Today I’ll point out an open access review of what is known of the activities of lipofuscin in neurodegenerative disease. The central nervous system falters and runs awry with age, and some fraction of that decline can be attributed to the growing presence of lipofuscin in long-lived neurons. Lipofuscin is a poorly categorized mix of hardy metabolic waste, such as oxidized lipids and sugars, much of it resistant to the comprehensive toolkit of enzymes and waste management processes that cells are equipped with. There is some debate over whether or not cells could, if less impacted by aging, clear out their lipofuscin, or whether even young cells would be challenged to carry out that task. It is probably the case that accumulation in old cells is some mix of failed housekeeping and compounds that even adequate housekeeping would struggle with.
The SENS rejuvenation research programs class lipofuscin as a fundamental cause of aging, a distinguishing point of difference between old and young tissues that is created as a side-effect of the normal operation of healthy metabolism. The suggested approach for dealing with this problem is to search for enzymes in soil bacteria that can break down lipofuscin constituents, tackling the many classes of unwanted compound in some order of priority. We know that these enzymes exist: graveyard soil is not enriched in lipofuscin. Exactly this sort of work led to the LysoClear program, targeting A2E in the retina, as well as efforts to break down 7-ketocholesterol, associated with cardiovascular disease. There are many more classes of compound to tackle, however, and a comparative paucity of players in this space. This is one of many areas of rejuvenation research where determined individuals with funding and the will to act could make a sizable difference.
For any factor to be considered a hallmark of aging, it should meet the following criteria: (I) it should be present during normal aging; (II) its exacerbation should trigger an accelerated aging; and (III) its amelioration should prevent the normal aging course, even extending lifespan. Accordingly, one of the most relevant features of aging is related to the increasingly dysfunctional mechanisms of renewal of cellular constituents that precludes the clearance of damaged biomolecules and organelles and its replacement by new functional structures. This sustained inefficient recycling mechanism leads to the accumulation of unfit molecules that further interfere with cellular functions, preferentially within long-lived post-mitotic cells such as neurons. Among the main components of this biological “garbage,” we could find indigestible protein aggregates, defective mitochondria, and lipofuscin (LF).
LF is a fluorescent complex mixture composed of highly oxidized cross-linked macromolecules with multiple metabolic origins. The nature and structure of LF complexes seem to vary among tissues and show temporal heterogeneity in composition of oxidized proteins (30-70%), lipids (20-50%), metals cations (2%), and sugar residues. Because of its polymeric and highly cross-linked nature, LF cannot be degraded, nor cleared by exocytosis, thus being accumulated within the lysosomes and cell cytoplasm of long-lived post-mitotic and senescent animal cells. Opposite, proliferative cells efficiently dilute LF aggregates during cell division, showing low or no accumulation of the pigment. For this reason, LF deposits are especially abundant in nerve cells, cardiac muscle cells, and skin.
LF is considered a hallmark of cellular aging. In normal aged mammal brains, LF distributes delineating a specific senescence pattern that correlates with altered neuronal cytoskeleton and cellular trafficking. Thus, as we age, the brain of the human adult becomes heavily laden with intraneuronal deposits of LF and neuromelanin pigment. However, in neurodegenerative disorders, LF aggregates appear to increase not only with age but also with pathological processes such as neuronal loss, proliferation, and activation of glial cells, and a repertoire of cellular alterations, including oxidative stress, proteasome, lysosomal, and mitochondrial dysfunction.
In order to discuss whether LF is a subproduct of defective cellular homeostasis associated with aging or it has a pathological role of its own in neurodegeneration, it is relevant to compare the temporal profile of accumulation of LF aggregates with pathognomonic protein deposits associated with diverse neurodegenerative disorders. Interestingly, the temporal pattern of accumulation is similar to the one observed for protein deposits in different neurodegenerative disorders. Data suggests a neuropathological role of LF by impairing the same mechanisms and acting like other protein aggregates (e.g., amyloid beta, tau, alpha-synuclein) of different neurodegenerative diseases.