Healthy aging requires maintenance of homeostatic control of the physiological systems and functions that are integrated by the hypothalamus. Driven by work in previous EU projects (Crescendo/Lifespan) highlighting insulin signalling and the hypothalamic/pituitary/adrenal and thyroid axes in the regulation of aging, SWITCHBOX will examine the flexibility of these neuroendocrine systems in response to environmental challenges in three established human cohorts with variable aging potential. These human cohorts include offspring of exceptionally long-lived siblings and their partners (controls), people with good vs bad cognitive performance or with high vs low cognitive engagement. Maintaining brain function is emphasised as it reflects an individual’s overall well-being, a major goal in aging research, and because age-related brain disorders represent a major socioeconomic burden. To determine the genetic and cellular underpinnings of the findings in humans, hypothesis-based studies in rodents sharing phenotypes with the human cohorts will be carried out. To clarify the role of the brain in the differential regulation of endocrine axes critical for healthy aging, SWITCHBOX will examine the neuroendocrine and metabolic effects of intranasal (humans) and intra-cerebroventricular (rodents) administration of peptides involved in controlling metabolic homeostasis (e.g. insulin, α-MSH). State-of-the-art technology will be used to measure circadian endocrine and metabolic profiles, brain structure and function (fMRI) and cognitive performance, as well as cellular and molecular features. All data will be entered into an already operational ‘open access’ database. The work aims to take key findings from basic research and translate them into clinically relevant concepts. It will benefit from combining expertise of gerontologists, endocrinologists, molecular and cellular neuroscientists and neuropsychologists. SWITCHBOX ultimately aims to develop conceptually new approaches for the prevention and treatment of age-related disorders.