Background: Senescent cells with critically short telomeres activate persistent DDR signaling through ATM/ATR-p53 axes. NK cell-mediated immunosurveillance is the primary mechanism for clearing senescent cells in vivo, yet clearance efficiency declines with age despite maintained NKG2D ligand expression on senescent targets.

Hypothesis: Telomere dysfunction-induced p53 activation represses PGC-1α transcription in senescent cells, collapsing mitochondrial oxidative phosphorylation and shifting metabolism toward aerobic glycolysis. This metabolic shift reduces surface calreticulin exposure — an eat-me signal dependent on ER-mitochondria calcium transfer via IP3R-VDAC1 tethering — while simultaneously increasing lactate secretion. Peri-senescent lactate accumulation (>10-15 mM) suppresses NK cell cytotoxicity by inhibiting NFAT-dependent perforin/granzyme transcription. This creates a bioenergetic threshold: senescent cells with mitochondrial membrane potential ΔΨm < 80 mV become resistant to NK clearance, accumulate preferentially, and drive inflammaging.

Testable Predictions: (1) p53-null senescent cells (irradiation-induced with p53 knockdown) will maintain PGC-1α, higher ΔΨm, surface calreticulin, and greater NK killing in co-culture. (2) PGC-1α agonists (bezafibrate, ZLN005) in wild-type senescent cells will restore calreticulin and NK susceptibility. (3) MCT1/4 lactate transporter inhibition (AZD3965) will rescue NK cytotoxicity in the senescent microenvironment. (4) In aged mice, ZLN005 + AZD3965 will reduce senescent cell burden comparably to dasatinib+quercetin but via immune-mediated clearance with superior selectivity.

Significance: This reframes senescent cell accumulation as immune evasion driven by telomere-mitochondria crosstalk rather than simple immune decline, suggesting that restoring senescent cell bioenergetics may outperform direct senolytics.