A Few Responses to the Edge Annual Question for 2017

Every year Edge runs an annual question, publishing a few hundred short responses from noted scientists and other thinkers. A number of the folk who run companies or otherwise make waves relating to the development of therapies to treat aging are in this list, so it is usually interesting to see what they have to say. These year, awareness of the prospects for aging to be treated as a medical condition appears to be spreading, as it is mentioned in passing in a number of responses beyond the two linked below. The question for this year is "What scientific term or concept should be more widely known?", but that is somewhat beside the point; it is just a prompt to encourage people to riff on whatever their particular areas of interest might happen to be at the moment.

The two people I pulled from the crowd for this post are Gregory Benford, who is now well underway on his third notable career, this time as a biotechnologist focused on the use of drugs to adjust epigenetics in aging, and Aubrey de Grey of the SENS Research Foundation, who should need little introduction to this audience. These are representative figures from the two sides of a very important divide in the research and development of therapies to treat aging. On the one side we have attempts to modestly slow the pace of aging and onset of age-related disease through drugs, largely attempting to mimic existing natural effects that enhance longevity, such as calorie restriction, exercise, or the outcome of selective breeding to postpone reproduction. This is strongly associated with ongoing efforts to map the biochemistry of aging at the detail level, such as epigenetic and other changes in cellular biochemistry and signaling: greater coverage of the map is needed in order to make progress. On the other side we have efforts like the SENS rejuvenation research portfolio, in which the existing long-established identification of the root cause molecular damage of aging is used as the guide to work towards therapies that can repair that damage, thus turning back aging. The more comprehensive the repair, the more that aging should be halted or reversed.

The difference between these two approaches is night and day. Mapping the biochemistry of cells is enormously expensive and slow, and even a perfect replication of the biochemistry of calorie restriction - something that will be very, very hard to achieve at our present level of technology - will do comparatively little for human longevity, even though it would be very beneficial for overall health. We know this because calorie restriction practitioners don't live very much longer than the rest of humanity. If the effect was as large as it is in mice - 40% or so - it would have been discovered in antiquity. On the other hand SENS-style damage repair therapies are comparatively cheap to build, and produce more reliably beneficial outcomes, as illustrated by present development of senescent cell clearance approaches. They don't require anywhere near as much expensive, time-consuming new research in order to guide this development. Collectively, the effects on human life span will be determined by the effectiveness of the repair, with what should be very high upper limits if started early enough in life. The essential opposition of these two approaches is highlighted in the commentaries below, independently and sight unseen on the part of the authors.

Gregory Benford: Antagonistic Pleiotropy

Aging comes from evolution. It isn't a bug or a feature of life; it's an inevitable side effect. Exactly why evolution favors aging is controversial, but plainly it does; all creatures die. It's not a curse from God or imposed by limited natural resources. Aging arises from favoring short-term benefits, mostly early reproduction, over long-term survival, when reproduction has stopped. Thermodynamics doesn't demand senescence, though early thinkers imagined it did. Similarly, generic damage or "wear and tear" theories can't explain why biologically similar organisms show dramatically different lifespans. Most organisms maintain themselves efficiently until adulthood and then, after they can't reproduce anymore, succumb to age-related damage. Some die swiftly, like flies, and others like we humans can live far beyond reproduction.

In 1957 George Williams proposed the theory called antagonistic pleiotropy. If a gene has two or more effects, with one beneficial and another detrimental, the bad one exacts a cost later on. If evolution is a race to have the most offspring the fastest, then enhanced early fertility could be selected even if it came with a price tag that included decline and death later on. Because ageing was a side effect of necessary functions, Williams considered any alteration of the ageing process to be impossible. Antagonistic pleiotropy is a prevailing theory today, but Williams was wrong: we can offset such effects. Wear and tear can be countered. Wounds heal, dead cells get replaced, claws regrow. Some species are better at maintenance and repair. Some pursued this by deliberately aging animals, like UC Irvine's Michael Rose. Rose simply didn't let fruit fly eggs hatch until half each fly generation had died. This eliminated some genes that promoted early reproduction but had bad effects later. Over 700 generations later, his fruit flies live over four times longer than the control flies. These Methuselahs are more robust than ordinary flies and reproduce more, not less, as some biologists predicted. I bought these Methuselah flies in 2006 and formed a company, Genescient, to explore their genetics. We discovered hundreds of longevity genes shared by both flies and humans. Up-regulating the functioning of those repair genes has led to positive effects in human trials. So though aging is inevitable and emerges from antagonistic pleiotropy, it can be attacked. Recent developments point toward possibly major progress.

Aubrey de Grey: Maladaptation

Many years ago, Francis Crick promoted (attributing it to his long-time collaborator Leslie Orgel) an aphorism that dominates the thinking of most biologists: "Evolution is cleverer than you are." This is often viewed as a more succinct version of Theodosius Dobzhansky's famous dictum: "Nothing in biology makes sense except in the context of evolution." But these two observations, at least in the terms in which they are usually interpreted, are not so synonymous as they first appear. Most of the difference between them comes down to the concept of maladaptation. A maladaptive trait is one that persists in a population in spite of inflicting a negative influence on the ability of individuals to pass on their genes. Orgel's rule, extrapolated to its logical conclusion that evolution is pretty much infinitely clever, would seem to imply that this can never occur: evolution will always find a way to maximize the evolutionary fitness of a population. It may take time to respond to changed circumstances, yes, but it will not stabilize in an imperfect state. And yet, there are many examples where that is what seems to have occurred. In human health, arguably the most conspicuous case is that the capacity to regenerate wounded tissues is lost in adulthood (sometimes even earlier), even though more primitive vertebrates (and, to a lesser extent, even some other mammals) retain it throughout life.

Why is this so important to keep in mind? Many reasons, but in particular it's because when we get this wrong, we can end up making very bad evaluations of the most promising way to improve our health with new medicines. Today, the overwhelming majority of ill-health in the industrialized world consists of the diseases of late life, and we spend billions of dollars in the attempt to alleviate them - but our hit rate in developing even very modestly effective interventions has remained pitifully low for decades. Why? It's largely because the diseases of old age, being by definition slowly-progressing chronic conditions, are already being fought by the body to the best of its (evolved) ability throughout life, so that any simplistic attempt to augment those pre-existing defenses is awfully likely to do more harm than good. The example I gave above, of declining regenerative capacity, is a fine example: the body needs to trade better regeneration against preventing cancer, so we will gain nothing by an intervention that merely pushes that trade-off away from its evolved optimum.

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