Fight Aging!

Do we need to fully understand aging, how exactly it works in fine detail, in order to create rejuvenation therapies that are effective enough to make the effort worthwhile? One would expect not, based on the present state of field, but also expect that the process of creating rejuvenation therapies should become ever easier as knowledge accumulates. One can find dead ends and failures by falling into them, or by knowing in advance not to go that way. The former requires considerably greater effort and expense. The present understanding of aging is much advanced over past decades, but still woefully incomplete: it is impossible to determine in advance whether any given mechanism is more or less important than any other; everything interacts with everything else, and researchers do not yet have a full map of those interactions; and what is cause and what is effect is often up for debate. Yet this incomplete state of knowledge exists in parallel with the generation of, for example, a mountain of preclinical data in aged mice for meaningful degrees of rejuvenation achieved via partial clearance of senescent cells.

Today's open access paper by a senior figure in the field of aging research is something of a complaint against engineering, against moving ahead with partial knowledge, and along the way a denial of meaningful progress to date via single interventions. Or at the very least, the author opposes the rhetoric of engineering ("we think we have it this time!") percolating back into the scientific community. A few fair points are made in there about the state of affairs in aging research, but it does represent a very conservative scientific viewpoint: understanding before action, and much of what presently looks promising in terms of addressing causative mechanisms of aging is a mirage. Both of these points can be strongly argued against. For the first, understanding before action is just not the way things work in the messy real world we live in. Partial understanding followed by many attempts at actions likely to fail is the usual path ahead - and we are almost certainly better off because eager engineers convince themselves that something is worth a shot, pick up incomplete science, and try to make it work, even if they talk about this process and gather support for their efforts in ways that annoy scientists.

The point here is that, in most fields, the fastest path to understanding is to repeatedly build and fail, and occasionally build and succeed, well before the point of sufficient understanding to succeed at the outset. To return to senescent cells, the sizable rejuvenation resulting from clearing senescent cells in aged mice was surprising to just about everyone in the aging field, and caused a sizable reallocation of resources towards this approach to aging. If no-one had forged ahead to try, then today the field of senescence in aging would still consist of a small number of researchers debating whether or not senescence was a meaningful contribution to degenerative aging.

Seven ways not to think carefully about aging

The principal theme of this polemic is that developing a consistent, defensible conceptual framework about aging and its control is the most important step towards developing ways to promote human health by postponing aging. Alas, the field is rife with indefensible, but highly influential conceptual frameworks and latent assumptions whose pursuit is leading to dramatic progress in the wrong directions. In this article, I will use "aging" to refer to the process that converts a healthy young adult, such as a college sophomore, into an aged person, perhaps 60 to 80 years old, with diminished functional performance in many domains, a growing collection of health concerns, and a progressively increasing risk of death.

It is important to note a key element of this definition. It defines aging as something that happens to a whole organism (mouse, worm, fly, human). This form of aging does not happen to something that is not a whole organism, like, for example, a cell in culture or a cell in an aging person. It is entirely possible, within this proposed definition, that aging (of a mouse or person) might lead to changes in their constituent cells, or might be caused by changes in their constituent cells. Those are interesting, empirical, testable questions. But to discuss them cogently, one cannot use the word "aging" in two different senses, i.e., to refer to a process that alters intact organisms and also to things that can occur in individual cells.

The underlying observation here is that among any representative set of older people, e.g., a batch of 70-year-olds, some will have strong evidence of age-related problems in multiple functional domains, and others will have escaped, to an impressive degree, most of the ill consequences that afflict those in the same age cohort. It is tempting to say that members of the latter group are "biologically younger" than average, and that they have a "biological age" that is less than their calendar age of 70 years. But the introduction of a construct like "biological age" to discussions of the biology of aging is a distinct step backward, a serious obstacle to thinking carefully about the biology of aging. The fundamental error here is "reification," the mistake of treating an abstract idea as though it were a real thing, as though the map were the territory.

"Aging clocks" appear to have value to researchers, to research administrators, to laypersons, and to worried people who are tempted to purchase a commercial estimate of their own biological age. This complacent acquiescence leads to acceptance of claims that "Taking Drug X made the treated population younger" based solely on clock data, without parallel evidence on well-validated age-sensitive functional outcomes. The use of some clock-branded metric as though it were measuring a real thing, i.e., measuring "biological age," has become a very common feature of modern biogerontological discourse, with major effects on the choice of problem by researchers and the choice of investment strategy by those with funds to allocate.

It is now common for scientific administrators and many researchers to endorse the solemn pledge that they are focused on healthspan, and definitely not on lifespan. Newcomers to the field quickly absorb the notion that research on how to keep old people healthy is good, and research on how to keep people alive for longer is bad, perhaps shameful. The error here is the assumption that there is a trade-off to be made between enduring health and increasing lifespan-the "seesaw" model in which improvements in lifespan require diminished health. But in the context of research aimed at extending healthy lifespan by modulating the pace of aging, both logic and experimental data support models in which good health and longer lifespan go hand in hand, more like an elevator than a seesaw. This is entirely to be expected because prolongation of good health is the most direct and obvious way to increase life expectancy in adults.

Far too many talks, pitches, and grant proposals begin with an image of a wheel showing purported hallmarks of aging, based initially on a series of papers that attempted to tabulate key aspects of cell and molecular biology that supposedly were the main elements of aging. The criteria themselves are highly problematic: processes that change with age, for example, are much more numerous and easier to discover than the very small subset of processes known to retard aging in mammals. They are also much less likely to be related to the factors that can retard the aging process, and are a relic of the attitude that discovering "the cause of aging" was a worthwhile endeavor.

But in addition to these conceptual weaknesses, the Hallmarks movement represents a significant obstacle to aging research, both for what it includes and for what it fails to include. A researcher trying to choose a new area for research, or an administrator or reviewer asked to judge the significance of a specific research proposal, is very often rendered complacent by the imprimatur conferred by Hallmark designation. If, for example, the authors of the Hallmarks table have decided that cellular senescence, or genetic instability, or changes in gut bacterial populations are important enough to include on their list, this designation tempts readers to avoid thinking about the nature, source, strength, and consistency of the evidence underlying Hallmark designation.

For many decades, biogerontologists devoted their careers to testing specific ideas about the (supposed) cause of aging. The hope was that once the cause of aging had been identified (perhaps it was cellular senescence, or mitochondrial mutations, or stem cell exhaustion, or somatic mutations...), this might point to identification of drugs that would slow aging by blunting its cause. Pointing out the weaknesses in this conceptual scheme has been a central goal of this review. Blocking any one of the dozens of insults that cause aspects of late-life decline would not be expected to retard the overall aging process to an important degree.