Telomere‐dependent senescent phenotype of lens epithelial cells as a biological marker of aging and cataractogenesis: the role of oxidative stress intensity and specific mechanism of phospholipid hydroperoxide toxicity in lens and aqueous

Abstract

Cataract formation represents a serious problem in the elderly and has a large impact on healthcare budget. Aging and cataract formation are relatively complex phenomena, both in vivo and in vitro. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication, and this has been characterized as a mitotic counting mechanism. Our review analysis in this work shows that the rate of telomere shortening in human lens epithelial cells during aging and cataract formation is modulated by oxidative stress as well as by differences in antioxidative defense capacity of the normal and cataractous crystalline lenses. Presented in this review studies suggest that telomere shortening in human lens cells and increased oxidative stress are the result of the peroxidative damage to the lens cell membranes and biomolecules induced in the lack of reductive detoxification of phospholipid hydroperoxides as the triggering mechanism of cataractogenesis. Lipid peroxidation (LPO) is a causative factor of cataract. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products were detected in the lipid moieties of the aqueous humor samples obtained from patients with senile and complicated cataracts when compared to normal donors. The progressive accumulation of oxidative damage may act as an important mechanism for organism aging and cataractogenesis. The oxidative stress form and intensity might determine the lens senescence rate and cataract type, making efforts in the cataract prevention challenge more complex. The analyzed challenge in this work is that the reduction in telomere shortening rate and damages in telomeric DNA make an important contribution to the anticataract and life-extension effect of carnosine administered systemically in the formulations stabilizing a dipeptide from the enzymatic hydrolysis with carnosinase, or topically administered to the eye with carnosine ophthalmic prodrug N-acetylcarnosine and lubricant formulations thereof including corneal absorption promoters. Telomere length in the human crystalline lens cells is a reflection of aging, cataractogenesis, and lifespan in biogerontological studies.

Influence of cataract maturity on aqueous humor lipid peroxidation markers and antioxidant enzymes

“…AH contains approximately 4 mg/ml of HDL lipoproteins whose PUFA can be subjected to LPO, but may include a broad spectrum of other molecules and LPO adducts originating from adjacent injured or apoptotic cells, resulting in LLF levels of about 130 RFU in aged noncataractous subjects. 2,17 In the current study, almost all biochemical variables displayed age-related Aqueous humor oxidants and antioxidants in cataract DJ Miric et al dependency ( Figure 1) in such way that levels of LPO adducts were increased, whereas SOD and, to some extent, total proteins and CAT were decreased in elderly groups (Table 1). Beyond ageing process, there could be multiple other factors influencing the AH oxidative stress markers.…”

“…The other reason is that in SC the antioxidant genes can be markedly downregulated, 29 and the progression of SC has already been associated with decreased GPx activity, both at local and systemic level. 2,3 Furthermore, lenses of acatalasemic mice were demonstrated to be almost as efficient in degrading the H 2 O 2 ex vivo as those of the wild type, 30 indicating that CAT itself may not be of critical importance for prevention of lens oxidative damage. In the current study, the average CAT activity in AH was 32 pmol/ml, and was unrelated to oxidative stress status and, as in a previous study, 5 unaffected by cataract maturity.…”

“…It is now well established that excess levels of ocular oxidants can cause damage to the lens and other tissues, which are implicated in normal ageing process and in pathogenesis of several eye diseases, such as pseudoexfoliation syndrome, diabetic retinopathy, glaucoma, and senile cataract (SC). [1][2][3][4][5][6][7] The toxicity of oxidants depends on their ability to induce cross-linking, aggregation, fragmentation, and insolubilization of structural proteins, inactivation of enzymes, and lipid peroxidation (LPO) of the membrane-bound polyunsaturated fatty acids (PUFA), leading to impaired cell function, apoptosis, and necrosis. 1,2 Unlike ocular tissues, AH contains only small quantities of proteins and antioxidant enzymes, and its antioxidant defense thus relies on unusually high levels of low-molecular weight antioxidants, mostly ascorbic acid, present at the level of B1 mM, even in SC.…”

“…[1][2][3][4][5][6][7] The toxicity of oxidants depends on their ability to induce cross-linking, aggregation, fragmentation, and insolubilization of structural proteins, inactivation of enzymes, and lipid peroxidation (LPO) of the membrane-bound polyunsaturated fatty acids (PUFA), leading to impaired cell function, apoptosis, and necrosis. 1,2 Unlike ocular tissues, AH contains only small quantities of proteins and antioxidant enzymes, and its antioxidant defense thus relies on unusually high levels of low-molecular weight antioxidants, mostly ascorbic acid, present at the level of B1 mM, even in SC. 7 There is, however, no reliable data about peroxide levels in AH under either physiological or pathological conditions, presumably because such amounts of ascorbic acid strongly interfere with most biochemical methods commonly used for the estimation of H 2 O 2 .…”

Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting

“…However, in this work, we raise a new therapeutic concept, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur, with the demonstrated evidence of telomere shortening appeared to be a hallmark of oxidative stress and disease [7][8][9][10].…”