Exploring DNA Repair for Longevity with Prof. Björn Schumacher - The VitaDAO Aging Science Podcast

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In this episode of the Aging Science Podcast by VitaDAO I had the pleasure of talking with Prof. Björn Schumacher (@schumacherbj) about his recent work identifying a novel way to boost DNA repair. I found this work unusual in many ways: not only is it urgently needed but he also identified a rather strange protein, with a strange name, as a player in DNA repair using a model species whose aging is not even particularly dependent on DNA repair! Wow.

Short bio

Since 2013, Björn Schumacher is full professor and director of the Institute for Genome Stability in Ageing and Diseases (IGSAD) at the CECAD Research Centre of the University of Cologne. 

Professor Schumacher is President of the German Society for DNA Repair (DGDR), co-Director of the Minerva Center of the Biological Mechanisms of Healthy Ageing at Bar-Ilan University (IL), and between 2014 and 2020 served as President of the German Society for Ageing Research (DGfA). 

His research interest focuses on the molecular mechanisms through which DNA damage contributes to cancer development and ageing-associated diseases.  Employing the C. elegans system and mammalian disease models, his group uncovered cell-autonomous and systemic responses through which the organism adapts to accumulating DNA damage with ageing. Through the understanding of the basic mechanisms of genome instability-driven ageing, Schumacher aims to contribute to the development of future strategies to prevent ageing-associated diseases.

Björn Schumacher, webpage: https://igsad.de

How important is DNA damage to aging?

We know that DNA is important because every cell has exactly two copies (or alleles) of a gene. If one or both or damaged through DNA mutations this can have severe consequences since all mRNA and protein is produced based on this DNA blueprint. Hence, cells have evolved a very complex machinery of DNA repair. This complexity has limited our ability to study and understand DNA repair for a long time.

While mutations in DNA repair proteins accelerate death and certain aspects of aging – causing progerias – so far no one has managed to extend lifespan by increasing DNA repair, it is not even clear if anyone has successfully and consistently managed to increase DNA repair to begin with. The main issue, just as with oxidative stress defenses, is that boosting a single function might have no impact or worse harm the whole system by causing an imbalance in the ration of different components!

However, there is very strong indirect evidence for the role of DNA repair in aging. Björn points out recent studies that allowed us to better quantify somatic mutations. These mutations are so heterogeneous that until recently we lacked the techniques for accurate measurements. These newer studies show convincingly that mutation rates are lower in short-lived species. Some of these we discussed in our Vera Gorbunova podcast.

In the end whether DNA damage is “just” a driver of cancer or also causes other age-related diseases is a moot point. We still lack tools to effectively prevent caner and we will need them to extend healthy human lifespan. Therefore, tackling DNA damage and mutations downstream of damage remains one of the most important tasks ahead.

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The many types of DNA damage

So far, we used the word DNA damage or DNA damage theory quite liberally. However, experts in the field like to distinguish between DNA damage and DNA mutations. One usually leads to the other, but not always. This can be important. Some species like the naked mole rate seem to have low mutation rates but high rates of transient DNA damage – this is still consistent with the DNA damage theory of aging. Ultimately the only thing that matters is the final, unrepairable type of damage: the mutation. Perhaps, as I suggested during the podcast, the word DNA damage theory could be confusing.

Conversely, making matters even more complicated, unrepaired DNA damage can lead to senescence or other issues without causing mutations. However, most DNA damage is not so severe.

In fact, DNA is constantly damaged and this damage is usually repaired efficiently. Some types of DNA damage are considered less toxic, like the famous pyrimidine dimers caused by ultraviolet radiation, single strand breaks, or nucleotide changes. These can induce harmful mutations but the damage is often very small or localized, like a single nucleotide change.

Much worse are crosslinks or double strand breaks. Interstrand crosslinks, for example, block the separation of DNA strands, which is essential for replication and transcription. Imagine your DNA being torn to pieces during replication. This cannot be good. Some cancer therapeutics induce exactly these kinds of mutations to destroy quickly dividing cancers! Similarly, double strand breaks. Perhaps temporarily not a problem but once the cell starts dividing it would lose whole stretches of DNA since the broken parts will not properly attach to the spindle that pulls replicated DNA apart to divide evenly across the new cells. We are dealing with the loss of hundreds of genes and not just single mutations. 

Now imagine there was a way to boost every single type of DNA repair in a balanced and natural way. Maybe we have found it.

The DREAM complex

This large multiprotein complex is involved in cell cycle regulation and repression of DNA repair. Now that makes it quite unusual since one would hardly expect the cell to turn off something as beneficial as DNA repair, would we? As Björn explains in the podcast, everything comes with a cost. It would be wasteful for a worm to boost DNA repair in their body cells to allow a few worms a longer life, when it would cost energy or time that could be invested in producing more eggs, or producing eggs faster. Most worms die early and do not need good DNA repair. If they are exposed to genotoxic stressors they prefer to increase stress resistance mechanisms like antioxidants instead of DNA repair.

Given that DNA damage seems to be a mechanism of aging “private” to long-lived species, i.e. limited to these, it is all the more surprising that Björn’s group discovered the importance of DREAM in C. elegans. It takes a lot of ingenuity and persistence to walk such a tortuous road towards discovery. However, this might have been the right call if, as Björn says, identifying transcriptional regulators of DNA repair was much easier in the worm. From there he just needed to assume that these mechanisms are conserved in higher mammals and get a bit lucky.

The basic idea was fascinating. As it turns out, the germline has 10-fold lower mutation rates than somatic tissues, making it an elite tissue. It stood to reasons that there should be an activator of DNA repair in the germline or an inhibitor of DNA repair in somatic tissues. Since we know that many important age-related pathways are regulated transcriptionally, e.g. multistress resistance via Nrf2 or autophagy via TFEB, it was an obvious choice to look for a transcriptional regulator. It turned out to be DREAM, which was aptly named that way by other researchers who had been studying this one for its role in cell cycle progression and differentiation.

The future of DREAM

Björn and others have identified drugs that repress this repressor of DNA repair. Which means they can activate DNA repair. This is one of the big breakthroughs that we need to finally test the DNA damage theory experimentally. I am optimistic that we are getting closer and that we will eventually find a way to increase DNA repair. Nevertheless, to temper our optimism we have to realize that DREAM has many functions, DNA repair is only one of them. As Björn noted, the whole system is even more complicated in humans than in worms. In the worst-case inhibiting DREAM could lead to unwanted side effects. However, this is only speculation one way or another. The only way to find out is to test existing and novel DREAM inhibitors in mice to see whether they are well tolerated and extend lifespan.

It may be a bumpy road but eventually we will get there. All the best to everyone working in this field!

The host – brief bio

Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research.

References and further reading

Bujarrabal-Dueso, Arturo, et al. "The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities." Nature Structural & Molecular Biology 30.4 (2023): 475-488.
https://www.nature.com/articles/s41594-023-00942-8

Telomeres vs DNA damage - battle of the aging theories
https://biogerontolgy.blogspot.com/2022/03/telomeres-vs-dna-damage-battle-of-aging.html