Fight Aging!

The lengthy and somewhat overwrought article I'll point out today is a good example of the way in which journalists fail when writing on the topic of the growing biotechnology industry that is making the first steps towards the medical control of aging. They talk to just a few people, and thus have a very narrow (generously) or absolutely incorrect (more accurately) view of what might be happening, the prospects for the future, and the shape of the field as a whole. In this case the few people are the folk at AgeLab at MIT, and George Church, with a focus on the veterinary deployment of gene therapies by Rejuvenate Bio, and a fairly traditional Alzheimer's researcher.

To speak directly, and without meaning to be cruel about it, AgeLab should not exist. It is an entity focused on coping with the realities of aging, making recommendations on small ways that older people might do a little better under the burden of aging. This is a waste of funding in a world in which there is even the slightest possibility of treating aging as a medical condition, and the present state of senolytics, among many other signs, shows that there is far more than a slight possibility of that outcome. Unfortunately AgeLab is far from the only organization set up on the premise that aging cannot be changed, and that the only thing to be done is cope. Holding it up in any discussion of where things might be going in the future is just silly. As rejuvenation works, the AgeLabs of the world will vanish, and rightfully so.

The genetic approach to aging, of using gene therapies of various sorts to adjust the operation of metabolism in late life is espoused by George Church and others. This seems to me just an incremental advance over small molecule calorie restriction mimetic or other stress response upregulation efforts. Gene therapy can be more precise, with fewer off-target effects, and a more flexible, direct development program. But at the end of the day this is still largely a case of altering metabolism to better resist aging rather than addressing the underlying causes of aging. This tweaking of metabolic processes simply cannot produce sizable benefits, as the underlying damage still exists, and the gene therapy can only tweak one set of mechanisms related to that damage, leaving all the others to fester. It will certainly look at lot better than the medicines of yesterday, which failed to even achieve this much, but why aim low? This type of approach to aging is the majority of the field still, but it is not the future of therapies for aging. The effect sizes won't be large enough and reliable enough in comparison to those of clearing senescent cells or other forms of damage repair.

The traditional Alzheimer's researchers, those associated with a few decades of failure to make progress towards therapies, can be pessimistic. If one talks to them, but not to the researchers running new ventures and new programs that offer real signs of progress in different approaches to treating the condition, then one comes away with the idea that everything is intractable and the field is making only slow progress, if it progresses at all. Similarly, in the bigger picture, one cannot look at the longevity industry, ignore the approach of rejuvenation through repair of damage, and come away with anything other than an incomplete view of what is taking place, an incorrect view of what is important for the future, and an incorrect view of what the plausible pace of progress might be in the years ahead.

Can We Live Longer but Stay Younger?

Where fifty years ago it was taken for granted that the problem of age was a problem of the inevitable running down of everything, entropy working its worst, now many researchers are inclined to think that the problem is "epigenetic": it's a problem in reading the information - the genetic code - in the cells. To use a metaphor of the Harvard geneticist David Sinclair, the information in each cell is digital and perfectly stored; it's the "readout," the active expression of the information, that's effectively analogue, and subject to occlusion by the equivalent of dirt and scratches on the plastic surface of a CD. Clear those off, he says, and the younger you, still intact in the information layer, jumps out - just as the younger Beatles jump out from a restored and remastered CD.

We don't have to micromanage the repair, the Harvard molecular biologist George Church observes: "If we think epigenetically, we can see that we can make the cells industriously do the repair themselves." He is among a group of engineer-entrepreneurs who are trying not to make better products for aging people but to make fewer aging people to sell products to. Perhaps aging is not a condition to be managed but a mistake to be fixed. Sinclair, for one, has successfully extended the life of yeast, and says that he is moving on to human trials. He is an evangelist for the advantages of what he calls "hormesis" - the practice of inducing metabolic stress by short intense exercise or intermittent fasting. "Every day, try to be hungry and out of breath" is his neatly epigenetic epigram.

Anti-aging research, in its "translational," or applied, form, seems to be proceeding along two main fronts: through "small molecules," meaning mostly dietary supplements that are intended to rev up the right proteins; and, perhaps more dramatically, through genetic engineering. Typically, genetic engineering involves adding or otherwise manipulating genes in a population of animals, often mice, perhaps by rejiggering a mouse's genome in embryo and then using it to breed a genetically altered strain. In mice studies, genetic modifications that cause the rodents to make greater amounts of a single protein, sirtuin 6, have resulted in longer life spans (although some scientists think that the intervention merely helped male mice to live as long as female mice).

Church and Noah Davidsohn, a former postdoc in his lab, have engaged in a secretive but much talked-about venture to make old dogs new. They have conducted gene therapy on beagles with the Tufts veterinary school, and are currently advertising for Cavalier King Charles spaniels, which are highly prone to an incurable age-related heart condition, mitral-valve disease; almost all of them develop it by the age of ten. Using a genetically modified virus, Church and Davidsohn's team will insert a piece of DNA into a dog's liver cells and get them to produce a protein meant to stop the heart disease from progressing. But the team has larger ambitions. It has been identifying other targets for gene-based interventions, studying a database of aging-related genes: genes that are overexpressed or underexpressed - that make too much or too little of a particular protein - as we grow old. In the CD replay of life, these are the notes that get muffled or amplified, and Davidsohn and Church want to restore them to their proper volume.

Many problems cling to this work, not least that there are surprisingly few "biomarkers" of increased longevity. One researcher makes a comparison with cancer research: we know a patient's cancer has been successfully treated when the cancer cells go away, but how do you know if you've made people live longer except by waiting decades and seeing when they die? Ideally, we'd find something that could be measured in a blood test, say, and was reliably correlated with someone's life span.

Church is optimistic about the genetic-engineering approach. "We know it can work because we've already had success reprogramming embryonic stem cells: you can take a really old cell and turn that back into a young cell. We're doing it now. Most of the work was done in mice, where we've extended the life of mice by a factor of two. It isn't seen as impressive, because it's mice, but now we're working on dogs. There are about nine different pathways that we've identified for cell rejuvenation, one of which eliminates senescent cells" - moldering cells that have stopped dividing and tend to spark inflammation, serving as a perpetual irritant to their neighbors.