Molecular Signatures of Senescence and Aging Characterized by Proteomics

As we age, the cells in our body accumulate damage and stress. In response, cells develop mechanisms to halt dividing permanently, a process known as cellular senescence. While this helps to prevent the spread of damaged cells, the accumulation of senescent cells contributes to aging and age-related diseases such as neurodegeneration, metabolic diseases and cancer. Senescence is a very complex process and involves major changes in the cellular environment. By analyzing the proteome and phosphoproteome of senescent cells, triggered by oncogene activation, I uncovered a major reorganization of the nuclear proteins. I also discovered that the enzyme Prolyl Isomerase Pin1 acts as a modulator for senescence, showing that Pin1 knockdown leads to a decreased OIS phenotype. I have also found that Pin1 is involved in regulating the subnuclear promyelocytic leukemia protein- nuclear body (PML-NB) structures, which are known to play important roles in tumor suppression. Comparative analysis of PML-NB compositions during oncogene-induced senescence and telomere-uncapping induced senescence, I uncovered major shifts in their make-up including decrease in proteins involved in DNA and chromosome maintenance, while RNA processing proteins are recruited to PML-NBs during senescence. As the accumulation of senescent cells is linked to aging, I also used an in-vivo mouse model to study the effects of aging in the brain and liver proteome, phosphoproteome, and kinome. In the aging brain, I observed significant changes in proteins and phosphorylation patterns linked to senescence, neurodegeneration, inflammation, the p53 hallmark pathway, and cytokine signaling. Several proteins implicated in Alzheimer's disease (AD) and Parkinson's disease (PD), including tau (Mapt), Nefh, and Dpysl2, also showed age-dependent changes. In the liver, aging was primary marked by metabolic changes and reduced protein phosphorylation. Overall, my findings reveal key links between proteins, phosphosites, and uncover both known and novel pathways, improving our current understanding of aging and providing the foundation for future studies on age-related diseases.