Abstract
One of the core regulators of cellular aging are telomeres, repetitive DNA sequences at the ends of chromosomes that are maintained by the ribonucleoprotein DNA polymerase complex, telomerase. Recently, we demonstrated that knockdown of the 37kDa/ 67kDa laminin receptor (LRP/LR), a protein that promotes cell viability in tumorigenic and normal cells, reduces telomerase activity. We therefore hypothesized that upregulating LRP/LR might increase telomerase activity and impede aging. Here we show that overexpression of LRP::FLAG resulted in significantly elevated hTERT levels, telomerase activity and telomere length, respectively, with concomitantly reduced levels of senescence markers. These data suggest a novel function of LRP/LR hampering the onset of senescence through elevating hTERT levels and telomerase activity, respectively. LRP::FLAG might therefore act as a potential novel anti-aging drug through the impediment of the cellular aging process.
Highlights
Aging is a degenerative process characterized by the accumulation of detrimental changes that cause deterioration of the physiological functioning of the organism [1]
In order to validate that upregulation of LRP/LR does increase telomerase activity, non-tumorigenic Medical Research Council (MRC) 5 cells, at population doubling 23, and Human Embryonic Kidney Cells hTERT (HEK293) cells were stably transfected with a pCIneo-moLRP-FLAG plasmid effectively elevating LRP::FLAG levels within the cells (Figure 1A, 1B)
We have shown that aside from tumorigenic and other highly proliferative cell lines that naturally transcribe telomerase reverse transcriptase (TERT); a functional relationship between LRP/LR and hTERT exists in somatic cells such as fibroblasts, which are only capable of displaying such an interaction provided TERT production is stimulated
Summary
Aging is a degenerative process characterized by the accumulation of detrimental changes that cause deterioration of the physiological functioning of the organism [1]. The process is characterized in cells by telomere erosion, genomic instability, mitochondrial dysfunction and stem cell exhaustion [1] These stresses drive cellular senescence by limiting the replicative and regenerative potential of cells, this drives functional decline and disrupts tissue homeostasis to accelerate the aging process [2, 3]. There have been a number of findings illustrating that in addition to its role in telomere extension, telomerase and its enzymatic subunit, telomerase reverse transcriptase (TERT), have other functions. We demonstrated that knockdown of LRP/ LR, reduces telomerase activity in tumorigenic and normal cells [14, 15] This suggests that LRP/LR, which promotes cell viability, plays a pivotal role in cancer processes via influencing telomerase activity [14]. Considering that telomerase and telomeres play antagonistic roles in cancer and aging [25], we postulated that an upregulation of LRP/ LR may increase telomerase activity and possibly impede the aging process
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