Fight Aging!

George Church is an important figure in the development of modern genomics and genetic engineering. Like a number of luminaries in the medical life sciences, in recent years he has become much more openly supportive of efforts to treat the causes of aging and extend healthy human life spans. You might recall the keynote he gave at the SENS6 rejuvenation research conference, and note that Church is a member of the SENS Research Foundation advisory board. With that context, I'll point you to recent remarks made to a journalist:

A Harvard professor says he can cure aging, but is that a good idea?

I mentioned to Church that CRISPR is the kind of work for which Nobels are awarded. He quickly responded that there are more important things in the balance than prizes. There are cures for human diseases, he said. Church thinks that one of the ailments he can cure is aging. When I met him early this year, in his laboratory at Harvard Medical School, where he is professor of genetics, he expressed confidence that in just five or six years he will be able to reverse the aging process in human beings.

"A scenario is, everyone takes gene therapy - not just curing rare diseases like cystic fibrosis, but diseases that everyone has, like aging," he said. He noted that mice die after 2.5 years but bowhead whales can live to be 180 or 200. "One of our biggest economic disasters right now is our aging population. If we eliminate retirement, then it buys us a couple of decades to straighten out the economies of the world. If all those gray hairs could go back to work and feel healthy and young, then we've averted one of the greatest economic disasters in history. Someone younger at heart should replace you, and that should be you. I'm willing to. I'm willing to become younger. I try to reinvent myself every few years anyway."

So on Tuesday, I asked him if he was still on track to reversing the aging process in the next five years or so. He said yes - and that it's already happening in mice in the laboratory. The best way to predict the future, he said, is to predict things that have already happened.

This is filtered through a layperson with mixed feelings about the whole business of trying to treat aging, so necessary context is lost. Church is big on the application of genetic tools to many present problems, no surprise given his background, and it is true that an entire class of solutions in medicine and other fields can be constructed atop robust, reliable gene therapy of the sort enabled by CRISPR. However, many types of genomic research into aging and longevity are presently taking place, and there are many types of intervention, existing and proposed, that can employ genetic engineering. Sadly, those gathering the greatest attention at the current time are also the least likely to produce meaningful results. Let me divide things up into a couple of categories:

Firstly, we have the search for longevity genes and the idea that we can use drugs, gene therapies, and other tools in the toolkit to adjust metabolism to look more like that of people with specific genetic or epigenetic traits that are linked to longer healthy lives. This covers a broad range of approaches, from calorie restriction and exercise mimetics to analysis of centenarian genomes in search of common factors. This is slow and expensive work, and so far has produced little more than knowledge. There is also the problem that in principle even complete success means tiny gains. What does it mean to have the full set of characteristic differences present in a centenarian's metabolism? It means you have perhaps a 1.5% chance of living to 100 rather than a 1% chance, to pull some numbers out of the air - the real numbers are along these lines. Identified genetic associations with longevity are a matter of a tiny increase in a tiny chance of survival, and if you get there you're still decrepit and age-damaged. The same goes for calorie restriction and exercise mimetics; even if completely recapturing the real thing, that gains a few years of additional life expectancy. You still age, you still die, and the schedule is much the same. This is not a goal worth spending billions and decades on, but it is nonetheless what most researchers are involved in.

Secondly we have classes of compensatory alteration to the genome, or equivalent therapies that change protein levels without changing genes. These are in principle capable of providing benefits that will have greater impact than any presently available option - such as calorie restriction - but they don't directly repair the damage that causes aging, and thus cannot on their own do more than delay the inevitable. In this category you'll find things such as follistatin or myostatin gene therapy to force greater maintenance of muscle mass, increased catalase production in mitochondria to slow their contribution to aging, attempts to mine regenerative and long-lived species for mechanisms that might be ported over to humans one day, and a range of gene and other therapies that spur old stem cells into action, overriding their response to cell and tissue damage, and restoring at least some of the tissue maintenance that falls off with age. The jury is still out on the degree to which these stem cell approaches raise the risk of cancer due to higher levels of damaged stem cell activity in damaged tissues, but so far it is less than expected. The bulk of researchers not involved in the first category above are working on something in the second, and this includes Church. I take his remarks quoted above to refer to the range of rodent studies from past years demonstrating a modest slowing of aging or partial restoration of some narrow set of measures relating to aging via gene therapies and the like.

Thirdly we have the role of gene therapies and genetics in repair therapies after the SENS model, addressing the causes of aging and thus in principle capable of producing indefinite healthy life spans if the repair is good enough and frequent enough. The SENS approach to mitochondrial DNA damage, currently in initial commercial development for inherited mitochondrial disease by Gensight, is a gene therapy, copying altered mitochondrial genes into the cell nucleus as a backup. Similarly forms of clearance of various forms of accumulated gunk - amyloid, lipofuscin, cross-links - that degrade cell and tissue function could well take the form of gene therapies to deliver additional tools needed for the job to cells, though it is more likely we'll see other forms of therapy at first. The SENS vision for preventing cancer may also be a gene therapy in its most complete form, acting to suppress the activity of all mechanisms capable of lengthening telomeres throughout the body. Here again, I suspect other less radical telomere extension blocking approaches will arise at first.

The point here is that genetic engineering and genomics covers a wide range of ground. A lot of it is pointless with respect to aging, at least from any perspective other than the scientific goal of full and complete knowledge of how the decay of the unmodified human machine progresses. Of the rest there are very definite classes of degree for the potential benefit that can be achieved. Not all approaches are the same, and in advance of trying them we can make reasonable predictions of the best possible benefit that could be achieved. We live in an age of rapid, radical progress in biotechnology. We should not be aiming low. I don't believe that slowing aging is good enough, and I don't believe that to be the best possible outcome achievable in the next few decades, were people to support the right lines of research. The weight of scientific evidence backing SENS rejuvenation approaches is compelling, and should be compelling enough to draw anyone away from tinkering with calorie restriction mimetic drugs or longevity-associated genes, lines of research with very limited best possible outcomes when it comes to translation to therapies for aging. Yet it is not, still, and this is why we continue to need advocacy and fundraising to advance the SENS cause, to produce more evidence, and persuade more support, and speed progress towards an end to aging.