Fight Aging!

The lack of consensus on aging is well known within the field of aging research and the longevity industry - good luck in trying to get any two research groups to agree on any specific declaration regarding the causes and progression of aging! That there are few points of consensus on aging is perhaps less well appreciated outside the field. Yet this seems inevitable for any very complex area of study. Researchers have produced an immense and growing body of data, but connecting these pieces together into a coherent map of cause and consequence remains a work in process, and will likely continue for decades yet.

We live in an era in which one can measure gene expression throughout the body and show how it changes with age, but we struggle to turn this data into an understanding of cause and effect. It seems likely that the fastest path forward to building that map of cause and consequence in aging is the direct one: produce therapies that repair and reverse specific age-related changes, and observe the results. Therapies targeting causes will do well. Therapies targeting consequences, not so well.

Disagreement on foundational principles of biological aging

While the field of aging has seen major advances, e.g. extending the lifespan of all major model organisms through genetic, pharmacological, and dietary interventions, there is no convincing evidence of the exact causes and mechanisms of aging, and no effective treatment proved to slow down or reverse the aging process in humans. Even the definitions of aging in the published literature are widely different and not easily reconcilable. Understanding how scientists who study aging view this process could help bridge this gap and accelerate progress in the field. With this in mind, we conducted a survey on the most basic features of aging with the participants of the 2022 Systems Aging Gordon Research Conference.

Notwithstanding the broad disagreement revealed by this survey, the answers nevertheless show elements of shared thinking, with most respondents aligning on certain principles and features of aging, as well as on what aging is not. First, there is a general consensus that aging - however it is defined - exists, has identifiable causes and effects, and can be studied experimentally. These views may be compared with the idea that aging as a unified phenomenon does not exist. Second, most scientists agree that aging is inherently deleterious, involving the accumulation of harmful changes, damage, degeneration, and loss of function. Third, aging is widely regarded as a process, with most respondents explicitly referring to it as such. It has certain characteristics, manifestations, a rate of progression, and outcomes - most notably, leading to death. Fourth, aging may be targeted, modulated, regulated, accelerated, and decelerated. Fifth, the aging process has a definable starting time or period within an organism's life. Sixth, rejuvenation is acknowledged as a real phenomenon (in that it can be defined), implying that aging can theoretically be reversed, not just slowed - though this does not imply feasibility. Seventh, a clear distinction exists between chronological age and biological age.

It is clear from the responses that aging remains an unsolved problem in biology. Scientists disagree over whether it is a universal property of life, whether it is pathological or normal, whether it is subject to natural selection, and whether it has a particular purpose. Interestingly, almost all respondents answered all questions, suggesting that they have a clear opinion on the subject. Yet, their responses were widely different. So, while most scientists think they understand the nature of aging, apparently their understanding differs. It is also clear from the responses that scientists working in the aging field have mixed opinions on the most fundamental definitions and mechanisms in the biology of aging. In the whole survey, no question received more than 50% of common responses. When discussing the biology of aging with colleagues, we often assume we are talking about the same process, but clearly, we are not. Some of us consider aging to be a loss of function, some accumulation of damage, some an increase in mortality rate, etc. While these and other features often go hand in hand, they are fundamentally different and therefore may be targeted differently.

Despite the importance of foundational issues in the biology of aging and the clear lack of consensus on these issues, little effort is being placed into directly addressing them. Moreover, there is a clear disconnect between what respondents think are the most important unanswered questions in the field and the ongoing research in the field. It is not necessarily because scientists are biased toward what they do. It is more likely that this is because these are very difficult questions to answer or to even design proper experiments and statistical treatments to address them. A part of the problem is also that most terms in the field are ill-defined, causing confusion due to different emphasis in different contexts and due to the variable use of the terms, including the term aging. For example, aging can be described as normal, normative, successful, healthy, pathological, premature, accelerated, etc., but what exactly all these terms mean is rarely discussed.

More generally, it is clear from the survey that in the most commonly referenced sequence of events - damage causes functional decline causes age-related disease causes mortality - different events are viewed as aging by different respondents. This may present a critical impediment to developing the most effective strategies to target aging. Depending on what one considers the essence of aging, experimental strategies may be disconnected from aging and directed either to the causes of aging and other upstream events or to the consequences and associations of aging.