Telomere uncapping and vascular aging

Abstract

Although most telomere biology research continues to focus on telomere shortening, there is increasing evidence that telomere deprotection, or "uncapping," is more biologically and possibly clinically important. Telomeres form t-loops to prevent the chromosome ends from appearing as a double-stranded DNA break and initiating a DNA damage response. Breakdown of the t-loop structure, referred to as uncapping, can lead to cellular senescence, increased oxidative stress, and inflammation in tissues. In this review, we describe how telomere uncapping potentially leads to age-related vascular dysfunction and increased cellular senescence, oxidative stress, and inflammation. Importantly, we present evidence to argue that telomere uncapping is more biologically relevant than telomere shortening and a better marker of vascular aging and target for antiaging interventions.

Keywords: aging; senescence; telomere dysfunction; vascular function.

Fig. 1.

Telomere uncapping induced cellular senescence. A: age-related shortening or damage to telomeric DNA may lead to uncapping of the t-loop and initiation of a double-stranded DNA break (DSB) response. The first step in the DSB response is phosphorylation of histone 2A.X (p-H2A.X) molecules within telomeric chromatin, which in turn leads to tumor suppressor protein-p53 (p53) activation. B: activated p53 localizes to its target gene promoters and mediates RNA polymerase (RNA Pol)-dependent expression of the corresponding genes, such as cyclin-dependent kinase inhibitor 1 (p21). p21 is a potent cell cycle inhibitor that physically binds and inhibits cyclin-dependent kinase complexes (CDKs), such as CDK2, to halt the cell cycle. Cellular senescence is a permanent halting of the cell cycle, which leads to secretion of proinflammatory and prooxidant factors.

Fig. 2.

Potential role of telomere uncapping in vascular aging and cardiovascular disease (CVD). Vascular telomere uncapping can lead to senescent cell accumulation and the senescence-associated secretory phenotype (SASP). Senescent cell accumulation leads to chronic SASP-mediated inflammation/oxidative stress, whereas chronically elevated inflammation/oxidative stress will promote further accumulation of senescent cells, as indicated by the bidirectional arrow. Vascular telomere uncapping increases with age (represented by blue line), and individuals with higher (pathological) amounts of vascular telomere uncapping at a given age may potentially have a greater CVD risk (represented by red line). The purple X indicates general targets of present therapeutic strategies for CVD. Green Xs indicate that clearance of senescent cells and attenuation of telomere uncapping represent hypothetical therapeutic targets that could improve CVD outcomes.