Overview of research interests
Why do we age, and can we do anything about it? Dr. Luke's laboratory tackles this question at its source: the small set of molecular processes — the primary hallmarks of aging — that malfunction in every age-associated disease. These hallmarks include telomere attrition, genome instability, loss of proteostasis, epigenetic alterations and disabled macroautophagy, and improving the function of even one has the potential to prevent or delay disease across multiple tissues and organ systems. Rather than treating age-related diseases one at a time, the lab asks why these processes fail as we age — and how they can be repaired. His group discovered that the non-coding RNA TERRA controls the rate at which telomeres shorten through the formation of R-loops, which has the potential to be developed into an RNA therapeutic for telomere biology disorders. In parallel, the laboratory showed that taurine and related osmolytes act as protein-folding agents in vivo, rescuing misfolding in models of ALS and ataxia and extending lifespan. A third arm investigates how Topoisomerase 1 drives the DNA mutation signatures that accumulate with age, and how interventions such as caloric restriction can counteract them. Together, these programs aim to move aging research with the ultimate goal of extending healthspan and delaying age-related diseases. We are always looking for curious and motivated trainees to join the team.
Current Projects
- TERRA as a modulator of replicative senescence
Telomeres cap the ends of linear chromosomes and shorten with every cell division; once critically short, they trigger cellular senescence, which suppresses tumours but drives aging when senescent cells accumulate. Across mammals, it is the rate of telomere shortening — not telomere length — that determines lifespan, and our laboratory has shown that the non-coding RNA TERRA regulates this rate by forming R-loops that trigger the repair of short telomeres. Our research program addresses three questions:
- What is the molecular mechanism by which TERRA-driven R-loops promote the repair of short telomeres?
- Can TERRA act as an exogenous molecule to drive telomere repair, and what is its mechanism of action?
- Can TERRA be developed as an RNA therapeutic to treat telomere biology disorders, in which shortened telomeres cause aging-associated disease?
- Osmolytes as chemical chaperones
With age, proteins progressively misfold and aggregate, underlying diseases such as Alzheimer's, ALS and ataxia with oculomotor apraxia type 2. Our laboratory has shown that taurine and related osmolytes act as protein-folding agents in vivo — rescuing misfolding in models of ALS and ataxia and extending lifespan — yet how this class of molecule works remains poorly understood. Our research program addresses these questions:
- How do osmolytes alter the gene, protein and metabolite landscape of aging cells and does this contribute to chemical chaperone function?
- Which misfolded proteins are particularly prone to being rescued by osmolytes during aging and thermal stress? Are there differences between osmolytes?
- Can optimized osmolyte combinations be developed as supplements for clinical trials to prevent protein misfolding driven by aging, disease and thermal stress?
- The regulation of Topoisomerase 1-mediated mutations
DNA mutations accumulate with age, driving spontaneous cancers and shortening lifespan, yet why mutagenesis increases with age is unknown. The age-dependent ID4 deletion signature depends on Topoisomerase 1 (Top1) acting at embedded ribonucleotides (rNMPs), the most common DNA aberration known. We have now shown that Top1 also drives mutations at sites of replication conflict in a manner independent of rNMPs, revealing a second route to age-dependent mutagenesis. Our research program addresses the following questions:
- How is Top1 recruited to — and regulated at — sites of replication stress, and does this change as cells age?
- Why does the ID4 mutation signature increase with age: is it driven by increased rNMP levels, or by the greater prevalence of replication conflicts?
- Can preventing Top1-mediated mutations — through interventions such as caloric restriction or rapamycin — extend lifespan?