Lipofuscin is the name given to a mix of modified proteins, lipids, and other compounds that accumulate with age in long-lived cells. The accumulation of lipofuscin has long been considered a form of damage by a minority of researchers; removal of lipofuscin was an early call to action for the Strategies for Engineered Negligible Senescence, for example. There were even a few early, unsuccessful efforts to provide technology demonstrations of approaches to break down lipofuscin, or at least some of its components. Unfortunately, getting rid of lipofuscin isn't a straightforward task. Chemically it is diverse, a mess of many very different molecules, and thus ill suited as a target for the enzyme, antibody, and small molecule development that dominates the field of medical biotechnology. Getting rid of one specific molecule is feasible, getting rid of a hundred very different molecules is much less feasible. Lipofuscin has been largely left alone in favor of easier goals.
In today's open access paper, the authors restate some of the arguments for lipofuscin to be important in the onset and progression of age-related neurodegenerative conditions, and thus to be a therapeutic target worthy of greater attention on the part of the research and development community. This has all been said before! One of the challenges inherent to the development of rejuvenation therapies at this stage of the growth of the field is that there are far more potentially worthwhile areas of focus than there are research groups, companies, and funding to carry out the work. This will likely remain the case until the first generation of therapies to treat aging are approved, widely used in the clinic, and their existence a matter of fact for the average physician, researcher, and person in the street.
Lipofuscin, which has long been considered a passive byproduct of aging, is increasingly being recognized as a dynamic modulator of cellular homeostasis. Lipofuscin accumulation is indicative of lysosomal dysfunction and is closely related to redox imbalance and lipid peroxidation - critical pathways implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). Lipofuscin accumulation may contribute to and exacerbate amyloid-β accumulation and toxicity by interfering with autophagic clearance and promoting a highly oxidative environment.
In this review, we propose a reconsideration of lipofuscin from the "aging marker" or "autofluorescence pigment" to an active player in neurodegeneration and AD pathology. This paradigm shift opens new research directions and therapeutic possibilities. Targeting lipofuscin and its clearance may allow interference of upstream of amyloid plaque formation, preserving proteostasis, reducing oxidative damage, and ultimately slowing or preventing neurodegeneration.
We examine the potential interplay between lipofuscin accumulation, lysosomal dysfunction, lipid peroxidation and amyloid-β pathology in AD. We explore how lipofuscin may influence amyloid-β aggregation, clearance, and toxicity and propose mechanisms by which lipofuscin modulates AD progression. Importantly, we summarize evidence demonstrating that lipofuscin is released extracellularly upon neuronal death, thus preparing a highly oxidized environment that results in toxicity and a cascade of events leading to plaque formation and amyloid-β pathology.
View the full article at FightAging
