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The interplay between mitochondria, epigenetics, and the microbiota is intricately linked to both health and disease. Within our cells, a complex molecular dance occurs, where these components intertwine in a mesmerizing ballet that plays a decisive role in our health. Mitochondria, beyond being energy powerhouses, modulate nuclear gene expression through messengers like reactive oxidative stress (ROS) and calcium. Epigenetics, acting as the molecular conductor, regulates the expression of both nuclear and mitochondrial genes through modifications like DNA methylation. The intestinal microbiota itself produces short-chain fatty acids (SCFAs) that influence mitochondrial activity. SCFA-induced epigenetic modifications, like histone acetylation, impact mitochondrial function which may lead to disease. Mitochondrial dysfunction generates retrograde signals that alter nuclear gene expression, as evidenced by increased histone H3 lysine 27 acetylation (H3K27ac) in genes essential for neuronal differentiation and mitochondrial reprogramming. Alterations in the mitochondrial-nuclear-microbiota axis are associated with diseases including diabetes, neurodegeneration, and cancer. Modulating the intestinal microbiota with probiotics or prebiotics can restore balance while intervening in mitochondrial pathways, which can be a therapeutic strategy. Additionally, using epigenetic agents like histone deacetylase (HDAC) inhibitors can reprogram gene expression and improve mitochondrial function. Finally, the present review aims to explore the central interplay between mitochondria, epigenetics modifications, and microbiota in a complex and dynamic molecular context that plays a fundamental role in human health. Specifically, it will examine the impact of microbiome components and metabolites generated from normobiosis and dysbiosis on mitochondria and epigenetic modifications across different diseases and metabolic conditions. This integrated understanding of the molecular players and their interactions provides a deeper perspective on how to promote health and potentially combat disease. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system (RAS)—a classical blood pressure regulator—largely contributes to healthy organ development and function. Besides, RAS activation promotes age‐related changes and age‐associated diseases, which are attenuated/abolished by RAS‐blockade in several mammalian species. RAS‐blockers also increase rodent lifespan. In previous work, we discussed how RAS‐blockade downregulates mTOR and growth hormone/IGF‐1 signaling, and stimulates AMPK activity (together with klotho, sirtuin, and vitamin D‐receptor upregulation), and proposed that at least some of RAS‐blockade's aging benefits are mediated through regulation of these intermediaries and their signaling to mitochondria. Here, we included RAS‐blockade's impact on other aging regulatory pathways, that is, TGF‐ß, NF‐kB, PI3K, MAPK, PKC, Notch, and Wnt, all of which affect mitochondria. No direct evidence is available on RAS/RAS‐blockade‐aging regulatory pathway–mitochondria interactions. However, existing results allow to conjecture that RAS‐blockers neutralize mitochondrial dysfunction by acting on the discussed pathways. The reviewed evidence led us to propose that the foundation is laid for conducting clinical trials aimed at testing whether angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)—even at subclinical doses—offer the possibility to live longer and in better health. As ACEi and ARB are low cost and well‐tolerated anti‐hypertension therapies in use for over 35 years, investigating their administration to attenuate/prevent aging effects seems simple to implement. [ABSTRACT FROM AUTHOR]