PYCR1 Levels Track with Premature and Chronological Skin Aging

Abstract

ABSTRACTDe Barsy syndrome is a recessive progeroid disease classified under the group of cutis laxa syndromes. The disease is attributed to loss-of-function mutations inPYCR1orALDH18A1, leading to premature skin aging. Here we report fivePYCR1pathogenic alleles and a mouse knockout model of the disease. Through these investigations, we have confirmed the key role of PYCR1 in preventing dermal thinning and other connective tissue abnormalities. However, it remains unknown whether endogenous PYCR1 levels undergo changes during normal aging. To address this query, we examined its levels in cultured human cutaneous fibroblasts subjected to induced or replicative senescence. In both instances, PYCR1 levels dropped and correlated with the loss of proliferative capacity. Furthermore, we validated the relevance of these findingsin vivo, by comparing young and chronologically aged human skin, and found that the levels of PYCR1 in the dermis, but not the epidermis, significantly decreased with age. Our results confirm that the loss of PYCR1 is a driver of human skin aging and that its levels in healthy individuals can serve as a biomarker for connective tissues undergoing normal chronological aging.