The role of apoptotic mechanisms in the pathophysiology of aging

The prevalence of age-related neurodegenerative disorders is increasing dramatically as people are living longer and now affects millions of people worldwide. Activation of caspases and cleavage of specific caspase substrates is an early, critical cellular event in several neurodegenerative diseases including Alzheimer (AD) and Huntington (HD) disease, and stroke. Caspase-6 (casp6) in particular has emerged as an important player in the neuronal degeneration in AD and HD where it is activated early (preclinical) in the disease process. Preventing the processing of amyloid precursor protein or mutant huntingtin (htt) by casp6 in the case of AD and HD respectively, has been beneficial in these conditions making casp6 a potential target for therapeutic intervention in neurodegenerative diseases. Neurodegeneration occurs not only in neurological disorders, but also under physiological conditions including aging. We undertook a study to determine the timeline of caspase activation and cleavage of casp6 substrates in peripheral organs and in the brain of young (3m) vs. mid (10-12m) and old (24-28m) wild type C57Bl6 mice. A significant increase in peripheral organ and brain weight is observed with aging (body (p = 0.04), liver (p = 0.0004), kidney (p = 0.0002), spleen (p = 0.013), heart (p = 0.0006) and brain (p = 0.04)) except for testes, which is decreased (p = 0.02). Within the brain, hippocampi weight decreases with age (p = 0.013). A significant increase in casp6 activity is detected by 10m of age in C57Bl6 cortex corresponding with the time point where brain weight is starting to trend downwards with age. Furthermore, there is an increase in full-length (p = 0.053) and fragment levels (p < 0.0001) of the novel caspase-6 substrate, STK3, a pro-apoptotic kinase, in the aging cortex. The caspase-6 substrate htt, a neuroprotective protein, demonstrates a trend decrease in cortical full-length levels (p = 0.09) and increase in htt fragments with age. Additional studies are ongoing. These data suggest that activation of casp6 and cleavage of casp6 substrates is an important event in the neuronal dysfunction and degeneration observed in the aging brain.