Hormones and nitric oxide (NO), a free radical, are ancestral molecules, conserved through evolution, that modulate many aspects of the physiology and pathophysiology of living organisms by regulating transcription of genes involved in development, metabolism, and differentiation. Of interest, both estrogen and NO signaling, specifically through the estrogen receptor-alpha (ERalpha) and the endothelial isoform of the nitric oxide synthase (eNOS), have been shown to counteract endothelial senescence through a shared downstream effector, the catalytic subunit of human telomerase (hTERT), a key molecule in the aging process. Since aging is the first and most relevant risk factor in cardiovascular diseases, it is tempting to speculate that hTERT may be at the cross point between the NO and estrogen pathways. The present review will focus on the evolutionary and molecular aspects linking eNOS, ERs, and hTERT in counteracting the process of endothelial cell aging.