Brain renin-angiotensin system in the nexus of hypertension and aging.

Aging is associated with an imbalance in sympathetic and parasympathetic outflow to cardiovascular effector organs. This autonomic imbalance contributes to the decline in cardiovagal baroreceptor reflex function during aging, which allows for unrestrained activation of the sympathetic nervous system to negatively impact resting systolic blood pressure and its variability. Further, impaired baroreflex function can contribute to the development of insulin resistance and other features of the metabolic syndrome during aging through overlap in autonomic neural pathways that regulate both cardiovascular and metabolic functions. Increasing evidence supports a widespread influence of the renin-angiotensin system (RAS) on both sympathetic and parasympathetic activity through receptors distributed to peripheral and central sites of action. Indeed, therapeutic interventions to block the RAS are well established for the treatment of hypertension in elderly patients, and reduce the incidence of new-onset diabetes in clinical trials. Further, RAS blockade increases lifespan and improves numerous age-related pathologies in rodents, often independent of blood pressure. The beneficial effects of these interventions are at least in part attributed to suppression of angiotensin II formed locally within the brain. In particular, recent insights from transgenic rodents provide evidence that long-term alteration in the brain RAS modulates the balance between angiotensin II and angiotensin-(1-7), and related intracellular signaling pathways, to influence cardiovascular and metabolic function in the context of hypertension and aging.