A new study ties the disappearance of capillary-associated macrophages to age-related vascular degeneration in the skin. Boosting their function with a growth factor offers a possible avenue for anti-aging interventions [1].
Macrophages, capillaries, and skin aging
Skin aging might not be the most dangerous aspect of aging, but it certainly is one of the most conspicuous. It also provides a valuable model for studying aging as a whole.
Skin thinning and pesky wrinkles have mutiple origins, including diminished blood supply from the capillaries that permeate the skin [2]. In this study published in Nature, researchers from New York University School of Medicine investigated the role of capillary-associated macrophages (CAMs): immune cells that reside near the capillaries, where they clean debris, fight pathogens, and facilitate tissue repair.
Aging tissues lose resident macrophages [3] and microvascular function, but how these are linked in living organisms is not clear. This study aimed to determine if CAMs in skin decline with age, if such a loss impairs capillary perfusion and repair, and if they can be restored.
In vivo imaging reveals waning function
The researchers used an ingenious technique for in vivo imaging, which allowed them to analyze blood flow and skin condition of live mice longitudinally, from 1 to 18 months of age. “Older tissues show fewer blood vessels,” said Kailin R. Mesa, currently assistant professor at Princeton and the study’s corresponding author. “To understand how these changes develop and lead to age-related dysfunction, we built a multiphoton light microscopy imaging system to track tissue aging in living mice.”
Time-lapse imaging showed that upper-dermal CAMs decline faster than epidermal or lower-dermal macrophages and faster than capillary rarefaction itself. Thus, “macrophage-deficient” vascular niches are created, with capillaries devoid of CAMs. These capillaries without nearby CAMs experience higher rates of obstructed red blood cell (RBC) flow.
Human skin samples analyzed by the researchers showed the same pattern: CAM decline outpaced capillary loss, implying diminished coverage with age. Acute macrophage depletion reduced blood flow even more. According to this paper, aging leads CAMs to significantly skew towards loss rather than proliferation, contributing to their decline.
Injury and a growth factor boost macrophage recruitment
The study also revealed that CAMs are required for capillary repair and preservation. Following precise laser clotting of single capillaries, nearby CAMs were rapidly recruited within about two days and engulfed RBC debris. Capillaries with local CAMs were significantly better at re-establishing blood flow after injury than CAM-devoid ones. Ablation of CAMs prior to clot induction impaired capillary repair, indicating their critical role in vascular recovery.
The researchers then applied larger laser wounds to the upper dermis or the overlying epidermis to test whether more serious tissue damage triggers CAM replenishment, which it did. “We found that large laser-induced epidermal damage resulted in a lasting increase in CAMs below the damaged regions compared with in the neighboring control regions,” the paper says. Basically, while CAMs hardly renew on their own in aging skin, the study suggests that environmental changes, such as injury, can stimulate CAM replenishment and enhance vascular function in older mice.
Colony-stimulating factor 1 (CSF1) is a growth cue that tells macrophages to survive and divide. The team used CSF1-Fc, an enhanced version that makes the signal hang around longer in tissue to test whether it can improve CAM function by micro-injecting it into the skin of old mice (20-24 months) once a day for four days. This treatment resulted in more capillary-associated macrophages (CAMs) lining the tiny vessels without noticeably changing the balance between long-lived resident cells and freshly recruited ones, which are derived from monocytes.
CSF1-Fc reduced the number of capillary segments with sluggish or blocked red blood cell flow at baseline, and when the researchers created pinpoint clots, treated areas cleared debris and reperfused more reliably over the next week. In other words, topping up the resident macrophage niche in old skin rejuvenated repair capacity. “We also found that dermal macrophage self-renewal and vascular support could be acutely enhanced in aged mice through local CSF1 therapeutic treatment,” the paper says.
The importance of this discovery goes beyond skin, since dense capillary beds in the brain, heart, kidney, and skeletal muscle are also maintained by perivascular macrophages. Their age-related decline probably produces the same pattern seen in skin: sluggish flow, failed micro-repairs, and gradual pruning of the network. Improving things in the macrophage niche might provide a general route to preserving microvascular health in multiple tissues and organs. “When macrophages disappear, skin blood vessels age. Loss of skin macrophages with age blocks blood vessel flow and clot repair, revealing a new cellular trigger of tissue aging,” said Mesa.
Literature
[1] Mesa, K. R., O’Connor, K. A., Ng, C., Salvatore, S. P., Dolynuk, A., Lomeli, M. R., & Littman, D. R. (2025). Niche-specific dermal macrophage loss promotes skin capillary ageing. Nature, 1-9.
[2] Bentov, I., & Reed, M. J. (2015). The effect of aging on the cutaneous microvasculature. Microvascular research, 100, 25-31.
[3] Park, M. D., Yatim, N., Zhang, J., Cho, B. A., Yoo, S. K., Schaefer, M. M., … & Merad, M. (2025). Restoring resident tissue macrophages to combat aging and cancer. Nature Aging, 5(8), 1383-1392.
View the article at lifespan.io
