Hypothesis: Caloric restriction mimetics (rapamycin analogs, metformin, spermidine) attenuate age-associated telomere shortening not through direct telomerase activation but by restoring SIRT6-dependent telomeric heterochromatin maintenance via AMPK-driven nuclear NAD+ compartmentalization.

Mechanism: During inflammaging, chronic NF-κB activation upregulates CD38 and PARP1, depleting cytoplasmic and nuclear NAD+ pools. Nuclear NAD+ depletion inactivates SIRT6, which normally deacetylates H3K9 and H3K56 at telomeric repeats, maintaining heterochromatin compaction. Loss of telomeric heterochromatin exposes telomeres to replication stress and DNA damage independent of telomerase activity, accelerating attrition by 50-120 bp/year beyond replicative shortening alone.

CR mimetics activate AMPK, which phosphorylates NMNAT1 (nuclear nicotinamide mononucleotide adenylyltransferase), increasing nuclear NAD+ biosynthesis while simultaneously inhibiting CD38 surface expression via reduced NF-kB signaling. This dual mechanism restores nuclear NAD+ specifically, reactivating SIRT6 telomeric heterochromatin maintenance.

Testable predictions: (1) Telomeric H3K9ac/H3K56ac levels correlate inversely with nuclear NAD+ concentration and positively with telomere attrition rate in human PBMCs stratified by age; (2) SIRT6 ChIP-seq signal at telomeric repeats decreases >40% in inflammaging subjects (CRP >3 mg/L) versus age-matched controls; (3) 12-week metformin treatment in non-diabetic adults aged 60-75 restores telomeric H3K9me3 levels and reduces telomere attrition rate by >30% measured by TeSLA; (4) NMNAT1 knockdown abolishes CR-mimetic telomere protection despite preserved cytoplasmic NAD+ levels, confirming nuclear compartment specificity.

Implications: This reframes telomere shortening in aging as partly an epigenetic maintenance failure driven by inflammaging-induced NAD+ depletion rather than purely replicative, suggesting CR mimetics protect telomeres through chromatin rather than telomerase mechanisms.