A Systems Pharmacology Model of Ageing Identifies Optimal Combination Therapies With Secondary Benefits on Weight Loss and Metabolic Health
Abstract
Background: : Ageing is a systems level biological process underlying the onset and progression of multiple chronic disorders. Rather than arising from a single pathway, age related decline reflects interacting disturbances in metabolic regulation, inflammation, nutrient sensing, cellular stress responses, and tissue repair. Although GLP1 receptor agonists, sodium glucose cotransporter2 inhibitors, metformin, and rapamycin are usually evaluated against disease-specific endpoints.
Objective:: To develop an SBML compliant quantitative systems pharmacology model in which ageing is the primary pharmacological endpoint and to evaluate which combination therapy provides the greatest benefit for both metabolic and ageing related outcomes.
Methods:: We developed model comprising four layers: a metabolic/pharmacodynamic layer describing weight loss, HbA1c reduction, and nausea with tolerance; a drug layer capturing class-specific effects of GLP1 agonists, sodium glucose cotransporter2 inhibitors, metformin, and rapamycin; an ageing layer representing damage accumulation, repair capacity, frailty, and biological age gap; and a biomarker layer generating trajectories and estimated glucose disposal rate. Calibration was staged across semaglutide clinical endpoints. Bayesian hierarchical meta analysis, global sensitivity analysis, and practical identifiability analysis were used to assess robustness and interpretability.
Results:: The model reproduced semaglutide efficacy and…
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