The molecular mechanism of the aging process

The molecular mechanism of the aging process.

Summary of major pathways involved in the aging process. Absorption of #UV radiation by chromophores in the #skin results in formation of reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide. Normal oxidative metabolism (mitochondrial oxidative energy generation) also results in formation of excess ROS. #ROS play a central role in #intrinsic and #extrinsic aging by increasing oxidative phosphorylation of cell surface receptors causing activation of one or more components of MAP kinase signaling pathways resulting in activation of transcription factors activator protein 1 (AP-1) and nuclear factor-kappa B (NF κ B).
AP-1 stimulates transcription of matrix metalloproteinase (MMP) growth factor genes in fibroblast and #keratinocytes, and inhibits type I procollagen gene expression in fibroblasts. Multiple studies have shown that activation of the MMP secretion as a result of intrinsic and extrinsic aging produces breakdown of dermal matrix. Different subtypes of MMP have different substrate proteins on which they act to produce a break in their primary sequence. MMP-1 (collagenase) produces cleavage at a single site in central triple helix of fibrillar type I and type III collagen. The cleaved subunits are further degraded by MMP-3 (stromelysine 1) and MMP-9 (gelatinase). Activity of MMP is decreased by binding with tissue inhibitors of metalloproteinase (TIMP). ROS inactivates TIMP thereby increasing MMP activity. AP-1 mediated reduction in synthesis of procollagen appears to result from two mechanisms, interference of AP-1 with type I and type III procollagen gene transcription and blocking the profibrotic effects of TGF β by impairment of TGF β type II receptor/ smad pathway. Activation of NF κ B stimulates transcriptions of proinflammatory cytokine genes including IL-1, TNF α , IL-6, and IL-8. Inflammation resulting from these cytokines increases secretion of ROS and more cytokines further enhancing the effect of UV exposure. Inflammation causes proteasemediated degradation of elastin and UV exposure causes formation of abnormal elastin by fibroblasts. UV light is also an inhibitor of leukocyte elastase thereby increasing accumulation of elastotic materials. The accumulation of elastotic materials is accompanied by degeneration of surrounding collagenous network. The overall effects of these interlinked biochemical activities is reduction of procollagen synthesis, increase of collagen degradation in the dermal extracellular matrix, and increase in irregular elastin deposition.