For those who choose to read the following I suggest you go brew a cup of coffee, because it's a long one, even by my standards.
Firstly, Aubrey de Grey (AG) has to be congratulated for the effort he has put towards shifting the inertia in the biogerontology community on treating aging as a disorder and coming up with real and practical solutions. He is an articulate, committed and resilient advocate for legitimate anti-aging research. Thanks to his strategies for engineered negligible senescence (SENS) he has brought credibility in using practical solutions for solving the aging problem and has fired the imagination of even the most conservative scientists and laymen (whether they choose to admit it or not). Furthermore he has rejuvenated the classic scientific approach of inventing new methods for solving problems as opposed to validating hypotheses for their own sake- what he calls the engineering approach. He has done much and we should all be grateful.
So it is with great respect and greater reluctance that I will deconstruct and criticize some of his theories, but in the spirit of science and with the hope that with critical analysis the objective that we all anticipate will be achieved sooner rather than later.
AG has admitted that he came up with what he calls "seven deadly things" during a sleepless night due to jet lag whilst he was visiting the states. They are derived from the book "Understanding Aging" by another famous aging researcher, Robin Holliday, after whom the term "Holliday junction", a DNA structure associated with recombination, is named after. The seven deadly things and his solutions can be summed up as follows:
1. Cell loss - treatable by stem cells
2. Cancer - treatable by WILT (Whole-body Interdiction of Lengthening of Telomeres)
3. Mitochondrial DNA damage - treatable by Allotopic expression of the 13 mitochondrial proteins
4. Cell senescence - treatable by destruction of unwanted cells
5. Extracellular cross-links - treatable by AGE-breaking molecules/enzymes
6. Extracellular junk - treatable by phagocytosis
7. Intracellular junk - treatable by transgenic microbial hydrolases
The strategies I have issue with are (2) and (3).
(2) concerns AG's remedy for cancer which is to prevent telomere maintenance throughout every cell in the body. His theory is since cancer cells are able to maintain their telomere length, by preventing them from doing so would eradicate the incidence of cancer. Aside from the fantastic difficulty of implementing this without having to resort to germline therapy, which would present further problems in development, it is an entirely unnecessary and physiologically incompatible strategy.
A telomerase primer: in the ends of eukaryotic chromosomes, are specialized structures called telomeres (in humans it consists of the sequence TTAGGG repeated thousands of times) that provide structural stability by preventing the ends of chromosomes from fusing with each other and from being degraded by nucleolytic enzymes. Furthermore, each time a cell undergoes division, due to the way DNA polymerase functions, it is unable to replicate the end of one side of the DNA strand (3' end). Consequently, a portion of the chromosome becomes lost with each cell division leading eventually to cell senescence and death due to chromosome instability. Some cells express an enzyme called telomerase that rebuilds the portion of telomere that is lost with each cell division, allowing a cell to divide indefinitely provided nothing else goes wrong with the cell. Telomerase positive cells include germline cells, and every stem cell type in the body including those that are constantly rebuilding epithelial structures (e.g. lining of the mouth, stomach, intestine, colon, hair follicle and skin), the hematopoietic system (all cells of the blood and immune system), those of the brain (e.g. in the hypothalamus and olfactory node) and many more stem cell reservoirs that regeneratively sustain various tissues and organs in the body. Cancer cells, however, also are telomerase positive.
A cancer primer: cancer is the result of a breakdown in the tight controls that regulate normal cell activity. For a cell to become carcinogenic, a multi-step process is involved, that can be generally summarized by the following cell behavior:
- independant of external growth signals
- insensitive to external anti-growth signals
- no longer able to elicit apoptosis
- able to divide indefinately
- able to induce angiogenesis
- able to migrate and invade other tissues
These changes come about as a result of alterations in such things as DNA methylation, oncogene activation and tumor suppressor gene mutation (loss of function). In other words, multiple changes must occur for a cell to become completely out of line with its intended destiny. One of these changes is that, at some stage, it will begin to express telomerase and consequently have the same ability as stem cells - that of being capable of indefinite division.
AG has chosen the step associated with the cell becoming telomerase positive as the mark for death. In doing so, however, he has also chosen every single other cell that gives life, namely stem cells. One of the conventional cancer strategies used today involves whole body irradiation or chemotherapy which specifically targets cells that rapidly divide and destroys them. This includes rapidly dividing cancer cells and healthy stem cells. When stem cells die, however, the patient endures tremendous side effects: the one's we see are the loss of hair, drop in weight, and constant fatigue. What we don't see are the constant body pains, burning throughout the entire alimentary canal (from mouth to anus and everything in between), severe nausea, vomiting, diarrhea, unusual pain and numbing (when nerves start to die), wart formation, anemia and of course drop in immunity. If the treatment has to be severe then the patient must have a stem cell transplant ready or else death ensues. The treatment relies on the body's capability to regenerate after being brought to the brink of cellular annihilation.
AG says that we can compensate for the loss in stem cells by having a replacement treatment every 10 years. This, of course, is not physiologically possible with extremely high cell turnover tissues such as the lining of the stomach wall, which requires new cells every 24 hours. Other obstacles include how every cell can have this modification made outside of using germline interventions. And even if germline interventions are used, what effect having no endogenous population of dividing stem cells would have on a developing human. Where will the necessary biomass of cells come from to build the growing body from embryo to fetus etc.
Naturally, one cannot walk away without offering an alternative solution. I have two. The first concerns the fundamental root of the cause for cancer: altered gene expression. We know that the changes associated with cancer commence with altered gene expression which has its origins in DNA damage. We know this from numerous studies where normal cells will turn cancerous providing they are exposed to sufficient mutagens either in the form of UV irradiation or chemicals. We also know that cells not exposed to these mutagens but that have their DNA repair systems knocked out will act as if they are exposed to mutagens and become cancerous. Finally we know that cells that are made to over-express certain DNA repair factors will be able to withstand higher concentrations of mutagens for longer periods without becoming affected. It is not unreasonable to suspect that by increasing the expression of specific DNA repair factors (I repeat some - not all - since some DNA repair factors can also be mutagenic) that we can reduce the probability of altered gene expression.
But the benefit does not lie solely with cancer prevention but with the process of aging itself. We know that cumulative oxidative and other damage in DNA results in senescence and cell death (or cancer). By reducing DNA damage we also keep cells alive and healthy for a longer period of time. Here too it is not unreasonable to suspect that the tissues from which those cells are composed of - and ultimately the entire organism would also remain healthier for a longer period.
Now for the second solution. This should run parallel with the first, however, we are a tad further from realizing it technologically until we have a more mature knowledge of immunological molecular interactions (not as far however as the fantastically ambitious WILT). This solution concerns a customized method of programming the adaptive immune response. It is effectively a step up from the use of vaccines which train our adaptive immune system to recognize and subsequently kill foreign cells based on antigen being processing from material delivered in the vaccine. By using immune stem cells that can be programmed genetically in the lab to respond to any target including any infective agent our immune response can be kept constantly optimized. This would include targeting cancer cells which are known to express alternative proteins on their cell surface once they "turn".
The second strategy I have issue with is (3). It involves the wholesale migration of the entire DNA apparatus of mitochondria to the nucleus. For those that may not be aware, mitochondria have their own DNA in a circular form, and whilst the majority of proteins that are utilized in mitochondria are actually encoded for by the nucleus and then transported to mitochondria, 13 mitochondrial proteins are encoded for by the mitochondrial genome. The mitochondria being the biggest producer of oxidants in the cell is also prone to the most damage. Some cells have up to 1,000 mitochondria at any one time. Consequently, the mitochondrion has become the achilles heel of the cell and it is the main cause of apoptosis. Also the rate of mutation inside mitochondria is increased due to the oxidative environment and even if mitochondria do not send the "death signal" they can still become sluggishly ineffective at doing their job and thereby making the entire cell ineffective. If that sounds mild, imagine all your heart cells and brain cells becoming "ineffective" and you get a clearer picture of the physiological consequences.
AG thinks that the best way to prevent mitochondrial damage from occurring is to shift the mitochndrial genes into the oxidation-wise relatively safer environment of the nucleus. The first problem we encounter is that the proteins that the mitochondrial genes encode for are fiercely hydrophobic and would not take too well to being transported around and end up in nonfunctioning conformations. The second is that the special mitochndrial gate that lets the nuclear encoded proteins in, the TIM/TOM complex, is itself compromised by oxidants and becomes less efficient at letting the necessary proteins in. Finally, if we are talking about replacing the production of the proteins in up to 1,000 mitochondria, we are talking about a very large scale production of mRNA from the nucleus and protein from the endoplasmic reticulum, the consequences of which we do not know.
Whilst this is not as difficult to envisage as WILT, it can be dealt with by a far more elegant solution. Considering once more that the primary causative factor of mitochondrial failure is oxidation-induced DNA damage, I propose the targeting of specific DNA repair factors and anti-oxidant factors directly into the mitochondrion. It is much easier to implement as this has already been demonstrated experimentally and and I suspect would be more effective.
In conclusion it is quite obvious by now that I am a great believer in enhancing the rate of DNA repair and believe that the positive effects would be multi-faceted particularly as DNA damage seems to be the primary factor associated with altered gene regulation that manifests as aging. Once more, this post should not be in any way interpreted as being negatively judgmental of AG's fine work. It is based on scientific fact and my conclusions drawn from those facts.
As always, please feel free to challenge.