Declining brain energetics has been implicated as the underlying factor for the development of multiple neurodegenerative conditions including Alzheimer’s disease (AD). At the same time, mitochondria are increasingly recognized as signaling organelles that could facilitate adaptation to energetic stress and promote organismal survival and function including energy restitution. Intriguing data generated in multiple model organisms and humans suggest that partial inhibition of mitochondrial function could promote health and increase life span. We developed small molecules that selectively and specifically inhibit the activity of mitochondrial complex I (MCI). New compounds penetrate the blood brain barrier and accumulate in mitochondria. Chronic application of these compounds over prolong period of time significantly increased the survival and health parameters in multiple mouse models of accelerated and chronological aging, AD and Huntington’s Disease (HD). In neurodegenerative models, compounds protected against cognitive dysfunction and neuronal loss even when were administered at symptomatic stage of the disease. Specifically, our compounds reduced inflammation in brain and periphery, markers of oxidative stress, improved physical endurance, motor coordination and cognitive parameters. Application of these compounds blocked neurodegeneration improving dendritic spine morphology, long term potentiation, and glucose uptake and utilization in the brain, which could be detected using translational imaging techniques (FDG-PET and 31P NMR). Next generation RNA sequencing provided additional support for the proposed mechanisms of neuroprotection. Collectively our data suggest modulation of mitochondrial activity, particularly a mild inhibition of MCI, could represent a strategy to enhance health span and delay age-related human diseases including neurodegeneration.