Caveolin-1, cellular senescence and age-related diseases

Abstract

According to the "free radical theory" of aging, normal aging occurs as the result of tissue damages inflicted by reactive oxygen species (ROS) when ROS production exceeds the antioxidant capacity of the cell. ROS induce cellular dysfunctions such as stress-induced premature senescence (SIPS), which is believed to contribute to normal organismal aging and play a role in age-related diseases. Consistent with this hypothesis, increased oxidative damage of DNA, proteins, and lipids have been reported in aged animals and senescent cells accumulate in vivo with advancing age. Caveolin-1 acts as a scaffolding protein that concentrates and functionally regulates signaling molecules. Recently, great progress has been made toward understanding of the role of caveolin-1 in stress-induced premature senescence. Data show that caveolin-mediated signaling may contribute to explain, at the molecular level, how oxidative stress promotes the deleterious effects of cellular senescence such as aging and age-related diseases. In this review, we discuss the cellular mechanisms and functions of caveolin-1 in the context of SIPS and their relevance to the biology of aging.

Figure 1. Caveolin-1 and age-related diseases

In vivo studies have shown a critical role of caveolin-1 in SIPS and age-related pathologies, such as cigarette smoking-induced pulmonary emphysema, atherosclerosis, osteoarthritis, microbial infections, human intervertebral disc degeneration, wound healing and fibrosis.

Figure 2. Caveolin-1, a pivotal regulator of cellular senescence

After oxidative stress, the caveolin-1 gene promoter is activated through p38 MAPK-Sp1-dependent and NF-κB-dependent pathways. COX2 and PC-PLC also regulates caveolin-1 expression. Upregulation of caveolin-1 promotes cellular senescence by activating the p53/p21^Waf1/Cip1, focal adhesion kinase (FAK), and small GTPases pathways and by inhibiting the EGFR/ERK-1/2 pathway. Activation of p53 by caveolin-1 occurs through different mechanisms: 1) interaction of caveolin-1 with Mdm2 prevents the Mdm2-dependent degradation of p53; 2) inhibition of TrxR1 through direct interaction with caveolin-1 activates p53; 3) sequestration of PP2A-C into caveolar membranes activates ATM, which in turns phosphorylates and activates p53. Activation of p53 leads to upregulation of p21^Waf1/Cip1 and induction of cellular senescence.