Decoding Longevity: DNA Mutations, Mole Rats, and Cancer Prevention with Prof. Vera Gorbunova on The Aging Science Podcast by VitaDAO

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In the 7th episode of the Aging Science podcast we talked with Prof. Vera Gorbunova about her most recent work, covering a wide array of topics from genome stability, naked mole rats, the role of hyaluronan in cancer prevention, fucoidan as a SIRT6 activator, to comparative transcriptomics and Peto’s paradox.

Short Bio — Vera Gorbunova

Dr. Vera Gorbunova is a Professor of Biology and Medicine from University of Rochester. Having earned her undergraduate degree at at Saint Petersburg State University (Russia) and her Ph.D. at the Weizmann Institute of Science (Israel), she has dedicated her career to understanding the mechanisms of longevity across species, exploring genome stability, sirtuins, and non-traditional animal models. Her pioneering work on SIRT6 biology and potential activators like fucoidan, along with contributions to studying hyaluronan for cancer prevention, could pave the way towards therapeutic applications.

“I would choose to live for as long as I am enjoying it[…]it is very difficult to set a limit for yourself. That is what we would want for every person that people can live as long as they are happy.” (Vera Gorbunova)

DNA damage and aging

One of Vera’s key interests is genomic instability, which has emerged as a likely driver of aging. Mutations can lead to cancer, disrupt gene expression and the epigenetic architecture of the genome. This explains why long-lived species had to develop effective mechanisms for repairing or preventing such damage.

In a recent study together with Jan Vijg, Vera discovered that short-lived rodents, and in particular mice, show higher levels of DNA mutations before and after a genotoxic stress (Zhang et al. 2021). The technique they used to show this is particularly interesting. Without going into details, it is difficult to measure DNA mutations using classical sequencing due to high levels of background noise that looks like mutations. Many workarounds exist, often focusing on clonally expanded stretches of mutations. Here, instead, the authors performed whole genome sequencing of single fibroblasts from five different species that differed in their maximum lifespan (mouse, human, guinea pig, blind mole-rat, and naked mole-rat).

While the finding of lower mutation rates in long-lived species is correlational and indirect, it has been replicated many times and there is no clear alternative explanation for it that would be unrelated to aging or cancer. This is one of the reasons why the “DNA damage theory of aging” is generally held in high regard by most people in the field.

Comparative biology of aging

Researchers doing comparative biology or biogerontology of aging, as the name suggests, want to compare species that have different lifespans to discover why some live longer than others.

On this podcast we often talk about the shortcomings of mice, like their short lifespans and susceptibility to cancer (1). Comparative biology avoids these pitfalls of mouse models since it allows researchers to study a wide variety of species, some of which live orders of magnitude longer than mice and are more similar to humans.

Comparisons come in many types. Some researchers study dozens or even hundreds of species, if they can access the right kind of data for these species (2), whereas others pick two closely related species that have different lifespans and compare them. Often this is the mouse and the naked mole rat, which while mouse-sized nevertheless lives up to 30 years. The techniques employed are as varied as the sample sizes of these studies. In principle, one can compare any phenotype or molecular marker between species. Recent studies have focused on high-throughput methods, comparing the genomes or transcriptomes of different species.

Transcriptomics and other “omics” of aging

The expression patterns of cellular mRNA, the template that gives rise to proteins, can be studied using RNA-sequencing which we call transcriptomics. Vera’s team recently published a large-scale comparison of different rodents (Lu et al. 2022) confirming some candidate pathways we believed are associated with longevity. For example, longer-lived rodents, let’s say capybaras or naked mole rats, were found to have better repair of DNA double strand breaks, while pathways involved in the repair of smaller lesions were unchanged. This is keeping with an emerging consensus that double strand break repair is the most important type of DNA repair for aging.

Also, not surprisingly inflammation was reduced in longer-lived rodent species. Transcription factors related to pluripotency were linked with the expression of “pro-longevity” genes while “anti-longevity” genes were related to circadian transcription factors.

The study also reported some beautifully odd findings implicating novel pathways in aging, including collagen synthesis or RNA export. This is the kind of finding that, if it pans out, can spawn a new field of research.

While I love comparative studies utilizing omics, it should not go unmentioned that they have certain limitations. Given the large amount of data generated it is quite easy to find support for some of the popular aging theories, whereas lack of evidence is often ignored. No one ever talks about the aging theories that were not supported by the data that and what this means.

Moving forward, Vera’s next goal is to apply proteomics and metabolomics approaches to these rodent species, integrating this data with the transcriptomic findings. We both agreed that proteomics, i.e. the systematic analysis of protein expression patterns, is very under-utilized in aging research.

Extracellular matrix (ECM) and aging

The importance of extracellular matrix (ECM) changes to cardiovascular aging was discovered by Blumenthal and Lansing in the early twentieth century. Despite this early and seminal work, for a while there was a lack of interest in studying extracellular matrix changes during aging and the field is having a renaissance now. While Lansing studied a protein called elastin, Vera’s work is focused on glycosaminoglycans, which are a type of large sugar chains (polysaccharides).

“The length of hyaluronan [=hyaluronic acid] can range from an oligomer to an extremely long form up to millions of daltons. The concept that emerged in the field is that high (HMW-HA) and low (LMW-HA) molecular weight hyaluronans have different biological properties and trigger different signaling cascades within the cells. LMW-HA is associated with inflammation, tissue injury and metastasis, while HMW-HA improves tissue homeostasis and has anti-inflammatory and antimetastatic properties.” (Gorbunova et al. 2020)

In this episode of our podcast Vera explains that hyaluronan forms a mesh between tissues and cells that may be able to slow down metastasis and the growth of cancer more generally. It appears that naked mole rats possess high molecular weight hyaluronan that is particularly effective at preventing cancer and perhaps we might be able to slow down cancer growth by boosting our own production of hyaluronan. Achieving this goal, however, will not be simple since such a large molecule cannot be absorbed well from the gastrointestinal tract, which rules out a simple supplementation approach. Similarly, although hyaluronan injections are a popular treatment for wrinkles and osteoarthritis, they will not work to increase whole body hyaluronan synthesis because the hyaluronan molecule is large and “sticky”.

Instead, the idea is to inhibit the enzyme that breaks down hyaluronan which would also cause a shift towards larger molecular weight species of hyaluronan.

Although it remains speculative whether boosting hyaluronan synthesis or increasing the molecular weight of our own hyaluronan will be beneficial, it is nevertheless a good working hypothesis. This kind of work beautifully illustrates how basic and comparative science can lead to potential clinical applications

Below you can read more about Vera’s recent project that was funded by VitaDAO: https://snapshot.org/#/vote.vitadao.eth/proposal/0x747f0e671d6e049ce501fba8067c9da3b0502b8945daa890ca98f36a63bc7246

Summary

Prof. Gorbunova’s work reveals a correlation between long lifespan and low DNA mutation rates. Among other things, she also found changes in the hyaluronan of long-lived species. There is ongoing work to utilize these findings to develop therapies that target human aging, e.g. fucoidan as a SIRT6 activator or inhibitors of hyaluronan breakdown.

References

Lu, J. Yuyang, et al. “Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation.” Cell Metabolism 34.6 (2022): 836–856.

Zhang, Lei, et al. “Maintenance of genome sequence integrity in long-and short-lived rodent species.” Science Advances 7.44 (2021): eabj3284.

Gorbunova, Vera, Masaki Takasugi, and Andrei Seluanov. “Hyaluronan goes to great length.” Cell stress 4.9 (2020): 227.

Notes

(1) The justification for mouse research is as follows. We do not use mice because they are a great model of long-lived mammals, instead you can consider them as “better worms”. They are simply the next best model after invertebrates that is still affordable for basic research.

(2) One accessible type of data is for example the sequence of the mitochondrial genome. Both Vera and I published research on this topic and as an “amateur” comparative gerontologist myself I always like following her work.

Pabis, Kamil. “Triplex and other DNA motifs show motif-specific associations with mitochondrial DNA deletions and species lifespan.” Mechanisms of Ageing and Development 194 (2021): 111429.

Yang, Jiang-Nan, Andrei Seluanov, and Vera Gorbunova. “Mitochondrial inverted repeats strongly correlate with lifespan: mtDNA inversions and aging.” PLoS One 8.9 (2013): e73318.

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