Considerations on Heterochronic Plasma Transfer in Aging Research

Dear Editor:

I read with great interest the narrative review by Ansere et al. entitled “Heterochronic Plasma Transfer: Experimental Design, Considerations, and Technical Challenges.” ¹ The authors are to be commended for summarizing heterochronic plasma transfer (HPT) as an important experimental paradigm to interrogate systemic regulation of aging. By integrating evidence from parabiosis, plasma transfer, and blood exchange models, the review highlights the central role of circulating factors in modulating aging phenotypes across multiple organs.

Heterochronic parabiosis (HPB), a surgical technique connecting two animals with different ages of the same species, facilitates the transfer of blood components. It was first discovered that HPB prolonged the lifespan of elderly individuals in 1972. ² Since that, young blood was gradually considered as a medicine treating aging. The deterioration of tissue and organ functions can be led by age-related changes in the blood system, including an increase in aging-promoting factors, a decrease in antiaging factors, senescence of blood cells, and vascular aging. ³ Given the presence of proaging factors in plasma, it is hypothesized that diluting aged plasma to decrease the levels of harmful factors may have antiaging effects. Therapeutic plasma exchange (TPE) is a medical procedure that entails the replacement of a patient’s plasma with replacement fluid, including normal human plasma, saline, and albumin. TPE removes inflammatory cytokines, metabolic waste, and senescence-associated proteins, while replenishing rejuvenating factors. ⁴

From an aging research perspective, several conceptual issues warrant further discussion. First, while HPT is frequently interpreted as evidence for the existence of “youthful” circulating factors, the review could more critically address the alternative hypothesis that dilution or removal of age-associated detrimental factors may play an equally, if not more, important role. Distinguishing rejuvenation driven by gain-of-function versus loss-of-function mechanisms remains essential for advancing mechanistic understanding of aging.

Second, aging is a multifactorial and time-dependent process, yet most HPT studies rely on relatively short intervention windows and a limited set of aging-related endpoints. Greater emphasis on long-term outcomes, health span-related measures, and tissue-specific aging trajectories would strengthen the relevance of HPT findings to biological aging rather than acute functional improvements alone. In addition, variability in donor age definitions, sex matching, and baseline frailty status may significantly influence aging phenotypes but is not consistently addressed across studies.

Finally, although the review briefly discusses clinical trials, the translational implications for aging interventions remain uncertain. Aging is not a single disease entity, and extrapolating preclinical HPT results to human aging requires careful consideration of heterogeneity, safety, and ethical concerns. Clearer discussion on how HPT findings inform geroscience-guided therapeutic strategies would be valuable.

In summary, this review provides an important foundation for understanding HPT in aging research. Further clarification of aging-specific mechanisms and conceptual frameworks would help advance the field and stimulate productive discussion. I look forward to the authors’ response.

Author’s Contributions

J.C. made all contributions. All authors read and approved the final article.