Background: Patients with systemic lupus erythematosus (SLE) exhibit accelerated biological aging as measured by epigenetic clocks (Horvath, GrimAge), partly driven by accumulation of senescent CD8+CD28− T cells that secrete pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ). These senescent T cells show profoundly impaired autophagy due to cytoplasmic sequestration of TFEB (transcription factor EB), the master regulator of lysosomal biogenesis.

Hypothesis: Treatment with caloric restriction mimetics (specifically spermidine or rapamycin at sub-immunosuppressive doses) will selectively restore TFEB nuclear translocation in senescent CD8+CD28− T cells, reactivating autophagy-mediated clearance of damaged mitochondria and cytoplasmic DNA. This will reduce cGAS-STING-dependent type I interferon production from these cells, thereby attenuating the SASP-IFN feed-forward loop that drives both lupus flares and epigenetic age acceleration.

Testable predictions: (1) Ex vivo treatment of SLE patient PBMCs with spermidine (10μM, 72h) will increase TFEB nuclear localization in CD8+CD28− cells by >50% vs vehicle, measurable by imaging flow cytometry. (2) This will correlate with reduced mitochondrial ROS (MitoSOX) and cytoplasmic dsDNA (PicoGreen) in the same population. (3) Conditioned media from treated senescent T cells will show reduced capacity to accelerate DNAm age in fibroblast reporter assays (Horvath clock). (4) In a longitudinal pilot (n=20 SLE patients, 12 weeks oral spermidine 1mg/kg/day), GrimAge acceleration will decrease by ≥1.5 years vs baseline, with concurrent reduction in SLEDAI-2K scores.

Significance: This links three previously siloed fields — caloric restriction mimetics, T cell immunosenescence, and epigenetic aging — in a disease where accelerated aging is clinically meaningful but mechanistically underexplored. If confirmed, it provides a non-immunosuppressive adjunctive strategy for SLE that targets the aging-autoimmune axis directly.