Key result
Multi-omic analysis identifies 37 cardiac aging genes, highlighting SMPX as the top rejuvenation target.
Why the study?
Endurance training counteracts cardiac aging decline, but the molecular mechanisms driving exercise-induced cardiac rejuvenation remain inadequately elucidated.
This network analysis identifies novel molecular targets, particularly SMPX, that may mediate the cardioprotective and anti-aging benefits of endurance training, offering potential avenues for exercise-mimetic therapies.
SMPX nomination as top effector is hypothesis-generating; leaves open therapeutic validation before any clinical consideration.
BACKGROUND/OBJECTIVES: Cardiac aging involves the progressive structural and functional decline of the myocardium. Endurance training is a well-recognized non-pharmacological intervention that counteracts this decline, yet the molecular mechanisms driving exercise-induced cardiac rejuvenation remain inadequately elucidated. This study aimed to identify key effector genes and regulatory pathways by integrating human cardiac aging transcriptomic data with multi-omic exercise response datasets. METHODS: = 634) from the MoTrPAC mouse dataset. Thirty-seven overlapping genes were identified and subjected to Enrichr for pathway enrichment, KEA3 for kinase analysis, and ChEA3 for transcription factor prediction. Candidate effector genes were ranked using ToppGene and ToppNet, with integrated prioritization via the FLAMES linear scoring algorithm. RESULTS: Pathway enrichment revealed complementary patterns: aging-associated genes were enriched in mitochondrial dysfunction and sarcomere disassembly, while exercise-responsive genes were linked to protein synthesis and lipid metabolism. TTN, PDK family kinases, and EGFR emerged as major upstream regulators. NKX2-5, MYOG, and YBX3 were identified as shared transcription factors. SMPX ranked highest in integrated scoring, showing both functional relevance and network centrality, implying a pivotal role in mechano-metabolic coupling and cardiac stress adaptation. CONCLUSIONS: By integrating cardiac aging and exercise-responsive transcriptomes, 37 effector genes were identified as molecular bridges between aging decline and exercise-induced rejuvenation. Aging involved mitochondrial and sarcomeric deterioration, while exercise promoted metabolic and structural remodeling. SMPX ranked highest for its roles in mechano-metabolic coupling and redox balance, with X-inactivation escape suggesting sex-specific relevance. Other top genes (e.g., KLHL31, MYPN, RYR2) form a regulatory network supporting exercise-mediated cardiac protection, offering targets for future validation and therapy.
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Wang et al. (2025) studied Cardiac aging. Endurance training vs. Sedentary control / Young healthy control was evaluated on Prioritization of effector genes linking cardiac aging and exercise-induced rejuvenation. Integrated multi-omic analysis identified 37 effector genes bridging cardiac aging decline and exercise-induced rejuvenation, with SMPX ranking highest as the most promising gene target.
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