Safety and Efficacy of Mesenchymal Stem Cell Therapy in Aging Frailty: A Systematic Review.

Aging frailty is a multifactorial geriatric syndrome characterized by reduced physiological reserve across multiple interrelated systems, leading to increased vulnerability to adverse health outcomes. Mesenchymal stem cells (MSCs) have emerged as a potential therapeutic intervention due to their immunomodulatory and regenerative properties. This systematic review aimed to evaluate the available clinical evidence regarding the safety and efficacy of MSC administration in individuals with aging frailty. A systematic literature search was conducted in PubMed, Scopus, and the Cochrane Library from database inception to 15 April 2026. Only randomized controlled trials (RCTs) were eligible. Data were extracted according to study design, participants' characteristics, MSC source and dosing, safety outcomes, functional performance measures, quality of life (QoL) indices, and inflammatory, immune, and vascular biomarkers. Three RCTs met the inclusion criteria, comprising a total of approximately 208 participants. MSC administration was well-tolerated, with no treatment-related serious adverse events reported. Signals of improvement were reported in mobility-related and physical performance outcomes, although the magnitude and consistency of the response varied across studies. A dose-dependent increase in 6 min walk distance was observed at nine months in one trial, while improvements in SPPB, TUG, and grip strength were reported in the other studies. Additionally, MSC therapy was associated with QoL improvement and reduction in circulating pro-inflammatory cytokine concentrations. MSC administration was also associated with changes in immune-cell activation and a dose-dependent reduction in circulating sTIE2. Because of substantial clinical and methodological heterogeneity among the included trials, a quantitative meta-analysis was not performed. Current randomized evidence remains limited but suggests that intravenous MSC therapy is generally well tolerated in older adults with aging frailty and may produce clinically relevant signals of improvement in mobility-related functional outcomes, quality of life, and selected inflammatory, immune, and vascular biomarkers. However, the small number of trials, heterogeneity in MSC source, dose, endpoints, and follow-up duration, and the exploratory nature of much of the evidence preclude definitive conclusions regarding efficacy. Larger, adequately powered trials with standardized frailty endpoints are required, while future trials specifically targeting sarcopenia should apply consensus diagnostic criteria and direct measures of muscle quantity, strength, and physical performance.