A recent study published in Aging Cell has uncovered a protein that exacerbates age-related heart disease, particularly in older male mice. This protein, known as Hevin, appears to worsen cardiac dysfunction by enhancing the activity of inflammatory macrophages. The research highlights the importance of age-related changes in heart disease and offers potential avenues for therapeutic intervention.

Inflammaging Contributes to Heart Disease

The study begins with a discussion on inflammaging, a term that refers to the chronic, low-grade inflammation that often accompanies aging. Inflammaging is closely linked to various progressive cardiovascular issues that lead to a gradual loss of heart function [1], [2]. Interestingly, previous research has indicated that reducing inflammatory cytokines can lead to improved cardiac outcomes in animal models [3]. Thus, targeting the mechanisms of inflammaging has emerged as an important goal in biotechnology aimed at prolonging lifespan and preventing related heart diseases.

The role of macrophages is crucial in this context. Two types of macrophages exist: the pro-inflammatory M1-polarized macrophages, which efficiently kill pathogens yet cause tissue damage, and the M2-polarized macrophages, which promote tissue repair. The aging process tends to shift macrophage behavior from M2 to M1 [4], with one of the key culprits being CCL5, a ligand known to inhibit M2 polarization [5].

Hevin is Hell for Older Animals

Hevin is found within the extracellular matrix and has diverse roles in various diseases. While it has been shown to possess anti-cancer properties by recruiting macrophages [6], this recruitment primarily involves M1 macrophages, potentially exacerbating conditions like pneumonia [7] and non-alcoholic fatty liver disease [8].

Notably, Hevin levels in plasma are known to rise with age, especially in individuals over 60 [9]. Consistent with its identification as a biomarker for heart failure [10], the study revealed that increased Hevin correlates with a reduction in ejection fraction in older mice. When introduced to 20-month-old mice, Hevin did not significantly alter blood pressure or heart rate, but it did promote cellular senescence, reduce telomere length in cardiac tissues, and increase both macrophage infiltration and inflammatory cytokines, ultimately leading to fibrosis and hypertrophy. Intriguingly, these detrimental effects were not observed in younger (8-month-old) mice.

The researchers employed an adeno-associated virus (AAV) technique to reduce Hevin levels. While this approach yielded no notable changes in younger animals, it significantly improved various age-related ailments in the older mouse cohort. Specifically, biomarkers associated with senescence were reduced, telomeres were lengthened, and both hypertrophy and fibrosis saw marked decreases.

Inflammation Plays a Key Role

The study further elucidated that the adverse effects linked to Hevin were primarily due to its influence on CCL5. Hevin significantly promotes CCL5 expression, which in turn encourages M1 macrophage polarization in cardiac tissues. Treatment of older mice with an anti-CCL5 antibody mitigated the inflammatory effects induced by Hevin and partially reversed hypertrophy and fibrosis. Moreover, blocking the toll-like receptor 4 (TLR4) and its downstream p65 pathway exhibited similar protective effects.

Limitations and Future Directions

Despite its findings, the study noted several limitations. For instance, it primarily utilized male mice, raising questions about Hevin's role in females. Additionally, the lack of observed effects in younger animals necessitates further investigation into the underlying mechanisms. The researchers highlighted the relationship between Hevin and adipose tissue, proposing that reducing body fat through interventions such as semaglutide might combat the age-related rise of Hevin; however, this remains an area requiring more research.

Interestingly, while Hevin has detrimental effects within the context of cardiovascular disease, its roles in other biological processes may warrant a nuanced approach in potential therapeutic targeting.

Conclusion

The implications of this study extend to both fundamental biology and the practical management of age-related heart diseases. Understanding the dual nature of proteins like Hevin may lead to innovative treatments that address the underlying inflammation while promoting positive health outcomes in aging populations.

Literature Cited

Reference Number Bibliographic Citation
[1] Liberale, L., et al. (2022). Inflammation, aging, and cardiovascular disease: JACC review topic of the week. Journal of the American College of Cardiology, 79(8), 837-847.
[2] Liberale, L., et al. (2020). Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. European Heart Journal, 41(31), 2974-2982.
[3] Hu, C., et al. (2022). Fibronectin type III domain-containing 5 improves aging-related cardiac dysfunction in mice. Aging Cell, 21(3), e13556.
[4] Becker, L., et al. (2018). Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut, 67(5), 827-836.
[5] Li, M., et al. (2020). CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization. Cellular & Molecular Immunology, 17(7), 753-764.
[6] Zhao, S. J., et al. (2018). SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/β-catenin signaling. Oncogene, 37(8), 1049-1061.
[7] Zhao, G., et al. (2024). Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation. Nature Communications, 15(1), 4235.
[8] Liu, B., et al. (2021). Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2. The Journal of Clinical Investigation, 131(20).
[9] Lehallier, B., et al. (2019). Undulating changes in human plasma proteome profiles across the lifespan. Nature Medicine, 25(12), 1843-1850.
[10] Di Salvo, T. G., et al. (2015). Right ventricular myocardial biomarkers in human heart failure. Journal of Cardiac Failure, 21(5), 398-411.

About the Author

Josh Conway

Josh has been writing and editing for Lifespan articles over the past decade and is responsible for the continued production of daily news content. He has a programming background and is a long-time supporter of anti-aging medicine.

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