Here is the full transcript of American physician and researcher Ronald DePinho’s talk titled “How Could We Reverse Aging?” at TEDxFordhamUniversity (May 29, 2025).
Listen to the audio version here:
The Universal Challenge of Aging
RONALD DEPINHO: I’m here to tell you about something that we will all get, and no one escapes. So aging is a mystery for millennia, but it’s now coming into focus, and I want to tell you about some really exciting things that I think are going to change the human experience. And so as I mentioned, no one escapes. This is a disease that actually underpins many of the great diseases, cancer, diabetes, heart disease, and Alzheimer’s. The processes that underlie aging also instigate those particular diseases.
Now this is a very significant economic and social issue because there are currently 1.2 billion individuals over the age of 60, and the significance of that is that after 60, there is a geometric increase in the incidence of these diseases. Every five years after 60, those diseases double in incidence, culminating in a lifetime risk of 40% of individuals getting cancer, one in two men, one in three women, or the incidence of dementia is also significant, with close to 40% experiencing some form of dementia by age 85. So these are significant issues.
Understanding What Aging Really Is
And the question is, what exactly is aging? Well, up until just a few decades ago, there was a descriptive definition, gradual accumulation of damage and loss of function in cells and organ over time, leading to a decline in physical and mental abilities, and increasing disease risk. Frankly, as a scientist, not very helpful. If you wanted to do something about the disease, you really have to understand its molecular and cellular mechanisms that drive that disease that would enable you to then intervene therapeutically.
So it now turns out that over the last couple of decades, there’s been a lot of progress.
Just like in cancer, we know mutations cause cancer, and those mutations instruct the host to create a supportive environment to form a tumor, we know what the rules are, and that has led to therapeutic interventions. Well, in much the same way, we know what the hallmarks of aging are, and those are graphically illustrated here.
The Hallmarks of Aging
So you have DNA damage, the accumulation of damage over time, which leads to genomic instability. You have chronic, unrelenting inflammation, called inflammaging, that also wreaks havoc on our organs. You have a decline in mitochondrial function, the powerhouse of our cells, so you have less energy as we age. Also, with diminished mitochondrial function, you have a diminished capacity to handle free radicals, which can also cause significant damage. And then there are these zombie cells, senescent cells that accumulate in our tissues that wreak havoc and also create these field effects of inflammation and injury in our organ systems, leading to organ atrophy and decline.
And then finally, you have telomere attrition. Now what are telomeres? Telomeres are the tips of the chromosomes. They help to maintain chromosomal integrity. And what happens as we age is those telomeres become frayed, they’re damaged, they’re shortened, and when they reach a critical level of damage and shortening, they lose their function and chromosomes become unstable. And that then sends out a dangerous signal to the cell, and the cell actually ages prematurely. So telomeres are particularly important, and they’re connected to all of these other hallmarks of aging as well.
The Discovery of Telomerase and TERT
Now let me tell you a little bit more about telomeres, something we’ve studied now for several decades. There’s an enzyme that was discovered, in fact, that won the Nobel Prize for its discovery. It’s an enzyme that maintains the telomeres. It catalyzes the addition of telomere repeats to maintain the length and function of the telomere. And a few years ago, we discovered that there’s a moonlighting function for TERT, telomerase reverse transcriptase, in that it associates with transcription factors that regulate genes, and it turns out that those genes are the genes that regulate the aging process. And so you have these two major functions of maintaining chromosomal integrity and also maintaining a gene expression program that’s actually associated with a youthful cell state.
Now what happens, though, and we showed this a few years back, is that the levels of telomerase reverse transcriptase acutely decrease with the onset of aging. And that then sets in motion a whole cascade of events that lead to the hallmarks of aging. And so the question is, if we could reverse that, could we also attenuate or reverse the aging process?
Developing TAC: A Breakthrough Compound
So we then asked, you know, are there drugs that we could potentially develop to reboot the aging system? Can we restore those youthful levels of telomerase reverse transcriptase in all cells of the body? And so we screened about a million compounds using high-throughput technology, and we identified two compounds that were very structurally related to one another, and they did the same thing. And this compound, which we dubbed TAC, for TERT Activator Compound, restored TERT levels to youthful levels. It also penetrated all cells, including getting past the blood-brain barrier, which is really important because brain aging is a critical aspect of the pathology that we experience. And it has a very short half-life, but it only has to be administered three times a week.
Remarkable Results in Aged Mice
And so we then moved this forward into an interesting set of experiments. The first experiment was to treat mice beginning at 22 months of age. So in humans, age onset is 50 years of age, plus-minus 5 years, depending on your lifestyle. Mice, that equivalent is 18 months of age. So we actually started the treatment in mice who were 22 months of age, which is the equivalent of somebody in their 70s. And then we treated them for six months and looked at the hallmarks of aging at 28 months, which is the equivalent of somebody in their 90s.
What did we find? Well, the results were striking. And what you see here is a region of the brain called the hippocampus, which is important for working memory. And for working memory, you have to maintain new neuron formation throughout life. And so, for example, chemo brain wipes out these new neurons and impacts memory executive function. So what you see here in the TAC-treated animals is that you see these brown stained cells. That’s a stain for newborn neurons, and they’re absent in the control animals that are quite elderly.
In addition to these results, we found we impacted all hallmarks of aging. We enhanced learning and memory. We eliminated senescent cells, those zombie cells. We reduced inflammation. We increased neuromuscular function, so enhanced strength, which is a major issue in the aged. So this atrophy of the muscles, sarcopenia, is a major cause of morbidity and mortality in the aged. So enhanced muscle strength, balance, speed, coordination. And we also improved immunity so that they could fight infections as well as fight cancer with their immune system to eliminate would-be aspiring cancer cells. And there were no side effects. Because again, short half-life, only three times a week. That was enough to get TERT levels up, and then before they came back down again, we administered and so on and so forth.
Targeting Alzheimer’s Disease
And so this teaches us that we can actually impact the aging process through science. And we can imagine that this could potentially also have a significant impact on those great four diseases, such as Alzheimer’s. So the mechanisms that drive the aging process are the same instigators that also drive these age-related diseases. And so we then asked, what if we were to take mice that have been genetically engineered with alterations in their DNA makeup that predisposes them to develop classical Alzheimer’s, as you see in humans? So these mice were then treated around the onset of pathology, about six months of age, and then treated for three to six months and analyzed.
And I’ll just show you two pieces of data. One of the things that happens in Alzheimer’s is you accumulate amyloid, this protein gunk that essentially ends up destroying your neurons. And you develop these plaques, and you can readily see here that the control animals had plaques, whereas the TAC-treated animals had greatly reduced amounts of amyloid. And then also there was less neuroinflammation, which is a co-conspirator in driving disease pathology. And what you see here are these brown cells that are stained. These are so-called microglia. They’re the inflammatory cells of the body. And you can look, they look angry, right? And they’re creating all of this field effect and cytokines that actually are injurious for the neurons. And you can see here that that has been largely quelled in the animals that have been treated with TAC.
And so we can imagine that aging is something that is not inevitable, that we can increase our health span, our years of healthy living, beyond this transition where we have this decline in all of these mechanisms that drive the aging process and underlie cancer, diabetes, heart disease, and Alzheimer’s. So rather than reacting to these diseases, we can actually cut them off at their source and intercept the process from the very beginning.
So we can imagine that aging is not simply inevitable, but it’s biology. And in science, we know that if we understand the mechanisms of biology, we can actually change the trajectory of that biological process. So biology can fall to the acts of science. Disease can bend to the acts of science. And so we can think of treating the root causes of aging and then usher in an era of regenerative medicine as opposed to reactive sick care medicine.
And that would lead to compressed mortality, because we’re not talking about lifespan, which is different from health span. But it would mean that you would have many, many more years of healthy living and go on. And imagine being in your 90s and playing hoops with your grandchildren and dancing your life away and having a great time and being productive. But you can also have a different perspective, and I’ll leave you with one final perspective. Stephen Colbert is one that often has an opposite view of everybody else. Thank you very much.
