A groundbreaking clinical trial has demonstrated that Therapeutic Plasma Exchange (TPE), a procedure traditionally used to treat autoimmune disorders and poisonings, may significantly reduce biological age in healthy older adults. Published in Aging Cell, the study reveals that TPE, especially when combined with intravenous immunoglobulin (IVIG), rejuvenates epigenetic clocks—molecular biomarkers of aging—by up to 2.6 years.
Study Design and Key Findings
The randomized, placebo-controlled trial involved 42 participants aged 50 and older, divided into four groups:
1. Biweekly TPE + IVIG (10 participants)
2. Biweekly TPE alone (11 participants)
3. Monthly TPE (11 participants)
4. Sham (placebo) procedure (10 participants)
Blood samples were analyzed using 36 epigenetic clocks, which measure DNA methylation patterns to estimate biological age (BA). Multi-omics profiling (proteomics, metabolomics, cytomics, etc.) tracked changes in immune cells, proteins, and other biomarkers.
1. Biweekly TPE + IVIG (10 participants)
2. Biweekly TPE alone (11 participants)
3. Monthly TPE (11 participants)
4. Sham (placebo) procedure (10 participants)
Blood samples were analyzed using 36 epigenetic clocks, which measure DNA methylation patterns to estimate biological age (BA). Multi-omics profiling (proteomics, metabolomics, cytomics, etc.) tracked changes in immune cells, proteins, and other biomarkers.
Key Results:
· TPE + IVIG was most effective, reducing BA by an average of 2.61 years (p < 0.05). Systems age clocks, which assess immune and inflammatory aging, showed the largest declines (up to 9.7 years).
· TPE alone (biweekly or monthly) also reduced BA but to a lesser extent (1.32 years).
· Safety: Only two adverse events (0.45% of procedures) were reported, both mild.
· TPE + IVIG was most effective, reducing BA by an average of 2.61 years (p < 0.05). Systems age clocks, which assess immune and inflammatory aging, showed the largest declines (up to 9.7 years).
· TPE alone (biweekly or monthly) also reduced BA but to a lesser extent (1.32 years).
· Safety: Only two adverse events (0.45% of procedures) were reported, both mild.
Mechanisms of Rejuvenation
The study identified several molecular and cellular shifts linked to BA reduction:
1. Immune Cell Reprogramming: TPE + IVIG increased naïve CD4+ and CD8+ T cells (critical for immune resilience) and decreased pro-inflammatory monocytes and NK cells—reversing hallmarks of immunosenescence.
2. Proteomic Changes: Proteins associated with chronic inflammation (e.g., IL13RA1) and cellular senescence were modulated. Complement system proteins (e.g., C7) surged, suggesting enhanced immune defense.
3. Metabolomic/Glycomic Shifts: Glycine levels correlated with reduced inflammation, aligning with its known role in suppressing NF-κB signaling.
1. Immune Cell Reprogramming: TPE + IVIG increased naïve CD4+ and CD8+ T cells (critical for immune resilience) and decreased pro-inflammatory monocytes and NK cells—reversing hallmarks of immunosenescence.
2. Proteomic Changes: Proteins associated with chronic inflammation (e.g., IL13RA1) and cellular senescence were modulated. Complement system proteins (e.g., C7) surged, suggesting enhanced immune defense.
3. Metabolomic/Glycomic Shifts: Glycine levels correlated with reduced inflammation, aligning with its known role in suppressing NF-κB signaling.
Predictive Biomarkers
Baseline health status influenced outcomes. Participants with higher mean corpuscular hemoglobin (MCH) or lower monocyte counts experienced greater BA reduction. Elevated glucose and lower calcium levels predicted better responses, hinting that TPE + IVIG may benefit those with suboptimal metabolic health.
Limitations and Future Directions
The small sample size and short duration (3–6 months) necessitate larger trials to confirm findings. Notably, BA reductions peaked after initial sessions, suggesting compensatory mechanisms may dampen long-term effects.
Expert Insights
Dr. David Furman, co-senior author, noted, "TPE + IVIG appears to reset inflammatory and immune aging pathways. This could be transformative for age-related diseases." The study’s multi-omics approach underscores the complexity of aging and the potential for personalized anti-aging therapies.
Conclusion
This first-in-human trial provides robust evidence that TPE, particularly with IVIG, can decelerate biological aging. By targeting systemic inflammation and immune dysfunction, the procedure offers a promising avenue for longevity research. Future studies will explore optimal dosing and long-term clinical benefits.
Source:
Fuentealba M. et al. Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange. Aging Cell. 2025 May 27:e70103. doi: 10.1111/acel.70103. Epub ahead of print. PMID: 40424097.
https://onlinelibrary.wiley.com/doi/10.1111/acel.70103
Fuentealba M. et al. Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange. Aging Cell. 2025 May 27:e70103. doi: 10.1111/acel.70103. Epub ahead of print. PMID: 40424097.
https://onlinelibrary.wiley.com/doi/10.1111/acel.70103