Women live longer than men in virtually all circumstances. However, a more common pattern among animals is that one sex lives longer under some conditions, the other lives longer under other conditions. In laboratory mice, interventions that extend longevity are surprisingly often sex-specific in their effects. Understanding these conditional sex differences could provide mechanistic insight into how longevity could be modulated in humans. One way that longevity can be consistently enhanced is by inhibiting reproduction or eliminating the capacity to reproduce. Thus, there appears to be a mechanistic link between gonadal activity and longevity. There also appears to be a mechanistic link between some types of neuroendocrine signaling and longevity. Combining these two observations suggest that communication between the brain and gonad is a ripe avenue for further exploring longevity-assurance mechanisms. Also, because the timing and activity of specific brain–gonad endocrine differs between the sexes, neuroendocrine linkages between the brain and gonad, particularly among the less obvious hormones such as activin and inhibin, could provide additional insight into mechanisms of sex differences in aging.