Age-Related Decrease in Heat Shock 70-kDa Protein 8 in Cerebrospinal Fluid Is Associated with Increased Oxidative Stress

Abstract

Age-associated declines in protein homeostasis mechanisms ("proteostasis") are thought to contribute to age-related neurodegenerative disorders. The increased oxidative stress which occurs with aging can activate a key proteostatic process, chaperone-mediated autophagy. This study investigated age-related alteration in cerebrospinal fluid (CSF) concentrations of heat shock 70-kDa protein 8 (HSPA8), a molecular chaperone involved in proteostatic mechanisms including chaperone-mediated autophagy, and its associations with indicators of oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and 8-isoprostane) and total anti-oxidant capacity. We examined correlations between age, HSPA8, 8-OHdG, 8-isoprostane, and total antioxidant capacity (TAC) in CSF samples from 34 healthy subjects ranging from 20 to 75 years of age. Age was negatively associated with HSPA8 (ρ = -0.47; p = 0.005). An age-related increase in oxidative stress was indicated by a positive association between age and 8-OHdG (ρ = 0.61; p = 0.0001). HSPA8 was moderately negatively associated with 8-OHdG (ρ = -0.58; p = 0.0004). Age and HSPA8 were weakly associated with 8-isoprostane and TAC (range of ρ values: -0.15 to 0.16). Our findings in this exploratory study suggest that during healthy aging, CSF HSPA8 may decrease, perhaps due in part to an increase in oxidative stress. Our results also suggest that 8-OHdG may be more sensitive than 8-isoprostane for measuring oxidative stress in CSF. Further studies are indicated to determine if our findings can be replicated with a larger cohort, and if the age-related decrease in HSPA8 in CSF is reflected by a similar change in the brain.

Keywords: 8-hydroxydeoxyguanosine; 8-isoprostane; HSPA8; aging; cerebrospinal fluid; oxidative stress.

FIGURE 1

Distribution of CSF HSPA8 concentrations as a function of age in healthy adults. HSPA8 concentration was negatively correlated with subject age (Spearman’s ρ = –0.47; p = 0.005). LOWESS curves (dashed lines, men; solid lines, women) suggested that HSPA8 may decrease similarly in men and women after age 45. An age-related decrease in HSPA8 was not seen in men prior to age 45. (HSPA8, heat shock 70-kDa protein 8).

FIGURE 2

Distribution of CSF concentrations of 8-OHdG as a function of age in healthy adults. Age and 8-OHdG were strongly positively associated (ρ = 0.61; p = 0.0001). 8-OHdG levels tended to increase with age with similar patterns for both genders. (dashed lines, men; solid lines, women; 8-OHdG, 8-hydroxy-2′-deoxyguanosine).