| dc.description.abstracteng | Brain function is highly dependent on a well-regulated, harmonic interaction of a multitude of cellular and molecular pathways. During aging, many of these pathways undergo progressive changes, leading to gradual deterioration of brain health and ultimately cognitive abilities. While neurodegenerative events likely occur throughout one’s lifetime, detrimental effects often only become apparent with high age, when homeostatic mechanisms finally fail to uphold full functionality. Aging is therefore the highest risk factor to develop dementia and neurodegenerative diseases, such as Alzheimer’s or Parkinson’s. With the increasing lifespan of humans, such defects become prominent, and dementia is predicted to affect 152 million people worldwide by 2050, almost tripling current numbers.
Several hallmarks of aging in general have been suggested. These include 1) alterations at the level of the genome, with DNA instability, chromatin modifications and nuclear architecture dysfunction. 2) Declining mitochondrial function and increasing levels of cellular oxidative stress. 3) Impaired intercellular signaling and shifting energy metabolism. 4) Widespread inflammation and activation of immune responses. And lastly, 5) dysregulation of protein homeostasis (proteostasis), with declining protein degradation capacity, stoichiometric imbalance of protein complexes, and protein aggregation. To what extent these alterations affect the brain and neuronal function is mainly studied in animal models, as human studies are limited to imaging and other non-invasive techniques or postmortem tissue analysis. Small rodents, especially mice, offer a high similarity in genetics, as well as in nervous system anatomy and function, combined with easy handling and relatively short lifespan. The genetic tools to manipulate single genes or pathways are becoming increasingly sophisticated, as are large-scale analysis methods to describe changes in transcriptomics, proteomics and other -omics levels. Nevertheless, the differentiation of organismal aging versus brain aging and the difficulty of defining core versus accessory alterations still hinders a detailed understanding of aging processes in the brain.
In this work, I provide a systematic investigation of aging in the mouse brain. I use RNA sequencing and liquid chromatography-mass spectrometry to study several subcellular fractions of the brain. Physiologically aged wildtype mice, 6, 12, and 24 months of age, are thoroughly described regarding total and nuclear transcript abundance, as well as total, soluble and insoluble protein content. Qualitative and quantitative measurements of more than 20,000 genes and 8700 protein groups implicate the expected mitochondrial function decline, neurodegeneration, protein aggregation and immune activation, but also ribosomal and intermediate filament-based reorganizations in the aging process. Further, 12 mouse models of aging, neurodegenerative disease, dietary supplementation, or environmental enrichment are analyzed in parallel to gain insight into their proteomic landscape and aging signatures, specific to the brain. An overall comparison between physiological aging and aging modeled in a range of different mice reveals overlapping, but also separate pathways being the main drivers of (phenotypical) aging. The collection of data presented here sheds light on some previously undiscovered or underappreciated concepts and serves as valuable database for the scientific community. Together with additional experiments and considerations prompted by this study, we will ultimately achieve a better definition of brain aging and perspectives for medically postponing or preventing cognitive decline. | de |