Considering Age-Related Changes in Molecules in the Bloodstream in the Context of Cell Therapies for the Old

Parabiosis studies in which the circulatory systems of an old mouse and a young mouse are linked, and in which the old mouse shows a reversal of some measures of aging, have given rise to a broadening exploration of age-related changes in the molecules carried in the bloodstream. The high level picture of what is taking place here is this: reactions to rising levels of the forms of cell and tissue damage that cause aging include changes in the signal molecules released by cells into the surrounding environment. These are influential on stem cell function, chronic inflammation, and other line items known to be important in aging.

The paper here picks out a few such molecules of the many under study and discusses their likely roles and activities. The focus of these authors is on enhancing regenerative cell therapies by finding ways to make the tissue environment more receptive to transplanted cells and their ability to spur greater regeneration. That signaling changes in old tissues dampen stem cell activity is a major concern for the regenerative medicine community. This is one part of a field of research that includes numerous other efforts to try to adjust the circulating levels of these molecules, and thus to try to block some of the consequences of the underlying damage of aging. Like all similar efforts, I have to feel it will be much less effective than actually repairing that damage: in principle that should result in a reversal of the signaling changes.

It is undeniable that the incidence of cardiovascular diseases, mainly heart failure, increases in the elderly population. Global aging is a hallmark of our century: the eldery population comprise roughly 15% of the population, and this scenario will increase of an additional 25% on average by 2050. This unprecedented population profile will inevitably imply, among others, an increasing burden of cardiovascular events, some of which are directly linked to cellular senescence and dysfunction. Thus, increasing knowledge on the various mechanisms causing the progressive decline of cellular and tissue function may aid in developing therapies to delay or treat age-related conditions and diseases. Consequently, the discovery of pathways responsible for increasing life span and health span, as both potential biomarkers and targets, is currently of primary interest.

Endothelial progenitor cells (EPCs) are considered a main circulating stem cell population finely controlling vascular homeostasis and repair, therefore representing an interesting crossroad between circulating markers, regenerative cells, and aging mechanisms. Importantly, the demonstration that EPCs can be systemically recruited from the bone marrow-associated niche, and that after engraftment are able to replace old vasculature with new mature endothelial cells, has completely overturned the theory about aging and can be considered a significant reference for the relationship between progenitor cells and aging. To date, EPCs represent one of the most studied example tools to rejuvenate the vascular system or to potentially delay the damages induced by aging.

Notably, multiple studies suggest that, in the settings of cell transplantation for cardiovascular regenerative purposes, it is important not only to enhance intrinsic "young" properties of therapeutic cells, such as EPCs, but also to grant an ideal host microenvironment where engraftment can occur. Therefore, approaches able to rejuvenate regenerative cells and/or preserve tissue homeostasis and physiology (i.e., delaying overall aging) should be synergistically combined.

One of the main mechanisms affecting senescence and aging at multiple levels is oxidative stress, which originates from several biochemical pathways triggered, among others, by environmental factors, and overall imbalancing the final amount of reactive oxygen species. In this review, we will discuss few circulating molecules, proteins and microRNAs, selected among those whose levels and related signaling pathways have been correlated to life span and healthy aging. In particular, we will discuss pathways with specific biological and rejuvenating roles in cellular senescence, cardiovascular functions, and with a potential or known role in the control of regenerative cell populations.



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