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Ophthalmic acid is a bloodborne metabolite that contributes to age-induced cardiomyocyte hypertrophy
Insights
Acute removal of age-accumulated blood factors reversed cardiac hypertrophy in aged mice. A specific metabolite, ophthalmic acid, was identified as a key driver of this age-related cardiac remodeling.
Area of Science:
- Cardiovascular Biology
- Aging Research
- Metabolomics
Background:
- Cardiac aging is characterized by left ventricular hypertrophy and reduced function.
- Systemic aging theories implicate overabundant plasma proteins in age-related tissue pathology.
- The specific blood factors driving cardiac hypertrophy in aging remain incompletely understood.
Purpose of the Study:
- To investigate the role of blood-derived factors in age-related cardiac hypertrophy.
- To identify specific blood metabolites contributing to cardiac remodeling during aging.
- To explore potential therapeutic targets for cardiac rejuvenation in aging.
Main Methods:
- Neutral blood exchange in aged mice to remove circulating factors.
- Analysis of cardiac hypertrophy and hemodynamic parameters.
- Serum metabolomics profiling to identify age-associated metabolites.
- In vitro studies using cardiomyocytes treated with identified metabolites.
Main Results:
- Acute removal of blood factors via exchange significantly regressed cardiac hypertrophy in aged mice.
- The observed reversal was independent of age-associated hemodynamic changes, suggesting a role for blood factors.
- Ophthalmic acid, a metabolite increasing with age, was identified.
- Ophthalmic acid treatment induced hypertrophy in isolated cardiomyocytes.
Conclusions:
- Age-accumulated blood metabolites, specifically ophthalmic acid, contribute to cardiac hypertrophy.
- This finding challenges the protein-centric view of aging pathology and highlights metabolites.
- Targeting ophthalmic acid may offer novel therapeutic strategies for age-related cardiac dysfunction and rejuvenation.
Abstract:
Cardiac aging involves the development of left ventricular hypertrophy alongside a decline in functional capacity. Here, we use neutral blood exchange to demonstrate that the acute removal of age-accumulated blood factors significantly regresses cardiac hypertrophy in aged mice. The reversal of hypertrophy was not attributed to age-associated hemodynamic effects, implicating a role of blood-derived factors. In addition, the overarching paradigm of systemic aging maintains that the age-related overabundance of plasma proteins are largely responsible for causing pathological phenotypes in tissues. Our results suggest that blood metabolites, not proteins, drive cardiac hypertrophy instead. Upon analyzing serum metabolomics data sets, we identified ophthalmic acid as a circulating metabolite whose levels increase with advanced age. Treatment of adult mouse and neonatal rat cardiomyocytes in culture with ophthalmic acid increased their relative surface areas. This study uncovers a non-protein metabolite that may contribute to cardiomyocyte hypertrophy during aging. Identifying a method to counteract ophthalmic acid's hypertrophic effects may reveal novel therapeutic opportunities for cardiac rejuvenation.
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