In the current study, we report that lifelong, voluntary wheel-running with onset at sexual maturity alleviated senescence and inflammaging, including the key drivers of the cytokine cascade and tumor progression (TNF-α, IL-6, and IL-1β), and protected against several different types of cancer (e.g., brain, liver, spleen, and intestinal) in naturally-aged mice. This evidence concerns the gene TNF and neoplasm.