Frontiers in Pharmacology · Nov 5, 2026
Beyond Age Per Se: The Senescence-Associated Secretory Phenotype as a Hidden Modifier of Drug Metabolism in Older Adults With Polypharmacy
By Wei CHENG, Juan CUI, Xiangdong WANG et al.
Older adults with polypharmacy bear a disproportionate share of adverse drug reactions (ADRs), yet much of the inter-individual variation in clearance at the same age remains unexplained. Acute inflammation down-regulates hepatic cytochrome P450 (CYP) enzymes and drug transporters through cytokine signalling, but this evidence comes almost entirely from acute infection, critical illness, cancer or short-term in vitro models, not the chronic low-grade inflammation of old age. Here we make explicitly testable a single hypothesis: that the senescence-associated secretory phenotype (SASP), the chronic, low-grade, sterile inflammatory milieu released by senescent cells, selectively suppresses hepatic and intestinal CYP enzymes and drug transporters through the IL-6, IL-1β, TNF-α and IFN-γ factor spectrum converging on JAK/STAT3 and NF-κB signalling, and so is a hidden, measurable and modifiable source of pharmacokinetic variability and ADR risk not captured by chronological age. The prediction is distributional rather than uniform: population-average suppression is small in an unselected cohort (≈5–7%) but rises to ≈10–15% in the SASP-enriched tail, where a sizeable minority of low-EC50 individuals cross the clinical threshold. As a single factor the SASP would then account for only about 0.3–4.5% of total CYP3A variance on average (about 10% in that tail), not the full 30–40-fold spread, and the panel is designed to identify that subgroup. Because the frailty and comorbidity that elevate the SASP could independently lower clearance, we do not assume mediation and give the competing "marker" hypothesis equal status. Four independently testable sub-hypotheses cover association, mechanism and isoform selectivity, chronic-state uniqueness and reversibility. The contribution is a layered phenotyping panel: its clinical tier (circulating markers plus a low-dose CYP/transporter cocktail) tests whether an inflammation–clearance association exists, while the translational and rescue tiers (tissue p16/p21, longitudinal and intervention data) separate mediator from marker. A preclinical three-dimensional EC50 go/no-go gate precedes it: the only published chronic 3D value (463 pg/mL) is in the no-go band, so the 2D Dickmann values are an upper-bound sensitivity case. If supported, it reframes elderly ADR risk from age and drug count to quantifiable biological burden, opening a route to mechanism-based prescribing and a defined experiment set to test it.