The Concept of Successful Aging is Harmful to Research and Development

As illustrated in today's research commentary, all too many researchers continue to view aging as something distinct from age-related disease, and this inevitably leads to a poor approach to research and development. In this case, a rejection of the idea that rejuvenation is possible in principle at the present time. If one believes that aging and age-related disease are distinct, then one can also think that it is possible to age successfully, or age healthily. That we should split out the concepts of aging and disease, and only treat disease. This is all abject nonsense. There is no such thing as healthy aging or successful aging. There are processes of aging that can clearly be reversed, either actually or in principle. Too many people in positions of influence are producing irrational strategies for medical research under the belief that healthy aging is a viable goal.

Aging is by definition the accumulation of damage and dysfunction that raises mortality risk over time; it is a process of harm and loss. A "healthy" 80-year-old is in no way healthy by any objective measure. Can he sprint the way he used to? No. Is his hearing and eyesight the match of a youngster? No. Are his arteries damaged and distorted? Yes. Does he have a mortality risk that would raise eyebrows in a 20-year-old? Also yes. This is not health. This is a considerable progression towards the polar opposite of health.

To call any particular outcome of the damage and dysfunction at the roots of aging a disease is to draw an arbitrary line in the sand and say that some dysfunction is healthy, and won't be treated, while a little more dysfunction than that is unhealthy, and a disease that should be treated. Sadly this is exactly how medical science has progressed for all too long, even as the scientific understanding of aging needed for a better approach was assembled over the past century or more. The outcomes on either side of that arbitrary line in the sand (yes, you have clinical arthritis and will be treated, versus no, you have signs of progression towards clinical arthritis and come back later) all result from the same processes of damage taking place under the hood. This damage grows with time and leads inexorably to organ failure and death. Thus we should develop rejuvenation therapies to repair that damage, ideally long before it rises to the level of causing pathology. History teaches us that any other path is doomed to failure at worst and marginal, accidental gains at best.

Are We Ill Because We Age?

In the optic of geroscience, if aging becomes a treatable disease/process, it will be the duty of medical doctors to treat it. However, not everything which seems to be aging is aging. Over the history of gerontology and geriatrics, many processes previously thought to be part of aging are now considered not to be age-related, but an overlaying pathology. One of the best examples is anemia, which for decades was considered as a solid attribute of aging but now is considered related to various pathologies and not to aging itself. So, an older individual who does not have relevant underlying pathomechanisms would not have anemia even at 100 years of age or more. The same applies to hypertension, to sarcopenia, to kidney failure, and to cognitive impairment.

So again, what distinguishes aging from a disease conceptually? First, the extent of aging is systemic and complex while that of a disease is mostly limited. Aging is an inevitable, universal process (concerning all humans living long enough) while most diseases are associated with individuals' susceptibilities/vulnerabilities, and most of them, even chronic, are preventable. The most important cause of aging is time, while diseases usually have specific known causes. In other words, aging is irreversible and progressive while diseases are reversible and discontinuous. Finally, and most importantly, aging may be modulable but not treatable, while diseases are ultimately treatable even if we do not know presently how, which is only a question of progress of science. So many essential differences clearly speak against the notion that aging is "just another" disease.

we should ask how we would know if an anti-aging therapy really could slow aging. The problem is that most of our definitions are circular or impractical. At the most macro level, we might ask whether it extends lifespan or life expectancy. We might ask if we reduce the incidence or burden of age-related diseases (ARDs) with anti-aging interventions. However, it is possible we could do this by counteracting negative aspects of modern lifestyle (e.g., obesity), without affecting aging per se, and conversely that we might find interventions that slow aspects of aging without having much impact on ARDs. Lastly, we might ask whether anti-aging interventions have impacts on metrics of biological aging. If these metrics are specific metrics of the processes being treated, the reasoning becomes circular. For example, we could not prove that senolytics affect aging simply because they reduce the number of senescent cells. Higher level indicators of biological age, such as homeostatic dysregulation indices or the epigenetic clock, are slightly more promising metrics. However, even here there is a problem: these various indices are only poorly correlated with each other and are themselves based on various theories about what aging is. For example, if senolytics lower (rewind) the epigenetic clock, is this simply because the epigenetic profiles of senescent cells are different, and we have removed these cells from the mix? Or was there really an impact on aging in the remaining cells?

At this stage of our knowledge there is no place in medicine for anti-aging medicine understood as treating symptoms of aging when aging has already happened. However, there might be a place for interventions/modulations that would delay the occurrence of aging, when applied early in life, before any time-dependent processes had accumulated and aging symptoms show up. Scientists should recognize at this stage that we know a lot but not enough yet to translate the scientific discoveries in the field of gerontology to interventions into the older subjects. However, a new approach is needed and should be oriented at a systemic conceptualization of the aging process and not at the fragmentation of its different components.

Thus, better assessment of the biological aging against the chronological aging holds promises to be able (e.g., by significant biomarkers) to assess the physiological aging processes in their complexity and act on them specifically and jointly. The concept that aging does not always lead to ARD, but that the same processes may lead to either ARD or successful aging in older persons depending on the homeodynamics, will also help to individualize the interventions. Furthermore, the recognition that not everything occurring in aging is detrimental will help to design purposeful interventions to reinforce what is necessary and combat what IS detrimental. Finally, the recognition of aging as a lifelong process and that chronic diseases start early in life would help to design interventions very early in life having consequences on ARD. So, we should move from the aging as a disease concept to the aging as an adaptation, which may result in ARD or successful functional healthspan.

Comments

I agree 1000%

But when $75 million gets given to people like Nir Barzilai to prove such nonsensical incrementalism, when such money could go to many other SENS startups, I want to vomit

Posted by: don dagle at January 30th, 2020 5:55 AM

"But when $75 million gets given to people like Nir Barzilai to prove such nonsensical incrementalism, when such money could go to many other SENS startups, I want to vomit"

75 million is not very much money in the world of drug development. The price tag of a novel drug is >1 billion, and these days more than 2 billion.

There is currently no evidence meeting clinical standards that aging in humans can be modified pharmacologically, no practical way to prove that, and as the authors of this article astutely observe, the way aging is conceived of/presented by many biogerontologists is circular, and does not constitute a viable clinical endpoint, both due to a lack of knowledge about how aging works IN HUMANS, and the limitations of the kinds of studies we can conduct in human subjects.

The importance of TAME is that it establishes a precedent for testing for the kind of clinical endpoint we CAN study which constitutes the most medically relevant aspect of aging, namely bioresilience. Whether or not that's due to amelioration of aging or modifying shared mechanisms of ARD pathophysiology (and whether aging, bioresilience ,and ARD pathophysiology can be considered in isolation, I would tend to agree that they cannot) is not what's relevant.

As far as the choice of target in TAME, while it could be argued rapamycin or a combination of metformin and rapamycin (or if you were EXTREMELY risk tolerant, D+Q) might be more appropriate, there is preexisting human data on metformin suggesting modification of multimorbidity, and that's worth more than a million mouse studies, even given the numerous caveats of the study in question. When it comes to drugs that are not yet approved for use in humans, those are off the table; no investor is going to fund a 5 year long study of multimorbidity with a new drug with phase II results that consist solely of biomarkers.

So, like it or not, that's going to have to be the path to clinical translation of gerontology research:

find a viable endpoint that this treatment will modify --> go through conventional drug testing and approval process --> conduct phase IV studies on bioresilience

Posted by: Dylan Mah at January 30th, 2020 10:57 AM

"Additionally, there is no disease that occurs inevitably with aging; thus, while aging is a risk factor, it is neither a necessary nor sufficient cause for chronic diseases"

How do these papers pass peer review? Any one diseases is not universal because people are killed by a variety diseases before any one can universally manifest. If you kept people alive but left cancer alone, cancer would almost certainly kill everybody with 100% certainty.

It's almost trivially false as well, because if everybody has a 1% constant, non-increasing chance of developing diabetes each year, then they are mathematically guaranteed to get it as their age approaches infinity.

Posted by: Christopher at January 30th, 2020 1:46 PM

Thank you for a refreshingly honest article. I hope you will set the trend for further developments in the ideas you outlined.

I look forward to reading more of your work.

Posted by: Verbieann Hardy at February 3rd, 2020 7:50 PM

But people will die anyway. If there are crazy volunteers ready to try something new, why not?

Posted by: Зайцев at August 13th, 2020 12:47 PM

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