Buck Institute

Scientists at the Buck Institute share a common goal: to understand aging. We have recently made key discoveries that point to a deep mechanistic relationship between disease and aging across diverse species and various age-related diseases. Our collective data suggest that, rather than viewing aging as a risk factor, it may be more accurately viewed as a principal causal factor of these disorders. We propose to test the hypothesis that age-related human disease is the result of segmentally-accelerated aging – in other words, that diseases of aging such as Alzheimer’s disease, prostate cancer and osteoporosis are part and parcel of the fundamental aging process itself, simply enhanced in the affected tissues. This is based in part on our recent discovery of an acceleration of the aging process in terms of oxidative modification to mitochondrial complex I (CI) in affected regions of the Parkinsonian versus the normal aging brain; selective inhibition of this enzyme complex has been long associated with Parkinson’s disease (PD). To test our hypothesis, we propose two experimental programs: (1) to undertake a functional analysis of mitochondrial post-translational modifications (PTMs) particularly in CI to determine which are critical for neuronal cell dysfunction, death and progression of PD; and (2) to test the generality of this mechanism by surveying Alzheimer’s disease models and post-mortem patient brain tissues for mitochondrial PTMs and their functional correlates particularly but not limited to mitochondrial complex IV whose inhibition has been suggested to be preferentially involved in this age-related disorder versus changes associated with normal aging.