Physical-psychological-cognitive multimorbidity (PPC-MM) is a critical challenge in aging. The distinct and combined roles of physiological dysregulation (allostatic load, AL) and psychological state (subjective well-being, SWB) in driving PPC-MM transitions remain unclear. This study investigates how AL and SWB independently and jointly influence multimorbidity progression across three national cohorts.

We harmonized data from the Health and Retirement Study (US), English Longitudinal Study of Aging (UK), and China Health and Retirement Longitudinal Study (CHARLS), comprising 5629 adults aged ≥45 free of baseline PPC-MM. AL was derived from cumulative biomarkers; SWB was standardized across cohorts. Multi-state survival models estimated hazard ratios (HRs) for transitions to physical-psychological (P1P2), physical-cognitive (P1C), psychological-cognitive (P2C), and triple (P1P2C) multimorbidity.

High AL increased overall PPC-MM risk (HR = 1.66, 95% CI: 1.16–2.38), specifically driving transitions involving cognitive decline (None→P1C: HR = 1.48). Conversely, low SWB acted as a broad risk factor, strongly predicting physical-psychological onset (None→P1P2: HR = 2.14). Notably, the combination of high AL and low SWB tripled the risk of developing complex multimorbidity (None→P1P2C: HR = 3.23). Meta-analysis confirmed high consistency across cohorts.

Low SWB functions as a generalized driver of multimorbidity, whereas high AL specifically accelerates cognitive pathways. Their combined presence creates a high-risk profile for complex multimorbidity. Effective prevention requires integrating physiological management with psychological support to mitigate these distinct but compounding pathways.