Heterochronic Organ Transplants Prove That Systemic Aging Can Override Local Tissue Age — And Vice Versa

When a young organ is transplanted into an old recipient, it ages faster than predicted. When an old organ is placed in a young recipient, it partially rejuvenates. This is the most direct evidence that aging is substantially a systemic, non-cell-autonomous process driven by the circulatory environment.

Specifically: young hearts transplanted into old recipients show accelerated epigenetic aging (Lehallier et al., 2019). Old kidneys transplanted into young recipients show improved function over time (Remuzzi et al., 2006).

Hypothesis: The systemic milieu (blood composition, innate immune tone, autonomic signaling) accounts for >60% of the rate of tissue aging, with cell-autonomous factors accounting for <40%. Rejuvenating the systemic environment alone — through plasma dilution, senolytic clearance, and inflammation reduction — will rejuvenate most tissues without any tissue-specific intervention.

Prediction: Comprehensive systemic rejuvenation (monthly TPE + quarterly D+Q + daily metformin) in mice starting at 18 months will reduce biological age of ALL measured tissues by >30% within 6 months, demonstrating the dominance of systemic over local aging.