From egg to exit, human life history is determined by environmental interactions with our genome (GxE). The Gero-Exposome provides a framework for analyzing GxE interactions with life style, biomes, and systemic factors. Lifespans difference of 15 years across the socio-economic status (SES) have corresponding differences in the onset of cardiovascular disease and dementia. Moreover, SES influences the development of brain and vasculature, by greater gestational exposure to air pollution and cigarette smoke in low SES. Multiple postnatal phases have environmental influences throughout the lifespan. As an experimental model for these complexities, mice were gestationally exposed to air pollution. Young adults had more body fat and glucose intolerance, while brains had lower levels of hypothalamic neuropeptides and neuronal stem cells in the hippocampus. These findings are relevant to the multi-generational stability of SES differences in health and lifespan, for which the GxE basis is undefined.