Lipofuscin is membrane-bound cellular waste that can be neither degraded nor ejected from the cell but can only be diluted through cell division and subsequent growth.
The fate of postmitotic cells is to accumulate lipofuscin, which as an "aging pigment" has been considered a reliable biomarker for the age of cells such as neurons and, by extension, their hosts.
In the aging human brain, deposits of lipofuscin are not uniformly distributed but are concentrated in specific regions of functional interest.
The prevailing thought is that the major source of lipofuscin is incomplete lysosomal degradation of damaged mitochondria.
Accumulating evidence suggests that lipofuscin is not benign but can impair the functioning of seemingly unrelated cellular systems, including the ubiquitin/proteasome pathway.
A damaging feedback loop of lysosomal and proteasomal inhibition may occur as lipofuscin accumulates, leading to what has been appropriately named a "garbage catastrophe". Reversing this catastrophe presents a formidable challenge.
Lipofuscin in the Human Central Nervous System
The age-dependent accumulation of lipofuscin in brain cells is one of the most consistent features of aging.
Lipofuscin granules are detectable in a small percentage of neurons in the brains of young children but become progressively and markedly more abundant between the second and ninth decade of life.
This age associated increase in the sheer amount of lipofuscin in brain cells is attended by alterations in its biochemical composition.
The topographic pattern of distribution of lipofuscin accumulation in the human brain is not uniform but displays a particular predilection for certain areas.
Lipofuscin is present in virtually every type of neuron but is most abundant in the largest neurons.
It is prominent in areas of the brain and spinal cord involved in initiating, monitoring, and controlling movement, including the inferior olivary nucleus (Fig. 1), the dentate nucleus of the cerebellum, the globus pallidus, and the motor neurons in the anterior horn of the spinal cord and brainstem.
The latter directly innervate muscles and provide the signals necessary for voluntary movement of the face, eyes, limbs, and trunk.
Lipofuscin abundance increases with age in the cerebral cortex.
Conversely, neurons in certain brain areas appear to be resistant to age-associated lipofuscin accumulation, including neurons in certain regions of the hypothalamus involved in fluid balance and cardiovascular control.
Fig. 1. Lipofuscin in neurons of the human brain.
The aging pigment is shown within (A and B) the cytoplasm of neurons in the inferior olivary nucleus (involved in motor coordination) [(A) and (B) are from adjacent sections]; (C) the hippocampus (involved in memory formation); and (D) a neuron in the substantia nigra (involved in motor control) (shown at high magnification).
In (A), (C), and (D), autofluorescent lipofuscin is visualized under UV light.
The sections have been counterstained with DAPI (blue).
In (B), lipofuscin has been stained red with the periodic acid-Schiff staining method.
Scale bars, 30 μm in (A), (B), and (C), 10 μm in (D).
If the accumulation of lipofuscin within neurons is involved in their age-related demise, it is tempting to ascribe a role for this substance, based on its prevalence in motor areas and cerebral cortex, in the changes in motor fidelity and cognitive decline that accompany aging.
This hypothesis is predicated on the existence of a deleterious influence imposed by lipofuscin accumulation on the integrity of the nervous system.
The observation that neurons that regularly contain abundant lipofuscin (such as the neurons of the lateral geniculate nucleus) are among the most resistant to age-associated degenerative changes represents an important caveat in this respect.
Indeed, it has been proposed that the ability to form lipofuscin is a successful adaptive response and neurons that lose this ability are susceptible to degeneration.
On the other hand, more recent evidence indicates that amassed lipofuscin may be hazardous to cellular functions.
It is well known that lipofuscin accumulation in cells lining the light-sensing organ of the eye (the retina) leads to the most common age-associated visual disorder, age-related macular degeneration.
In addition, a group of inherited, fatal neurological disorders known as the neuronal ceroid lipofuscinoses (NCLs) are illustrative of the destructive capacity of lipofuscin accumulation.
Collectively, these diseases, consisting of eight genetically distinct disorders, comprise the most common pediatric neurodegenerative disease (see Obeid Perspective).
Clinically, they usually present during infancy or childhood, although rare adult forms are recognized.
They are progressive in nature, presenting with (i) visual disturbances leading to blindness, (ii) neurocognitive and physical decline, (iii) increased severity of epileptic seizures, and (iv) premature death.
Pathologically, the diseases are characterized by the aberrant progressive accumulation of an autofluorescent proteinaceous storage material similar to lipofuscin in many cell types.
However, cell death is specific to the central nervous system.
There is considerable evidence that the accumulation of the lipofuscin-like material that characterizes these diseases is secondary to impaired lysosomal function.
Specifically, four of the human genes that are mutated in NCL encode proteins that are located in the lysosome; two of these genes, CLN1 and CLN2, code for enzymes (palmitoyl protein thioesterase 1 and tripeptidyl peptidase 1) that degrade proteins within the lysosome.
Elucidation of the genetic, biochemical, and pathophysiological aspects of the NCLs might shed light on mechanisms underlying lipofuscin accumulation in normal aging.
In the context of the current discussion, they underline two important points.
First, they provide evidence that lipofuscin accumulation can be secondary to impaired lysosomal function as elaborated above.
Second, in most forms of NCL, the major component of the proteinaceous storage material is subunit c of the mitochondrial ATPase synthase complex [F0F1-ATPase].
This finding is compatible with the hypothesis that lipofuscin accumulation is related to impaired lysosomal degradation of mitochondria.