Here, Greg Fahy interviews George Church on the topic of gene therapies, gene expression changes in aging, and the aim of treating aging as a medical condition in a recent issue of Life Extension Magazine. Both of these researchers are enthusiastic about the path of identifying and reverting age-related changes in gene expression, something I consider to be most likely less useful than targeting root cause damage after the SENS model for rejuvenation therapies. Still, present day stem cell therapies are probably a good indication of the sort of result that can be achieved through gene expression alteration, as they largely work through signaling changes: putting damaged machinery back to work without fixing the underlying damage that causes aging. It can be argued that these gains are large enough to pursue, and we should just be aware that it isn't the path to controlling and halting aging, only the path to a class of therapies for age-related disease that are incrementally better than existing ones.
Fahy: If aging is driven by changes in gene expression, then the ability to control gene expression using CRISPR technology could have profound implications for the future of human aging. Why do you think aging may be at least partly driven by changes in gene expression?
Church: We know that there are cells that deteriorate with age in the human body and that we have the ability to turn those back into young cells again. This means we can effectively reset the clock to zero and keep those cells proliferating as long as we want. For example, we can take old skin cells, which have a limited lifetime, and turn them into stem cells (stem cells are cells that can turn into other kinds of cells) and then back into skin cells. This roundtrip results in the skin cells being like baby skin cells. It's as if my 60-year-old cells become 1-year-old cells. There are a variety of markers that are associated with aging, and those all get reset to the younger age.
Fahy: There are several very exciting stories in aging intervention these days. In 2013, the Sinclair lab at Harvard came out with the revelation that the aging of mitochondria (which are the producers of usable energy within cells) is driven in significant part by reduced levels of one particular molecule in the cell nucleus: oxidized NAD (NAD+). Now your lab showed that there is a very exciting gene engineering alternative involving TFAM (Transcription Factor A, Mitochondrial). Why is TFAM important, and what have you done with it?
Church: TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside. Ideally, you don't want to have to take NMN for the rest of your life, you want to fix the body's ability to make its own NMN and buy yourself rejuvenation for at least a few decades before you have to worry about NMN again. In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent. When we activated TFAM, these changes returned to what you would expect of a younger cell state. And we built this anti-aging ability into the cell, so it's self-renewing and eliminates the need to take pills or injections.
Fahy: GDF11 has been reported to rejuvenate the heart, muscles, and brain. It restores strength, muscle regeneration, memory, the formation of new brain cells, blood vessel formation in the brain, the ability to smell, and mitochondrial function. All of this is done by just one molecule. Infusing young plasma, which contains GDF11, into older animals also provides benefits in other tissues, such as the liver and spinal cord, and improves the ability of old brain cells to form connections with one another. How would you use CRISPR to make sure that GDF11 blood levels never go down?
Church: The CRISPR-regulating GDF11 could be delivered late in life, which is exactly when such an increase would be welcome. If you really wanted to stay at a certain level, you might want to put in a GDF11 sensor to provide feedback so you could automatically control GDF11 production so as to lock in a specific GDF11 level. If necessary, you could recalibrate and fine-tune this maybe once every few decades with another dose of CRISPR. But yes, it's a great molecule, and we've got a handle on it. We are also doing a number of other projects now, dealing with a range of muscle diseases such as muscle wasting. We're working on possible treatments involving proteins such as myostatin and follistatin.
Fahy: Speaking of myostatin, the lack of which causes super-development of muscles, you mentioned in your 2014 SENS talk that you are interested in the possibility of enabling better muscle strength and less breakable bones. Is this another good treatment path for aging?
Church: Muscle wasting and osteoporosis are symptoms of aging. The key to dealing with them is to get at the core causes, even if they're complicated. There are genes known to be involved in muscle wasting and genes that can overcome that.
Fahy: What about going beyond just correcting aging and actually super-protecting people by making them augmented with stronger bones or muscles than what they would normally have?
Church: Rather than waiting until the muscles are wasting and then trying to correct the problem, or waiting until someone breaks a bone and putting a cast on, the idea is to make the muscles and bones stronger to begin with. Think of it as preventive medicine. You have to be careful, but there are people naturally walking around with much denser bones and much stronger muscles that have no particularly bad consequences, so we know such things are possible. I would say osteoporosis definitely could be reversed. The process of bone building and bone breaking down is a regulated process that responds to conditions such as the good stress of standing or running. So yes, it's an example of something that's reversible.
Fahy: Using your most favorable pathway for intervention, how long will it take before a human trial might be possible?
Church: I think it can happen very quickly. It may take years to get full approval, but it could take as little as a year to get approval for phase one trials. Trials of GDF11, myostatin, and others are already underway in animals, as are a large number of CRISPR trials. I think we'll be seeing the first human trials in a year or two.