Hypothesis

Aging triggers the release of specific mitochondrial-derived peptides (MDPs) that act as circulating signaling molecules, directly modifying cysteine residues on hub proteins within the mTOR interactome and thereby driving coordinated PPI network remodeling across tissues.

Mechanistic Basis

1. Mitochondrial stress and altered mitophagy with age increase the cytosolic availability of MDPs such as humanin and MOTS-c, which have been shown to circulate in blood and influence inflammation and metabolism (4).
2. These peptides contain reactive thiol‑reactive motifs that can form disulfide bonds or S‑nitrosylate cysteine residues on target proteins, a post‑translational modification known to alter protein‑protein interaction affinities without changing overall expression levels.
3. Hub proteins in the mTOR interactome (e.g., FRAP1, Raptor, mLST8) are enriched in surface-exposed cysteines that regulate their conformational state and binding partners; age‑dependent oxidative shifts favor formation of inhibitory disulfide linkages, reducing hub connectivity and rewiring downstream signaling.
4. Because MDPs are released systemically, they produce a synchronized wave of cysteine modification across organs, matching the observed organism‑wide shifts in cell type proportions and chromatin accessibility (5).

Testable Predictions

• Prediction 1: Plasma concentrations of specific MDPs (e.g., humanin) will correlate positively with the degree of cysteine oxidation on mTOR hub proteins in multiple tissues of aged mice, and this correlation will be absent in young animals.
• Prediction 2: Administration of a cell‑impermeable scavenger that blocks extracellular MDPs (such as a monoclonal antibody against humanin) will attenuate age‑dependent cysteine modifications on mTOR interactors and preserve PPI network density, as measured by quantitative affinity‑purification mass spectrometry.
• Prediction 3: Genetic overexpression of mitochondrial proteases that degrade MDPs (e.g., overexpression of OMA1) will extend lifespan and reduce tissue‑specific PPI remodeling, whereas loss‑of‑function of these proteases will accelerate interactome decay.
• Prediction 4: Introducing cysteine‑to‑serine mutations at predicted modification sites on FRAP1 will rescue age‑related interaction loss in a knock‑in mouse model, without altering FRAP1 expression levels.

Falsifiability

If plasma MDP levels do not correlate with hub cysteine oxidation, or if scavenging extracellular MDPs fails to alter PPI network architecture in aged tissues, the hypothesis would be refuted. Similarly, if mutating cysteines on FRAP1 does not restore interaction patterns despite normal MDP levels, the proposed mechanism would be insufficient.

Broader Implications

This hypothesis integrates mitochondrial signaling, redox biology, and network biology to explain how a single class of circulating factors could drive the synchronized interactome remodeling highlighted by recent organism‑wide atlases. It suggests that targeting extracellular MDPs—or the cysteine chemistry they provoke—could serve as a systemic strategy to delay age‑associated network decay and extend healthspan.