Abstract
Cellular senescence is a physiological process reacting to stimuli, in which cells enter a state of irreversible growth arrest in response to adverse consequences associated with metabolic disorders. Molecular mechanisms underlying the progression of cellular senescence remain unclear. Here, we established a replicative senescence model of human umbilical vein endothelial cells (HUVEC) from passage 3 (P3) to 18 (P18), and performed biochemical characterizations and NMR-based metabolomic analyses. The cellular senescence degree advanced as the cells were sequentially passaged in vitro, and cellular metabolic profiles were gradually altered. Totally, 8, 16, 21 and 19 significant metabolites were primarily changed in the P6, P10, P14 and P18 cells compared with the P3 cells, respectively. These metabolites were mainly involved in 14 significantly altered metabolic pathways. Furthermore, we observed taurine retarded oxidative damage resulting from senescence. In the case of energy deficiency, HUVECs metabolized neutral amino acids to replenish energy, thus increased glutamine, aspartate and asparagine at the early stages of cellular senescence but decreased them at the later stages. Our results indicate that cellular replicative senescence is closely associated with promoted oxidative stress, impaired energy metabolism and blocked protein synthesis. This work may provide mechanistic understanding of the progression of cellular senescence.
Highlights
Aging is characterized by a progressive loss of physiological integrity, leading to impaired functions and increased vulnerability to death [1]
To establish the cellular replicative senescence model, human umbilical vein endothelial cells (HUVEC) cells underwent a total of 61 population doublings level (PDL) till passage 18 (P18)
The replicative senescence of HUVECs was further confirmed by the following results obtained from SA-β-gal assay and proliferation detection: 1) HUVECs exhibited increasing positive rates of SA-βgal-staining cells from 9% up to 91% during serial subcultivation (Figure 1B, 1C); 2) the cell index (CI) values of the cells at the later passages (P10, P14 and P18) were lower than those at the early passages (P3, P6) (Figure 1D); 3) HUVECs showed declining growth rates as the cells were continually passaged (Figure 1E)
Summary
Aging is characterized by a progressive loss of physiological integrity, leading to impaired functions and increased vulnerability to death [1]. Endothelial cells undergo a series of changes at cellular and molecular levels. Apart from the morphological changes, they possess abnormal physiological functions, encompassing the loss of proliferative capacity, apoptosis, G1 phase arrest, morphological and functional alterations of the mitochondria, etc. Senescent cells exhibit increased levels of oxidatively modified proteins, elevated activity of senescence-associated β-galactosidase, and shortened length of the telomere DNA at the www.aging-us.com molecular level. Previous works have identified several cellular and molecular hallmarks of aging, including: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication [1]. It is indicated that several metabolic alterations accumulate over time along with a reduction in biological fitness, suggesting the existence of a “metabolic clock” that controls aging [9]. Metabolisms and metabolic control plays crucial roles in aging [9]
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