The Life Extension Advocacy Foundation volunteers recently interviewed researcher Vadim Gladyshev. He has an interesting viewpoint on aging; he is one of the faction in the scientific community who think that near future significant progress in treating aging is unlikely, as greater understanding is required. This is more or less the polar opposite of the SENS rejuvenation research viewpoint, which states that the present understanding of the root causes of aging is sufficient for progress, and implementation is lagging far behind the state of the science. Gladyshev's laboratory is focused on the genetics of aging and redox biology - the modern end of the evolving view of how oxidative damage is involved in aging.
The early views of aging as being driven by an accumulation of oxidative damage to important molecules have been put aside as too simplistic. Numerous examples of life extension in lower animals have involved modest increases in the production of oxidative molecules: oxidation isn't just a form of damage, it is also a signal in a very dynamic, self-repairing system, one that can have positive outcomes. Oxidative molecules are required for the benefits of exercise to manifest themselves, for example, and those benefits can be blunted by overuse of antioxidants. So while it is clearly the case that older individuals have far greater levels of oxidation in their cells and tissues, that is probably secondary to issues such as mitochondrial and immune system dysfunction.
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.
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.
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.
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, 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.
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.