ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways

Table 1

Interactions of H₂O₂ and aging pathways.

Mechanism	Target	Finding	Ref.
Inflammation	Nf-κB/AP-1	H2O2-induced Nf-κB/AP-1 phosphorylation and promoted cytokines releases such as Tnf-α, IL-6, and protein expression VCAM-1 and ICAM-1, plus increasing senescence markers such as β-galactosidase activity and γH2AX, which result in HUVEC aged phenotype	[188]
Proliferation	Ki67/p16/p21/DNA	H2O2 showed a dramatic decrease in Ki67 expression, indicating cell cycle arrest, which was confirmed by an increase in subG1 phase and low S phase proportion, high p16 and p21 levels, and positivity for SA-β-Gal, indicating age phenotype in SH-SY5Y neuroblastoma cells	[189]
Telomere dysfunction	8-oxoG/TRF1/ TRF2	H2O2 induces 8-oxoG formation and reduces telomeric binding proteins TRF1 and TRF2 expression, leading to telomere shortening/dysfunction, which results in chromosome instability, especially end-to-end fusions, leading to senescence in fibroblast-derived from human fetal lung	[190]
Epigenetic alterations	Elovl2	H2O2 increases Elovl2 gene methylation, which disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to metabolism dysfunction and senescence morphology, being correlated with human fibroblast aged phenotype	[191]
Loss in proteostasis	Cytosolic and nuclear proteins	H2O2 induced protein carbonylation, especially in the cytoplasm of young and senescent cells, whereas nuclear protein carbonylation was found only in senescent cells upon oxidative stress conditions, indicating that proteasomal systems can clear oxidized proteins in young but not in aged phenotype fibroblast cells	[192]
Deregulated autophagy	LC3/LC1/p62	H2O2 decreased autophagic flux by reducing the LC3/LC1 ratio and raising the p62 level, in addition to lowering pRb expression, which is essential to cell cycle progression, leading to HUVECs senescence	[193]
Bioenergetics	ETC/ATP	H2O2 promotes mitochondrial failure by decreasing mitochondrial membrane potential, oxygen consumption, ATP levels, and raising mitochondrial and cytosolic ROS in human neuroblastoma SH-SY5Y cell line	[194]
Cell death	Bax/Bcl-2	H2O2 reduces cell viability and increases the apoptotic rate by increasing Bax/Bcl-2 ratio, raising caspase levels, plus SA-β-Gal and inflammatory cytokines such as IL-6 and Tnf-α, leading to an aging phenotype in HUVECs	[195]
Senescence	β-galactosidase/p16/p21	H2O2 stimulate premature senescence by increase p16 and p21 expression which result in cell cycle arrest, in addition to enhance β-galactosidase activity in human skin fibroblast	[196]

Abbreviations: Nf-κB (nuclear factor kappa B); AP-1 (activator protein 1); Tnf-α (tumour necrosis factor-alpha); IL-6 (interleukin 6); VCAM-1 (vascular cell adhesion molecule 1); ICAM-1 (intercellular adhesion molecule 1); γH2AX (H2A histone family member X); HUVEC (human umbilical vein endothelial cells); Ki67 (marker Of proliferation Ki-67); SH-SY5Y (human neuroblastoma cell line SH-SY5Y); 8-oxoG (8-oxoguanine); TRF1 and TRF2 (telomere repeat binding factor 1 and 2); ELOVL (protein coding fatty acid elongase 2 gene); LC3 and LC1 (microtubule-associated protein light chain 3); ETC (electron transport chain); ATP (adenosine triphosphate); BAX (BCL2 associated X-apoptosis regulator); and Bcl-2 (BCL2-apoptosis regulator Bcl-2).