Daily 6mg spermidine supplementation for 13 weeks reversed cellular aging markers in immune cells and significantly enhanced COVID vaccine responses in older adults who initially failed to respond. The compound specifically targeted non-responders showing elevated p16 senescence markers, mTOR signaling, and DNA damage in lymphocytes, restoring spike-specific antibody production and memory B cell function through enhanced autophagy pathways. This represents a potential breakthrough in addressing vaccine failure among aging populations. The mechanistic precision is striking—spermidine activated TFEB autophagy targets specifically in B cells, suggesting direct cellular rejuvenation rather than general immune stimulation. While the 40-person pilot study requires larger validation, the results challenge the assumption that immune aging is irreversible. The identification of p16 and DNA damage markers as predictors of vaccine failure could enable personalized vaccination strategies. Most significantly, this suggests that targeting fundamental aging processes like autophagy decline may restore immune function rather than merely compensating for it, opening new therapeutic avenues for age-related immune dysfunction beyond vaccines.