As noted here, joining the circulatory systems of an old and young mouse results in some degree of rejuvenation in the old mouse. Where brain function is improved, researchers are interested in how changes in the blood signaling environment might be involved. While research initially focused on factors in young blood that are reduced in old blood, it is increasingly thought that the important mechanism is a dilution of harmful factors carried in the old bloodstream. This has led to a few studies of plasma transfer and dilution in humans, and at least one company attempting to determine the optimal dose and protocol to make this approach into a widely used therapy.
Researchers have recently leveraged evolving proteomic approaches and single-cell RNA-sequencing technologies to begin to decode the functional impact of intertissue communication on brain aging. The application of molecular approaches to investigate systemic and lifestyle interventions, such as heterochronic parabiosis (in which the circulatory systems of young and aged animals are surgically connected), young blood plasma administration, exercise, and caloric restriction, has uncovered broad rejuvenating effects on the aged brain that are mediated through blood, which question the very notion that brain aging is immutable.
To what extent do pro-aging and pro-youthful factors act through convergent or divergent mechanisms? With respect to a common tissue of origin, the hematopoietic system and inflammatory processes emerge as a source of pro-aging factors. Nevertheless, in many cases, the cell type or tissue sources remain obfuscated. Although earlier work identified a series of muscle-derived myokines, the liver as a major secretory organ is rapidly emerging as an additional source of exercise-induced factors, with IGF1, GPLD1, SEPP1, and clusterin all being putative liver-derived exerkines.
Regarding mechanisms of action, numerous aging and rejuvenating factors exert similar effects on the brain; therefore, it is important to understand whether each factor acts through the same or parallel cellular targets and molecular pathways. Given the predominant immune nature of pro-aging factors in old blood, microglia appear an obvious first target. However, several recent studies are highlighting brain endothelial cells as a potential nexus by which pro-aging factors, including VCAM1, ASM, CyPA, and CCL2, regulate brain aging. Conversely, pro-youthful factors identified across interventions, such as GDF11, clusterin, GPLD1, and α-klotho, may likewise exert their rejuvenating effects indirectly on the aged brain by restoring function to the aging vasculature and additional peripheral targets.
Additionally, a series of pro-youthful factors, including TIMP2, osteocalcin, SPARCL1, and THSB4, appear to selectively enhance synaptic or cognitive functions; whereas others, such as FGF17 and SEPP1, have been demonstrated to regulate regenerative and stem cell functions. Collectively, these findings indicate that brain function can be restored through several parallel targets as well as direct and indirect mechanisms with relevance for future therapeutic approaches.