Abstract：
Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age-related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age-associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5-22.1 years (human equivalent ≈30-88 years). Weighted-gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism-oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid β-oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose-dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix-induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy-related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age-related cardiac diseases, offering novel insights into early age-related mechanisms.
摘要：
年龄是心脏代谢疾病的主要危险因素，经常导致心脏结构和功能的变化。然而,仅由生理衰老引起的心脏重塑和功能障碍的精确分子机制仍然难以捉摸。以前的研究表明与年龄相关的狒狒功能改变，类似于人类。这项研究的目的是确定功能适应之前的早期心脏分子改变，阐明年龄相关变化的调节。从7.5-22.1岁（相当于人类约30-88岁）的雌性狒狒进行左心室样本的无偏转录组学。进行加权基因相关网络和途径富集分析，组织学验证。转录本模块与年龄负相关，涉及代谢-氧化磷酸化下降，三羧酸循环，糖酵解,和脂肪酸β-氧化。转录本与年龄呈正相关，提示代谢向葡萄糖依赖性合成代谢途径转变，包括己糖胺生物合成途径(HBP)。这种转变与糖胺聚糖合成增加有关，修改,通过HBP合成前体，和细胞外基质的积累，组织学验证。上调的细胞外基质诱导的信号与糖胺聚糖积累同时发生，其次是心脏肥大相关途径。总的来说,这些发现揭示了在心脏肥大之前,代谢的转录变化有利于糖胺聚糖通过HBP积累.揭示这种代谢转变为与年龄相关的心脏病提供了潜在的目标，提供对早期年龄相关机制的新见解。
