Mitochondria, a powerplant of the cell, have developed an elaborate communication network within the cell communication with the nucleus and other subcellular organelles using a broad array of signaling molecules, including the components of the TCA cycle, reactive oxygen species, and other messenger molecules.  This mitocellular communication ensures an orchestrated response to everchanging energy demands and energetic stress, ultimately preserving cell survival. Using small molecules mild mitochondrial complex I inhibitors, we demonstrated that activation of mitocellular communication promotes health and lifespan in chronologically aged wild-type mice and in wild-type mice fed with a high fat diet, a model of accelerated aging. Efficacy of this approach was demonstrated based on increased survival, improved energy homeostasis in brain and periphery, reduced oxidative stress,  multiple behavior and cognitive tests, and biochemistry and systems biology approaches. These methods allowed to identify key mechanisms essential for health- and life-extending  therapeutics. Most importantly, such an approach results in the activation of multiple neuroprotective mechanisms mimicking a polypharmacy approach that is necessary to treat complex human conditions. Consistent with the hypothesis that improved aging will result in a delay of the onset of age-related neurodegenerative diseases, we demonstrated that treatment with mitochondria-targeted molecules blocked the ongoing neurodegeneration and cognitive dysfunction in multiple mouse models of Alzheimer’s Disease. Taken together, our data suggest that activation of mitocellular communication could be achieved with mild mitochondrial complex I inhibitors. This approach could be beneficial to promote health and longevity restoring mitochondria function and energy balance in brain and periphery [1-3].