Cells become senescent constantly throughout life, in tissues throughout the body, for a variety of reasons. Some senescence is a response to damage or stress or inflammatory signaling, some cells become senescent to help coordinate regeneration following injury, but most senescence is the result of cells reaching the Hayflick limit on replication. A senescent cell ceases to replicate, becomes larger, primes itself for programmed cell death, and secretes a potent mix of pro-growth, pro-inflammatory signals that attract the attention of the immune system.
In youth, senescent cells are efficiently removed by the immune system. In later life, this process slows as damage and stress increases, leading to the accumulation of senescent cells over time. Senescent cell signaling sustained over the long term by this growing, lingering population becomes increasingly disruptive to tissue structure and function, an important contribution to degenerative aging.
The research community is engaged in finding ways to selectively destroy senescent cells, reverse the normally irreversible senescent state, or shut down senescent cell signaling. A range of programs are scattered across the length of the slow and expensive path that leads towards clinical trials and eventual regulatory approval. At the same time, researchers continue to expand on the presently understanding of how exactly senescent cells cause harm to their host tissues. Today's open access paper is an example of this sort of work, focused on skin aging. As is usually the case in biology, nothing is direct and simple.
Endothelial senescence drives intrinsic skin aging via the neuroimmune CGRP-mast cell axis in mice
Endothelial cells (ECs), lining the inner surfaces of blood vessels, are particularly vulnerable to senescence, a state of irreversible cell cycle arrest triggered by telomere dysfunction, oxidative stress, and chronic inflammation. Senescent ECs secrete a senescence-associated secretory phenotype (SASP), a pro-inflammatory mix of cytokines, chemokines, and matrix-degrading enzymes that disrupt tissue homeostasis and propagate senescence. Although EC senescence has been implicated in age-related pathologies such as neurodegeneration, metabolic disorders, and pulmonary dysfunction, its contribution to skin aging remains poorly understood.
Skin aging is classified into two distinct types: extrinsic aging, driven primarily by environmental stressors such as ultraviolet (UV) radiation and pollution, and intrinsic (chronological) aging, mediated largely by genetic, metabolic, and vascular factors. While extrinsic aging manifests as epidermal hyperplasia, elastosis, and pigmentation, intrinsic aging is characterized by dermal thinning, collagen degradation, and impaired wound healing. Given the high vascular density within the dermis, microvascular dysfunction may contribute significantly to intrinsic skin aging by disrupting tissue homeostasis. However, the precise molecular mechanisms underlying the relationship between vascular dysfunction and intrinsic skin aging remain unknown.
Here we show that EC senescence contributes to intrinsic skin aging through immune dysregulation. Using an EC-specific senescent mouse model, we observe mast cell activation driven by the neuropeptide calcitonin gene-related peptide (CGRP), independent of traditional immunoglobulin E mediated pathways. Senescent ECs secreted pro-inflammatory SASP factors, activating dermal neurons to produce CGRP, leading to mast cell degranulation and subsequent skin aging phenotypes. Pharmacological stabilization of mast cells or inhibition of the EC-SASP-CGRP pathway significantly attenuate dermal thinning, collagen degradation, and delayed wound healing, which are hallmarks of intrinsic skin aging. These findings identify vascular senescence as an upstream regulator of skin aging through a neuroimmune mechanism and suggest potential therapeutic targets for age-related skin deterioration.
View the full article at FightAging
