It seems too simple to explain much, but according to a study out of Northwestern University, large proteins are more prevalent in young animals compared to old.
For those of us who believe that aging is programmed into the life cycle, gene expression seems the most likely transmission of information about age through the body. Different genes are turned on and off at different stages of development and through the lifetime. This has been, in my opinion, the most fruitful basis for understanding aging and its remediation. For example, methylation patterns affect gene expression, and methylation patterns are the best measure we have of biological age.
The reason that this hypothesis doesn’t lead immediately to a treatment protocol is that evolution has not engineered the body the way a human would design a machine. Human engineering is based on understanding and isolating causes. One mechanism is designed for each desired effect. Biochemistry doesn’t work that way. Every molecule has multiple functions and every function requires many chemical components to make it work. In an engineered system, there is a hierarchy of causes and effects, a few high-level switches and many low-level switches. In a biological system, there is a network of interactions. Chemicals may have a primary (low level) biological function, but the same molecule also serves as a transcription factor, affecting at a high level the output of related chemicals.
The advantage of human engineering is that it is comprehensible. It is relatively easy to fix. If you see something that’s not working, the design specs tell you what component is likely malfunctioning and you can replace it.
The advantage of nature’s way is robustness. When a component fails, alternative pathways open up to take up the slack.
Last year, my left leg was injured so severely after I was hit by a car that the main vein returning blood from the leg was irreparable, and was surgically sealed off. During the first weeks in the hospital, my left leg swelled up to twice the size of my right because the arteries bringing blood down were fully open, but the return pathway was blocked. But over the ensuing months, other veins gradually expanded to accommodate the increased flow, and my left leg now is almost the same size as my right.
The take-home message is that we think that if we could change gene expression in an old person to mimic the gene expression of youth, the body would look and act young again. But there are thousands of genes that are differentially expressed, and the questions are still up in the air:
- Is there some small subset of genes that controls the others sufficiently that we can add and subtract some manageable number of components from the blood to recreate a youthful metabolism?
- Are these all proteins? Or are there RNAs or other signals that are essential to the process?
- How can we determine what is the minimal set of molecular species that needs to be modified?
- And if we restore the youthful balance of signal molecules through the body, will this recreate a stable, youthful state, or is it necessary to treat the body frequently to prevent relapse to the old metabolic state?
There are presently several laboratories working with this paradigm from different angles, for example at Berkeley, Stanford, the Salk Inst, Mt Sinai and Einstein Hospital of New York.
Leapfrogging ahead of these research institutes with a practical demonstration has been Harold Katcher. Katcher’s method is proprietary. He tells us that it is a “plasma fraction”. When I first heard this several years ago, I thought of the pioneering work of scientists in St Petersburg using peptides, which are very short proteins. I used to think the fraction must be the shortest proteins.
In light of this new paper from Northwestern, I thought it must be the longest proteins. A brief email exchange with Katcher confirmed this guess.
Both Katcher and the Northwestern authors mention the possibility that mRNA splicing might be impaired with age. In all eukaryotes (that’s everything larger than bacteria), genes are not stored contiguously in our chromosomes, but rather in segments that code for modules, or pieces of a protein. The mRNA is copied from the chromosome, and then various pieces of mRNA are spliced together to form a full, functional gene before the reconstituted mRNA is delivered to a ribosome to be read and translated into a protein. Presumably, longer proteins require more splicing, so impaired RNA splicing could account for a deficit of longer proteins as we age.
Katcher’s E5 is based on a process of filtering proteins from pigs’ blood plasma and selecting the largest molecular weights. It seems to work in rats, but the process of ramping up to create sufficient quantities of E5 for human trials is proceeding slowly, dragged down in part by the IP that Katcher and his partner are holding close to their chests.
Meanwhile, the four questions I listed above are not being addressed. Patent law is working against us, since Katcher’s E5 patent is for a process of extraction. If a subset of active ingredients is identified and the minimal set of rejuvenating proteins becomes known, his patent becomes worthless. Naturally occurring proteins cannot be patented.
This is the maddening influence of capitalism and intellectual property law on anti-aging science. The most promising avenue for rejuvenation (IMO) is not attracting research attention because it cannot attract venture capital; it can’t attract venture capital because there is no attractive business model; and there is no business model because of the structure of our patent law.