This review says that tiny proteins made by mitochondria, like humanin, can help keep blood vessels healthy by reducing cell death, inflammation, and oxidative stress, and by supporting the energy factories in cells. They work through well‑known pathways (AMPK, mTOR, sirtuins) that are linked to metabolism and longevity, suggesting they could become future supplements or biomarkers for aging blood vessels, but no concrete dosing or protocols are given yet.

Vascular aging profoundly affects the onset of cardiovascular diseases in the elderly, mostly as a result of mitochondrial dysfunction. This review examines the protective roles of mitochondrial-derived peptides such as humanin, MOTS-c, and small humanin-like peptides in mitigating vascular aging. These peptides, encoded by mitochondrial DNA, are crucial for regulating apoptosis, inflammation, and oxidative stress, which have a major role in vascular health. MDPs have significant prospects as therapeutic and biomarker possibilities for the early diagnosis and intervention of vascular aging. MDPs influence the functions of endothelial and vascular smooth muscle cells by modulating critical signaling pathways, including AMPK, mTOR, and sirtuins. These pathways are essential for facilitating cellular metabolism, enhancing stress resilience, and prolonging longevity. Moreover, MDPs are essential in mitochondrial bioenergetics and dynamics, vital for mitigating endothelial dysfunction and enhancing vascular resilience. Furthermore, MDPs contribute to immunological modulation and the regulation of inflammatory responses, underscoring their potential therapeutic applications in the treatment of age-related vascular disorders. This review analyzes the various functions of MDPs in vascular health and their therapeutic importance, advocating for more studies to optimize their clinical benefits. By understanding the comprehensive roles and mechanisms of these multifunctional peptides, we can better appreciate their capacity to prevent and treat vascular aging and associated cardiovascular disorders. Future research should aim to further elucidate their therapeutic effects and optimize their clinical applications.