Skin Healthspan

The skin is the most extensive and abundant tissue in the human body and, like many organs, undergoes gradual atrophy in both the epidermis and dermis with age. ^[1] Skin aging is a multifaceted process involving intrinsic mechanisms, associated with programmed aging and cellular senescence caused by endogenous oxidative stress, and extrinsic mechanisms driven by environmental factors such as ultraviolet radiation and pollution. ^[2] As the largest and most exposed organ, the skin can be viewed as a window for the deep exploration of the exposome and its effects on systemic aging. ^[3]

Age-related thinning of the epidermis and dermis is primarily attributed to the decline of epidermal stem cells and the loss of dermal collagen, which is the most abundant protein in the human body. ^[4] During aging the accumulation of excessive reactive oxygen species triggers a series of aging events, including imbalanced extracellular matrix homeostasis, accumulation of senescent fibroblasts, loss of cell identity, and chronic inflammation mediated by the senescence-associated secretory phenotype. ^[5] Collagen, a major component of the extracellular matrix, becomes fragmented and coarsely distributed and decreases in total amount with age, mainly due to increased activity of matrix metalloproteinases and impaired transforming growth factor-beta signaling induced by reactive oxygen species. ^[6] The primary environmental factor that causes human skin aging is ultraviolet irradiation from the sun, and this photoaging shares fundamental molecular pathways with chronological aging. ^[7]

The complex interplay across hallmarks of aging in the skin and systemic biological aging suggests that physiological processes associated with skin aging influence, and are influenced by, systemic hallmarks of aging in a bidirectional relationship. ^[3] Senescent skin cells can induce or accelerate the age-related dysfunction of nearby cells and cells of different origin, and skin senescence may contribute to the induction of aging phenotypes in other organs, contributing to whole-body aging. ^[8]

The most efficacious topical rejuvenation treatment is application of tretinoin, all-trans retinoic acid, a prescription-only medicine considered to be the clinical gold standard. ^[9] A systematic review and meta-analysis of 23 randomized controlled trials with 1474 participants found that collagen supplements significantly improved skin hydration, elasticity, and wrinkles overall, but high-quality studies and studies not funded by pharmaceutical companies revealed no significant effect, leading the authors to conclude there is currently no clinical evidence to support their use to prevent or treat skin aging. ^[10] The authors of a narrative review suggested that the future of skin aging management would appear to lie in the use of senolytic and senomorphic agents targeting senescent cells in the skin. ^[11]