Bioinformatics applications to the study of longevity, ageing and cancer

Abstract

Death is something we all face, starting from the moment we are born. As we grow older, our bodies change, and the way we age can be affected by our genes, how we live, and the environment around us. Aging is something that happens to everyone and it involves many changes in our bodies, both at the physical and cellular level, which lead to a decrease in our ability to do things as we get older. The process of ageing is a complicated decline in our physical well-being caused by the time. While advances in technology and medicine over the last century have increased the average lifespan of humans, there have been minimal improvements in the maximum age that people can reach. More worryingly, on average we are likely to spend the last decade or two of our lives afflicted by chronic and progressive diseases which greatly impairs our quality of life. This is important because it has a big impact on public health, healthcare systems and the overall well-being of societies.

In this thesis, I’ve explored different aspects of longevity, ageing and ageing related pathologies. In chapter 2 I compare the genomes of 46 mammalian species and reveal that a set of gene families enriched in immune system functions have expanded along with the evolution of longer lifespans. Notably, these gene families are enriched in gene lists previously associated with longevity in humans and other longevity related molecular functions suggesting that common molecular pathways may underlie between-species differences in maximum lifespan and between-individual variations in longevity within a species. We further show that these changes are largely shared when brain size relative to body mass is examined supporting a common evolutionary path for both traits.

Progressive loss of muscle mass and function is one of the main characteristic of ageing. To have a better understanding of this mechanism, in chapter 3, I explored the changes in gene expression levels by age in human skeletal muscle tissues. This investigation revealed significant differences in gene activity between older and younger individuals, especially in genes related to muscle function and the immune system.

Cancer is a common disease and one of the main causes of death. Chapters 4 and 5 concentrate on cancer and transcriptomic changes observed in cancer vs controls as well as exploring the transcriptome signatures associated with longer survival times. I discovered that certain genes related to the immune response are more active in cancer, and this may have implications for cancer diagnosis and treatment.

Together the findings presented in this thesis represent an exploration of longevity and ageing, and provide insights into the molecular changes associated with the evolution of longevity across the mammalian phylogeny, transcriptomic changes observed during healthy ageing and in cancer.

Ageing is a significant risk factor for various diseases and mortality in human. This is important for public health, as it relates to diseases like cancer and dementia, an aspect explored further in a review paper in the appendix section of this thesis, that affect older people. Taking an evolutionary perspective, can provide important insights into common molecular underpinnings in the evolution of longevity which can in turn better inform our understanding of molecular changes in our own species.

Date of Award	27 Mar 2024
Original language	English
Awarding Institution	University of Bath
Supervisor	Tamas Szekely (Supervisor) & Araxi Urrutia (Supervisor)