Lipofuscin Accumulation and Ageing of Fibroblasts

Zglinicki, Thomas von; Nilsson, Evalill; Döcke, W D; Brunk, Ulf T.

doi:10.1159/000213728

Cited by 85 publications

(64 citation statements)

References 10 publications

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“…A vicious circle involving ROS production might reinforce the mitochondrial defects and promote the accumulation of lipid and protein peroxidation products. 37 ROS accumulation can also result from and activate cellular stress pathways that participate in cell growth arrest. 23 Furthermore, ROS can trigger DNA damage, and a defective DNA repair response has been shown to be an important pathophysiological mechanism in premature ageing linked to genetically altered prelamin A maturation.…”

Section: Discussionmentioning

confidence: 99%

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

et al. 2007

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Lipodystrophic syndromes associated with mutations in LMNA, encoding A-type lamins, and with HIV antiretroviral treatments share several clinical characteristics. Nuclear alterations and prelamin A accumulation have been reported in fibroblasts from patients with LMNA mutations and adipocytes exposed to protease inhibitors (PI). As genetically altered lamin A maturation also results in premature ageing syndromes with lipodystrophy, we studied prelamin A expression and senescence markers in cultured human fibroblasts bearing six different LMNA mutations or treated with PIs. As compared to control cells, fibroblasts with LMNA mutations or treated with PIs had nuclear shape abnormalities and reduced proliferative activity that worsened with increasing cellular passages. They exhibited prelamin A accumulation, increased oxidative stress, decreased expression of mitochondrial respiratory chain proteins and premature cellular senescence. Inhibition of prelamin A farnesylation prevented cellular senescence and oxidative stress. Adipose tissue samples from patients with LMNA mutations or treated with PIs also showed retention of prelamin A, overexpression of the cell cycle checkpoint inhibitor p16 and altered mitochondrial markers. Thus, both LMNA mutations and PI treatment result in accumulation of farnesylated prelamin A and oxidative stress that trigger premature cellular senescence. These alterations could participate in the pathophysiology of lipodystrophic syndromes and lead to premature ageing complications. LMNA-linked lipodystrophies and progeroid syndromes form a clinical continuum of related phenotypes. 2-8 Otherwise, HIV-infected patients receiving antiretroviral therapy frequently develop a lipodystrophy syndrome associated with a high risk of metabolic and cardiovascular complications. 9 These patients also face a growing number of other agerelated comorbidities, such as neurodegeneration, osteopenia and malignancies. 10 A-type lamins are nuclear proteins required for the structural and functional integrity of the nucleus. Lamin A is translated as a protein precursor that undergoes several maturation steps, including the addition of a C-terminal farnesyl residue, which is subsequently removed by proteolytic cleavage (reviewed by Mattout et al 1 ). Defective physiological maturation of prelamin A is the main pathophysiological mechanism underlying several premature ageing syndromes, including the Hutchinson-Gilford progeria syndrome (HGPS) (reviewed by Young et al 11 ). Several studies have convincingly demonstrated that the retention of the farnesylated residue confers toxic properties to the partially processed prelamin A. 11-13 Both cellular abnormalities [14][15][16][17] and premature ageing phenotype in mice 18 are significantly improved by using drugs that inhibit prelamin A farnesylation.

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Section: Discussionmentioning

confidence: 99%

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

et al. 2007

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“…The expression of a telomerase transgene in cell lines derived from patients with Werner syndrome results in lengthened telomeres and replicative immortalization, thus indicating that the shortening of telomeres is a trigger of premature senescence in these cells (107). Several more recent reports showed that telomere shortening can be induced in fibroblasts by mild oxidative stress (533,602,603).…”

Section: E Oxidative Induction Of Telomere Shorteningmentioning

confidence: 99%

Free Radicals in the Physiological Control of Cell Function

Dröge

2002

Physiological Reviews

8,379

5,836

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At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, however, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and reestablish “redox homeostasis.” Higher organisms, however, have evolved the use of NO and ROS also as signaling molecules for other physiological functions. These include regulation of vascular tone, monitoring of oxygen tension in the control of ventilation and erythropoietin production, and signal transduction from membrane receptors in various physiological processes. NO and ROS are typically generated in these cases by tightly regulated enzymes such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. In a given signaling protein, oxidative attack induces either a loss of function, a gain of function, or a switch to a different function. Excessive amounts of ROS may arise either from excessive stimulation of NAD(P)H oxidases or from less well-regulated sources such as the mitochondrial electron-transport chain. In mitochondria, ROS are generated as undesirable side products of the oxidative energy metabolism. An excessive and/or sustained increase in ROS production has been implicated in the pathogenesis of cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and other diseases. In addition, free radicals have been implicated in the mechanism of senescence. That the process of aging may result, at least in part, from radical-mediated oxidative damage was proposed more than 40 years ago by Harman ( J Gerontol 11: 298–300, 1956). There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.

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“…Cell injury by accumulation of lipofuscin arises due to the large amount of iron, which facilitates the generation of oxygen free radicals causing lysosome damage and destabilization of the cell by releasing free radicals or enzymes hidrolases 29 . It was suggested that this accumulation reduces the cellular protein turnover and the half-life of mitochondria causing degeneration and cell death 30 .…”

Section: Long Term Evaluation Of Morphometric and Ultrastructural Chamentioning

confidence: 99%

Long term evaluation of morphometric and ultrastructural changes of testes of alloxan-induced diabetic rats

Trindade¹,

Simões

Silva

et al. 2013

Acta Cir. Bras.

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PURPOSE:To evaluate in a long term the morphometric and ultrastructural changes in seminiferous tubules (ST) of normal and diabetic rats, and to correlate any changes with animal age and diabetes duration. METHODS:Sixty male Wistar rats, three months-old, were randomly divided into two groups: 30 non-diabetic controls (N) and 30 alloxan untreated diabetic (D). After one, six and 12 months of follow-up or diabetes induction rats were sacrificed and the testes examined. Morphometric measures of the ST were performed by digital imaging analysis. ST ultrastructure was analyzed by transmission electron microscopy. RESULTS:Sustained hyperglycemic state was observed in all diabetic rats throughout the study. Serum testosterone was also significantly decreased in these animals. The diameter, total area, epithelium area and epithelium thickness of ST were lower and tubular density was higher in diabetic animals. Diabetic rats also showed ultrastructural changes compromising the whole testis including germ-, Sertoli-, and Leydig cells, and also the mithocondria and cellular nuclei. Most frequent of these consisted of vacuolization and/ or accumulation of lipid droplets and electron dense dark material in cell cytoplasm and/or in membranes, cellular degeneration, and apoptosis. Non-diabetic control rats also showed testicular lesions that resemble to the diabetic lesions, although much less severe and with later onset in life of these animals. CONCLUSION:Histopathological changes observed in testes of normal and diabetic rats are closely related to the animal age and/ or duration of the hyperglycemic state, being progressively more severe in animals sacrificed belatedly. These changes may play an important role in male infertility observed in diabetic subjects.

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Lipofuscin Accumulation and Ageing of Fibroblasts

Cited by 85 publications

References 10 publications

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence

Free Radicals in the Physiological Control of Cell Function

Long term evaluation of morphometric and ultrastructural changes of testes of alloxan-induced diabetic rats

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