Fight Aging!

Most research programs that purportedly aim to extend human life by intervening in the aging process do not in fact have a good expectation of producing meaningful results. They typically involve searching the existing drug catalog for ways to alter the operation of metabolism so as to, for example, recapture some of the effects of calorie restriction, as lowering calorie intake is well proven to improve health and slow aging. This has turned out to be expensive, time-consuming, and challenging. So far very little of practical use has been achieved on this front after fifteen years of focus involving hundreds of scientists, at a cost of billions of dollars. Expense and difficulty are not the primary objection, however: it comes with the territory at the cutting edge of the life sciences. The primary objection to this branch of research is that even if these researchers achieved a perfect replication of calorie restriction, and so far they aren't close to achieving even a fraction of this goal, that wouldn't extend human life by more than a couple of years.

If all that the research community could do was this, then so be it. We would have to resign ourselves. But it isn't: much greater goals in extended health life span are possible with the same expenditure of time and funding, given a different research strategy. It is particularly frustrating to see this continued focus on slightly slowing aging at great cost when there is, in fact, a much better path forward. That better path consists of the research strategies described in the SENS vision for rejuvenation biotechnology, a package of approaches to aging and its causes drawn from the work of researchers across the breadth of the field. In short, the research community has a good catalog of the forms of cell and tissue damage that distinguish old tissue from young tissue, has had that catalog in a fairly complete state for more than two decades, and there exist detailed plans for treatments capable of repairing the damage. Repairing the damage that causes aging will be no more expensive and challenging than trying to alter metabolism to slow aging, but it has the possibility to create rejuvenation, to extend healthy life span indefinitely when the repair is comprehensive enough. Some of the technologies needed to create repair therapies to treat aging have been demonstrated in the laboratory, and a few are even at the stage of startup companies building treatments.

These days there is a lot of agitation for greater progress and greater investment in efforts to find drug candidates to alter metabolism in ways that may modestrly slow aging: calorie restriction mimetics, autophagy enhancers, exercise mimetics. This coincides nicely with the scientific urge to completely map the large blank regions in the grand map of human biochemistry. It is a huge project. But as Aubrey de Grey of the SENS Research Foundation points out below in a quite clear outline of his view of the field, metabolic adjustment to slightly slow aging is the wrong focus. The majority of the research community is forging ahead on a path that will produce only very small gains in lifespan and health, while ignoring what is known of how to repair the causes of aging completely. While there is certainly progress towards both repair therapies and persuading more of the research community to support that path to rejuvenation therapies, it is taking far too long and far too much effort to turn this ship. There is optimism in some quarters, but I fear that this process will remain slow and painful even after the first of the portfolio of SENS rejuvenation therapies, such as senescent cell clearance, are robustly demonstrated in human studies, as they have been mice. The inertia of large, heavily regulated research and development communities is a hard thing to wrestle with.

Future Trends in Aging Research

I'm going to make a claim that will outrage many of my colleagues, but which I think is robustly defensible: in the last 35 years we have not made one single discovery that has substantially changed what we think we know about mammalian aging. The last two discoveries that, in my view, reach that level of significance were made just around that time and were first published that year and the following year. Specifically, certain nonenzymatic changes were found to accumulate throughout life with potentially deleterious consequences in old age. Initially, such changes were found to affect long-lived proteins in the extracellular matrix; subsequently, they were found to affect the epigenetic state of the genome.

Is this a basis for consternation and despondency? Quite the opposite: it is a cause for unalloyed celebration. The analytical methods available to biologists have advanced beyond all recognition in those years, and the number of laboratories studying aging has also risen dramatically. Therefore, the lack of any major breakthrough in understanding aging constitutes extremely strong, albeit admittedly circumstantial, evidence that there is probably no such breakthrough yet to be made: in other words, that we really truly do already understand aging pretty well.

The modern restoration of biogerontology began with the discovery of simple genetic and pharmacological interventions that can greatly extend the lifespans of rodents. The implication that we will soon be able to do the same in humans is too obvious to ignore, especially since (at least in rodents) the extra life is added overwhelming to the healthy period before decline set in and not to the frail end of life. Since their very discovery (or very soon after, anyway), it was established that the most successful laboratory interventions I referred to above achieved, in one way or another, the same end. They tricked the organism into performing very much the same changes of gene expression and consequent metabolic activity that occur when it is starved.

So here's the problem. As biogerontology has become more intervention-friendly again, its translational research focus has centered overwhelmingly on this class of manipulations. Well, you may retort, so it should, since they are the things that work! But there's a catch-well, two catches. First, they don't work nearly so well when started in middle age as when lifelong, and second, they work far less well in long-lived species than in short-lived ones. In combination, these facts make the biomedical relevance of such manipulations very modest indeed. Unfortunately and inevitably, however, the field is spectacularly adhering to Upton Sinclair's aphorism that it is hard to make people understand something when their salaries depend on not understanding it, and is single-mindedly maintaining its intense focus on such interventions both in the lab and on camera, so as to similarly maintain its ability to keep funders convinced that they placed good bets in the past and to induce them to carry on funding the same people.

In the relative shadows, a few biogerontologists have been beavering away developing an alternative approach to maintaining health in old age-and though such work is at an early stage, its logic is steadily chipping away at the old-style thinking in the field and it is rising to bona fide orthodoxy. I speak, of course, of regenerative medicine for aging-a concept that I habitually refer to as rejuvenation biotechnology. There are many distinct avenues of research encompassed by this, but they have one thing in common: rather than manipulating our metabolism to slow the rate at which it inflicts accumulating damage on our tissues and organs, rejuvenation biotechnology is all about repairing that damage even after it has accumulated substantially. In the past few years, key proof-of-concept breakthroughs have been made in both realms, and highly respected and credentialed biogerontologists have endorsed a combined approach as a (or even the most) promising way forward, even to the extent of presenting it as if it were their idea. In conclusion, therefore, I can say with confidence that the future of aging research is extremely bright, both scientifically and medically. The pace of progress must now be sharply accelerated, via the injection of the funds that should for many years have been allocated at far higher a level than has actually occurred.