Lysosomes and Brain Aging in Mammals

Hypotheses about the factors controlling the rate of brain aging are usually derived from 1) correlates of maximum life span across mammals or 2) investigations into the causes of age-related neuropathologies in humans. With regard to the former, the strong correlation between metabolic rate and longevity prompted a variety of free radical hypotheses of aging. There is also evidence that brain size affects life span independently of body metabolism rates. The second approach has led to a diverse array of pathogenic mechanisms and, importantly for the development of general hypotheses, the discovery of animal analogues. The present paper discusses the possibility that age-associated lysosomal dysfunction constitutes a generalized mammalian phenomenon that accounts for specific features of the aged human brain. Immunocytochemical studies using rats and dogs have identified lysosomal changes that begin early in adulthood and are most pronounced in brain areas known to be particularly vulnerable to age-related pathogenesis in humans. Experimentally induced lysosomal dysfunction in cultured brain slices from rats and mutant mice triggers a wide array of changes associated with the aged human brain, including meganeurites and intraneuronal tangles. Finally, there is evidence that at least some forms of proteolysis decrease with increasing brain size across the mammals. The above observations lead to the suggestion that the expansion of neuronal arborizations that occurred in conjunction with increases in brain size secondarily slowed both neuronal metabolism and protein turnover. These events could have served to reduce the rate at which lysosomes (and other organelles) fail.