. Sirtuins and the quest for an anti-aging pill
By Daniel Merino
To say the body is complicated is like saying the universe is big – it does not even begin to convey the mind-numbing intricacy and scale of what goes on to keep you alive every day. Modern medicine has gotten very good at keeping people alive through unexpected events like disease and injury but there is only so much medicine and the natural mechanisms of the body can take. While some lucky people manage to make it to a magical 100th birthday, that seems to be roughly the upper limit. Eventually, the machine simply breaks down beyond repair.
But what if instead of repairing our biological machines when the break, you could simply maintain them, prevent the breakdowns before they occur? Of course this is the idea behind the mantra of eat healthy and exercise, but in the last 20 years, an enormous amount of research has begun to unravel the mysteries of how and why we age and die. As science’s understanding of aging has progressed, some prominent experts, venture capital groups, and a lot of fans on the internet have grown to believe that we are on the verge of being able to not just understand aging, but actually delay it with drugs.
Incredible hype, billions of dollars, a massive unregulated supplement market, and a burgeoning field of research have emerged in the last two decades around anti-aging molecules. The focus of much of these resources has been on a group of proteins known as the sirtuins. Nearly all scientists agree that sirtuins play an important role in aging, but some think they may be a key pathway to actually control aging itself. In mice, drugs known as Sirtuin Activating Compounds (STACs), delay the onset of age-related diseases, extend healthspan, and even prolong lifespan. Clinical trials are currently underway in humans and with these trials, scientists are hoping to prove that they have developed the first pill that isn’t designed to change what you die of, but when.
Yet for all the promise these molecules hold, there are many challenges that come with a quest for a pill of youth. Difficulties in study design due to lack of accurate measures of aging, very few clinical trials, and a huge amount of private sector influence cast doubt on the carefully worded claims made by proponents of these drugs. It is hard to parse fact from hype from hope, but researchers, investors, and early adopters of these drugs all agree that the potential benefits could be staggering. The conflict right now lies in the risks some people are willing to take in the early phase of this research.
In the 1990s Dr. Shin-ichiro Imai and Dr. Leonard Guarente, both then at MIT, were searching for the genetic keys to aging in yeast. Nearly all diseases share the common risk factor of old age, and the thinking was that if you could prevent the upstream causes of aging, you would also prevent the downstream age-related diseases. In 2000 they found one of those keys: the SIR2 gene (hence the name of the proteins it codes, sirtuins). When the SIR2 is removed from the genome of a yeast cell, the live half as long. If a second SIR2 gene is added, their lifespans increase by 30 percent. At the time, the discovery of a single gene that could control aging went against conventional medical wisdom. Death and aging were not considered to be so closely tied and this pursuit challenged the entire approach of modern medicine.
“We are trying to make the point that all of the chronic diseases share the same common risk factor, and that is aging,” says Dr. Christopher Martens of the University of Delaware. Instead of curing individual diseases, researchers like Dr. Martens, Dr. Imai, and many others are looking for ways to prevent them.
Much has been learned about sirtuins since Dr. Guarente and Dr. Imai first linked them to longevity. In humans, the sirtuins are a group of seven proteins coded by seven sections of DNA known as sirt1 – sirt7 that are evolutionary cousins to the yeast SIR2 gene. At their most basic, sirtuins react to stress signals and modify certain proteins in the cell. What they modify and how depends on the signals they receive, and these actions control everything from DNA repair to mitochondrial function and a multitude of other processes within cells. Many of these processes are understood, but many more remain partially or completely unknown.
But in spite of this complexity, there are a few important things scientists do know about these genes and the proteins they encode. When sirt1 and sirt6 – or their other-species equivalents – are overexpressed, yeast, worms, flies, and mice all experience delays in the onset of age-related diseases. This results in the extension of both healthspan and lifespan in these organisms. Scientists also know that for sirtuins to function, they need NAD+, an extremely common but important molecule that is involved in metabolism and acts like a fuel for sirtuins. And finally, researchers know that NAD+ declines by up to 50 percent by the time people reach their 70’s or 80’s. Dr. Imai believes this reduction to be part of what causes aging. “Because of that [reduction], sirtuin activity decreases in multiple tissues which causes tissue degradation,” he says.
It is on this linkage between sirtuins and NAD+ that the sirtuin activating compounds known as STACs are designed to work. “Animal studies have shown that in mice, NAD+ boosting compounds can activate or turn on these sirtuins by giving them fuel to run,” says Dr. Martens. There are natural versions of STACs, like resveratrol, which is found in red wine and the reason people say a glass a day can make you live longer, but a lot of research has been dedicated to developing more efficient NAD+ boosting compounds. There are already a few of these man-made STACs on the market and dozens more are under development with Dr. David Sinclair of Harvard leading the way. When looking specifically at NAD+ levels, they seem to work. In one study, researchers found that consuming one type of NAD+ precursor increased NAD+ levels by up to 60 percent in the blood cells of healthy middle-aged humans. As for longevity, at least in mice, these drugs work as intended. They boost the function of sirtuins and delay the onset of cancer, diabetes, neurodegenerative disorders, vascular disease and overall slow aging. The theories are convincing, the science cutting edge, but the question remains, do they actually work in humans?
While some scientists seem to believe they do – Dr. Sinclair has publicly said he takes these drugs himself – others remain skeptical. “Unless you have done very careful studies on potential side effects, first in mice and then in humans, you can’t be certain about any of this,” says Dr. Richard Miller, director of the Nathan Shock Center for the Biology of Aging at Michigan University. Mice are – obviously – very different from us. Science has cured cancer in mice, given them super strength, super speed, super intelligence, and made them live for nearly twice as long as they normally do. But none of these results have been replicated in humans. “The efficacy of these NAD+ boosting compounds are demonstrated in mice, whether they work in humans we don’t know,” says Dr. Imai. “But we are doing the trials and in 2 or 3 years we will have answers.”
For any treatment, especially drugs, to be considered both safe and effective, scientists must conduct full-scale clinical trials in humans. The problem with testing longevity drugs is that the average American lives for 78.69 years. Even if scientists started tomorrow, it would be 80 years – or more, if the drugs work – before the results were in.
If researchers want to know if STACs work this century, there are two possible ways to get around this issue. One option is to give these drugs to older people and see if the onset of age-related diseases is delayed. A second, and potentially much more useful option, would be to simply measure signals of aging and see how STACs affect these biomarkers. This would be the best approach as these studies could be done quickly, but accurate biomarkers of aging have been surprisingly difficult to find. Only in 2015 with the MARK-Age study was a good set of aging biomarkers finally developed and more work needs to be done before they can be used to say anything about a drug that may affect lifespan.
Despite these difficulties though, some clinical studies have been done with synthetic STACs and the results hint at potential benefits. In a Phase 1 clinical trial performed in 2018, Dr. Martens gave patients Nicotinamide Riboside (NR), a popular synthetic NAD+ precursor, for 12 weeks. He wanted to test for negative side effects and to see if NR actually boosts NAD+ levels in humans. After 12 weeks, his patients had no measurable side effects, experienced 60% increases of NAD+ in their blood, and were found to have both lower blood pressure and less arterial stiffness, two measures associated with cardiovascular disease and aging. Since it was a Phase I trial primarily designed to test for safety, it only included 6 patients. With such a small number of patients the results are far from definitive, but Dr. Martens was excited about the results. ”We demonstrated it is safe and healthy in healthy individuals, now it is time to try it in a larger group,” he says.
The research into STACs is incredibly hopeful, but with so little research done on their effectsin humans, the risks are great and the benefits unknown. This has not stopped enterprising companies from monetizing these compounds though. If you go to Amazon.com and type “anti-aging pill” into the search bar, mixed in among supplements claiming to whiten and tighten skin, maintain your membrane integrity (whatever that means), or prolong life through the power of turmeric and ginger, bottles of pills claiming to contain resveratrol or advertising the NAD+ boosting power of NR hide in plain sight. People are already paying $40+ a bottle for what is as of yet unproven science. While taking these drugs is certainly risky, it not necessarily a mistake. Unproven does not mean false and if these molecules do end up being the “wonderdrugs” some claim them to be, $40 a month to prevent cancer, diabetes, Alzheimer’s and a heart attack is the bargain of the century.
If they work, the benefits won’t be limited to healthy people wanting to live longer. As Dr. Martens says, “There is a large fraction of the population that aren’t willing or aren’t able to participate in the healthy lifestyles that are so beneficial to health. We need to find a way to give them access to those benefits.”
The global anti-aging market is expected to reach $331 billion by 2021 and there are enormous amounts of money to be made selling things that claim to fight back father time. Tech money investors are pouring funding into anti-aging labs around the nation and many university researchers are on corporate advisory boards earning undisclosed and most certainly enviable salaries. This has rightly drawn scrutiny towards what appears to be a potentially huge conflict of interest. For a field already fraught with confusing information, nuanced results, and tied to the emotional topic of death, conflicts of interest are not making it any easier to understand what is going on in the world of anti-aging research.
There are many reasons to be hesitant when a company claims they have a pill that will make you live longer. Doubts and caution are justified because when it comes to the safety and efficacy of these molecules on people, the science just isn’t there yet. “The most obvious risk is to patients. If one of these drugs has side effects that is incredibly dangerous,” says Dr. Miller. But that science is happening, it is happening fast, and people like Dr. Miller have big hopes for the future. “We certainly hope that our work and the work of other scientists will eventually produce drugs that can reduce human aging. We believe it is the best way to improve human health.”