Background <p>Mitochondrial Derived Peptides (MDPs) are a novel class of bioactive molecules encoded within short open reading frames (sORFs) of mitochondrial DNA, overturning the traditional view of the mitochondrial genome as solely dedicated to energy metabolism.</p> Objective <p>To review current knowledge of key MDPs, including humanin, MOTS-c, and SHLPs, with emphasis on their molecular mechanisms, interactions with aging pathways, roles in age-related diseases, and therapeutic potential.</p> Methods <p>This review synthesizes recent literature on the biology, signaling pathways, and clinical relevance of MDPs, while addressing emerging technologies for their discovery and controversies in their biosynthesis.</p> Results <p>MDPs function as regulators of cellular stress resistance, metabolism, inflammation, and survival. They interact with canonical aging pathways such as AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and sirtuins, and modulate hallmarks of aging including mitochondrial dysfunction, proteostasis, and cellular senescence. Endocrine-like actions of MDPs contribute to protection against age-related diseases such as Alzheimer’s disease, cardiovascular disease, and metabolic syndrome. Synthetic analogs, gene therapy approaches, and biomarker applications are advancing their therapeutic exploration.</p> Conclusions <p>MDPs provide a mitochondria-centered paradigm for understanding aging and age-related diseases. Despite ongoing controversies regarding their biosynthesis and translational relevance, MDPs represent promising targets in geroscience and therapeutic development.</p> Graphical Abstract <p></p>