A Short Interview with George Church on Genetics and the Treatment of Aging

The Life Extension Advocacy Foundation volunteers recently interviewed George Church, one of the leaders in the research community who has come around these past few years to speak out in public as being very much in favor of treating aging as a medical condition. I point this out largely because they ask about some of his recent comments regarding timelines in the near future development of anti-aging therapies. He thinks that the first are only a few years away, which is indeed true from my perspective given what is happening in the development of senolytics to clear senescent cells, but Church doesn’t have senolytics in mind when he says this. He is one of the luminaries of modern genetic biotechnology, and he sees the future through that lens.

Professor George Church – Turning Back Time to End Age-related Diseases

You recently said that you “predict we are about to end the aging process. In the next five years no less!” Whilst progress has indeed been rapid in the field of rejuvenation biotechnology, could you clarify, is this five years to achieving this in human cells, to clinical trials or what exactly?

Within five years it seems plausible to have some gene therapies in FDA approved clinical trials in dogs – aimed at general aging reversal, but quite likely, labeled for specific diseases (and in humans soon thereafter). This means combinations of gene therapies aimed at most of the known major aging pathways, though there are major challenges in efficient delivery.

Do you agree that epigenetic alterations as described in the Hallmarks of Aging are a primary driver of the aging process, and if so do you think we can safely use cell reprogramming factors OSKM (OCT4, SOX2, KLF4 and MYC) to turn back cellular aging?

Yes. Epigenetics are important drivers, but it are only part of the Hallmarks of Aging – and OSKM would, in turn, be only part of that. Other examples are factors behind heterochronic parabiosis. Efficacy may depend on the various tissue types.

DNA damage is proposed to be a primary reason we age. Can it be repaired by targeting TFAM (Transcription factor A, mitochondrial precursor) to increase NAD (a coenzyme in all living cells that facilitates the production of energy) levels that are known to facilitate DNA repair?

We have targeted TFAM and consequently raised NAD successfully. The NAD-facilitated repair is not the only route – we can prevent DNA damage (via the management of radical oxygen species), prevent the impact of such damage (e.g. duplicating tumor suppressor genes), favor specific types of DNA repair, or induce apoptosis in cells which appear to acquire potentially oncogenic mutations.

Cancer is caused by an unstable genome resulting from DNA damage and could be considered the poster child of aging diseases, can we use CRISPR to defeat cancer?

Genome editing (TALENs, CRISPR, etc.) and transgenic methods (CART) are being ‘successfully’ applied, but proof of generality and long remission is not here yet. Effective alternatives are preventative – vaccines against some of the 11 infectious, cancer-causing agents (e.g. HPV), inherited genome sequencing, genetic counseling, prophylactic surgery and avoiding environmental risk factors. Some strategies which work to preventatively reduce cancer in mice might benefit from engineering germline or more efficient delivery of gene therapies (since single untreated cells matter more for cancer than other diseases).

Do you think we can learn useful knowledge that can be applied to humans from the whole-genome sequencing of long lived species such as the 400-year-old greenland shark?

The most promising sequencing insights will probably come from genomes closest to average humans, such as naked mole rat, bowhead whales and human supercentenarians. Even more crucial is low-cost, high-accuracy testing of hypotheses flowing from those sequences, plus already hundreds of hypotheses from model organisms and cell biology (see the GenAge database).

Genetics is an enormous area, even when you narrow down the scope to genetic biotechnologies that can be used to build therapies relevant to aging. There are numerous different things going on, not all of which we should be equally enthused by. I’ll draw some fairly arbitrary lines here to demarcate three classes of genetic therapy. The first broad class of work is very similar to existing pharmaceutical development: the construction of means to temporarily alter the level of a particular protein or interfere in one or more interactions carried out by this protein. Genetic technologies hold the promise of being able to carry out this task with far greater accuracy and control over the size of the outcome. The second class of work involves the creation of permanent effects by adding or removing DNA in a targeted fashion, such as to provide a functional copy of a gene that is broken as a result of an inherited mutation. This is not yet practical for therapies applied to human adults due to challenges in obtaining reliable, comprehensive cell coverage, meaning introducing the new DNA into enough cells, and especially stem cells, to produce a significant and lasting effect. But that goal lies very close in the near future.

The third class of work involves more complicated use of genetic machinery. The production of programmable DNA machines that can read cell state, react, and carry out logical operations to produce different outcomes for different circumstances, for example. The Oisin Biotechnologies approach to targeted cell destruction is one such early, simple machine. Far more complex machinery is obviously possible, given the existence of cells in the first place. This class of more complicated uses also include applications of gene therapy that achieve a more devious and multi-layered goal than just inserting a gene that will result in proteins being produced. For example, allotopic expression of mitochondrial genes involves inserting altered versions of mitochondrial genes into nuclear DNA, their usual sequences wrapped in such a way that cellular transport machinery will pick it up these altered proteins, move them back to the mitochondria, and then import them into mitochondria, ending up with a copy of the original protein at the end of that process.

Now, much of the first category of genetic engineering, tinkering with levels of specific genes, will be just as marginal for the treatment of aging as the pharmaceutical approaches that preceded them. That is inherent in the proteins and genes being targeted. When the goal is mimicking the response to calorie restriction, or increasing autophagy, or similar alterations shown to modestly slow down aging in laboratory animals, then the small size and lack of reliability in the outcome is as much inherent in the target as it is in the method used to manipulate the target. These mainstream efforts are only slightly increasing resistance to the consequences of molecular damage in aging, or slightly slowing the accumulation of that damage. They are not truly effective means of addressing aging.

We should nonetheless expect to find that some targets accessible to genetic methods are a lot better than those that can be or have been manipulated via drugs. There are some promising genetic variants that exist in the wild and have far larger effects on human cholesterol levels than the best drugs, such as statins, for example. There is myostatin and follistatin, that can be targeted to increase muscle growth to a far greater degree than any pharmaceutical method, and thus resist age-related loss of muscle mass. But these are still not repair therapies. They are only ways to better compensate somewhat for the losses and damage of aging. The damage will still win if it is not addressed.

So what George Church describes in the short term is really just the application of genetics to the ongoing pharmaceutical tinkering with metabolism that has achieved little of any practical use in the past few decades. All that has been gained is knowledge. What he describes in the longer term is the much more ambitious project of rebuilding the human genome, one small step at a time, to create packages of changes that result in slower aging, greater resistance to the consequences of aging, and other enhancements to the human condition. This is an immense project of vast scope and complexity. It will happen in the fullness of time, but it cannot possibly produce anywhere near as good an outcome in the next few decades as the alternative approach of keeping the present baseline human genome unmodified, and focusing on periodic repair of the molecular damage that arises as a side-effect of the normal operation of metabolism. The research community has a far better roadmap for this goal, there is far less to achieve, and it is a much easier set of projects, where far more is known of what must be done. Genetics with the goal of improving humanity is seductive, as the long-term potential is truly amazing – but unless we address the damage first, we’ll all be long dead before that potential is reached.

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