In today's open access paper, researchers add to the present body of evidence for loss of capillary density to be an important mechanism of aging. All tissues are packed with capillaries, hundreds passing through every square millimeter in cross-section. This density is lost with age, and that reduces the supply of nutrients and oxygen to cells. Like the raised blood pressure of hypertension, loss of capillary density is a fair way downstream from the molecular damage that causes aging. Also like hypertension, loss of capillary density may make a large enough contribution to further tissue damage and dysfunction to be worth targeting independently of its causes.
Blood vessel formation is a complex process in which numerous populations of cells are involved. More is known about the response to injury than of the normal maintenance of capillary networks in the absence of injury, but it may be the case that the lessons of one can be applied to the other. A range of interesting research in recent years has shown that mobilizing hematopoietic cells from the bone marrow into circulation, such as via targeting CXCL12, CXCR4, and their receptors, will increase blood vessel formation following injury. A number of drugs can achieve this goal, some of which are already commonly used when collecting hematopoietic cells from donors for transplantation. It is possible that this could be the basis for a therapy that will increase blood vessel density in older individuals, but animal studies would have to be conducted first to prove the concept.
The identification and regulation of signals driving the aging process are long-standing goals in physiology. Aging negatively affects organ function. The description of the tissue-level age-associated changes in the literature remains restricted to the gross structural and tissue changes such as the increase in tissue stiffness and adiposity. In this study, we implement a large-scale 3D spatial comparison of vascular cells and molecules in young and aging mouse tissues from several organs to define the major changes across both axes. This in-depth analysis of aging tissues revealed vascular attrition as a primary hallmark of aging and provides unprecedented insights into the microenvironmental tissue-level changes during aging.
Our imaging datasets reveal that the loss of vascular abundance accompanied by the decline in pericytes is a key feature of aging tissues. This is the first comprehensive study highlighting age-dependent vascular changes across several organs. Loss of vessel density and pericytes emerges as the mark of aging organs and tissues; however, highly remodeling tissues with high regeneration potential, such as the skin, gut, and uterus, preserve the abundance of the blood vessels and pericytes with aging. Similarly, vessel densities remain unaffected in aging bones, which have relatively higher regeneration potential compared to tissues such as the kidney, spleen, heart, or brain. Thus, stage and extent of vascular attrition are likely to direct the regenerative limitations of a tissue.
Further, observations described herein corroborate the findings in injury-induced organ fibrosis where pericytes differentiate into fibroblasts to drive fibrosis. Our findings also demonstrate that pericytes are a source of fibroblasts in joint inflammation and that the differentiation of pericytes to fibroblasts increases with aging. Last, endothelial cell specific genetic manipulations prove that vascular loss drives cellular changes such as senescence. Together, these findings imply that the strategies to inhibit age-dependent changes in vasculature such as the loss of vascular abundance and pericyte to fibroblast differentiation have the potential to delay or even prevent cellular dysfunction during aging.