Abstract
“No sooner landed, in his den they found the Triple porter of the Stygian sound, Grim Cerberus.”
I believe that the main reason for this ostensibly misguided caution is that biogerontologists simply do not have good evidence that such a quest would even modestly succeed, even with a dramatic rise in the funds allocated to it. Though they are quite good at convincing themselves and each other of the promise of hypothetical “magic bullet” interventions—the most popular within the field being drugs that would mimic calorie restriction (CR)—they essentially never convince anyone with purse strings to hand. In my view, this is not because they lack marketing eloquence or motivation, but because the hard facts do not inspire objective confidence that successes seen thus far in the laboratory will ever, even in principle, translate to the clinic. The recent negative results in primate calorie restriction have surely rendered this problem even more intractable.
Followers of these editorials will be well aware that my personal prognosis for the future of anti-aging medicine is not so bleak as the foregoing paragraph suggests: I believe that a radically different approach to delaying age-related ill health has great promise. Namely, rather than try to slow aging down by somehow activating a hypothetical dormant mechanism for enhancing our internal self-repair machinery (“retardation”), we should simply augment that machinery with regenerative medicine (“rejuvenation”).
The rejuvenation approach is, of course, also open to claims of implausibility, but maybe less so than the more traditional gerontological alternatives, because there is an abundance (indeed, an accelerating abundance) of data showing the efficacy of many of its component therapies. Stem cell and tissue engineering therapies are the subject of a tidal wave of clinical trials at present, and the media attention around the more spectacular successes shows no sign of faltering.
Unfortunately, the fact that the rejuvenation approach has components at all—in other words, that it is a “divide and conquer” strategy— is also a handicap. From a regulatory standpoint, combination therapies are always more challenging to force through the system, ultimately because the medical profession is all too aware of how hit-and-miss medicine really is and of the importance of keeping treatments as simple as possible. This issue may be viewed as one for the future, since so many of the interventions needed for a truly comprehensive regenerative assault on aging are still at an early stage of development, but from the perspective of those deciding whether to invest in that early-stage work and evaluating their exit strategy it is an issue for today.
And there is a second way in which divide-and-conquer approaches to combating aging are at a disadvantage: Mainstream biogerontologists, by and large, do not believe that they will ever be comprehensive enough to work, because aging is just too complex. This is, in a real sense, the flip side of the biogerontology community's over-optimism about the prospects for CR-mimetic magic bullets and the like.
An important contrast between the retardation and rejuvenation approaches to postponing age-related ill-health is that retardation is more useful when initiated early in life, whereas rejuvenation is of more value when there is already a reasonable amount of damage to repair. This poses a problem for fans of retardation, because those who make funding decisions are generally old enough that they will gain rather little from even an impressively effective therapy. The options are stark: Either try to develop therapies that work impressively even when initiated in middle age, which may be very hard, or stick with developing early-onset ones and crow about them enough that funders are distracted from the relative irrelevance to them or their spouses. To my intense dismay, the field has overwhelmingly preferred the latter option. Even after the wholly accidental discovery that rapamycin can significantly extend mean and maximum life span when administered starting in middle age, virtually no experiments have been forthcoming seeking comparable results. The reasons are, of course, obvious—scientists need high-profile papers, which requires positive results.
And I'm not done. The retardation strategy is handicapped by the bias toward early-onset work that offers false therapeutic hope, and the rejuvenation strategy by the technical and regulatory obstacles facing combination therapies—but they both face an additional handicap that may be even greater. In both cases, the target population is not those who are suffering severe functional deficit (i.e., disease or disability), but those who are still well, whether in early adulthood or in middle age. And it is an unfortunate but indisputable, and indeed understandable, fact that people do not like to submit to medicine—especially not to new, experimental medicine—unless they are already sick. They simply do not trust the risk/benefit ratio to be favorable. Who can blame them? It is not for nothing that Hippocrates admonished doctors to “first do no harm.” If we survey the landscape of common drugs for preventative therapies, very few are to be found. Statins are a shining example, but they were initially approved because they are effective in treating atherosclerosis, and they only edged sideways into a more preventative pattern of usage as their efficacy and safety became apparent. Angiotensin-converting-enzyme (ACE) inhibitors are perhaps the only other major category, and, given the very widespread appreciation of hypertension as a progressive precursor to various age-related conditions, it may have had an unusually easy ride.
So here we are. The nature of medicine—how it is developed, how it is disseminated, how it is perceived—poses a three-headed monster of a challenge to the defeat of aging. What is to be done? I believe that a two-pronged strategy is needed. On the one hand, we must persevere as best we can, with the funds we can scrape together, to achieve incremental progress. And on the other, we must devote far more effort to educating humanity—funders, of course, but also those to whom they answer, which basically means everybody—as to the potential for enhancement of the quality and quantity of life of untold millions, even billions, of people. Ultimately, when understanding of what is needed and what is possible becomes sufficiently widespread, the rest will follow.