The hallmarks of aging
Sinclair claims no less than that his Information Theory of Aging explains all hallmarks of aging. Let me give you his complete list (p. 17):
- Genomic instability caused by DNA damage
- Attrition of the protective chromosomal endcaps, the telomeres
- Alterations to the epigenome that controls which genes are turned on and off
- Loss of healthy protein maintenance, known as proteostasis
- Deregulated nutrient sensing caused by metabolic changes
- Mitochondrial dysfunction
- Accumulation of senescent zombielike cells that inflame healthy cells
- Exhaustion of stem cells
- Altered intercellular communication and the production of inflammatory molecules
If I understand Sinclair correctly, his own unified theory of aging is supposed to explain all hallmarks of aging.
The Information Theory of Aging
The short version of the Information Theory of Aging is this:
Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death (p.41).
Others have proposed that DNA damage causes aging. However, this is not Sinclair’s point. First, we are dealing here with a particular form of DNA damage, that is, DNA double-strand breaks. These breaks happen trillions of times every day in an organism the size of a human. Most of them occur (accidentally) when cells multiply, from natural radiation, or simply from chemical reactions inside the cell.
Thus, broken DNA is a very common phenomenon, and you shouldn’t worry too much about the countless DNA breaks happening right now inside your body while you read this blog post. Our cells are well prepared for this kind of damage and repair these breaks as fast as they occur.
However, as you can imagine from this sheer number of breaks occurring during the lifetime of an organism, sometimes things go wrong during the repair process. This is the crucial point of Sinclair’s theory.
The best way to understand his theory is to look at a concrete example. The Sir2 protein in yeast cells is one enzyme responsible for repairing such DNA breaks.
However, this protein has a second job. It silences mating-type genes by removing acetyls from histones. If Sir2 didn’t remove these acetyls, the DNA packaging at this location would loosen, and the corresponding genes would turn on.
A crucial point here is that during the time Sir2 is busy repairing a DNA break, both female and male genes turn on, the cell loses its identity and becomes infertile. As odd as this may sound, the coupling of these two functions of Sir2 has an important biological reason. Yeast cells need to avoid mating until the DNA break is fixed because reproduction would most likely fail otherwise.
Now comes the important part that, according to Sinclair, causes aging. Sometimes Sir2 doesn’t find its way back to its original position, and the cell becomes permanently sterile and therefore senescent. If you check the list of the aging hallmarks above, you will find it includes cell senescence.
Sir2 (the corresponding gene is SIR2) belongs to class of proteins, the so-called sirtuins, which are Sinclair’s major research focus. In mammals, seven such genes exist (SIRT1–SIRT7), and their main task is cellular regulation.
Regulating gene expression is the job of the epigenome. Thus, the core of the Information Theory of Aging is that epigenetic noise (like when Sir2 doesn’t find its way back from its repair job) results in a loss of epigenetic information (the cell no longer knows if it is male or female in the example here).
Of course, the other sirtuins have other epigenetic functions, and epigenetic noise can mean different kinds of epigenetic damage. However, the main point here is that aging occurs when genes that are supposed to be silent (or active) in a certain cell type are turned on (or off). In other words, the pattern of gene expression becomes abnormal, the cell malfunctions and loses its identity. As the number of these malfunctioning cells increases during a lifetime, the entire organism “malfunctions” more and more, which we perceive as aging. Once the number of abnormal cells surpasses a certain threshold, the entire organism fails, and we call this death.
Because of their important role in aging, Sinclair calls the sirtuins “longevity genes.” There are other longevity genes, such as mTOR and AMPK. It is common to all longevity genes that stressors (DNA breaks, inflammation, food shortage, etc.) activate them. This forces the system to hunker down (for instance, to stop mating) during the stressful period and focus on dealing with the stressor. Thus, the reason why stressors such as calorie restriction increase longevity is because cells take more care of damage in those times.
Telomeres and the Information Theory of Aging
Sinclair doesn’t outline how his theory explains all the hallmarks of aging mentioned above (although some explanations are self-evident). However, he briefly discusses one popular approach: the telomere theory of aging.
You’ve probably heard that the telomeres located at the end of the chromosomes shorten with every cell division (mitosis). Once the telomeres have shortened to a certain length, they lose their histone packaging. The end of the DNA becomes exposed, and the cell interprets this as a DNA break.
The problem is that there is no second piece of DNA to reattach because we are at the end of the DNA molecule. The result is that epigenetic factors such as the sirtuins leave their main post forever because a dangling piece of DNA they can’t rejoin fools them. The cell shuts down and permanently stops dividing, which nicely explains the Hayflick limit.
Thus, Sinclair’s theory doesn’t contradict the telomere theory of aging. It rather explains why telomeres play an important role in aging. However, the Information Theory of Aging also claims telomere shortening is just one factor or hallmark of aging.
Conclusion and questions
Sinclair clearly is in the camp of those scientists who support the damage theory of aging. His theory differs from other similar approaches only in the emphasis on epigenetic damage. If I understand his main point correctly, epigenetic noise or information loss is the major cause of aging. My conclusion is that once a cell is no longer able to express the right set of genes, other forms of damage accumulate in the cell simply because the repair mechanism is impaired.
On first sight, this all seems very plausible. However, I still have a hard time believing this is the entire story. I have two major problems with Sinclair’s theory and any theory that claims the major cause of aging is just accumulated damage.
First, why don’t cells simply make more repair enzymes? For instances, if Sir2 doesn’t sometimes find its way back to its original position, why not simply make more Sir2? In fact, Sinclair has shown that adding an extra copy of SIR2 increases the lifespan (the number of divisions) in yeast cells (p. 48).
Sinclair’s resolution of this contradiction is that the advantage of living longer does not justify the additional energy costs of making more Sir2. This sounds plausible. But did anyone really do the math here? How much energy does it actually cost to make a little more Sir2, and what exactly would be the biological advantage if a yeast cell can create more copies of its DNA because it lives longer?
The thing is that cellular damage is the major obstacle life faces. As mentioned above, DNA breaks alone occur trillions of times every day in our bodies. If cells go through so much effort to repair all of this damage, why not take this tiny extra step and also repair the damage that causes aging?
The fraction of unrepaired damage must be incredibly small compared to the damage cells actually repair every second in our bodies. Wouldn’t the tiny extra energy needed for this justify the enormous advantage to staying strong and healthy—at least until the organism dies of other natural causes (predators, infections, accidents, etc.)?
My second problem with the damage theory of aging is that it has a hard time explaining why organisms exist that don’t age at all or can even reverse aging. Why exactly do these creatures invest this extra energy to avoid aging whereas most other organisms do not? If evolution already figured out how to get rid of all cellular damage, why hasn’t this wonderful technology found its way into all organisms?
Because of these unanswered questions, I still feel that aging is not a bug but an important feature of biological evolution. My guess about the main biological function of aging is that it increases diversity in the gene pool. Genetic diversity is perhaps the most important factor when it comes to combating pathogens. So why waste the limited available resources to add the same or similar genetic variations again and again to the gene pool?
In other words, evolution not only favors species that maximize the quantity of their offspring, but quality is just as important. Whereas aging reduces the quantity of offspring, it enhances the quality of the gene pool. Thus, I think aging improves evolvability.
Of course, I am only an interested layman and no match at all for a high-class scientist like David Sinclair. Thus, my criticism should only be seen as the questions of a puzzled student. If you can answer my questions, feel free to post a comment below.
In my next post, I will discuss the second major topic of Sinclair’s book—the question “why we don’t have to age.”