Another new theory of aging, is it the right one?
Updated: Apr 15
Last week, Harvard scientist David Sinclair wrote a piece in the Wall Street Journal detailing a new theory of aging - the epigenetic theory of aging. Some of you contacted me with excitement. Indeed, It is a fascinating theory that applies cutting edge molecular genetics. The article is well written and understandable, and I suggest you read it - if for nothing more than to learn about molecular genetics and epigenetics.
Your first question probably is, “what is the likelihood this new theory is correct?”. Maybe 50%, maybe 25%? The real number is likely much lower than you think. Let me show you how I estimate this likelihood; and more generally, how I estimate the likelihood of any medical theory or treatment working.
A generalist perspective
In my opinion, one of the most important roles of a general internist is to help a patient determine if a new theory or treatment is likely to work or not. The generalist has a unique perspective compared with a specialist. Why? The generalist is not prone to the specialty bias. A bias that ties specialists to their theories. They are professionally and financially dependent on their theories being true, and thus, become “true believers” in the mechanisms and pathways of their specialty. To avoid falsification, they live in echo chambers receiving only evidence confirming their theories and easily disguarding evidence that does not. Most importantly, specialists tend to ignore the big picture - the history of our prior successes and failures in medicine.
Prior success rate and Bayesian thinking
It has been said that “those who do not learn from history are doomed to repeat it”. The history of our prior successes and failures in medicine is critical to help us estimate the probability of a new theory or treatment working. Although this kind of reasoning seems intuitive, it is known formally as ‘prior probability’ and is part of Bayesian inference.
As it turns out, our prior success rate in medicine is dismal. Even though there are many treatments that do work, they stand on a mountain of failed ones. For example, only one out of every hundred drugs developed by pharmaceutical companies make it to market. The rest fail despite rigorous vetting from basic science research. Remarkably, this is the failure rate from our best and most plausible ideas; ideas that pharmaceutical companies are willing to risk billions. Imagine the failure rate of our less vetted ideas - such as supplements, elixirs of life, and other pipe dreams?
In longevity medicine, there are many theories of aging: the telomere theory, the immune senescence theory, the mitochondrial theory, the disposable soma theory, the mutation accumulation theory, the wear-and-tear theory, etc. Each theory, in turn, has launched hundreds of potential treatments. They can’t all be right. Most must be wrong. Indeed, the explosion of theories and treatments just makes it more likely that any single theory or treatment is wrong.
At present, the majority of these theories and treatments of aging have not been subjected to formal testing in large human trials. However, the two most promising theories of the twentieth century have: the hormone theory of aging and the anti-oxidant theory of aging. Both failed. It is truly mind-boggling to contemplate the amount of time, money, and false hopes spent on hormones and antioxidants in the past hundred years. Everything from the one-a-day multivitamin to transplanted monkey testicles.
David Sinclair, Resveratrol, and another failed treatment for aging
David Sinclair, the author of the WSJ article, is a Harvard molecular biologist with a long career in the field of longevity. In fact, twenty years ago he and his colleagues popularized another theory of aging - the Sirtuin pathway - part of the calorie restriction theory of aging. Sirtuins are a set of genes that, when activated, seem to improve the overall health of a cell. They are activated by fasting and may be responsible for some of the salubrious effects of fasting.
Sinclair’s lab found that Sirtuins were also activated by the supplement Resveratrol. It seemed Resveratrol could be a fasting mimetic, giving the effects of fasting without actually fasting. He said, “It’s as close to a miraculous molecule as you can find”. Watch his 2009 TEDMED talk. With references to his tenured Harvard professorship and videos of experiments showing mice on Resveratrol outrunning mice not on Resveratrol, he is very convincing.
Some of you may remember Resveratrol. It was a very popular longevity supplement in the 2000’s. An additional reason for its popularity was that it linked itself to another immensely popular hypothesis - the red wine hypothesis. In some observational studies, drinking 1-2 glasses of red wine a day is associated with better health than drinking no red wine at all. It turns out that Resveratrol is found in red wine! Finally, an explanation (or for some of you, a justification) for why red wine is good for you.
And good for Sinclair. He started his company Sirtris in 2004 to study Resveratrol and related compounds. He and his partners eventually sold it to GlaxoSmithKline (GSK) for $720 million in 2008.
Other researchers study Resveratrol
Resveratrol was a hot topic and other researchers naturally jumped on the bandwagon to study it. Unfortunately, medical journals, academic centers, and the media prefer positive studies over negative ones. Studies showing that a treatment works, not that a treatment does not work. Nobody's ever won a Nobel prize proving that something does not work. To make their studies look positive, researchers will resort to “p-hacking” and other manipulations of study design and analysis. Some even resort to outright fraud. Resevertrol research was victim to a particularly egregious case. Dr. Dipak Das was considered one of the world's foremost and prolific Resveratrol researchers. He was found guilty in 2012 of 149 counts of fabrication and falsification of data and fired from his university position. Nineteen of his papers have been retracted.
When GSK started to do higher quality research and better controlled studies on Resveratrol, they ran into several problems. It turns out that Resveratrol does not activate the Sirtuin pathway. Prior researchers misinterpreted the fluorescent assays. Furthermore, Resveratrol caused nausea in subjects and had low bioavailability. GSK shut down Sirtris in 2013.
The bad science and fraud in the Resveratrol story highlights the fact that there are so many ways for a theory to be wrong, even though it is supported by attractive mechanisms and positive preliminary studies. It is important to let these theories run the gauntlet of replication, trials in humans, and time. This is the rule in medicine, not the exception. A vital lesson. Yet, the failed supplement Resveratrol, and Sinclair’s enthusiasm for it, faded into obscurity.
Some of us did not forget
Fast forward to last week when I was sent David Sinclair's piece on the latest and greatest longevity idea. Maybe you can understand why I was not so excited. Instead, I felt like Bill Murray in Groundhog day. Not to pick on Sinclair, I would have healthy skepticism for any scientist presenting a new theory or treatment of aging.
I believe, equipped with the knowledge of prior success rates in medicine, you too would approach this article with some healthy skepticism. As I see it, providing you with this background is my duty.
The likelihood of a new theory or treatment of aging working is lower than you think. Why? There are hundreds of ways for a theory or treatment to be wrong and only one way for it to be right:
1. Basic science research is prone to false positives and even fraud.
2. Most theories and treatments fail when replication is attempted.
3. Most theories and treatments fail when tested in humans.
4. Most theories fail when hard outcomes are required.
5. The theories and treatments of aging that have been subjected to rigorous testing have all failed.
6. With so many theories and treatments of aging, most must be wrong.
7. Prolongation of lifespan is likely not an easy fix - like turning on or off a single pathway.
8. We don’t know the cause of aging. It’s hard to find a target for something you don’t understand.
The lesson here is: don’t trust individual scientists or ideas. Scientists are prone to bias and science, by its very nature, produces many false positives. Instead, trust the process of science - where scientists and their competing ideas fight it out. The best ideas eventually rise to the top after thousands of experiments, replication of those experiments, and peer review. One by one, we eventually get answers to important questions. But it takes time. It took six decades to disprove the antioxidant theory of aging.
To put this into perspective, imagine if a scientist discovered a bone fide longevity molecule in her lab today - a drug that could actually make us live longer. How long would it take to translate the basic science experiments to clinical trials? And how would we distinguish this discovery from all the other false positives drug discoveries? Many decades at least.
I do believe it is possible to increase lifespan. But it will take longer than we think. The process of science is slow. Very slow. It is unlikely that anyone reading this post today will achieve the longevity escape velocity. Possibly the next generation? How sobering is it to realize that of the tens and thousands of human generations that lived before us, we may be the last generation to live a normal lifespan? And if so, it is our generation that will provide the science for it. Seems just a little ironic?