Six

THE QUEST TO PROVE AGING CAN BE TARGETED

As geroscientists continued researching aging and longevity, we were convinced that the biological processes that drive aging in humans could be targeted. We had already seen how knowledge about variants of CETP and APOC3 contributed to drug development. And in animal studies, we had successfully targeted common aging processes with genetic, nutritional, and pharmacologic interventions that improved health and increased longevity. These findings showed that the biological rate of aging could indeed be slowed. This alone was incredibly promising, and the skeptics who had initially rolled their eyes at our theory were starting to raise their eyebrows with interest.

Meanwhile, I couldn’t help wondering if we could prevent, or at least delay, the onset of all the age-related diseases by targeting the primary processes that drive aging. For example, we knew that impaired metabolism was contributing to all chronic diseases and that improving it through caloric restriction in animals prolonged health span and life span. If targeting just one of the processes could do that, what would happen if we figured out how to focus on the ones that could do the most good for each individual? And what would happen if we targeted all of them?

These questions and dozens of others prompted me to collaborate with colleagues to convene a conference to determine what we could do to move toward an indication that aging deserved to be studied as if it were a disease, because without this indication, the FDA will not approve drug treatments for it. Thankfully, seven primary hallmarks of aging had already been identified by the Geroscience Interest Group, a trans-institute group in the NIH, formed by the hero of the geroscience movement—Felipe Sierra, director of the Division of the Biology of Aging at NIH. Another project that the NIH initiated is the Interventions Testing Program (ITP), designed to investigate treatments that have the potential to delay disease and extend life span. Studies conducted by the ITP confirmed that it’s possible to alter several molecular and physiological processes simultaneously and that improving one of them will frequently benefit the others. These hallmarks of aging are fundamental to the biology of aging.

The hallmarks have evolved, and maybe more will be discovered, but each one of them is a target for aging therapy as has been demonstrated in animal models. They are also interconnected, and relieving one problem can relieve others as well. Our challenge is to find the time line for best intervention, identifying personalized therapy, and combination therapy.

Chromosome Maintenance: Damaged DNA and other cellular components can either lead to loss of cells or initiate cancers. Such damage may be initiated in part when telomeres (DNA strands at the end of chromosomes) get shorter.

Senescence: Len Hayflick has shown that there are limits to the number of times a cell can divide. When cells divide for the last time, their appearance and functions change, and these are called senescent cells. These cells become more plentiful with age, but there are also other reasons for senescent cells to appear. If a cell’s DNA is damaged by a severe mutation, it has two choices:

  1. Commit self-destruction through a process called apoptosis.
  2. Become a senescent cell and stop dividing.

In principle, senescence is a good thing—if the damaged cells could not become senescent, they could become cancerous, so it’s a defense mechanism. But this defense does not last forever. When these “zombie” cells accumulate and are not cleared (they cannot commit suicide), they secrete inflammatory factors and other proteins known as SASP (senescence associating secretory proteins) that may change their local environment and cause cancer. So a cell could have become senescent to escape cancer, but accumulation of these cells in tissues may now actually cause it and maybe other aging diseases. Senolytics is the name of a group of drugs that geoscientists and biotechs are trying to develop to decrease the numbers of these cells. In preclinical rodent models, the overall health of animals with a lot of senescent cells improves significantly when they receive senolytics.

Inflammation: Inflammation is typical in aging and reflects the body’s effort to repair itself when it senses breakdown. Unfortunately, this chronic inflammation is not well regulated and contributes to aging.

Mitochondria Quality Control: Mitochondria, intracellular organelles known mainly as the energy generators of cells, decrease in number, shape, and function with aging and with age-related diseases.

Proteostasis (Protein Homeostasis): The process within cells that regulates proteins’ fate. Proteostasis is impaired when, for example, there is a decline in the body’s ability to conduct autophagy—the process of clearing out or disassembling proteins that have misassembled in cells.

Immune Dysfunction: There is a decline in immune response against viruses, germs, and other pathogens. This increases the harmful effects of these insults, makes symptoms worse, and delays recovery. It’s immune dysfunction that makes viruses like Coronavirus life-threatening to the elderly. After they have the virus for a few days their immune systems create an immunological storm that causes the clinical features that can lead to death. Rejuvenating the immune response may lower or eliminate this effect on the elderly.

Metabolic Dysregulation: Metabolism slows in conjunction with declines in the activity of hormones (such as insulin), and there are changes in cholesterol and lipid metabolism and in body fat and its distribution.

Epigenetic Changes: Several biological molecules can disrupt connections between chromosomes or disrupt the transcription from the DNA, both of which cause rapider aging. The main epigenetic players mentioned are changes in histone acetylation, DNA methylations, and microRNAs. Some of these changes are activated by interaction with the environment and can increase or decrease the activity of many genes without causing mutations. This includes stunted stem cells and regeneration. As stem cells age, they lose their capacity to regenerate new tissues.

For all hallmarks, there are mechanisms to resist and repair them that decline because of lack of adaptation to stress, which used to be a hallmark on its own. As elderly people find it harder to manage activities that had been easy for their entire lives, they experience more stress on cellular levels as well as personal levels, which accelerates most of the processes of aging.

We wanted to find an existing drug that could target many or all these hallmarks, but even if we just identified one that could target a few of them, it would be strong evidence that drugs can target the roots of age-related illnesses.

We already knew that pathologies we thought were unrelated are actually so closely connected that it’s impossible to disregard the integrative nature of human physiologies as we search for answers to our questions about the biology of aging. This understanding suggested that the best way to reach our goal of greater health span and life span might be with integrated approaches like developing new multi-disease preventions and therapies. For example, we have discovered that the same interventions that extend the life span of mice often improve their muscle function and heart function, reduce age-related cognitive loss, and prevent or slow the progression of several types of cancer.

It’s never too late to add quality years to our lives. If we can keep our aging population healthy and active, we will prevent unnecessary suffering and offset the economic burdens of elderly people with multiple chronic diseases. By intervening early, we can minimize or avoid the damage that would otherwise be done. The ability to slow aging used to be confined to the pages of science fiction novels, but today, it has scientific credibility. The findings that show we can delay aging in mammals give us promise that we can prolong human health span, too. In fact, animal models for aging have been more representative than many models of disease because of the similarity in the biology of aging among most animals. Most animals slow down their activity and have morphological changes in their body shapes as they age and before they die. Mammalians, in particular, experience fur loss, changes in bone, muscle, and blood, and diseases specific to aging. So some of the drugs that target mechanisms of aging are effective in animals as primitive as worms and flies and as complex as monkeys.

Needless to say, everyone at the conference we’d convened had different opinions about which drug offered the most promise for our purposes, and after much discussion, we agreed to conduct a trial with the humble antidiabetes medication known as metformin. Generic and therefore relatively inexpensive, metformin is a biguanide, a type 2 diabetes drug that helps correct the body’s faulty glucose production by improving insulin action on the liver. I was very pleased with this choice for many reasons, one of which was that I was the first researcher to describe the effects of metformin on harnessing glucose production in diabetic subjects with Ralph DeFronzo, my first mentor in the United States when I was a fellow at Yale in the late 1980s. People with type 2 diabetes who take metformin have lower glucose levels in the morning, and that influences glucose levels for the rest of the day. While we understand mechanisms that lower glucose levels, we’re still investigating some of the ways that metformin targets cellular aging.

At the time of our meeting, there had been evidence that when metformin was added to the diets of nematodes and several rodent strains at various ages, it:

The ITP had also shown that mice given a combination of metformin and rapamycin, an antibiotic used to prevent organ-transplant rejection, experienced a 23 percent increase in median longevity (greater than the 10–13 percent effect of rapamycin alone for males and the 18–21 percent effect for females). While rapamycin also showed promise as a drug that might increase life span, we chose not to use it, because rapamycin’s targeting abilities are still inefficient and it has major side effects in humans, including diabetes.

But the main reason I had suggested metformin for a study targeting the hallmarks of aging was because of what had been discovered in a human study. Researchers were given access to data from British pharmacy records that identified people with type 2 diabetes who were being treated by particular doctors as well as people who were not diabetic but were being treated by the same doctors and lived in the same general environment. The researchers showed that diabetics who were taking metformin and who were also suffering from other diseases had less mortality than members of the group who were not diabetic and who had less obesity and fewer diseases in general. They also had half the mortality of diabetics who were taking other diabetes medications. Specifically, the study, which included 156,000 people of about age seventy-five, found that the 78,000 taking metformin had about 17 percent less mortality than the 78,000 people in the control group. What makes this so dramatic is that in addition to not having diabetes, the people in the control group were leaner and had fewer diseases to begin with but still had more mortality than the obese and diabetic people who were taking metformin. These observations were unanticipated and very promising.

Choosing an Existing Drug to Prove Our Point

After the conference in Spain, the evidence in metformin’s favor became overwhelming. In addition to the safety factor—metformin has sixty-plus years of safe use, compared with the unresolved safety issues of many other drugs that can target aging—new clinical trials reported significant reductions in the risk for type 2 diabetes, cardiovascular disease, cognitive decline, dementia, and cancer among subjects taking metformin. A randomized clinical trial known as the Diabetes Prevention Program found that metformin reduced the incidence of type 2 diabetes among more than three thousand adults by 31 percent compared with a placebo, across all ages. And the United Kingdom Prospective Diabetes Study (UKPDS) reported that metformin reduced the risk of diabetes-related death among type 2 diabetics by 42 percent compared with conventional treatment.

The UKPDS also found that among subjects taking metformin, the risk of cardiovascular disease was reduced by about 20 percent, and other studies reported similar metformin-related improvements. Among them, the study “Hyperinsulinemia: The Outcome of Its Metabolic Effects” (HOME), which looked at insulin-treated patients with type 2 diabetes, found a 40 percent reduction in cardiovascular-disease outcomes when metformin was administered, compared with a placebo.

Cancer incidence and cancer-related mortality had also been shown to decline in association with metformin in several epidemiological studies. In an analysis of multiple studies of metformin’s effects, cancer incidence was reduced by 31 percent, and cancer-related deaths were reduced by 34 percent. And metformin has demonstrated efficacy against breast, colon, pancreatic, prostate, liver, and lung cancers, which suggests that it works against the biology of aging itself, since that’s the only risk factor these cancers share.

As for cognitive decline, cognitive performance was shown to improve among nondiabetic subjects with mild cognitive impairment (MCI) and among type 2 diabetics suffering from depression in separate clinical trials. In another study, MCI patients taking metformin showed improvement in executive functions—such as attention and memory—after just eight weeks. And observational studies reported 51 percent lower risks of cognitive impairment—with the risk being lowest among those who had been on metformin the longest—and lower rates of dementia among type 2 diabetics on metformin than among subjects on other diabetes medications.

Meanwhile, further observational studies largely confirmed what the British study comparing type 2 diabetics and nondiabetics had found: better survival rates among the diabetics on metformin than among the control group. And overall mortality was also shown to be improved when metformin regimens were begun late in life for patients with age-related diseases, such as chronic liver disease and chronic heart failure.

It’s important to recognize that not all studies conducted on metformin replicate the results we have seen in many of the metformin studies, but the ones that don’t are typically less rigorous. Perhaps more important, though, is that none of the studies have shown that metformin is bad for humans.

At Einstein, under the supervision of diabetologists Jill Crandall and Meredith Hawkins, we conducted a small clinical study—the Metformin in Longevity Study (MILES)—of fifteen people of an average age of seventy. For the first six weeks of the randomized, double-blind trial, each subject received metformin or a placebo, and then we biopsied skeletal muscle and adipose tissues. Next, there was a two-week period of no treatment, and then the subjects who had received metformin for the first six weeks were given the placebo for six weeks and vice versa, followed by more biopsies. And the results showed that they all had experienced metabolic improvement. Along with my doctoral student Ameya Kulkarni and biologist Jessica Mar, we also studied the biological part of the equation by examining their tissues before and after metformin treatment, and what we found was that metformin significantly influenced both metabolic and nonmetabolic pathways inside their cells in ways that had positive effects on some of the hallmarks of aging. In fact, when we compared their fat and muscle biopsies with the biopsies of young people, the older people’s pathways looked younger.

As far as we were concerned, the case had been made. If metformin could do all these things in studies about individual diseases, didn’t it mean that it could achieve all of this by targeting aging itself? Metformin affected each of these diseases by delaying aging, so we had more evidence that aging is what’s driving the diseases. If we can show that metformin will protect against a cluster of age-related diseases in humans and enhance longevity, we’ll prove that the causes of aging can be targeted with safe drugs.

To be clear, it’s unlikely that metformin works directly on all the hallmarks of aging that have so far been identified. The likelier scenario is that metformin moderately modulates the oxidative pathway of the mitochondria, which results in metabolic adaptation that causes improved insulin sensitivity and induction of autophagy. On another level, the diminished action of the mitochondria also happens to protect against oxidative stress and DNA damage, and the results reflect the fact that the cells and tissues have become biologically younger. In other words, metformin probably has a restorative effect on cells that ultimately delays the onset of these diseases and increases health span. But the important thing is that the results are the same regardless of whether the effects are direct or indirect.

So, with widespread support from biologists and gerontologists, we began to formulate a trial to prove that a drug can target the biology of aging itself: the Targeting Aging with Metformin (TAME) study.

Getting the FDA on Board

Before designing the study, there was one crucial component of success that we needed: FDA input. If we proceeded without it, we might complete the study only to have the FDA tell us afterward that we should have done something differently and that they couldn’t approve drug development based on our findings. And FDA approval is critical, because without it, a drug cannot become a standard treatment in the medical profession, and health care providers will not cover its use by patients. And, of course, if there’s no demand, pharmaceutical companies will not produce the drug, and so the condition in question will not be treated with this medication despite its potentially profound benefits.

So we went to the FDA and presented our argument for a metformin trial that would test the viability of targeting aging directly. We also discussed how outcomes of the studies would be consistent with our targeting of aging. And by the time the meeting was over, they’d given us their blessing to proceed.

After the meeting, Robert Temple, deputy center director for clinical science for the FDA’s Center for Drug Evaluation and Research, commented for Ron Howard’s The Age of Aging, a documentary about the science of aging: “Loss of muscle tone, dizziness, falling, dementia, loss of eyesight, all those things—to [approach] them all at once with a single treatment … might make a convincing case that you’re doing something beyond just treating the disease. That would be something never done before. If you really are doing something to alter aging, the population of interest is everybody. It surely would be revolutionary if they can bring it off.”

We had done it. TAME would move forward. There was one wrinkle, though—the FDA didn’t want us to look at diabetes in the study.

“We don’t care about preventing diabetes,” one of the officials had said.

Being a diabetologist, I felt insulted. Whoever had been sitting next to me quickly grabbed my hand to signal me not to blurt out the first thought that had occurred to me. I managed to keep my mouth closed even though prevention of diabetes would have a huge health and economic impact!

Although the Diabetes Prevention Program has shown that metformin prevents diabetes, a recent effort to get an indication to use metformin to prevent diabetes in prediabetic patients with HbA1C levels above 5.8 percent was rejected. The FDA had argued that if diabetologists think HbA1C levels above 5.8 are dangerous, they should call it diabetes and prescribe accordingly. (Levels of 6.5 percent and higher are considered diabetic.)

In the case of our own study, the FDA’s reasoning was that a diabetes diagnosis doesn’t guarantee that everyone diagnosed will experience complications from the disease. Only 40 percent of newly diagnosed diabetics develop diabetes complications—and typically not for about ten years. The diagnosis is based on a biochemical marker that’s called hemoglobin A1C. If you have hemoglobin A1C at about 6.5 percent, you can be diagnosed with diabetes and should get treatment to prevent complications. So demonstrating that metformin can delay the onset of diabetes complications is not as clear-cut a matter as demonstrating the delay of the onset of heart disease, Alzheimer’s, or cancer. By the end of the meeting, I had a deeper appreciation for the fact that different organizations have different vantage points and agendas and that all need to be accommodated. The most important thing was that we had our go-ahead.

How the TAME Study Works

Overseen by the American Federation for Aging Research (AFAR), TAME is a six-year, double-blind, placebo-controlled trial in which we have enrolled a diverse population of about three thousand adults, ages sixty-five to eighty, who do not have diabetes but who have begun to contract age-related chronic diseases or have begun to show decreased function or other markers for high risk of major age-related disease or death. People who have conditions for which metformin is currently inadvisable (such as severe kidney disease), those being treated with chemotherapy, and people who already have Alzheimer’s or physical disabilities that would prevent them from attending the visits are being excluded.

Our modeling suggests that about half of adults in the study’s age range meet eligibility requirements. Incidentally, although metformin may have many benefits for people younger than sixty-five, the study would take longer—and cost more—if younger people were included, because it takes longer for diseases to set in at younger ages.

Our primary aim in the study is to test whether metformin delays the onset of a group of age-related chronic diseases and whether it also decreases mortality. We are looking for the initial diagnosis of a composite of major diseases of aging, including myocardial infarction, stroke, congestive heart failure requiring hospitalization, cancer (excluding prostate cancer and nonmelanoma skin cancer), mild cognitive impairment, and dementia. At the FDA’s suggestion, we are also assessing a broad array of characteristics that serve as a gauge of aging, such as physical functions, skin condition, hair color, and how often subjects require hospitalization.

One of the novelties of this first study of its kind is that all diseases are equally weighted when it comes to how we will analyze outcomes. Because aging increases the risk for each of the diseases in our composite, we don’t know which disease will appear next for a given individual, especially when interactions between environment and genetic tendencies are considered. Research conducted by the ongoing Health, Aging, and Body Composition (ABC) Study shows that when someone is diagnosed with a chronic disease between ages seventy and seventy-nine, their chances of developing another chronic disease—any chronic disease—is the same as their chances were for getting the first disease or any other diseases.

Let’s say we follow people who have cardiovascular disease over time and determine their chances to get cancer or cognitive decline or to die. The rate is about ten events per one hundred person-years. Now, if we look at people in the same population who have cancer, their chances of developing cognitive decline or cardiovascular disease or dying is also ten. It really doesn’t matter what disease you have to begin with; your chances of getting any of the other diseases is the same because aging drives them all. That’s aging in a nutshell, and our hope is that by intervening with metformin after the appearance of the first disease in any given subject, we can push back the appearance of the second disease and any subsequent disease. Ultimately, we aim to push back aging itself.

We are also testing the hypothesis that metformin will preserve physical and cognitive function, which are obviously critical to health span. To do this, we hope to measure the time until the onset of a group of aging indicators, including major declines in cognition and mobility and severe limitations in the ability to do everyday tasks that the subjects had easily done when they were younger. And then we will see whether metformin influences the rate of decline in these areas or in slowing the decline of other quality-of-life functions. We’re also collecting data on common geriatric conditions, such as fractures and pneumonia, and syndromes, such as frailty and fall-related injuries. When TAME concludes, this information will be made available to the broad research community and health care providers to guide and accelerate the pace of applied geroscience.

Although functional decline is often caused by the burden of multiple diseases, in many other cases, the decline occurs without the presence of disease, suggesting that it’s simply a result of the aging process. This explanation is supported by animal studies showing that rapamycin preserves physical and cognitive function in older rodents.

The results of these studies suggest that there are functional benefits to be had by targeting aging pathways with metformin, per our hypothesis. As for gauging biological outcomes in TAME, we will test the hypothesis that metformin alters biomarkers in a manner consistent with slowed aging. Linking biomarkers to outcomes this way will allow future studies to use biomarker composites in the investigation of new age-targeting pathways and the development of new geroscience-guided therapies. We have not arrived at a consensus about a biomarker panel that would be reflective of the hallmarks of biological aging that is also feasible for a large multisite clinical trial, but we have devised a strategy to test participants on a set of blood-based biomarkers that include metformin levels, glycemic effects of metformin, and markers of clinical disease. We will conduct smaller ancillary studies to discover and evaluate new biomarkers that might be used and provide resources for ancillary studies of emerging markers and technologies for analyzing genes, proteins, and other important molecules. We are also creating a unique biorepository that will serve as a resource for identifying biomarkers that predict age-related outcomes to enhance gerontologists’ understanding of metformin’s aging-targeting abilities.

The protocol for the TAME study will be 1,500 mg of extended-release metformin in pill form taken once a day, and the placebo will be physically identical. We had considered using both a greater dose for greater effect and a smaller dose for safety’s sake, but this is the average dose used in most clinical studies and has an excellent safety profile. Gastrointestinal symptoms like diarrhea and nausea are common but disappear in most cases after a week. Using extended-release drugs and increasing the dose weekly will also help avert side effects. There will be a three-week lead-in phase so that people with persistent GI intolerance can be removed from the study. To ensure that patients adhere to the protocol, we will use strategies that were successfully employed in the Diabetes Prevention Program, in which 75 percent adherence was achieved (several TAME investigators participated in that program). The importance of sticking to the regimen will be reinforced in phone calls and in-person visits, and subjects’ pill supplies will be counted twice a year to ensure adherence.

We will conduct the study at fourteen clinical centers across the United States that were selected in a competitive review of applications, and they all have principal investigators with extensive experience with metformin and the field of aging. They are also members of the TAME steering committee and have collaborated on both the study design and the protocol. And Merck & Co. will generously provide the metformin and the placebo at no cost.

Who’s Going to Pay for All of This?

We had thought that designing the study would be the hardest part of the battle. Once again, we were wrong.

The problem with studying a concept that has never been studied—the problem with innovation—is that it’s inherently risky. What if we don’t prove what we set out to prove? There’s always the chance of that, but even more so when what you propose really would mean a revolution in health care. That’s how we lost our shot at obtaining the financial support of the National Institutes of Health, which funds biomedical and public health research for the U.S. government and which we had been counting on to cover half of our $77 million budget. There’s also the fact that there’s a lot of competition for funding and the NIH only has so much it can allocate, so they prioritize based on diseases that are most prevalent.

The fund-raising campaign started out wonderfully, with an extremely generous commitment from a young billionaire to fund half the study in hopes that the NIH would match his contribution. An interesting note: I had initially tried to raise funds among older people, thinking that those who best understand the decline that comes with aging would best understand our reasons for wanting to delay it, but it seemed that older people didn’t believe we could truly do something about aging. While they may have had the money to help, they didn’t have the hope. On the other hand, young billionaires have both. (The billionaire philanthropist who wishes to remain anonymous is in his forties.)

As for that match, although the NIH had initially expressed interest in partnering with us on the project, the reviewers ultimately turned us down for a grant—twice—ostensibly because they were not convinced that the biology of aging can be treated as a whole. And that sums up the NIH’s level of risk tolerance. Obviously, the role of a medical trial—or any trial—is to make a case for a particular argument. If the judge is already convinced of the merits of the argument, there would be no need for a trial. As we have learned the hard way, governmental conservatism can be an impossible obstacle to raising funds for an innovation that promises to improve the health of a large segment of the population in a radically different way from anything else that has been attempted.

In addition to conservatism, there was the fact that the reviewers of our proposal were unfamiliar with the latest developments in geroscience, and as could be expected, politics were also involved. In the end, our expectation that we would receive the NIH grant cost us precious time that we could have spent fund-raising, and the whole process was set back by two years. Suddenly, we had to scramble to come up with $38.5 million.

Fortunately, we have AFAR as a partner. My history with AFAR goes back to 1996, when the field of aging studies was sparsely populated and the organization gave me my first grant, which allowed me to gather the data I needed to then get an NIH grant for much more. As it turned out, both grants were for similar research (I hadn’t expected to get them both), so I went to AFAR and told them about something else I wanted to do: a study of centenarians. They liked the idea, and so I got my first official funding for studying centenarians. (My father-in-law had actually been the first person to provide me with funding, and I used the $25,000 that he gave me to compile the preliminary data that I presented to AFAR. Preliminary data is very important to getting grants.)

A few years later, AFAR began offering the Paul B. Beeson Emerging Leaders Career Development Award in Aging, which is named for the infectious diseases expert who served as Yale’s chief of medicine for thirteen years. The grant is given to ten M.D.s a year with an interest in the biology of aging and, potentially, careers in gerontology. And this support of budding gerontologists has transformed the field of aging research to the point where there is a large pool of scientists with diverse areas of expertise—most of whom have received AFAR grants. For example, Dr. Ned Sharpless, who is director of the National Cancer Institute (NCI), is a Beeson scholar and has shown great interest in TAME for some time.

I serve on the AFAR board’s executive committee as scientific director, so when it came time to publicize the TAME study and raise funds for it, I knew they would help. AFAR has contributed to the costs of our meetings with the FDA, members of the U.S. Senate, and several NIH institutes, and it also organized the competitive review process for choosing the clinical centers where the study will be conducted. I couldn’t have asked for a better partner or nicer, more committed people to work with, in particular Executive Director Stephanie Lederman and Deputy Director Odette van der Willik, whose vision is as expansive as mine.

And when it comes to fund-raising, you need all the help you can get. A good example of the diverse challenges of raising money for a particular piece of the health care puzzle is what happened when I requested funding from the Department of Defense, which invests significant resources into disease research. During my meeting with then Senate Appropriations chairman Thad Cochran, who’s from Mississippi, I made sure to tailor my pitch to his sense of regionalism.

“You know, your state is doing really poorly,” I said. “You have more strokes than anyone, you have more cardiovascular disease.”

“Why is that?” he said.

“Well, there are two answers. First of all, your people take less metformin than any other state. But there’s really a much more important reason—your people are victims of the good food of Mississippi, this food you can’t stop eating.”

He burst out laughing. “That’s great! I’ll remember that! I’ll use it! My people are the victims of the good food of Mississippi. I love it.”

One of the reasons that getting funding is an uphill battle is that the Defense Department has a list of diseases it will fund research for, and while aging itself isn’t represented on that list, diabetes is, and I had argued that metformin appears to treat the aging biological background that allows diabetes to set in, along with other age-related diseases. But the reviewers found this too hard to believe, and we were turned down for funding.

The fact is that taxpayer-funded aging research amounts to a small fraction of the funding for research into individual diseases, and this can be interpreted only as a sign of shortsightedness when considering the potential health care crisis posed by the increase in the elderly population that will occur in the coming decades.

What’s ironic is that while some funding agencies think our research quest is a long shot, we’ve also been turned down for it not being high risk enough.

But when you cast a net as broad as the one we cast investors do turn up. One example occurred in Berlin, where I was speaking at the Undoing Aging conference. I was scheduled to do more interviews than I could count, and a couple of guys from the Boston Consulting Group, which matches biotechs with pharmaceutical companies, tracked me down.

“We need to talk to you,” one of them said.

“You’ll have to wait in line,” I said, looking at my watch.

“You don’t understand. We have a client who represents an interest that wants to invest a lot of money in aging research, and I think it’s important that you meet him.”

So I met with him and told him about TAME and connected him with AFAR. A week later, AFAR informed me that he believed in our research and wanted to contribute a significant amount to the study. Every time I hear about a new investor, it’s music to my ears.

Metformin Is the Tool, Not the Goal

When people hear me mention metformin, they often think I’m suggesting that it’s the best way to target the causes of aging. While this is true, there’s a lot more to the story. The reason metformin is so important is that if our trial is successful, it will pave the way for even better drugs. The TAME study also serves as a template for a drug approval pathway that is more efficient and less expensive than the existing route of seeking approval to target one disease at a time. In other words, as biotechnology companies develop more drugs that target each of the hallmarks of aging, pharmaceuticals will be able to follow our study model and bring the drugs to market relatively quickly. This will allow us to make a difference for patients that much sooner—even for those who start them late in life.

Of course, it helps if the drug you’re developing replicates genetics found in the human body. Because the drug’s function in the body is already understood, safety issues are minimized, and development happens much faster. If a drug that replicates the function of the mutation in the CETP gene were successfully developed, for example, it could feasibly reach the market in ten years rather than the twenty it typically takes an experimental drug that requires years of preclinical testing.

Genetic studies will be a key to accelerating the drug development process as the world awaits medications that can extend their health span, and a perfect example of that is that metformin seems to do the same thing as the mutation we’ve seen in our centenarians.

And the broad approach to addressing disease modeled by the TAME study will be another key. Funded by hundreds of millions of dollars contributed by investors, many biotechnology companies are pursuing drugs to kill senescent cells, but they target only individual diseases rather than clusters. And most of the studies involved have been done on mice, with human trials only now beginning. So while the results have been promising—molecular biologist Jan van Deursen of the Mayo Clinic eliminated senescent cells from both younger and older mice, resulting in improved metabolism, cognition, and energy levels—these senolytic drugs aimed at disintegrating senescent cells have a long way to go before they can fulfill that promise. In the meantime, while we push for the paradigm shift toward expedited drug development, there’s no substitute for the scientific process, and it’s worth waiting for—remember the significant incidence of cancer among women who underwent hormone replacement therapy only to later learn that it was doing more harm than good. I promise that your patience will be rewarded with treatments that are even more effective than metformin at holding off the effects of aging. Metformin will likely be the first one available, but it will be replaced with a next generation of treatments that may incorporate metformin in combination with other drugs and will have much more powerful effects. And with the precedent established by the TAME study, those treatments will become available sooner rather than later.