Recent clinical trials with stem cells to slow or reverse normal aging processes

**Background:** Aging is associated with a decline in the regenerative potential of adult stem cells, which may contribute to age-related conditions such as physical frailty and skin aging. Preclinical studies have shown that mesenchymal stem cell (MSC) transplantation can increase lifespan in animal models. This review aims to identify and analyze recent clinical trials investigating stem cell preparations for slowing or reversing normal aging processes.

**Methods:** Clinical trial registries from the US (ClinicalTrials.gov), EU, China, Japan, and the WHO were searched from August 2022 to January 2023. Trials were included if they were interventional, updated on or after January 1, 2019, not terminated, included healthy participants, and declared 'Aging' as a condition with 'stem cell' as an other term. Data extracted included identifier, aging condition, stem cell preparation, sponsor, main outcomes, duration, number of patients, and status.

**Key Results:** Twenty clinical trials were identified. For physical frailty, 11 trials were found: six with allogeneic human bone marrow MSCs (hBM-MSCs), three with human umbilical cord MSCs (hUC-MSCs), one with autologous adipose-derived MSCs (hAD-MSCs), and one with G-CSF-mobilized fresh frozen plasma (GMFFP). The leading preparation, Lomecel-B (Longeveron), was evaluated in the CRATUS trial (phase I/II). In the phase I open-label trial (n=15, mean age 78.4 years), no therapy-related serious adverse events occurred. The 6-minute walk distance (6MWD) significantly increased by 37.2 m in the 20-million cell group and 76.6 m in the 100-million cell group at 6 months. In the phase II RCT (n=30, mean age 75.5 years), the 100-million cell group showed a significant increase in 6MWD from 345.9 m at baseline to 410.5 m at 6 months. TNF-alpha levels significantly decreased in the 100- and 200-million cell groups. A phase IIb multicenter RCT (NCT03169231, n=150) has been completed, with preliminary biomarker results showing a significant reduction in serum soluble TIE-2 levels. For facial skin aging, seven trials were identified, including four with stromal vascular fraction (SVF). One RCT (NCT02923219, n=50 women, mean age 35.4 years) showed that SVF-assisted fat grafting resulted in significantly higher whole face volume retention (77.6% vs 56.2%, p<0.001) and improved wrinkles and texture at 6 months compared to fat transfer alone.

**Clinical Implications:** Stem cell therapies for aging are in early clinical development. Lomecel-B has shown promising safety and efficacy signals for improving physical function and reducing inflammation in frail older adults, but larger phase III trials are needed. For facial skin aging, SVF-enriched fat grafting appears effective for volume restoration and skin quality improvement. Key limitations include lack of standardized protocols, few pharmacokinetic studies, and the complexity of treating frail, poly-medicated elderly patients. Future directions include preconditioning or genetically modifying MSCs, exploring MSC-derived exosomes, and repurposing approved stem cell products like Hemacord for aging frailty.