The amyloid hypothesis suggests that the progressive accumulation and deposition of central nervous system amyloid with aging is the proximate cause of Alzheimer’s disease (AD). Thus, targeting molecular mechanisms of aging may represent a viable treatment approach. Caloric restriction prevents diseases of aging, including AD, in animal models, perhaps by activation of sirtuins. The sirtuins (such as mammalian SIRT1) are deacetylases that link energy balance (NAD+/NADH) to regulation of gene transcription. Resveratrol is a potent activator of SIRT1, and thus may mimic caloric restriction to prevent diseases of aging. We conducted a randomized, double blind, placebo-controlled, phase II trial of resveratrol for individuals with mild to moderate AD. Resveratrol (1) is detectable in cerebrospinal fluid (at low nanomolar levels), (2) is safe and well tolerated, (3) alters AD biomarker trajectories, (4) preserves blood–brain barrier integrity, and (5) modulates the CNS immune response. Further studies are needed to determine the safety and efficacy of resveratrol and the validity of this approach in the treatment and prevention of AD and other diseases of aging.