Skin-aging pigmentation: the role of cellular senescence and emerging therapeutic approaches

Skin aging is influenced by both intrinsic factors, like genetics and hormonal changes, and extrinsic factors, such as UV radiation. Photoaging, caused primarily by UV exposure, is a major contributor to pigmentation issues like senile lentigo and melasma. Cellular senescence, a state of irreversible cell-cycle arrest, plays a critical role in these processes, affecting key skin cells such as fibroblasts, keratinocytes, and melanocytes. Senescent cells secrete pro-inflammatory factors, known as senescence-associated secretory phenotypes (SASPs), which disrupt the pigmentation system’s homeostasis. For instance, UV-induced senescence of keratinocytes and fibroblasts amplifies melanogenesis, resulting in hyperpigmentation.

Research highlights that the senescence of fibroblasts accelerates pigmentation disorders by releasing factors like hepatocyte growth factor and basic fibroblast growth factor, which stimulate melanocytes. On the other hand, UV-irradiated melanocytes and keratinocytes activate pigment-producing pathways through mechanisms involving p53 and α-MSH. Therapeutic strategies to counteract skin-aging pigmentation include senolytics, which target and eliminate senescent cells, and senomorphics, which modify SASP secretion. Promising treatments like topical rapamycin and BCL-2 inhibitors have shown effectiveness in reducing age-related skin changes and restoring skin elasticity.

These findings suggest that targeting senescent cells could revolutionize the management of age-related pigmentation disorders, providing new avenues for skin rejuvenation and protection against photoaging.