionally distinct cochlear compartments, or potential age-dependent changes.…”