The Lack of Consensus on Approaches to Aging as a Flaw to be Fixed

It can be argued that the largest challenge facing the development of means to treat aging as a medical condition is that there is, as of yet, no useful consensus position on how to measure aging, how to define aging, or which of the countless measurable aspects of biochemistry that change with age are the most appropriate targets for therapy. This means that any given research group or biotech startup has a lot of leeway to argue that their approach is the right one - and it might take twenty years to establish the effects of their therapies on long-term health and life span, even given a successful development program. There is a shotgun approach underway, in which the research and development communities try many different things and see how it goes, only limited by their ability to persuade sources of funding to support the work. I imagine that this will continue for the foreseeable future, given just how long it takes to assess the efficacy of a given approach to therapy.

From a funding perspective, should the first generation of therapies to slow and reverse aspects of aging start to produce very promising data on long-term health by the end of the 2030s, there will be thereafter be funding for just about every option on the table to treat aging. The hype cycles will come and go, and it may well be the case that enough funding to try all of the available options will in fact be needed. It seems to me that the most straightforward way to reverse engineer the biology of aging, to decide on which of the many identified mechanisms are the most important, the closest to being root causes, is to produce prototype and first generation therapies for all of the plausible approaches to rejuvenation, the various means of repair of cell and tissue damage, and compare the resulting benefits in human trials. It won't be a fast process, but likely faster than the other options on the table.

We need to shift the focus of aging research to aging itself

The field of aging is at a precipice. Attention and funding are increasingly focused on this area, and exciting, fundamentally important findings are being reported literally every day. As the great promise of targeting aging comes into sharper focus, we are rapidly approaching the point where we must face the elephant in the room: We lack any semblance of a consensus on the nature of aging or, more fundamentally, on the essence of this process. Taking steps to resolve these foundational issues in aging biology will enable us to advance this field to the next level.

As a field, we claim to study aging - but what, in essence, do we study? What is that most basic, fundamental feature of the process that we call aging? Is it functional decline, damage accumulation, increased mortality rate, continuation of development, increased biological age, decrease in the strength of natural selection, the totality of age-related changes, loss of homeostasis, loss of information, their combination, or something else? After organisms reach adulthood, all of these features seemingly go hand in hand, but their coordination is not perfect, and there must be one underlying, explanatory feature that leads to the others. What is it, and can we truly advance the field without identifying it?

Aging biology is exponentially growing as a field, and talented scientists are designing and carrying out many elegant studies. However, in many ways, we are attempting to construct a building without a foundation. One can see this by the lack of clear answers to some of the most basic questions: When does aging begin? To what extent, if any, is biological age dynamic and potentially reversible? Which biomarkers are most appropriate to measure biological age, and do any of them actually measure aging directly?

To begin answering these questions and ensuring the future success of this field, we propose two critical concepts on which aging biologists can actively focus their collective attention: the essence of aging and the nature of aging. To be clear, we are not suggesting that either a formal definition or a unified theory of aging is an immediate need for the field. The essence and nature of aging represent more fundamental concepts, from which we envision that a consensus definition and theory of aging may proceed in the future. In the immediate term, these concepts may serve as building blocks to form the basis of our understanding of aging biology.

We define the "essence of aging" as the most basic, essential, explanatory, and causative feature of biological aging. It is the underlying driving force of the manifestations of advanced age, such as frailty, loss of function, and age-related diseases. Identifying the essence of aging is critical if we wish to study and target aging itself, rather than its later-stage manifestations. Many aging biologists invoke the hallmarks or pillars of aging as a basic starting point for conceptually framing aging biology. However, the essence of aging, in our minds, represents a more fundamental concept underlying these and other characteristics of aging. In the same way that the Hallmarks of Cancer can be reduced to a single essence - mutations - we should be able to, and should strive to, distill a single essence of aging that drives all of the hallmarks/pillars and higher-level manifestations of aging.

We define the "nature of aging" as the inherent properties and dynamics that characterize aging as a biological phenomenon. The nature of aging is conceptually related to critical outstanding questions in the field, such as the behavior of biological age over the life course; the point at which aging begins; and the extent to which aging of a subset of cells or tissues impacts the aging of surrounding or distant cells/tissues. The nature of aging is a much broader concept than the essence of aging, but understanding the nature of aging is no less critical to our ability to target this process.