Neurolipofuscin in Aging and Aluminum-Induced Aging: Possible Therapeutic Interventions

Abstract

Neurolipofuscin is considered a reliable biomarker of aging. Accumulating evidence indicates that it is not simply an inert, harmless, wear and tear pigment but it distorts the protein building machinery of the cell and interferes with the important autophagic process. Numerous forms of cellular stresses activate macroautophagy. Increased autophagic vacuoles (AVs) are associated with not only aging and ceroid disorders but also Alzheimer’s disease. Mitochondria may have means for specifically targeting macroautophagy degradation which would be particularly important for the healthy long axons and distal terminals. The decomposition of mitochondrial material is not only an important source of lipofuscin, but is at the same time a key to the understanding of mechanism of aging. Lipofuscin may become indigestible because the proteins are ‘fixed’ via aldehyde bridges between amino groups. The increasing proportion of defective mitochondria and an ever decreasing supply of functional lysosomes are postulated to hasten the senescence and/or demise of the postmitotic cells. Oxidatively damaged mitochondria may contain some already peroxidized undegradable macromolecules. Brain aluminum content is known to increase with age Aluminum toxicity might be one of the underlying causes of Alzhemier’s disease. Accumulation of this element in aged neurons has been demonstrated along with increment of lipofuscin. Both aluminum and iron bind to transferrin receptor before crossing the blood-brain barrier via transferrin mediated endocystosis. High level of iron, concomitant with increased aluminum content, has been detected in the aged rat brain. Accumulating evidence indicates that chronic aluminum administration accelerates aging process. A number of antioxidants have been reported to decrease lipofuscin content of neurons. Centrophenoxine facilitates elimination of lipofuscin. Also, citiolone retards lipofuscinogenesis. Recently, some Ayurvedic herbal remedies, such as Maharishi Amrit Kalash, have been found to reduce lipid peroxidation and lipofuscin deposition. Administration of extract of Bacopa monnieri, which possesses strong antioxidant activity, has also successfully reduced lipofuscin content of neurons subjected to aluminum-induced lipofuscinogenesis. We thus conclude that accumulation of lipofuscin, mitochondrial dysfunctioning and increased reactive oxygen species may be significant indicator of aging—perhaps even central to our understanding of the complex phenomenon of aging.