Aging is characterized by a progressive increase in proinflammatory status. This state, known as inflammaging, has been associated with cognitive decline in normal and pathological aging. However, this relationship has been inconsistently reported, likely because it is conditioned by other factors also affected by the aging process. Sleep and adiposity are two factors in particular that show significant alterations with aging and have been related to both cognitive decline and inflammaging. Given the consequences this state also has for brain integrity and cognition, we discuss here evidence supporting the potential mediating role of chronic low-grade systemic inflammation in the complex relationship between impaired sleep, dysfunctional adiposity, and cognitive decline through the common pathway of neuroinflammation. This review proposes a multi-factor model of aging-related cognitive decline that highlights the reciprocal interactions between sleep, the circadian system, and inflammation on the one hand, and between sleep, adiposity, and hormone resistance on the other. The model identifies sleep and adiposity as modifiable lifestyle factors that can be targeted to maximize cognitive function and quality of life in the elderly.