Lipofuscin

Oxidative stress plays a crucial role in the development of the aging process and age dependent diseases. Both are closely connected to disturbances of proteostasis by protein oxidation and an impairment of the proteasomal system. The final consequence is the accumulation of highly cross-linked undegradable aggregates such as lipofuscin. These aggregates of damaged proteins are detrimental to normal cell functions. Here we provide an overview about effect of these aggregates on the proteasomal system, followed by transcription factor activation and loss of cell viability. Furthermore, findings on the mechanism of radical genesis, proteasomal inhibition and the required components of lipofuscin formation were resumed.

BackgroundsSelenium (Se) as one of the essential trace elements for human plays an important role in the oxidation reduction system. But the high toxicity of Se limits its application. In this case, the element Se with zero oxidation state (Se0) has captured our attention because of its low toxicity and excellent bioavailability. However, Se0 is very unstable and easily changes into the inactive form. By now many efforts have been done to protect its stability. And this work was conducted to explore the antioxidant capacities of the stable Se0 nanoparticles (SeNPs) stabilized using chitosan (CS) with different molecular weights (Mws) (CS-SeNPs).ResultsThe different Mws CS-SeNPs could form uniform sphere particles with a size of about 103 nm after 30 days. The antioxidant tests of the DPPH, ABTS, and lipid peroxide models showed that these CS-SeNPs could scavenge free radicals at different levels. And the 1 month old SeNPs held the higher ABTS scavenging ability that the value could reach up to 87.45 ± 7.63% and 89.44 ± 5.03% of CS(l)-SeNPs and CS(h)-SeNPs, respectively. In the cell test using BABLC-3T3 or Caco-2, the production of the intracellular reactive oxygen species (ROS) could be inhibited in a Se concentration-dependent manner. The topical or oral administration of CS-SeNPs, particularly the Se nanoparticles stabilized with low molecular weight CS, CS(l)-SeNPs, and treated with a 30-day storage process, could efficiently protect glutathione peroxidase (GPx) activity and prevent the lipofusin formation induced by UV-radiation or D-galactose in mice, respectively. Such effects were more evident in viscera than in skin. The acute toxicity of CS(l)-SeNPs was tenfold lower than that of H2SeO3.ConclusionsOur work could demonstrate the CS-SeNPs hold a lower toxicity and a 30-day storage process could enhance the antioxidant capacities. All CS-SeNPs could penetrate the tissues and perform their antioxidant effects, especially the CS(l)-SeNPs in mice models. What's more, the antioxidant capacities of CS-SeNPs were more evident in viscera than in skin.

β-Secretase (BACE1) is a major drug target for combating Alzheimer's disease (AD). Here we show that BACE1(-/-) mice develop significant retinal pathology including retinal thinning, apoptosis, reduced retinal vascular density and an increase in the age pigment, lipofuscin. BACE1 expression is highest in the neural retina while BACE2 was greatest in the retinal pigment epithelium (RPE)/choroid. Pigment epithelial-derived factor, a known regulator of γ-secretase, inhibits vascular endothelial growth factor (VEGF)-induced in vitro and in vivo angiogenesis and this is abolished by BACE1 inhibition. Moreover, intravitreal administration of BACE1 inhibitor or BACE1 small interfering RNA (siRNA) increases choroidal neovascularization in mice. BACE1 induces ectodomain shedding of vascular endothelial growth factor receptor 1 (VEGFR1) which is a prerequisite for γ-secretase release of a 100 kDa intracellular domain. The increase in lipofuscin following BACE1 inhibition and RNAI knockdown is associated with lysosomal perturbations. Taken together, our data show that BACE1 plays a critical role in retinal homeostasis and that the use of BACE inhibitors for AD should be viewed with extreme caution as they could lead to retinal pathology and exacerbate conditions such as age-related macular degeneration.

ObjectivesThere is a lack of evidence linking oxidative stress to muscle dysfunction and the worsening of obstructive sleep apnea (OSA). Lipofuscin is a permanent intracellular deposit that accumulates with aging or oxidative stress. Its increase in skeletal muscles may lead to limitations in muscle function, such as weakness and fatigue. We aim to investigate whether lipofuscin deposits in the upper airway muscles of patients with severe OSA are increased compared to those in patients with primary snoring or very mild OSA.MethodsWe studied pharyngeal framework muscle tissue samples from non-obese adults, with one group having severe OSA and another having primary snoring or very mild OSA (snorer group). Lipofuscin was identified by analyzing staining patterns from Sudan Black B and fluorescence microscopy. We compared lipofuscin levels and distribution in the muscle fibers between the groups.ResultsDespite presenting similar age and body mass index, patients with severe OSA exhibited markedly larger and more concentrated deposits of lipofuscin in the upper airway muscles, particularly along the borders of the muscle fascicles, compared to the snorer group.ConclusionCompared to primary snorers, patients with severe OSA accumulate lipofuscin in their pharyngeal muscles. Our findings may provide novel insight into the role of lipofuscin as both a marker and a cause of the aggravation of OSA, in light of a possible lipofuscin-induced progressive myopathy.Level of evidence: 3