For those interested in longevity research and the science of important factors such as NAD+, the name David Sinclair is likely familiar. David Sinclair is a Professor of genetics at Harvard Medical school and co-director of the Paul F. Glenn Centre for Biology of Aging Research. His book entitled Lifespan: Why we age and why we don’t have to was published in 2019 and outlines his theory as to why we age and the latest science regarding what we can do to slow the aging process.
Previous understanding of the aging process was limited to the effects of aging. What are the consequences we see in our cells as a result of the aging process? This question continues to be a prominent area of research and has led to the development of the ‘Hallmarks of Aging’. These are a group of characteristics that are often present in aging cells, that contribute to the signs of aging we feel. However, more recent research has increased our understanding of these hallmarks and has led to interventions to slow their impact on our cells. But there is still a lack of understanding as to why these hallmarks develop in the first place. So, what is the underlying driver of the aging process?
DNA structure regulates gene expression
After years of researching aging in various organisms (yeast, worms, mice) David developed his theory of aging termed the ‘Information Theory of Aging’ which he describes in his book and podcast. Cells contain two main types of information: genetic information which is our DNA and also epigenetic information. How epigenetic information changes as we age is pivotal to David Sinclair’s theory of aging.
Before we discuss his theory, we first need to look at the structure of our DNA. DNA is the genetic code which provides our cells with instructions on how to function. Each cell contains a huge amount of DNA, so it has to be packed neatly into the nucleus of the cell. Within the nucleus, double stranded DNA is wrapped neatly around structures called histones, this looks like beads on a string. These histones are then organized neatly to form chromosomes. For the cell to reach the DNA and interpret it, some parts of the DNA need to be accessible and some parts which are not needed are tightly wrapped up and hidden.
Epigenetics controls DNA structure
An important point to note is that all of our cells contain the same DNA. But if all cells contain the same set of DNA instructions, then how do cells have specialized and individual functions? For example, a skin cell looks and functions very differently from a brain cell. This is where epigenetics comes in. Epigenetics attaches different chemical markers on top of DNA which change its structure and how it is packaged up - dictating which parts of the DNA are accessible and which parts are hidden. This means the genes that are open to a skin cell are different to the genes that are available to a brain cell.
The benefit of epigenetics is that it is flexible. Therefore, it can be changed depending on the environment and individual needs of the cell. In fact, it is by altering epigenetics that our lifestyle has such an impact on our biology. For example, exercise causes changes to the cells environment which changes epigenetic markers, DNA accessibility and therefore which genes are expressed. It is via these mechanisms that our lifestyle accounts for around 80% of our longevity while our DNA only accounts for around 20%.
Aging is due to a loss of epigenetic information
The problem is, research has shown that epigenetic information becomes altered as we age, and David Sinclair believes this is a root cause of aging. Genes which shouldn’t be switched on become active, as changes in epigenetic markers mean that the cell accesses large portions of DNA it shouldn’t. This causes cells to lose their specialty and their identity. They no longer behave as they should due to this ‘cellular confusion’ and David Sinclair terms this process ‘ex-differentiation’.
Unlike differentiation which is the process where cells become specialised and gain their cellular identity during development, David Sinclair coined the term ex-differentiation to describe the process by which cells lose this cellular identity and specialization during aging and stop functioning correctly.
And that is David Sinclair’s Informational Theory of Aging: as we age cells lose epigenetic information, causing changes in DNA structure and gene expression, creating cellular confusion and cells which do not function correctly. Ultimately this causes the Hallmarks of aging that are seen in older cells, and the signs of aging that we feel.
Read more about David Sinclair’s insights into longevity and NAD+ along with the importance of a multitargeted approach to effectively address the complex biology associated with it.