Sci. Aging Knowl. Environ., 2 February 2005
Vol. 2005, Issue 5, p. re1
[DOI: 10.1126/sageke.2005.5.re1]


Lipofuscin and Aging: A Matter of Toxic Waste

Douglas A. Gray, and John Woulfe

Douglas A. Gray is at the Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada K1H 1C4 and the Ottawa Health Research Institute, Ottawa, Ontario, Canada K1Y 4E9. John Woulfe is at the Ottawa Health Research Institute, Ottawa, Ontario, Canada K1Y 4E9 and in the Department of Pathology, Ottawa Hospital, Ottawa, Canada K1Y 4E9. E-mail: dgray{at} (D.A.G.)

Key Words: lipofuscin • biomarker • mitochondrial-lysosomal axis theory of aging • ubiquitin/proteasome system • neuronal ceroid lipofuscinoses • garbage catastrophe

Abstract: 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.

What Is Lipofuscin? Back to Top

Lipofuscin (meaning "dark fat," drawing from both Greek and Latin) is a complex entity that is currently defined operationally rather than structurally. It is yellow-brown in appearance by conventional microscopy, detectable across a broad spectrum by fluorescence microscopy, and in all metazoans for which information is available is more abundant in aged individuals than in young ones (hence the alternative designation "age pigment" or "aging pigment"). The nearly linear accumulation of lipofuscin with increasing age in the nervous systems of creatures in the wild has made possible the reliable estimation of absolute age, serving as a particularly useful biomarker where physical metrics may be influenced by environmental conditions [for example, in crustaceans (1)].

Lipofuscin (which is used here in preference to ceroid, a term often used to denote disease-associated lipofuscin) is a complex mixture of oxidized protein and lipid degradation residues, along with lesser amounts of carbohydrates and metals. The relative contribution of the major components can be approximated to two-thirds protein, one-third lipid (2). Iron is predominant among the metals in lipofuscin (3, 4); copper, zinc, and other metals have also been detected (5). As will be discussed below, the complex composition of lipofuscin is likely the consequence of failed degradation of a complex organelle: the mitochondrion. Decades might be required for the "natural" accumulation of lipofuscin in the human brain, but in the laboratory one can generate a very good facsimile with all the properties of the body's aging pigment in a good day's work. By purifying mitochondria from the mouse liver and extensively cross-linking their constituents with ultraviolet (UV) irradiation, one can obtain a substance with properties quite like those of aging pigment (6). With UV cross-linking, the synthetic lipofuscin (Fig. 1) develops the spectral properties of the natural substance, with maximal excitation at about 360 nm and a broad emission spectrum with its peak at 540 to 650 nm [lipofuscin can also be detected by histochemical methods, including Sudan black staining for lipid moieties or period acid-Schiff for carbohydrates (5)]. Like the "natural" lipofuscin, the UV-cross-linked product is taken up by cells in culture through endocytosis but cannot be degraded (Fig. 2). The invulnerability of natural lipofuscin to cellular proteolysis has been attributed to aldehyde cross-linking of peptide amine groups to create stable polymeric structures (7).

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Fig. 1. Substance with properties of lipofuscin, prepared by UV cross-linking of mouse liver mitochondria. The pellet in the tube on the right was obtained from homogenized tissue prior to cross-linking; the pellet on the left was from cross-linked material. In the lower panel, the tubes were illuminated under fluorescent light using a filter cube designed for the detection of fluorescein isothiocyanate. [Fluorescence of the cross-linked material was also evident using 4',6-diamidino-2-phenylindole-2HCl (DAPI) or Cy3 filter cubes.]


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Fig. 2. Accumulation of synthetic lipofuscin in cultured cells. Midpassage human WI-38 fibroblasts were cultured with (lower panel) or without (upper panel) UV-cross-linked mouse liver mitochondria in the culture media. After two weeks of culture, autofluorescent granules could be detected in the cytoplasm of treated cells. In this experiment, autofluorescence was detected using a rhodamine filter cube. Nuclei were counterstained with a fluorescent dye that reveals cell nuclei (DAPI, blue). Scale bars, 50 µm.


The Free-Radical Model of Lipofuscin Accumulation Back to Top

The free-radical theory of aging, as set out by Harman in 1956 (see Harman Classic Paper), casts oxygen radicals produced by "interaction of the respiratory enzymes involved in the direct utilization of molecular oxygen, particularly those containing iron..." in the starring causative role (8) (see "The Two Faces of Oxygen"). Harman's paper cites the work of Fenton, whose eponymous chemistry is based on the reactive properties of ferrous iron in the generation of the highly reactive hydroxyl radical. Much subsequent work has localized this iron to mitochondria, residing in the cytoplasm or within autophagolysosomes, wherein damaged mitochondria are disassembled for recycling (9, 10). The cascade of events initiated by the hydroxyl radical is thought to culminate with the formation of aldehydes such as malondialdehyde [a quantifiable product of lipid peroxidation (11) and a suitable proxy for reactive oxygen status within mitochondria]. It is probably the aldehyde bridges linking amino groups that make the proteinaceous component of lipofuscin so refractory to lysosomal degradation. The mitochondrial-lysosomal axis theory of aging (12) posits that the futile task of attacking lipofuscin acts as a sink for lysosomal enzymes, impeding the degradation of damaged mitochondria. 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 cell.

Lipofuscin and Proteasome Inhibition: Yet Another Vicious Circle Back to Top

The mitochondrial-lysosomal axis theory of aging (12) makes the very clear prediction that lysosomal dysfunction should be evident in aging postmitotic tissues, and there is published evidence from immunohistochemical studies of mammalian brains in support of the theory. Whereas the activity of the lysosomal protease cathepsin L was reported to decrease by 90% in the aging rat brain (13), the activities and/or immunostaining of cathepsins B and D were found to be increased in some brain regions (14-17). Also in agreement with the theory are experiments wherein direct inhibition of cathepsin activity in vivo by the pharmacological agent leupeptin resulted in the accumulation of a substance with the properties of lipofuscin in the brains of young rats (18).

What was harder to predict from the mitochondrial-lysosomal axis theory was the effect of lipofuscin on the ubiquitin/proteasome pathway (UPP). The UPP is a second major proteolytic system within the cell and, like the lysosomal system, it becomes less efficient with age [reviewed in (19)]. The UPP provides the more rapid mechanism for the elimination of cellular proteins and is charged with the proteolytic degradation of substrates throughout the cytosol and nucleus but not within membrane-bound organelles (in fact, the cell has a specialized apparatus for extracting substrates from the endoplasmic reticulum so that they can be degraded by cytoplasmic proteasomes). The separation of the lysosomal system and the UPP into distinct cellular compartments might make it seem less likely that these systems impinge on one another, but with regard to lipofuscin this is clearly the case. Loading cells with lipofuscin was shown to decrease proteasomal activity, and although within cells their physical interaction should be infrequent, the direct inhibition of proteasomes by lipofuscin was demonstrated in vitro (20). The reciprocal experiment has also proved informative: Inhibition of the proteasome with the highly specific agent MG-262 enhanced the accumulation of lipofuscin in cultured human fibroblasts (21). Human neural SH-SY5Y cells exposed to low concentrations of this proteasome inhibitor exhibited features of altered mitochondrial function, including (i) diminished energy production from respiration with a compensatory increase in glycolysis, (ii) increased production of reactive oxygen species (ROS), (iii) increased numbers of autophagic bodies containing mitochondria, and (iv) increased concentrations of material with the properties of lipofuscin (22).

Why should interference with one degradative pathway affect the other? Proteasomes appear to turn over through lysosome-mediated autophagy (23), and a bolus of nonfunctional proteasomes might present a problematic burden to the lysosomal system. The longer-lived ROS produced by defective mitochondria within autophagic lysosomes could be expected to diffuse out of the lysosomal compartment and cause oxidative damage to cytosolic proteins. Such damaged proteins are normally degraded by the proteasome (24-27), so a lysosomal system that was overloaded with ROS-generating mitochondria or lipofuscin would eventually swamp the UPP with oxidized protein substrates. The mitochondrial-lysosomal axis theory of aging (12) suggests that this scenario will accelerate with age; the correlation of accumulating oxidized or cross-linked protein with declining proteasome activity is well established (28) and has been well reviewed elsewhere (29). There is the potential for a self-amplifying feedback loop in the aging cell. Regardless of which becomes inhibited first, lysosomes (from their burden of defective mitochondria) or proteasomes (from their burden of oxidized or otherwise damaged proteins), the result will be that both systems will become overwhelmed. In this light, lipofuscin cannot be seen as a benign entity, merely an aging pigment, but must be recognized as a clear threat to homeostasis in the postmitotic cell. A further prediction, then, is that the regions of the brain in which lipofuscin accumulates should suffer deleterious effects. Is this the case?

Lipofuscin in the Human Central Nervous System Back to Top

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 (30). This age-associated increase in the sheer amount of lipofuscin in brain cells is attended by alterations in its biochemical composition (30). 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. 3), the dentate nucleus of the cerebellum, the globus pallidus, and the motor neurons in the anterior horn of the spinal cord and brainstem (31). 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 (32). 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 (33).

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Fig. 3. 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).


Lipofuscin in Human Brain Aging: Friend or Foe? Back to Top

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 (34). On the other hand, more recent evidence indicates that amassed lipofuscin may be hazardous to cellular functions (2). 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 (35).

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 (36) (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 [see (37) for review]. 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 (38).

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; (39)]. This finding is compatible with the hypothesis that lipofuscin accumulation is related to impaired lysosomal degradation of mitochondria.

Waiting for the Garbage Catastrophe Back to Top

Terman has lucidly and convincing highlighted the cumulative, ultimately fatal consequences of incomplete elimination of cellular waste in his "garbage catastrophe theory" (40). Such a theory fits well with the prevailing evolutionary theory of aging (41, 42) in that the accumulation of toxic waste would occur in the somatic cells (particularly postmitotic cells such as neurons) of postreproductive individuals but would not affect the germline; lipofuscin should be eliminated by dilution in the germ cell lineage, because with each generation the germline is expanded from one cell (the totipotent zygote) to many primordial germ cells and ultimately to the gametes. The accumulation of lipofuscin in postreproductive somatic lineages (the neurons of an octogenarian, for example) would be quite irrelevant with respect to the selective pressures that drive evolution.

For reasons outlined above, however, the accumulation of lipofuscin in somatic cells should be of considerable concern to their owner. Apart from the obvious implications of lipofuscin accumulation in the brain and heart, there are other sites at which lipofuscin might wreak havoc in the elderly. Lipofuscin may play a causative role in age-related macular degeneration, already a leading cause of vision loss and a growing problem in developed countries (35). What are the prospects for some sort of intervention that might forestall the "garbage catastrophe," or even reverse the accumulation of the toxic entities that precipitate such a catastrophe? To date, no pharmacological agent has proved efficacious; centrophenoxine showed early promise as an agent that could reduce neuronal lipofuscin in guinea pigs (43), but its efficacy was cast in doubt by subsequent studies (44-46). Caloric restriction, a regimen that has been shown to delay the rate of aging in many species (see Masoro Subfield History), increases protein turnover (47), and there may exist pharmacological agents that can act through the signal transduction pathways affected by caloric restriction to enhance macroautophagy and lysosomal degradation systems (48). If there are no enzymes in mammalian cells with the capacity to degrade lipofuscin once formed, it may be necessary to look elsewhere for such reagents. It has been speculated that soil microbes are to be credited with the disposal of lipofuscin in nature (49); perhaps they possess enzymes that could be mobilized as "xenohydrolases" in some sort of intervention (possibly a gene therapy scenario). A recent publication reports that in the freshwater crayfish the exocytosis of lipofuscin from neurons can be induced by damage to the nervous system (50), and although exocytosis of lipofuscin has not been described in mammalian neurons, there may be some way to stimulate them to put out their garbage. At present, these strategies for assisted cellular housekeeping might seem far-fetched, but while you await your own garbage catastrophe it might be prudent to give the matter some thought.

February 2, 2005
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J. M. Calandria, P. K. Mukherjee, J. C. de Rivero Vaccari, M. Zhu, N. A. Petasis, and N. G. Bazan (2012)
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Suppression of Phosphoinositide 3-Kinase Prevents Cardiac Aging in Mice.
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