Abstract
“The art of simplicity is a puzzle of complexity.”
The September, 2012, issue of Scientific American includes a commentary contrasting two approaches to combating aging. Like almost all general-audience pieces, and despite the best efforts of most experts in the field, it highlights the goal of life extension rather than stressing that any longevity benefits will be a side effect of health benefits—but I have complained quite enough in this space about that fixation, so I will not repeat myself today. The value of the article, though diminished thereby, is still substantial, in that it provides a clear description of the contrast between the “combat one disease at a time” approach generally taken by geriatricians and the holistic “combat aging itself” approach favored by most biogerontologists.
As those readers familiar with my work will know, I view both such approaches as highly unlikely to deliver substantial postponement of age-related ill health in the remotely foreseeable future, but not for the reasons generally given by the proponents of the other approach. Geriatricians reject the combating of “aging itself” because they don't generally view aging as a medical condition at all, but instead merely view chronological age as a risk factor for various types of ill health. Biogerontologists, conversely, reject the “one disease at a time” approach because they believe that there will always be something—the very same “aging itself,” of course—that will be a source of exponentially accelerating ill health however many specifics are defeated. The SENS perspective is that it is inaccurate and misleading to draw a sharp distinction between “aging itself” and the specific aspects of age-related ill health, first because where one draws that distinction is arbitrary—Are foam cells atherosclerosis yet, for example? Are fatty streaks?—and second because the lifelong changes that drive eventual ill health, and thus hold the only logical claim to be lumped under the term “aging,” are themselves not aspects of any meaningfully unitary process, but are instead relatively independent processes occurring as side effects of different aspects of metabolism. This matters, because it shows that the one-at-a-time approach is not necessarily doomed, and may in fact be the most promising option, just so long as it is implemented on those lifelong changes and not only on the diseases that ultimately result.
But does it matter today? Would it not be enough to have the divide-and-conquer approach (a name I will shift to for the rest of this editorial, because I hope to have justified its distinctly greater positivity in the foregoing) in our back pocket for the future world in which the various necessary components have been developed individually? No it would not—and the main reason why not is very topical, leading to my choice of this subject for discussion here.
Arguably the biggest negative consequence of the substantial postponement of heart disease seen in the Western world over recent decades is the epidemic of Alzheimer disease (AD), an age-related disease that is not particularly good at killing people and has not been similarly postponed, hence is necessarily made more prevalent when the population's #1 killer is postponed. AD is a multifactorial disease, defined (though this definition was until recently only useful after autopsy) as the combined presence of two types of aggregate: (1) Senile plaques in the extracellular space, mainly composed of the protein β-amyloid, and (2) neurofibrillary tangles inside neurons, whose main constituent is a hyperphosphorylated form of the protein tau. Additional structural changes occur in AD, including synaptic degeneration and full-blown neuronal death, but the point I wish to make need not appeal to those aspects, so for clarity I will restrict myself to discussing plaques and tangles.
The SENS approach to combating the accumulation of β-amyloid and hyperphosphorylated tau, and thus ameliorating their putative consequences for cognitive decline, is of course to remove them periodically before they become pathogenically abundant. Ways to do this for tau are still some way from clinical trials. In the case of β-amyloid, however, the breakthrough in mice first published in 1999 has moved rapidly (though not entirely smoothly) through the trial process, with the result that two Phase III trials have been in progress for a few years.
Now for the topical aspect: The trials have both just been abandoned, due to disappointing results. The details have not yet been published, but news of the decisions, made by two of the largest firms in big pharma, has reverberated to absolutely the degree you might expect through the AD community.
But what were these disappointing results? They consist of failure to meet end points defined in terms of cognitive function. Specifically, we have not been told that the therapy failed to remove amyloid! And in fact, as things stand, the widespread presumption remains that amyloid was indeed substantially removed. The presumption is also, however, that hyperphosphorylated tau was not removed.
What do these trials actually, then, tell us? The following possibilities are available:
1. Until suitable analysis has been done and released, it's possible that the treatment actually failed (for whatever reason) to remove amyloid at all.
2. Maybe amyloid was removed but cognitive function was unaffected because amyloid is irrelevant to cognitive decline in AD.
3. Maybe amyloid was removed and had benefits, but the treatment also did harm in some way that negated those benefits.
4. Maybe benefits can only result when both amyloid and tau are removed.
I invite you to take a moment to consider what these various hypotheses recommend in terms of next steps in the quest to cure AD. It's easy to see that they make very different recommendations. Specifically, option 2 is the only one that suggests that treatments for eliminating amyloid in AD can now be abandoned as a useful therapy. Options 1 and 3 motivate refinement of the therapies used so far. Indeed, option 3 is exactly what happened to the first trial of a similar therapy, several years ago. And option 4 motivates keeping the current therapies in our back pocket, ready for co-administration with future anti-tau therapies.
And that is the point. “Co-administration” is a word that sends shivers up the spines of medical researchers, because both the clinical trials themselves and the regulatory process are fraught with difficulties over and above those facing any single treatment. It is that, I believe, which has allowed the conversation about these trials to be dominated by proponents of option 2 above, leading to the very real risk that amyloid will now be ignored by many AD researchers.
This must not happen. Rather, researchers across the whole of medicine—but particularly in areas where the basis for pursuing a multi-component therapy is clear—must work strenuously to shift the regulatory and research environment in the direction of greater acceptance of therapeutic complexity. While we continue to reject such options as too daunting, we will inherently close off what may well be the only viable avenues to truly effective treatments for the diseases and disabilities of old age.