Senescence is characterized by the decline in the ability to cope with stress. Hormesis regulation of opposing biological effects of low and high dosages, can determine longevity, and disease vulnerability at appropriate doses. Regulation of age-related changes in micro RNA opens new areas of therapeutic targets. Micro RNA downregulates stress response pathways with age establishing vulnerability to multiple age related disease which, if targeted could theoretically delay senescence. Mitochondrial targeted drugs have intervened in seemingly otherwise unrelated pathologies like neurological diseases, Alzheimer’s disease, infections, diabetes, acute ischemic shock, and wound healing; an example of a common magic bullet for intervention in mitochondrial dysfunction pathologies of oxidative stress. The telomerase subunit, TERT, the promiscuous reverse transcriptase, exhibits hormetic activity, benefit at low levels, dysfunctional at high levels, and is required for signally survival. The appropriate targeted telomerase therapy is key for optimal desired drug therapy for inhibition in cancer and HIV infected therapy and enhanced in bystander cells for oxidative stress tolerance. Comparative biology studies reveal the role of Neuregulin and Nrf2, as key players in the puzzle of the long lived disease free mole rat despite high levels of oxidative stress. A hibernation stress response cold shock peptide restores synaptic plasticity, and is beneficial in neurodegeneration. Muscles and gut are not only responsible for their respective roles in locomotion and digestion but also regulate systemic responses in the body. New insights into the roles of muscles and gut change how drugs affect multiple organs and impact the route of administration. While oxidative stress can either signal metabolic benefits, death or be neutralized by a wheelhouse of antioxidant pathways, recent technological advances and conceptual shifts, allow regulation of opposing consequences by appropriate targeting of drugs to achieve protective effects in multiple age related diseases.