interventions and brain aging are currently understudied in humans. Behavioral interventions in brain aging are popular at the community level, but clinical studies in patient populations are greatly lacking, as are mechanistic studies in animal models.


In the propagation phase, mechanisms including apoptosis, inflammation, and oxidation are activated either in combination or chronically beyond a certain level. Homeostatic balances are exceeded and dyshomeostasis prevails. This phase illustrates the importance of homeostasis in brain aging and the identification of mechanisms that can lead into dyshomeostasis. The discussion below illustrates the key principles. Apoptosis normally serves during development to remove excess cells, and in disease or injury it serves to destroy damaged cells. This is a well-accepted concept in all basic biological systems. With age, a variety of stimuli accumulate in the brain that may induce apoptotic pathways in neurons. In the aging and Alzheimer's-affected brain, β-amyloid, a 40–42 amino acid peptide, accumulates in the extracellular space as small deposits and senile plaques. Based on the observation that neurites surrounding β-amyloid deposits exhibit both sprouting and degenerative responses, we proposed that this peptide is not metabolically inert, but rather possesses biological activity. Our findings established two key principles: β-amyloid induces neurotoxicity in a conformation-specific manner, and apoptotic mechanisms underlie this toxicity (Cotman and Anderson, 1995; Anderson et al., 1995; Loo et al., 1995, 1993; Watt et al., 1994); these observations have since been confirmed by many others. Interestingly, prior to causing cell death, β-amyloid also induces the formation of dystrophic-like neurite morphology in cultured neurons (Pike et al., 1992; Fraser et al., 1994).

Oxidative insults also readily initiate apoptosis (Whittemore et al., 1994), and oxidative damage is known to occur in the aging and Alzheimer's-affected brain (Benzi and Moretti, 1995). Similarly, reductions in glucose metabolism have been suggested to contribute to neurodegeneration in Alzheimer's disease (Beal et al., 1993; Goto et al., 1993; Haxby and Rapoport, 1986; Hoyer et al., 1988; McGeer et al., 1986), and β-amyloid has been shown to exacerbate neurodegeneration in cultured neurons when glucose levels are reduced (Copani et al., 1991). Furthermore, excitotoxic damage can, under some conditions, initiate apoptosis, and many investigators have suggested that excitotoxic damage contributes to neurodegenerative diseases, including Alzheimer's disease (Dodd et al., 1994). Recent studies have also shown that glutamate transport proteins may be greatly reduced in the Alzheimer's-affected brain (Masliah et al., 1996; Simpson et al., 1994), which could exacerbate excitotoxic mechanisms. The profile of initiating factors strongly sug-

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