Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D; community with critical information on the tools, technologies, and trends that drive the biotech industry.
Issue link: http://gen.epubxp.com/i/695748
Genetic Engineering & Biotechnology News | GENengnews.com | JULY 2016 | 33 Aubrey D.N.J. de Grey, Ph.D. It's instructive for those of us who study the biology of aging to look back to how our feld was in 1981, the year of GEN's launch. What has changed and what has not—in terms of our understanding of what aging consists of, and also in terms of our sense of how it might be combated medically? First let's consider our understanding of the nature of ag- ing—with a focus on mammals. I'm going to make a claim that will outrage many of my colleagues, but which I think is robustly defensible: in the 35 years since GEN began, 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 signifcance were made just around that time and were frst published that year and the following year. Specifcally, 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. Since these fndings emerged, we have discovered a huge number of details about both those processes and the other aspects of aging that had been elucidated over the previous few decades, but they are all just that: details. They make next to no difference to our overall picture of what aging comprises at the molecular and cellular level. Is this a basis for consternation and despondency? Quite the opposite: it is a cause for unalloyed celebration. The ana- lytical methods available to biologists have advanced beyond all recognition in those years, and the number of laborato- ries studying aging has also risen dramatically. Therefore, the lack of any major breakthrough in understanding aging constitutes extremely strong, albeit admittedly circumstan- tial, 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. When we turn to the topic of interventions, on the other hand, I believe the situation is far more mixed. In some re- spects there is good news; in others, an alarming lack of it. Translational Focus Regained First the good news. Back in 1981, biogerontology was in translational purgatory. The unashamed ambition of its early leaders, such as Strehler and Comfort, to maintain youth in the chronologically elderly had—with rare and time-honored exceptions, such as Harman—been submerged by a wave of political correctness designed to assure purse-string-holders with no goals beyond reelection that experts were not seek- ing to enable people to live forever, swamp the planet, etc. As is the way with such matters, the avoidance of exces- sively optimistic predictions had been taken much too far, with virtually all senior biogerontologists entirely eschewing all mention of intervention. For practical purposes, the feld had become like seismology: its leaders understood that the phenomenon they study kills people, but they evinced no in- tention ever to intervene in it, only to get out of its way to the limited extent possible. Since then, biogerontology has slowly but surely recov- ered its soul, and the discussion of postponing the ill health of old age, far from being verboten, has become virtually mandatory. This 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. So, biogerontologists are fnally not ignoring it. Instead they are touting it as their overarching goal, as they should never have ceased to do in the frst place. Hang on, you may be thinking: doesn't that discovery of interventions fatly contradict my earlier claim that basically everything that really matters about aging was already un- derstood by 1981? I'm afraid it does not, and my explana- tion for why not will entail my description of the bad trans- lational news. Starved for Interventions Since their very discovery (or very soon after, anyway), it was established that the most successful laboratory interven- tions 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. Starvation in the laboratory, when not so severe as to be fatal, and especially when micronutrient intake is main- tained, is generally termed "calorie restriction"—and its life- extending properties in rodents was discovered nearly half a century before GEN was launched. By 1981, it was a fairly major focus of gerontology: avowedly not so as to emulate it pharmacologically in humans—perish the thought!—but to understand its mechanism. So here's the problem. As biogerontology has become more intervention-friendly again, its translational research focus has centered overwhelmingly on this class of manipu- lations. 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 com- bination, these facts make the biomedical relevance of such manipulations very modest indeed. Unfortunately and inevitably, however, the feld is spec- tacularly adhering to Upton Sinclair's aphorism that it is hard to make people understand something when their salaries de- pend on not understanding it, and is single-mindedly main- taining 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. Rejuvenation Biotechnology The consternation and despondency that I mentioned, and that I have now detailed, is—mercifully—not the whole story any more. 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 feld and it is rising to bona fde orthodoxy. I speak, of course, of regenerative medicine for aging—a concept that I habitually refer to as rejuvenation biotechnol- ogy. There are many distinct avenues of research encom- passed by this, but they have one thing in common: rather than manipulating our metabolism to slow the rate at which it inficts accumulating damage on our tissues and organs, rejuvenation biotechnology is all about repairing that dam- age even after it has accumulated substantially. This is a "sweet spot" between calorie restriction and its ilk on the one hand and geriatric medicine (the treatment of the pathologies of old age) on the other. In the past few years, key proof-of-concept breakthroughs have been made in both realms, and highly respected and credentialed biogerontolo- gists have endorsed a combined approach as a (or even the most) promising way forward, even to the extent of present- ing it as if it were their idea. In conclusion, therefore, I can say with confdence that the future of aging research is extremely bright, both scien- tifcally 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. TRANSLATIONAL MEDICINE Future Trends in Aging Research 35th Anniversary Feature Biomedical Gerontology Unabashedly Resumes— and Expands—Its Translational Mission Aubrey D.N.J. de Grey, Ph.D. (aubrey@sens.org), is a biomedical gerontologist who co-founded the the SENS Research Foundation (Strategies for Engineered Negligible Senescence Research Foundation), where he currently serves as chief science offcer.