dh003i's Journal: The Aging Brain and Dietary Restriction

Introduction

• Dietary restriction (DR) is a diet in which animals are fed 40% fewer calories, and is the most reliable way to lengthen life span and reduce deterioration in old age. Recent experiments show that DR ameliorates age-associated protein damage and cognitive- and motor-function degradation (i.e., spontaneous locomotion, sensorimotor coordination, and active avoidance learning degradation). DR may ameliorate behavioral deterioration because of its ability to reduce free radical (FR) concentrations as FR accumulation in aging mice (fed ad libitum [AL], a normal diet) appears to cause cognitive and motor deterioration.

Free Radical Generation and Neutralization

• FRs are highly reactive molecules with unpaired electrons. FRs include superoxide, hydroxyl, hydrogen peroxide, alkoxyl, and nitric oxide. FR sources include extracellular sources of oxidant species from Maillard reactions and glycosylation; dehydrogenases and oxygenases; and oxidases (Freeman, 1984; Kristal and Yu, 1992). Mitochondria, microsomes, and peroxisomes are primary FR sources in the cell (Yu, 1996). Because of the brain's demanding energy needs, it is mitochondria-rich and thus particularly vulnerable to FR and oxidative damage. The production of superoxide (SO), a highly reactive FR, is organ-dependant, but highest in the brain (Sawada et. al., 1992). Dopamine deamination in the brain also produces toxic metabolites, including hydrogen peroxidase (Archer and Harrison, 1996). FR accumulation in turn leads to protein damage in the cell.

  Enzymatic and dietary antioxidants neutralize FRs. Dietary antioxidants include Vitamin E, 2-Mercaptoethylamine, Santaquin, Tocopherol-p-chlorophenoxyacetate, d-Tocopherol, and Sulfhydrl agents (Yu, 1996). Enzymatic antioxidants include catalase, glutathione peroxidase, and superoxide dismutase (SOD) [Wickens, 2001].

The Aging Brain and DR's Ameliorating Effect

• FR levels are empirically determined by ascertaining the extent of oxidative protein damage in brain tissue. Whole brain homogenates of old mice relative to young mice display an increase in protein oxidative damage, as indicated by protein carbonyl content (Dubey et. al., 1996). Oxidative damage in old mice varies between different brain-regions. The greatest increase is in the striatum, then cortex, midbrain, hippocampus, cerebellum, and finally hindbrain, where there is no significant increase with age. While the striatum displays the greatest increase, the hippocampus has the greatest amount of oxidative damage in young and old mice, as indicated by protein carbonyls. Decreased membrane protein sulfhydryl content, another measure of protein damage, shows that protein damage is uniform across different brain regions, except the hippocampus, which displays no change (Dubey et. al., 1996). Uniform sulfhydryl content indicates that different regions of the brain are susceptible to various forms of protein damage. Generally, the brains' of aged mice exhibit more oxidative protein damage; thus, FR levels are higher than in young mice.

  DR mice display lower oxidative protein damage levels in old age relative to AL mice (Dubey et. al., 1996). Protein carbonyl content in the whole brain of old DR mice (relative to old AL mice) indicates that DR attenuates oxidative protein damage. DR produces the greatest attenuating effect on the striatum, where oxidative damage increase is the greatest with age; and lesser so in the cerebellum, midbrain, cortex, and hippocampus. Conversely, no significant attenuating effect is observed in the hindbrain, where there is no oxidative damage increase with age. The reduced protein sulfhydryl reduction in DR versus AL mice is roughly uniform across different brain regions of old mice, except for the hippocampus, where DR produces no ameliorative effect.

  Studies on DR and AL mice also reveal that DR attenuates age-related deteriorations in avoidance learning capacity, motor performance, and spontaneous locomotion (Dubey et. al., 1996). Active avoidance learning deteriorates in AL mice, but DR retards that deterioration. Likewise, coordinated running ability deteriorates in AL mice, but DR retards that deterioration. Finally, spontaneous locomotion decreases in AL mice, but not in DR mice.

  Aging mice display deterioration of learning and memory capacity, motor coordination, and spontaneous locomotion (Forster et. al., 1996). The deterioration rate varies and occurs independently for different functional losses. As protein carbonyl content indicates, cognitive impairment correlates with increasing protein damage in the cortex, while motor deficits correlate with increasing protein damage in the cerebellum and hindbrain (Forster et. al., 1996). In addition, cognitive deficits do not correlate with motor deficits and that protein damage in one brain region does not correlate with damage in other regions. Hence, protein damage varies in different brain regions (Forster et. al., 1996). Confirming Forster et. al. (1996) and Dubey et. al. (1996), Ingram et. al. (2001) show decreasing locomotion in rhesus monkeys with aging; however, Ingram et. al.'s (2001) results are mixed with respect to the ameliorating effect of DR on decreasing locomotion with age.

  Consistent with other results, Carney et. al. (1994) find an accumulation of protein oxidation in the aging brain, which correlates with decreasing cognitive performance, cytoskeletal function, and creatine kinase and glutamine synthase activity. Manipulations that increase reactive oxygen species (ROS) worsen oxidation-related effects, while those that decrease ROS concentration ameliorate such effects. Hence, Carney et. al. (1994) provide strong support for the theory that protein damage is a cause of brain aging and behavioral deterioration. Thus, it is likely that the ameliorating effects of DR are partially due to DR's ability to reduce FR concentration.

  Discerning the effects of DR, Prolla (2002) uses microarrays to determine the gene expression profiles of old DR and AL mice. Gene expression profiles of old AL mice suggest reduced neural plasticity and neurotrophic support, oxidative stress, and inflammatory response; however, profiles of old DR mice indicate that DR attenuates age-associated increases in stress responses and inflammatory protein production (Prolla, 2002).

  Several conclusions regarding protein damage in aging mammals and the deterioration of motor- and cognitive-function, as well as the ameliorating effect of DR, can be made. (1) Age-related protein oxidative damage varies in different brain-regions. (2) DR ameliorates age-associated deterioration of behavioral functions and some types of oxidative protein damage, prominently in regions that display heavy oxidative damage with age. (3) Brain aging, cognitive function deterioration, and oxidative damage correlate; suggesting a possible causation in which FR oxidative stress promotes protein damage and causes brain aging and behavioral deterioration. (4) Varying levels of protein oxidative damage may be the cause of individual variations in age-related deterioration. (5) Age-related decline of motor and cognitive-function progress independently and involve oxidative damage to different brain regions. Further studies on the deterioration of cognitive- and motor-function in DR and AL monkeys are needed.

Dietary Restriction Ameliorates Cognitive Decline Caused by Free Radical Accumulation

• In aging animals, various cognitive and motor functions deteriorate, and oxidation-stress induced protein damage increases. As oxidative stress damages nucleic acids, lipids, and proteins, it may cause brain function deterioration (Mattson et. al., 2001). The precise relationship between damage at the molecular level and functional deterioration at the behavioral level is not understood; however, widespread damage at the molecular level causes deterioration at the behavioral level.

  DR may ameliorate brain function deterioration through several mechanisms. DR up-regulates cellular stress proteins, which protect neurons against excitotoxic and oxidative damage. For example, DR rats display higher cellular stress protein (HSP-70) levels in the brain than do AL rats (Mattson et. al., 2001). DR also increases neurotrophic factor (e.g., BDNF) concentration in the brain, which increases antioxidant enzyme (e.g., Bcl-2) concentrations and other oxidative stress suppressor concentrations (Mattson et. al., 2001). Furthermore, DR may increase the survival of newly generated neural cells in the brain (Mattson et. al., 2001).

  DR affects oxidative stress reduction and up-regulates FR scavenging proteins and other oxidative stress suppressors. AL rat livers exhibit greater production of superoxides and hydroxy radicals compared to DR rats of the same age. Correspondingly, DR rat livers display greater mitochondrial and cytosolic SOD activity. Thus, DR reduces FR accumulation in the liver (Lee and Yu, 1990). As the effects of DR are specific to the mitochondria and cytosol, such effects may be present in mitochondria-rich brain tissue. DR partially prevents age-related decreases in glutathione reductase, glutathione peroxidase, and catalase. Furthermore, DR reduces SO and hydrogen FR levels in liver mitochondrial and microsomal membranes.

  Summarily, DR affects biochemical composition at the cellular level: (1) Reduces age-related decreases in mitochondrial oxidation of malondialdehyde and allows better removal of oxidative byproducts in DR rats (Yu and Chen, 1994); (2) Affects the antioxidant defense systems by modulating age-related changes in ascorbic acid, catalase, GSH, GSH-PX, GSH reductase, and GSH transferase (Yu, 1996); (3) Decreases the production of toxic metabolites (e.g., hydrogen peroxide) in the brain from dopamine deamination (Archer and Harrison, 1996); (4) Reduces DNA oxidative modification in aging animals and humans (Mullaart et. al., 1990; Inoue et. al., 1993). DR ameliorates the age-related deterioration of brain function by reducing the production of FRs and up-regulating the antioxidant defense system, reducing widespread damage in brain-tissue at the molecular level.

Conclusion

• Age-related cognitive- and motor-function declines correlate with increasing oxidative protein damage. Furthermore, oxidative protein damage is probably the cause of age-related cognitive- and motor-function deterioration. Interestingly, different regions of the brain are subject to different types of oxidative damage. Furthermore, oxidative damage in various brain-regions correlates with behavioral deterioration in the behavior that the region regulates. Future studies may lend further support to the theory that oxidative protein damage is the cause of the various behavioral changes; and show the various gene-expression changes that occur in aging AL versus DR animals, as well as how those gene-expression profiles change in response to increased oxidative stress and other factors. At the molecular level, further studies on the effects of aging and DR on FRs and antioxidants are needed. In the future, primate studies may be beneficial, as primates are closely related to humans.

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