PSORALEN PHOTOACTIVATION PROMOTES MORPHOLOGICAL AND FUNCTIONAL-CHANGES IN FIBROBLASTS IN-VITRO REMINISCENT OF CELLULAR SENESCENCE

Premature aging of the skin is a prominent side effect of psoralen pho toactivation, a treatment used widely for various skin disorders. The molecular mechanisms underlying premature aging upon psoralen photoact ivation are as yet unknown. Here we show that treatment of fibroblasts with 8-methoxypsoralen (8-MOP) and subsequent ultraviolet A (UVA) irr adiation resulted in a permanent switch of mitotic to stably postmitot ic fibroblasts which acquired a high level of de novo expression of SA -beta-galactosidase, a marker for fibroblast senescence in vitro and i n vivo. A single exposure of fibroblasts to 8-MOP/UVA resulted in a 5. 8-fold upregulation of two matrix-degrading enzymes, interstitial coll agenase (MMP-1) and stromelysin-1 (MMP-3), over a period of >120 days, while TIMP-1, the major inhibitor of MMP-1 and MMP-3, was only slight ly induced. This imbalance between matrix-degrading metalloproteases a nd their inhibitor may lead to connective tissue damage, a hallmark of premature aging. Superoxide anion and hydrogen peroxide, but not sing let oxygen, were identified as important intermediates in the downstre am signaling pathway leading to these complex fibroblast responses upo n psoralen photoactivation. Collectively, the end phenotype induced up on psoralen photoactivation shares several criteria of senescent cells . In the absence of detailed molecular data on what constitutes normal aging, it is difficult to decide whether the changes reported here re flect mechanisms underlying normal cellular aging/senescence or rather produce a mimic of cellular aging/senescence by quite different pathw ays.