The “young-to-aged” paradigm: fantasy or feasible strategy for cardiovascular and systemic rejuvenation?

Cardiac rejuvenation

In the cardiac system, HP studies established that exposure to young circulation reverses age-related cardiac hypertrophy in aged mice. Along with reduced cardiomyocyte size, molecular remodeling occurs via normalized natriuretic peptide expression, and restored sarco/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity, primarily mediated by circulating factors such as growth differentiation factor 11 (GDF11), but not hemodynamic effects of HP^[9,10]. The vascular system can also similarly benefit from the “young-to-aged” paradigm. A previous HP study has indicated that exposure to young circulation could attenuate endothelial dysfunction, vascular oxidative stress, and potentially reverse age-related mitochondrial dysfunction in the aged vasculature^[11]. Another HP study showed that young circulation facilitated neurovascular rejuvenation in aged mice through increasing the cortical capillary density and restoring blood-brain barrier integrity^[12].

Gut-vascular connection

Functionally, the gut microbiota can be treated as a “virtual endocrine organ”^[13], with fecal microbiota transplantation (FMT) from young donors potentially producing multifaceted rejuvenating effects in aged hosts. For instance, FMT from young mice has been shown to rejuvenate HSC in aged mice by mitigating inflammation, upregulating the forkhead box O (FoxO) signaling pathway, and facilitating lymphoid differentiation^[14]. Meanwhile, transplanting gut microbiota from young mice into aged mice reversed age-related inflammation and functional decline in the intestines, eyes, and brain by restoring intestinal barrier integrity and suppressing systemic inflammation^[15].

Notably, the vascular system can also benefit from the young systemic factors derived from the intestine through the gut-vascular axis. Our laboratory has previously shown that FMT from young donor mice improved endothelial function via reduced oxidative stress and activation of Adenosine Monophosphate (AMP)-activated protein kinase (AMPK)/sirtuin 1 (SIRT1) pathway, preserved telomere integrity in vascular tissues, and alleviated systemic inflammation through restoring intestinal barrier function^[16]. Furthermore, our laboratory has also extended the paradigm to perivascular adipose tissue (PVAT). Co-culture experiments demonstrate that aged mouse PVAT induces endothelial dysfunction and inflammation in young mouse aortas, while young PVAT partially reverses vascular aging phenotypes in aged vessels. This cross-talk is mediated by growth differentiation factor 15 (GDF15)-dependent mechanisms^[17], highlighting PVAT as a paracrine regulator of vascular health.

Collectively, these findings establish that youthful systemic factors, whether circulating proteins, microbial ecosystems, or adipose-derived signals, can rejuvenate aged cardiovascular tissues through conserved mechanisms involving inflammation resolution, metabolic reprogramming, and senescence attenuation. The gut-vascular connection also emerges as a critical intervention target for age-related cardiovascular pathologies.

Ethical and biological safety risks

Sourcing young biological materials (e.g., plasma, tissues, and organs) raises profound ethical dilemmas, including donor exploitation and equitable access. Specifically, the procurement of young biological materials, such as plasma or stem cells, raises significant ethical questions regarding donor consent and the potential for exploitation, while the widespread adoption of rejuvenation therapies could precipitate profound societal challenges, including equitable access and the redefinition of the human lifespan.

Across different “young-to-aged” interventions, immunological risks represent a major clinical hurdle. These adverse reactions can range from minor infusion-related allergic responses to severe, life-threatening conditions such as graft-versus-host disease following bone marrow transplants, or the transfer of pro-inflammatory immune cells in plasma that can exacerbate a recipient’s pre-existing conditions. Importantly, a definitive clinical trial conclusively establishing the safety of young plasma infusion remains lacking, necessitating future studies to critically and systematically investigate.

Additionally, senescence propagation can occur bidirectionally. Notably, aged recipient microenvironments could potentially accelerate damage in young transplants, while aged organs/tissues might induce cellular aging in young recipients^[18]. In general, older donor age is often associated with worse clinical outcomes (e.g., reduced graft survival and higher risk of graft failure) for various organs (e.g., liver, kidney, heart, and lung) in young recipients^[19]. Coherently, in the context of FMT, our laboratory has previously shown that gut microbiota from aged mice could induce endothelial dysfunction, vascular inflammation, and telomere dysfunction in the vasculature, potentially promoting premature vascular aging^[20]. Although stem cell-derived artificial tissues potentially offer a scalable source, the issues concerning xenogeneic immune compatibility and tumorigenic risk should not be overlooked.

Technical and mechanistic hurdles

Age-related damages beyond critical thresholds, such as mitochondrial DNA mutations or epigenetic alterations, often limit rejuvenation effect to “slowing” rather than “reversing” the age-related decline. In other words, it remains doubtful whether the “young-to-aged” paradigm can effectively target mitochondrial DNA mutations and epigenetic alterations.

This introduces the critical concept of a biological “point of no return”, a threshold of accumulated damage that becomes refractory to paradigmatic rejuvenation. While some alterations may be malleable, we speculate that certain forms of damage are fundamentally irreversible with current approaches. Prime candidates include the accumulation of mitochondrial DNA mutations to a level that causes bioenergetic collapse, and the progressive cross-linking of structural proteins (e.g., collagen) in the extracellular matrix, which could create a permanent structural scaffold resistant to systemic factors. Identifying which age-related lesions constitute this “point of no return” is a central challenge for the field.

Neurointegration, particularly the re-establishment of neural connections between the transplanted organs/tissues and the recipient nervous system, remains another key technical hurdle. Moreover, although endocrine organs/tissues (e.g., ovaries and adipose tissues) show heightened therapeutic efficacy in murine studies due to systemic hormonal influence (e.g., estrogen-mediated cardioprotection), other non-endocrine organs/tissues might face engraftment inefficiencies. Importantly, individual heterogeneity, driven by genetics, microbiota, and lifestyle, further complicates the efficacy of the “young-to-aged” paradigm.

Translational and measurement gaps

The translational discrepancies can largely be attributed to fundamental physiological distinctions between species (e.g., human and mouse), coupled with challenges in accurately replicating therapeutic windows, both in terms of dosage and the timing of intervention relative to disease progression. Besides, the divergent outcomes in different human trials can potentially arise from variations in sourcing of biological materials (e.g., plasma) and processing protocols, heterogeneity in participant demographics (e.g., age and baseline health), and the ongoing challenge of validating robust, standardized biomarkers for biological age.

The absence of highly standardized biomarkers for biological age impedes outcome evaluation. Current metrics (e.g., epigenetic clock) might suffer from poor reproducibility across studies^[21]. Furthermore, preclinical models for multi-organ transplantation, even in murine systems, are lacking, restricting insights into systemic interactions of the paradigm. To our knowledge, longitudinal human lifespan data are scarce, with evidence limited to short-term surrogate markers rather than mortality outcomes. Crucially, the mechanistic underpinnings of aging remain enigmatic. While twelve hallmarks (e.g., mitochondrial dysfunction, stem cell exhaustion, telomere attrition, and chronic inflammation) are established^[22], their hierarchy in vivo is still poorly defined, hindering interventions targeting “point-of-no-return” thresholds.