Molecular Biology of Cancer

The overarching goal of the Bjedov Laboratory is to improve our understanding of the ageing process, and to explore anti-ageing interventions as therapeutic strategies to prevent or delay cancer.

Dr Ivana Bjedov

Principal Research Fellow

UCL Cancer Institute

Research

Ageing is a complex process and presents a major challenge to modern societies. Recently, many interventions have been discovered that extend lifespan and healthspan in model organisms such as yeast, worms, flies and mice. Current interest in ageing research stems from evidence that anti-ageing treatments are evolutionary conserved, and have the potential to delay or prevent age-related diseases.

In order to understand better the ageing process, our work focuses on DNA repair, as well as on the mTOR pathway and its downstream effectors, such as protein synthesis and autophagy. To discover fundamental evolutionary conserved anti-ageing mechanisms, we use a variety of models such as yeast, Drosophila, mice, human cells, and mouse and patient organoids.

We combine different approaches, such as functional genomic screens, whole genome sequencing, DNA methylation analysis, phosphoproteomics, confocal and confocal spinning disc microscopy, as well as molecular and cell biology approaches, which altogether enable us to capture a more complete overview of the ageing process.

Our research addresses the following complementary questions.

Can we prevent DNA damage and enhance DNA repair to reduce genome mutations and selectively improve normal tissue radiation resilience?

Maintaining genome integrity is key for longevity and reduced cancer risk, therefore interventions that lower mutations are expected to improve ageing and delay cancer. Despite mutations being essential for evolution, they are mostly detrimental, and repair of DNA damage must therefore occur effectively to prevent both mutations and excessive cell death, which would otherwise lead to increased cancer risk or accelerated ageing, respectively. Understanding how enhanced DNA repair capacity can confer protection against DNA damage infliction will be critical to simultaneously reduce cancer risk and promote healthy longevity. Understanding how enhanced DNA repair capacity can confer protection against DNA damage infliction will be critical to simultaneously reduce cancer risk and promote healthy longevity.

What is the role of translation errors in ageing?

In contrast to the well-established effects of DNA mutations on ageing and disease in multi-cellular organisms, the role of translation errors is understudied and poorly understood. This is despite mistranslation being the most erroneous step in gene expression.

Proteostasis disruption is a critical factor underlying ageing and age-related diseases, with translation being one of its key determinants. Therefore, improved understanding of the biological impact of translation errors in the context of organismal ageing is urgently needed. To reduce errors in translation, we mutated RPS23, a key protein in the ribosomal decoding centre, and identified a lysine residue, which is almost universally conserved across all domains of life, but is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologues, this specific substitution leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. This study (PMID: 34525330) demonstrated for the first time in metazoan species that increased protein synthesis fidelity is a novel anti-ageing intervention.

Schematic representation of the effect of RPS23 K60R hyperaccuracy mutant on lifespan, heatshock stress, and development

Can we use a cell population-based epigenetic clock to discover novel anti-ageing drugs?

We have a strong interest in pharmacological anti-ageing interventions, and provided initial demonstrations that rapamycin, now a gold standard in the ageing field, extends lifespan (PMID: 20074526 and PMID: 31570569). The recent development of DNA methylation-based clocks was a key breakthrough in the ageing and epigenetic fields, enabling accurate measurement of human age. Despite certain unknowns about the underpinnings of DNA methylation clocks, they are expected to help understand human ageing and why we all age differently.

We generated the CellPopAge Clock, specifically designed to monitor changes in the age of in vitro cell populations at the epigenetic level. Using human adult primary fibroblasts, we show that the CellPopAge Clock can detect decelerated ageing of cell populations following pharmacological interventions. We believe that the CellPopAge Clock has future utility as a new screening platform for the identification of novel compounds, which delay ageing of cell populations and extend in vivo lifespan.

In the news

Fixing protein production errors lengthens lifespan

Fixing protein production errors lengthens lifespan

Reducing naturally occurring errors in protein synthesis (production) improves both health and lifespan, finds a new study led by researchers at UCL and MRC London Institute of Medical Sciences.