Aging drives a progressive decline in cognitive function that renders the brain susceptible to devastating neurological disorders, including Alzheimer disease. Aging is the strongest risk factor for the development of Alzheimer disease, a neurodegenerative disease with no effective treatment that culminates in synaptic dysfunction, neuronal death, and impaired memory and other cognitive functions. By 2050, the number of elderly individuals older than 80 years is projected to triple globally, many of whom will have cognitive impairment, Alzheimer disease, or 1 of several other neurodegenerative diseases for which age increases risk. As the number of aged individuals increases dramatically in the next several decades, widespread social and economic consequences of these and other aging disorders will be felt on an unprecedented scale. One strategy to meet this growing public health threat is to elucidate the mechanisms that underlie cognitive decline to inform therapeutic strategies aimed at ameliorating age-associated disease. As the brain ages, various cell types exhibit hallmark changes, including increased astrogliosis and microgliosis, alterations in the blood-brain barrier, decreased generation of new neurons in specialized areas, and decreased synaptic function, all of which may contribute to impaired cognitive function. The hippocampus in the temporal medial lobe is a region particularly sensitive to the ravages of aging.1 Cellular changes in this structure manifest as striking impairments in cognitive tasks ascribed to normal hippocampal function, including spatial and episodic learning and memory function. The brain is not unique in its predisposition to age-associated functional decline. Muscle, liver, pancreas, heart, and other organ systems also exhibit declines in function with age, leading to conditions associated with frailty and loss of independence, including sarcopenia, age-associated diabetes mellitus, and cardiac hypertrophy or failure. While many cell-autonomous and tissue-intrinsic mediators of aging have been proposed, recent data support the emerging concept that there is much to learn from potential overlap in the aging process across diverse tissue types. Indeed, a key hallmark shared among age-sensitive organs is a dramatic decline in regenerative potential in specific cell populations. A seminal study2 published 1 decade ago discovered that the loss of proliferative capacity for aged satellite cells and hepatocytes is not immutable; the exposure of aged tissue to young blood restores latent regenerative capacity, which rejuvenates the muscle and liver. Given the close contact made between the vasculature and a vulnerable brain region, such as the hippocampus, it was hypothesized that the systemic environment could influence or drive how the brain ages. We and others3- 6 provided evidence that age-related changes in the blood regulate brain function, raising the possibility that central nervous system (CNS) function can be shaped throughout aging by the combined influence of peripheral organ systems via circulatory factors or changes at the interface of communication between these compartments (Figure 1).