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.
Highlights
Aging is the most consistent known risk factor for developing progressive neurodegenerative disease (Jeppesen et al, 2011)
An age-related increase in oxidative stress was suggested by the association between age and 8-OHdG (ρ = 0.61; p = 0.0001) no associations with age were found for the other oxidative stress marker 8-ISO or for TAC
These findings suggest that the age-related increase in oxidative stress in the CNS might contribute to an age-associated decrease in HSPA8
Summary
Aging is the most consistent known risk factor for developing progressive neurodegenerative disease (Jeppesen et al, 2011). HSPA8, Oxidative Stress, and Aging mechanisms are likely to play a role in the formation of misfolded protein aggregates that are pathological hallmarks of ageassociated neurodegenerative disorders, because they promote protein aggregation (Squier, 2001). We measured HSPA8 in 11 younger control subjects ranging from 20 to 43 years of age who were not included in the study. We present our findings with regard to age-related changes in CSF HSPA8, and the associations between this protein and oxidative stress biomarkers 8-hydroxy-2 -deoxyguanosine (8-OHdG) (Valavanidis et al, 2009) and 8-isoprostane (8-ISO) (Morrow et al, 1992) as well as total antioxidant capacity (TAC) (Bartosz, 2003)
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