We have recently had occasion to have a chat with Dr. Vadim Gladyshev, Professor of Medicine and Director of Redox Medicine at Brigham and Women’s Hospital, Harvard Medical School, in Boston, Massachusetts. He is an expert in aging and redox biology and is known for his characterization of the human selenoproteome. His research laboratory focuses on comparative genomics, selenoproteins, redox biology, and, naturally, aging and lifespan control.

Dr. Gladyshev graduated from Moscow State University, in Moscow, Russia; his postdoctoral studies in the 1990s took place at the National Heart, Lung, and Blood Institute, and the National Cancer Institute, in Bethesda, Maryland. Even when he was young, he was very much interested in chemistry and experimental science: he twice won the regional Olympiad in chemistry and graduated from high school with a gold medal. He also graduated with the highest honors from Moscow State University. This enviable track record is even more impressive considering that Dr. Gladyshev completed music school and high school at the same time and became a chess player equivalent to national master during his college years.

You’ll have a chance to meet Dr. Gladyshev at our upcoming New York City conference, Ending Age-Related Diseases, on July 12; if you can’t attend, you can at least enjoy our interview with Dr. Gladyshev below.

How did you become interested in aging research?







I’ve been working in the area of redox biology, which is often discussed in the context of aging. I soon realized that nothing is certain in aging, even the definition of this process. I was attracted by this challenge and the importance of the problem.

Why do you think we age?

We age because the process of living is associated with deleterious consequences (in the form of molecular damage, mutations, epigenetic drift, imbalance, dysfunction, etc.), which accumulate over time. We call these deleterious changes the deleteriome, as they are much broader than molecular damage. So, we age because of the increasing deleteriome.

Some scientists suggest that aging is a disease or, more specifically, a co-morbid syndrome; would you agree or disagree with this, and why?

I think aging is neither a disease nor not a disease. On one hand, aging is a process, whereas disease is a condition. So, the question may need to be reformulated to whether being older is equivalent to having a disease. On the other hand, conceptually, both aging and disease are associated with deleterious changes, with pathology. Therefore, I think aging includes a combination of chronic diseases together with their preclinical development and other age-related, deleterious changes.







Do you agree that targeting the processes of aging directly has the potential to prevent multiple age-related diseases at once, and why do you think medicine is struggling to move away from the “infectious disease” model when it comes to treating age-related diseases?

I agree, if by ‘targeting the processes of aging directly’ you mean that we alter an organism in such a way that it accumulates fewer deleterious changes over time. However, by targeting aging, we will likely delay the onset of these diseases rather than prevent them. As aging is associated with deleterious changes and pathology, they will unavoidably come, although if we significantly extend lifespan, we may encounter different age-related diseases. I think medicine may be struggling to move away from the “infectious disease” model because no real aging interventions are currently available. I hope it will change completely once the first effective treatments become available.

According to our current understanding, aging is the result of the accumulation of different types of damage and errors in the body. Which of these issues do you think will be the hardest to address?

Aging is not only the result of the accumulation of damage and errors but also other deleterious changes. This is why I think the term ‘deleteriome’ better reflects what happens during aging. In live organisms, every biological process produces deleterious changes. These changes are so diverse and numerous that it would be impossible to fix them all or even sense most of them. Instead, it may be best to alter an organism so that it accumulates fewer deleterious changes (i.e. its deleteriome grows slower) or dilute damage by cell replacement and cell division. I think focusing on a particular damage form is akin to focusing on a particular age-related disease. This approach has some merit, but it would not stop, reverse, or even significantly affect aging, as there could be no main or major damage form. Damage and other deleterious changes act together and need to be dealt with together if we are to target the aging process itself.

Do you have a favorite aging theory in particular, and why?







I think most classical models of aging have good ideas, but these theories are incomplete. We proposed the concept of the deleteriome, which extends and integrates various aging theories. For example, some people consider that aging happens due to stochastic damage, whereas other researchers prefer programmatic ideas consistent with the antagonistic pleiotropy theory. However, much of the damage is clearly not stochastic. For example, cells have specific enzymes that act on metabolites, and therefore, these enzymes will produce particular damage forms rather than any other damage when they make errors. In essence, production of these damage forms is encoded in the genome through the genes that encode the enzymes that create this damage. So, the production of damage may be viewed as programmatic, or, one may say, quasi-programmed. Extending this logic to other enzymes, and in fact to any biomolecule purposely used by organisms, we may say that the use of any biomolecule has two sides. One side is beneficial, and this is the reason why these molecules were selected during evolution. However, the other side is bad, as their use also results in the production of damage and other deleterious changes that accumulate over time. These two sides correspond directly to the two sides of antagonistic pleiotropy. It is just that the antagonistic pleiotropy theory proposed the appearance of certain genes that are beneficial when organisms are young but deleterious when organisms are old. However, it is clear that, first, such genes cannot suddenly emerge because all genes have these properties from the start. Second, these two-side properties apply to all molecules purposely used by organisms, not just some genes. So, while the antagonistic pleiotropy theory and the concept of stochastic damage have been very useful, they are incomplete. However, they can be extended and integrated.

Redox biology is one of the main focuses of your research, and, indeed, you are considered a redox pioneer. Could you summarize for us how it affects human aging?

Any global cellular process is important in aging because, when manipulated, it affects everything else in the cell. Examples are protein synthesis, mitochondrial function, DNA biology, etc. The role of redox biology in aging should be viewed from that perspective. Redox processes are central to cell metabolism and other functions, so they are important in aging, but they are not the most important, because there are no most important processes.

Mitochondrial dysfunction, and the consequent increase in oxidative stress as we age, is thought to be one of the causes of biological aging; allotopic expression of mitochondrial genes is one proposed approach to obviate this problem. Are you optimistic about this approach or not, and why?

I am not super optimistic about the approach of allotopic expression of mitochondrial genes, although it is an interesting direction of research. We must appreciate that everything changes with age, and most of these changes are in the direction of dysfunction. None of these changes are the most important, yet all of them can be viewed as the causes of aging. Targeting individual causes, or even a few causes together, can only lead to marginal effects on lifespan. These approaches may be good in the short term, but we should think beyond them.







Your paper on mammalian selenoproteomes [1] was a very important one, as it was cited nearly 2000 times since 2003. Could you tell us, in simple terms, about selenoproteomes and why they are so important?

In humans, selenium is an essential element. It is present in proteins in the form of selenocysteine residue, the 21st amino acid encoded by UGA codon. We identified a full set of human genes (25 genes) that code for selenoproteins through a combination of computational and experimental approaches. This allowed us to link the biology of selenium with the defined set of genes and identify new functions dependent on this trace element. I agree that this is an important study, yet perhaps it is cited so well in part because everybody can remember the number 25.

There are many different approaches being developed now to address the aging processes; which ones are you the most optimistic about?

Immediate approaches to extend lifespan may involve pharmacological interventions. Several of them work in mice, so there is no reason why some interventions would not work in humans. However, here we may be limited by the degree of lifespan extension made possible by these interventions. Future approaches may involve rejuvenation by reprogramming somatic cells, or, more generally, by the presence of younger and longer-lived cells and organs in older organisms. Eventually, we may begin cleaning up deleterious mutations from human genomes and incorporating pro-longevity genes and variants.

It seems that senolytics might be the first rejuvenation therapy to make it to patients in the relatively short term. How confident are you that they will be beneficial in humans, and how impactful you do think they might be in terms of healthspan and lifespan?







I have not worked with senolytics myself. While the initial data are exciting, it seems more evidence is needed to support the idea that senolytics may have a significant impact or that they may represent rejuvenation. As of now, I do not see why they would be advantageous over other pharmacological interventions.

What piece of the aging puzzle are you and your lab tackling right now?

We work both on mechanisms of aging and mechanisms of longevity. To begin to target aging, first we need to understand what aging is, which, in turn, should lead to better approaches for lifespan extension. An important element in this research is the ability to measure the biological age of organisms. The first-generation biomarkers of aging, most notably the DNA methylation clock but also other clocks, have now been developed by Steve Horvath and others, and they should be useful in testing longevity interventions, rejuvenation approaches, and other treatments and manipulations. For this purpose specifically, we have developed the mouse blood DNA methylation clock.

Aging research could definitely use wider public support. If early trials on senolytics, for example, prove successful, do you think that this might increase the public’s interest and approval?

Most definitely.







Different scientists have different views on how close we are to developing the first rejuvenation therapies against human aging. What do you think?

We are not close. We do not even agree on what aging is, when it begins, whether aging is a disease, or what exactly should be targeted. If we consider the analogy to the history of chemistry, we are just moving away from alchemistry and developing the first chemical principles. In aging, we do not yet have the analog of the periodic table. As a field, we often apply approaches akin to alchemists trying to make gold from other metals. I firmly believe that we cannot solve the problem before we understand it, and the longer we avoid trying to understand it, the longer we will remain aging alchemists.

Do you have a personal longevity strategy to mitigate aging while we wait for the development of rejuvenation therapies?

We do not know a single treatment that could extend human lifespan. We know how to shorten it (smoke, eat unhealthy foods, do not exercise, etc.) but not how to extend it. So, I do not have a personal strategy.

What are the main bottlenecks in aging research at the moment?







Lack of understanding of aging and limited resources.

Do you have a take-home message for our readers?

Let’s work together to solve this most interesting puzzle and most important problem in biomedicine.

Thanks to Dr. Gladyshev for this interview. We look forward to his talk at our conference.







Literature

[1] Kryukov, G. V., Castellano, S., Novoselov, S. V., Lobanov, A. V., Zehtab, O., Guigó, R., & Gladyshev, V. N. (2003). Characterization of mammalian selenoproteomes. Science, 300(5624), 1439-1443.