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The Waste Accumulation Theory of Aging

Lipofuscin is a complex mixture of oxidized protein and lipid degradation residues, along with lesser amounts of carbohydrates and metals.

Iron is predominant among the metals in lipofuscin (3, 4); copper, zinc, and other metals have also been detected (5).

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.


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.

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).

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.

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).

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);