Perspectives

Causes:

• Vitamin A and Vitamin E deficiency
• Ischemia
• Free radical damage
• Proteolytic reactions
• Increased intake of PUFAs
• Senility associated reduction of protelolytic pathways
• Certain chemicals
  
  Drugs that induce Lipofuscinosis:
• Phenothiazines
• Phenacetin
• Leupeptin ( protease inhibitor)
• Clofibrate
• Phthalates
• Amiodarone
• Rifabutin ( Antitubercular agent)
• Avasimibe
  
  Putative Mechanism of Lipofuscinosis
  
  It is widely theorized that the damage to the cellular organelles by oxidative processes, in particular lipid per-oxidation, contributes to the Lipofuscin formation (Tsai et al., 1998). It has also been reported that incubation of various amine-containing compounds with lipid peroxidation products, such as malonealdehyde or 4-HNE, which leads to the protein-protein cross-linking, results in the appearance of fluorescence reminiscent of Lipofuscin and ceroid .
  
  The drugs which are foreign to the organism can increase the production of free oxygen radicals either spontaneously or by means of metabolic activation, or they can act as inhibitors of protective enzymic systems. They can thus activate the process of peroxidation of lipids causing gradual structural degradation of biomembranes. The protease inhibition has been previously shown to cause an intralysosomal accumulation of Lipofuscin and is sufficient to cause accumulation of Lipofuscin in several species and organ systems.
  
  Consequences (in humans):
• Neuromuscular dysfunction
• Macular degeneration
• Dementia
• The proto-oncogene bcl-2 produces its protein product in direct response to Lipofuscinosis. This protein inhibits generation of free radicals. This hyper response could lead to increased concentration of bcl-2 protein inside the cells and increases the probability that carcinogenesis will occur and rapid division of these bcl-2 active cells is not hindered by the normal concentration of Lipofuscin that is present in cells where bcl-2 protein levels are lower. This selective advantage helps to speed up cell division and metastasis.
• In autonomic nervous dysfunction concentration of LF correlated well with distension of neural structure. LF accumulation appears to directly affect cell integrity and to disrupt metabolic processes in these cases.
• Cochlear edema causes nerve-pressure deafness. It has been positively correlated with LF accumulation in the subcuticular cytoplasm of hair cells of the cochlea.
• Oxidative stress leads to arrest of the cell cycle in G1 (measured by flow cytometry), an acceleration of telomere degradation from 90 bp per doubling to 500 bp per doubling, and a sharp increase in lipofuscin content. These authors propose that LF presence might be contributing to telomere damage and possibly to other failures in accurate genetic replication.
• A young adult domestic cat, euthanized because of severe neurologic disease, was found to have high levels of LF in neurons of the CNS and PNS. The cat suffered from seizures, blindness, and diminished motor control.
• Palsy, dementia, weakness, malabsorption and organ failure may occur.
  
  Possible Avenues of Intervention:
• Vitamin E supplements reduced LF-related neuromuscular dysfunction.
• Physiological levels of spermine reduce LF accumulation by 20%, and that antioxidative effect compares with that of Vitamin E. Spermine prevents accumulation of free iron in myocytes, probably acting as a chelating agent.
• Methods of increasing glutathione (a natural antioxidant) production (creating a hostile environment to Lipofuscin) could retard neuronal accumulation of Lipofuscin. This might be accomplished through supplements or even using gene therapy.