sugars to free amino groups, with the subsequent formation of pentosidine and other condensation products that can cross-link adjacent protein molecules (Cerami, 1996; Baynes, 1991; Sell and Monnier, 1995). Several different types of advanced glycation end-products have been shown to accumulate progressively, with a nearly linear time course from birth onward. In the skin, for example, pentosidine accumulates in skin collagen, at rates that are in proportion to the life spans of humans and other mammals of short- and intermediate life spans (Sell et al., 1996). In the human eye, a different oxidation product, LM-1, a blue fluorophore covalently associated with lens crystallins, accumulates linearly with age; in this case, the reducing sugar may be ascorbic acid rather than glucose (Nagaraj and Monnier, 1992). These examples suggest the complexity of the biochemistry of aging, where there are important variations between tissues and multiple substrates from intermediary metabolism.

Certain targets in tissues of glycoxidation by glucose and other reducing sugars can be modified through diet and drugs. For example, glycooxidation is accelerated by chronic elevations of blood glucose, as in diabetes (Schnider and Kohn, 1980). Correspondingly, food restriction, which lowers blood glucose, has been shown to decrease oxidative damage to proteins in rats (Reiser, 1994; Youngman et al., 1992). This finding points to the potential impact of nutrition across the life span on amount of damage that may accumulate in slowly replaced molecules. The nontoxic antioxidant aminoguanidine appears to block glycooxidation in animal studies and is in clinical trial (Cerami, 1996). Because minimum levels of blood glucose and other reducing sugars found both extra-and intracellularly are essential to physiological function, it would appear that glycooxidative damage to long-lived proteins may set some ultimate limit on plasticity of human life histories. The high blood sugar of birds (5- to 10-fold that of mammals) would predict intense glycooxidative damage to proteins (Monnier et al., 1990; Finch, 1990:405; Holmes and Austad, 1995). In view of their long life spans, special antioxidant mechanisms must have been evolved during the evolution of birds.

DNA damage from oxidation and a variety of other mechanisms is also observed in chromosomal and mitochondrial DNA of tissues with little cell replication like brain and muscle (Linnane et al., 1989; Randerath et al., 1993; Fraga et al., 1990; Soong et al., 1992; Mecocci et al., 1993). The age-related accumulation of mutations during aging is of unquestionable importance to one or more steps in malignant transformation and may be important to other dysfunctions of nondividing as well (Finch and Goodman, 1997).

Recent findings from van Leewen's group indicate that some mutational processes are under physiological control. The Brattleboro rat carries a germ-line mutation causing a frame-shift in the vasopressin gene. Remarkably, about one hypothalamic neuron per day reverts to acquire the normal vasopressin peptide: the reverted neurons accumulate in an age-related schedule from birth onward—

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