Deciphering the Cell Senescence Code to Improve Healthspan – S-ENCODE

We combined several OMICs technologies, including transcriptomics, epigenomics, and metabolomics, and integrated the generated data sets using our bioinformatic pipeline. We have used biochemical and molecular biology approaches to dissect the role of pericentromeric heterochromatin in senescence.

The consortium generated and published the first epigenomic senescence clock, defining a hierarchical transcription factor (TF) network and previously unrecognized enhancer classes that govern senescence in human fibroblasts. By functionally perturbing key TFs, we showed that targeting senescence-regulatory circuits has therapeutic potential in cancer and age-related pathologies. We generalized these seminal findings across multiple senescence inducers and cell types, establishing a pan-senescence biomarker gene signature and developing a gene-regulatory network model for senescence. In parallel, we completed and published an integrated epigenomic and metabolomic analysis of distinct senescence programs, identifying shared metabolites that are critical for senescence establishment. We further discovered that pericentromeric heterochromatin is selectively dismantled at senescence onset in a p53-dependent manner, challenging prevailing models of heterochromatin remodeling and the canonical view of p53 as a pure genome guardian. Finally, we demonstrated that the senescence-associated subtelomeric transcriptome is specified in a chromosome-end-specific manner, dictated by the underlying higher-order chromatin architecture.

Future efforts will systematically integrate transcriptomic and epigenomic datasets from cells driven into senescence by diverse stressors and across multiple cell types, to define a robust pan-senescence gene-regulatory signature to guide therapeutic intervention strategies. In a second step, we will extend this effort by jointly integrating transcriptome, epigenome, and metabolome data to converge on actionable targets. To dissect mitochondrial alterations during senescence, we will label the outer mitochondrial membrane with a molecular beacon, enabling immunopurification and functional characterization of mitochondria in senescent cells. In parallel, we will elucidate how TRF2 downregulation activates subtelomeric gene expression and precipitates mitochondrial dysfunction. Ultimately, these insights will pave the way for initiating first-in-class senotherapeutic approaches in age-related diseases.

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Chronological age is the most important individual risk factor for the development of many chronic diseases and cancers (hereafter designed as age-related diseases), accounting for the majority of societal morbidity, mortality, and public health costs. The common pathophysiological mechanisms underlying age-related diseases are poorly understood, impeding the development of rational therapeutic interventions to prevent and treat these diseases and maximize healthy aging. Recent findings strongly suggest that changes in common basic cell-autonomous and non-autonomous processes play a critical role in aging. Importantly, these common aging pathways can be altered in diseases as diverse as neurodegeneration, cardiovascular disorders, chronic obstructive pulmonary disease (COPD), osteoarthritis, diabetes to name a few. Intervening into such a fundamental process to prevent multiple diseases simultaneously, rather than treating age-related diseases individually, as is current practice, would transform modern medicine in causative and economical way. There is a growing consensus that the accumulation of senescent cells in tissues is a common aging process contributing to age-related diseases. Senescence is a cellular response to nonlethal genotoxic and oncogenic stress that results in a permanent cell cycle arrest. Cellular senescence is a double-edged sword process playing beneficial roles during embryogenesis, wound healing, and tumor suppression while contributing to age-related diseases. Consistently, senescent cells are enriched in the affected tissues of these diseases. Regarding cancer, senescence can be induced by oncogenic activation behaving as an intrinsic onco-suppressive mechanism while the accumulation of senescent stromal cells creates fertile soil for carcinoma development. Importantly, senescent cell elimination in animals prevents the appearance of age-related diseases. However, there are still many unresolved questions before to envisage anti-senescence therapies as to the clock and cell-type specificity of the senescence program, the interplay between different senescence inducers such as telomere shortening, oxidative stress and oncogenic activation, to what extent senescence drives age-related diseases, how senescent cells can be recognized in affected tissues and selectively targeted for elimination and whether such elimination would prevent or treat age-related diseases.
To address these issues, we propose the program S-ENCODE to comprehensively identify the clocks driving the senescence program of different types of cells using a time-resolved, multi-layered, integrative profiling approach.
The realization of S-ENCODE will reveal the key molecular programs underlying cellular senescence and thus will pave the way to the development of innovative strategies for the specific detection, reprogramming and elimination of senescent cells in age-related pathologies using small molecules or genetic interventions. Within S-ENCODE, four prominent senescence and aging research groups will join forces in an interdisciplinary endeavor that brings together scientists with unique expertise, skills, technologies and highly visible contributions to the field of aging in the past. We anticipate that accomplishing these objectives will lay the foundation for a new biomedical research and technology field implicating reprogramming of senescence clocks to prevent and treat age-related diseases.