Fraser, Helen Christina;
(2022)
Hallmarks of aging predict age-related disease multimorbidities in patients.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age-related diseases in laboratory animals, including rhesus monkeys. These findings imply that mechanisms of aging, or aging hallmarks, might also contribute to age-related disease multimorbidities in humans. Therefore, aging hallmarks could potentially be targeted to prevent multiple diseases in the same individual. To address this question, 917,645 literature abstracts were text mined followed by manual curation, and they showed strong, non-random associations between age-related diseases and aging hallmarks, which were confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age-related diseases associated with each of five aging hallmarks were more likely than expected by chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signalling pathway, and the Ras-ERK pathway played a significant role across multiple, diverse, aging hallmark-associated age-related diseases. Network propagation demonstrated that aging hallmarks may explain the occurrence of age- related diseases with an incompletely understood pathogenesis, such as essential tremor. Nine random forest classifiers were trained to accurately detect sentences from scientific abstracts that reported aging hallmarks contributed to the pathogenesis and pathophysiology of diseases. The relevant sentences were displayed in a novel web resource, AgingHallmarkDB, to drive future research in the field. Overall, the findings of this research suggest that aging hallmarks contribute to patterns of human age-related disease multimorbidity and could potentially be targeted to prevent more than one age- related disease in the same patient.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Hallmarks of aging predict age-related disease multimorbidities in patients |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10146945 |
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