Akap1 deficiency accelerates cardiovascular aging via microbiota–gut–heart axis dysregulation and metabolic reprogramming of sphingosine-1-phosphate and phenylacetylglycine
R Paolillo, L Coretti, P Polese, M Carotenuto, M P Mollica, M Caterino, A Lama, G Trinchese, D Ioele, G Aviello, M Ruoppolo, F Lembo, G Esposito, C PerrinoAbstract
Background
Mitochondrial dysfunction, chronic inflammation, and gut barrier abnormalities are key regulators of cardiovascular aging and heart failure progression. To investigate the interplay between genetic predisposition, gut microbiota, and age-related cardiac dysfunction, we used young and old mice with global heterozygous genetic deletion of the Akap1 gene (Akap1+/-), encoding mitochondrial A-kinase anchoring protein 1, and their wild-type littermates (Akap1+/+).
Methods
Young (4–6 months) and old (18–24 months) Akap1⁺/⁺ and Akap1⁺/⁻ mice were assessed for cardiac function via transthoracic echocardiography. Gut barrier integrity was evaluated through expression analysis of junctional proteins occludin (Ocln) and zonulin (Tjp1), FITC-dextran permeability assay, and histological assessment by hematoxylin and eosin staining. Systemic inflammation was quantified by serum levels of tumor necrosis factor-α (TNF-α), lipopolysaccharide (LPS), interleukin-1 (IL-1), and interleukin-10 (IL-10). Fecal microbiota transplantation (FMT) was performed to explore the causal role of gut microbiota in modulating cardiac and intestinal phenotypes. Stool metataxonomic profiling and serum metabolomics were conducted before and after FMT to identify key microbial taxa and metabolites involved in gut–cardiac crosstalk.
Results
Akap1 heterozygous deletion impaired cardiac function and increased intestinal permeability and systemic inflammation. Distinct bacterial metacommunities were observed in both young and old Akap1+/− mice, with more pronounced microbiota alterations in aged Akap1+/− mice compared to Akap1+/+ controls. Reciprocal FMT between Akap1+/− and Akap1+/+ mice significantly modulated gut barrier permeability, inflammatory markers, and cardiac dysfunction, supporting a functional microbiota-dependent effect (Figure 1). Metabolomic analysis identified sphingosine-1-phosphate (S1P) and phenylacetylglycine (PAG) as key mediators of gut–heart crosstalk, with circulating levels significantly influenced by both genotype and age (Figure 2).
Conclusions
Akap1-encoded proteins are critical regulators of gut–heart axis homeostasis during aging, contributing to preservation of intestinal barrier integrity, balanced microbiota composition, and cardiac performance. Targeting the gut microbiota and its associated metabolites may represent a promising therapeutic strategy to attenuate inflammaging and prevent age-related cardiac dysfunction.