Oxidative Stress and Mitochondrial Dysfunction in Down’s Syndrome: Relevance to Aging and Dementia

Figure 3

Modulation of DS phenotypes by oxidative stress and mitochondrial factors. Fetal oxidative stress (OS) levels could be determined by the mother’s age and initial mtDNA mutation levels in oocytes. Besides the genetic/intrinsic factors that create the genomic instability in DS, environmental factors and lifestyle modulate the initial OS further. Since all these factors that play a role in the level of OS differ individually, the OS-related changes will also be observed in variation. Simply, while the low level of OS could initiate the positive adaptive response by activating proper defense signaling, high level of OS will start destructive signaling where the adaptive response could not be able to accommodate the clearance of the damage. More positive factors (e.g., lifestyle, advantageous genetic background—mitochondrial haplotype, APOE, BDNF genotype, etc.—and nutrition) will feed the adaptive response positively, while negative factors (e.g., congenital defects, sedentary lifestyle, genotypes, etc.) will increase the OS further. In both low and high levels of initial OS conditions, aging will affect this process negatively by increasing OS, such as increasing mtDNA mutation accumulation and decline in mitochondrial functions. Under increasing OS conditions with aging, individuals with DS will be prone to develop more morbid conditions and prone to death depending on their initial adaptive response signaling. In other words, negative factors will lead to earlier clinical manifestations of age-related conditions, while positive adaptations (e.g., conditioned hormetic signaling) may support normal cellular and systemic functions for longer periods of time.