History of Telomere Biology from a Front Row Seat

William Andrews, PhD

Well, I got, I mean I’ve been in telomere biology for 40 years. I guess I started in 1992 yeah almost 40 years, 39 years, 40. And mostly, I got into telomere biology because of previous thoughts on what aging is and stuff like that. I always thought aging had to do something to do with the Hayflick limit. Leonard Hayflick has shown that our cells can only divide a certain number of times and then they stop. And before I knew about the Hayflick limit, it used to always bother me that we’re made up of cells and when cells get old and unhealthy, why isn’t it that other cells don’t divide and replace those cells? 

Just like bacteria in a Petri dish, if some bacteria get sick or unhealthy or something like that, they just disappear because the healthy bacteria outgrow ’em. Well, that might happen to us in our younger years, but why doesn’t that happen to us when we get older? And so that was always a bother to me. I mean I’m not talking right now about the cells that don’t divide, like our nerve cells, but those are also, like they have cells that take care of them, I call them caregiver cells, like glial cells and Schwann cells that take care of the neurons. Those do divide a lot. 

So division is still involved even in the non-mitotic cells. But why is it that we don’t, we know that our cells are dividing, why is it that they get old? There had to be something going on because the bacteria culture doesn’t get old. Why do human cells get old? So then I learned about the Hayflick limit. I guess Leonard Hayflick learned about it in 1961, but I didn’t hear about it until I would say early, mid 1970s. And at that point, and actually so it was early 1970 ’cause I know that when I started applying to graduate schools and stuff, I started saying that I want to go someplace that’s looking at what’s causing the Hayflick limit ’cause I kind of felt it had something to do with aging. And so what would cause something so specific to happen? There had to be something like almost a program in our cells that told our cells to stop dividing. 

I kept coming up with the analogy, it was like ride tickets at an amusement park. Okay, every time our cells divide, you lose a ticket and you only have a certain number of tickets. So I’m just struggling with this year after year, I’m talking to people like Dr. Mike Rose and Harveeb Sarbor about starting companies and stuff like that back in the late ’80s, early ’90s, about focusing on trying to find out what’s causing this Hayflick limit. And then just one day I’m sitting in a conference in Lake Tahoe and a guy named Calvin Harley is getting up on stage to talk about telomeres and I had no idea, I knew what telomeres were ’cause of my background in biology and stuff like that, but I had no idea that he was gonna say what he did. 

And that’s when he said that telomeres shorten as you get older and that you can actually measure the length of the telomere and you can tell how old a person is, and more importantly, you can guess how long it would be before they die of old age. Well, I’m jumping up and down in my seat ’cause I thought, my God, these could be those ride tickets. And they’re the only thing that I ever heard of that could be those ride tickets. Everything else, every theory about aging, did not have the twos and twos all adding up to something that made sense about aging. So this telomere stuff sounded fantastic. And as soon as Calvin got done, I was at the bottom of the podium as he was coming down the stairs before he even got off the stage just saying, “I want to work with you. I want to get involved in this.” And I literally jumped ship. 

I was working with a company called Berlex Biosciences and I used to call myself a lifer, I was never gonna leave that company, I loved it so much, but all of a sudden here I am getting ready to go work with Calvin Harley. And so it was literally three months later that I was actually working with Calvin at Geron Corporation as the director of molecular biology. That was I think 1992, it might have been 1993. But that’s when my career in telomere biology occurred and I just became obsessed with it because suddenly I found these ride tickets. And so I wanted, the way to show that the ride tickets were causing the aging was to figure out a way to add more ride tickets back and see if they gave you more rides or more cell divisions. So I became just obsessed with that. I literally, Geron Corporation had to build a separate, bring in a trailer with beds so that I could sleep there ’cause I was working there around the clock.

Joseph M. Raffaele, M.D.

Wow.

William Andrews, PhD

And there were other people working on trying to discover the enzyme telomerase at the time and suddenly I found myself working with them, collaborating with them and stuff, but I felt like everybody was making too many assumptions and going the wrong way. So I started a whole program at Geron Corporation, Geron put three-quarters of the employees all working for me. So we started a program to start working on some other approaches that I thought made more sense. And lo and behold, three months later, we were able to discover the RNA component of human telomerase, which didn’t have any similarity at all to the previous one that had been discovered in Tetrahymena. 

And that was one of the mistakes that other people were making is they were expecting it to be similar and so they thought they could identify the human one by sequence identity to the, but it wasn’t. So we ended up discovering it through probably one of the toughest research projects I’ve ever been involved in of brute force, but we ended up discovering it and then people still wouldn’t believe we discovered it. And to prove that we had discovered it, we mutated the sequence in the RNA component so that instead of encoding the normal TTA-GGT, TTA-GGT, TTA-GGT repeats, we mutated it so it now would produce TT-GGGG, TT-GGGG, or TTT-GGG, TTT-GGG. So we made these things and put these RNA components in the cells and then isolated the telomeres and sequenced them. 

And lo and behold, they were the sequence we wanted them to be. So that proved that we had discovered the RNA component of telomerase. And then that shortly thereafter led us to the discovery of the protein component of telomerase. And the very first thing we did was, okay, let’s see if this abolishes the Hayflick limit. And lo and behold, it did. Now at the same time, we did an experiment where we took the antisense of telomerase and put it into cancer cells and we showed that it killed every cancer cell. So it was almost in the exact same week that we’d come up with a potential cure for cancer and a potential cure for aging at the same time.

Joseph M. Raffaele, M.D.

Wow.

William Andrews, PhD

That was exciting.

Joseph M. Raffaele, M.D.

Heady times.

William Andrews, PhD

But the frustrating part of it was that all biotech companies are business first, science second. And so there was a big meeting, all the investors came to a big meeting, we had a big board meeting with all the investors. I gave a presentation, I discussed those things and I’ll never forget the head of the scientific, or head of the board of directors, chairman of the board said, “Well, we can’t do both. We’ve got a cure for aging, a cure for cancer, we can’t do both. We have to pick one. Which one gives the quickest return on investment?”

Joseph M. Raffaele, M.D.

Obviously.

William Andrews, PhD

Well, even though Geron was short for geronotology, aging, they chose to go for the cancer. Now, I had previously had many discussions with Calvin Harley and others saying because of my background in cancer was, I’d already been awarded the second place for National Inventor of the Year for my cancer research, I had been involved in a lot of cancer research prior to going to Geron Corporation. So I knew a lot about cancer. And I was saying that inhibiting telomerase with an antisense isn’t going to cure cancer. 

It’s gonna make it go away, but it’s gonna cause telomeres to get shorter. And we already knew that mutation rates skyrocket when telomeres get shorter and that inhibiting telomerase was just gonna make telomeres get really shorter, mutations rates were gonna skyrocket and some of those mutations were gonna convert those cells into ways to survive any cancer treatments or in fact start producing their own telomerase. So I was pretty upset when they decided to focus on that. I am the real inventor of Imetelstat. I’m not even certain I’m pronouncing it correctly, which is the antisense that’s in clinical studies now for Geron Corporation that they use to inhibit to telomerase. And I would always say that that’s, the cancers are always gonna come back and then they’re gonna be resistant to the Imetelstat or resistant to whatever you treat ’em with.

Joseph M. Raffaele, M.D.

But if it gives six months, it’ll get approved.

William Andrews, PhD

Yeah, well, I mean it is, anything that helps, I strongly agree that they should continue pushing it because it does very effectively makes the cancer go away, but people always have to be aware of the fact that it’s gonna come back. So people do live longer because of it. But it’s not really the cure for cancer. And we do have a cancer program here at Sierra Sciences, but we’re trying to focus on not inhibiting telomerase. We’re trying to poison cells that produce telomerase. So instead that keeps the telomeres long. In fact, it’s a two hit kind of thing where we first, even if it’s a cancer cell, we induce telomerase to lengthen telomerase and then take the telomerase inducer away so that all the other cells in your body shut the telomerase gene down and then add a poison. We have two different types of poison. 

One is a nucleotide analog that incorporates into the telomere that will actually kill the cell that other telomerases won’t recognize. And the other one’s using that same approach that we use to prove that we have telomerase. It was to make a mutation to the RNA and infect cells with a gene therapy that delivers this mutated RNA to actually produce a mutant telomere that would kill cancer cells. And even though the ones we originally used, the ones that converted TTA-GGG to TT-GGGG or TTT-GGG, we’ve done a lot of work on like all the different 5,000 plus different combinations of telomere sequences and have found some that are very, very lethal to cells. 

The problem is delivering the gene therapy to all the cells is the issue. But the nucleotide analog, which we don’t have yet, we’re still searching for things. Woody Wright and Jerry Shay, or just Jerry Shay because Woody Wright passed away, Jerry Shay published a paper recently on a nucleotide analog. But it’s not sufficient, a nucleotide analog that actually poisons cells, but it still gets incorporated by the polymerases. So we’re looking for is something like that that would be totally ignored by RNA polymerases and DNA polymerases besides telomerase. 

So we do have a cancer program, but the idea is to keep telomeres long, not get telomeres short. So getting back to the subject, as soon as they decided that cancer had a quicker return on investment despite everything that I had said, I resigned. In fact, I stayed there a little while and I led the first studies that showed that we could overcome the Hayflick limit. And when I presented the data at a strategy meeting, I was reminded that I wasn’t supposed to be working on that, I was supposed to be working on cancer. And at that point I kinda like walked in my office and called a venture capital firm that I’m friends with and said, “Hey, I’m looking for something else to do. I want to start my own company now. Is there something I can help you guys with to earn some money while I’m trying to start my new company?” And they just had me consult a lot, go to other companies to salvage their science and things like that.

 And so that was a win-win situation for me and them and it allowed me to get time to write a business plan and get investors and start Sierra Sciences. So Sierra Sciences has been focused on trying to find a way to produce telomerase inside of all your cells, despite the fact that some people believe that that’s gonna cause cancer. I can’t really say if it is or isn’t. I mean, there’s no data yet. Everything is hearsay so far. I go to conferences and there’s people, scientists and doctors, that believe that there’s actually been studies showing that when you put the telomerase gene into a cell, it becomes a cancer cell, but there is no data at all saying that at all.

Joseph M. Raffaele, M.D.

And there’s data that shows that when you turn on telomerase in a model that it doesn’t necessarily get cancer.

William Andrews, PhD

Yeah, actually cancer gets decreased. There’s several studies now showing that surprisingly, in fact, Dr. Ron DePinho, he’s a cancer researcher, when he did his mouse studies, he wasn’t trying to say that mice were gonna have a reversal of the aging process, which he called it. He was actually trying to show that they were gonna get cancer ’cause he was gonna try to use it as proof of how important it was to find a way to inhibit telomerase.

Joseph M. Raffaele, M.D.

So you should probably just explain a little bit about that experiment that was so serendipitously good for aging research and for telomeres as anti-aging, what he did ’cause I don’t think we’ve talked about that at length and you’re a perfect person to talk about it.

William Andrews, PhD

Yeah well what Ron had done, he got the genes from Geron when I was there. Ron and I actually collaborated a lot on trying to figure out whether or not like Maria Blasco’s original data, where she originally announced that telomerase and telomeres have nothing to do with aging because when she put telomerase into mouse, or when she knocked out the telomerase gene in mice, they still died at the normal age. But mice don’t age by telomere shortening, they age by other mechanisms. And their telomeres were so long that it had to go, Ron DePinho and I worked together to show that it was actually predicted that it would take six generations of mice before the telomeres got short enough that they would start showing signs of aging like humans. 

Then, lo and behold, that turned out to be the case. So Ron and I had a good working relationship. Geron Corporation provided him with the tools, but he wanted to show that the telomerase causes cancer and I was all for it, let’s get this done and let’s see it. So what he did is he first engineered mice that were knocked out for the telomerase gene, for the mouse telomerase gene and he then incorporated a new telomerase gene that was under the control of the-

Joseph M. Raffaele, M.D.

Tamoxifen.

William Andrews, PhD

I was gonna say inhibitor of the estrogen receptor.

Joseph M. Raffaele, M.D.

Tamoxifen, yeah.

William Andrews, PhD

4-Hydroxytamoxifen or dihydroxytamoxifen. So he put it so the mice had telomerase turned off in the absence of the Tamoxifen drug and then when they got old and the telomeres got really short and they got old, so he let him go the six generations to get short telomeres. Then, when those six generation mice started to show signs of human aging, he then fed them with the 4-Hydroxytamoxifen and they got younger by every measurement he could do. Brain sizes got bigger, memory came back, spleen size came back, I can’t remember, it’s been 10 years now, but all this-

Joseph M. Raffaele, M.D.

Yeah, the pictures of the gray coat went to a nice and glossy brown and they had good subcutaneous fat, they just looked like younger mice and on the inside, they were younger mice too. Refresh my memory, was it a 50% knockout so that they only had 50% of telomerase?

William Andrews, PhD

No.

Joseph M. Raffaele, M.D.

It was a full?

William Andrews, PhD

Full knockout, so they had regular telomere shortening. But when he got interviewed by Barbara Walters on that, he called it a remarkable reversal of the aging process. And I was then thinking that just destroyed his whole theory, you know? I mean, what is he gonna do now? He had a very successful career and as a result, he became the head of MD Anderson in Texas, still focused on cancer. And probably, there’s still probably benefits in cancer cells, inhibiting cancer, inhibiting telomerase to kill the cancer, you’ve just got to do it in a way that doesn’t increase the mutation rates at the same time. So I’m hoping that some of our research here will contribute towards Ron DePinho’s recent.

Joseph M. Raffaele, M.D.

I think that’s what a lot of people, doctors and other health care practitioners that think about doing something to a therapy that will increase telomerase activity. They say, well, gee, what I know about telomeres and telomerase is that all cancer cells, 95% of them, have turned on telomerase and that’s what helps them do the job. So what if we turn on telomerase, aren’t we gonna cause a problem with our cancer cells? And you know, it’s on the surface reasonable to think that way, but the details which you’re just about to explain are that it’s more complicated than that.

William Andrews, PhD

Well, yeah, one of the main causes, reasons we get cancer, is a weakened immune system. And keeping the telomeres long in our immune cells is gonna help our body fight the cancer. But also one of the main causes of cancers is the short telomeres. And one of the reasons why cancers evolve so late in life is because of the telomeres get shorter and the mutation rates go higher to increase the chances. I mean, people use to talk about accumulation of mutations with age and you just build it up more and more and more mutations, but a lot of studies have come out lately, in the last like five, 10 years, showing that these accumulations don’t occur gradually, they occur all of a sudden in the older cells. And so it’s probably being induced by the short telomeres. 

I mean I’m not saying short telomeres are the only cause of these mutations, other things can cause ’em too. But usually when you get a mutation, it causes the cell to be unhealthy somewhere, recognizable by the immune system. So either other dividing cells will replace it or the immune system will knock it out until the immune system gets weak ’cause of short telomeres and then you get immunosenescence. Now this is still theory because the only way we’re gonna ever know is to find a way to actually lengthen telomeres. I’m not talking about just some of the telomeres. Like some great products on the market right now will lengthen telomeres, but they’ll lengthen the shortest telomeres, they’ll lengthen maybe the average telomeres in some of the cells. But what we need to do is we need to make it so that all the cells in the body have their telomeres lengthened so that they have a young phenotype and also that they’re not causing high mutation rates, to actually see if telomerase is gonna cause cancer or prevent cancer. 

And when I take all the pros and cons and read all the papers and do my critical meta-analysis of the scientific peer reviewed studies and try to weigh different things, I come up always with the idea that if I had to bet money on it, I’m gonna say that inducing telomerase is gonna decrease cancer incidences more than it’s gonna increase. It can do both, it’s just that in the long end, what caused more cancer, lack of telomerase or presence of telomerase? And I think it’s the lack of telomerase that’s gonna cause more cancer than the presence of telomerase. But we won’t know until we can actually test it. And we can’t test it until we have a drug or a gene therapy that does lengthen the telomeres in all the cells. And that’s what I’m trying to do. I’m trying to come up with something to do that. And something like that doesn’t exist in my opinion, even though there are some papers that I wish I would see reproduced to see if they actually can be reproduced.

Joseph M. Raffaele, M.D.

Right. You’re talking about more like a 30% increase in telomere length that would have those kinds of super rejuvenating effects and in every cell. There’s been some signals in papers with increase in telomere length, but not like the Stanford paper where they did it with, I think it was an RNA, RNAi, a messenger RNA, where they lengthened in vitro telomere length by 30%, something like that might have these incredible effects. What was the lengthening of DePinhos telomere length?

William Andrews, PhD

30%. He had 30% increase in telomere length. I thought that was why you just picked 30%.

Joseph M. Raffaele, M.D.

Well no, there was a Stanford study as well I think that had somewhere around that length.

William Andrews, PhD

In vitro in Petri dishes.

Joseph M. Raffaele, M.D.

That’s what I’m saying.

William Andrews, PhD

And we’ve been able to do that for 40 years. We did RNA back when I was still at Geron. We took the telomerase mRNA and put it into cells and that will work. But the big problem with the mRNA is the delivery. Delivering it to all the cells is really a big problem. But it’s really, there’s all kinds of publications coming out where people are saying they’ve got big new breakthroughs on how to do it, but the bottom line is I just really want to see it get done. I’m not trying to get publications myself. I’m not trying to make a lot of money myself. I just want to cure aging. And right now I think the best way to cure aging is to lengthen telomeres. And I don’t want to waste my time on things that really are just gonna give me a paper published. ‘Cause I really think we got to find a drug. 

We do have a gene therapy that I’m hoping will be effective, but I don’t believe that’s the end-all either because it still doesn’t get delivered to all the cells. I think the best way to actually lengthen telomeres is to find a small molecule drug, which for some reason has a lot of bad feedback on too. People are saying small molecule drugs don’t work, but that’s because there’s been a lot of poorly designed small molecule drugs. There’s a lot of small molecule drugs that work really well. I believe that designing a small molecule drug that induces the telomerase gene is a much better way to get delivery of the telomerase to every cell in the body. And so that’s my focus.

Joseph M. Raffaele, M.D.

Do we know, I mean we’ve talked about this before, but telomerase is repressed, suppressed in most cells in adulthood even after birth. Do we know, what’s the mechanism? The mechanism of some of the small molecules is to derepress the repressor. But I know you’ve said that, well, I don’t know that anybody’s ever really shown that. I mean, the reason I’m asking you this is then could, if we know what the mechanism is or have an idea, then it could well be that a small molecule will work quite well. Is that an active area of research for people or are they just looking to do gene therapy?

William Andrews, PhD

Yeah, no. We spent over 10 years just trying to figure out how is the telomerase gene repressed or is it repressed or maybe it’s just so coiled up in the chromosome that it needs some strong activators? And we came up with a lot of candidates, we found a lot of things that worked in ectopic expression of telomerase or in a test tube, but we could not get any of these things to work in vivo. And when I say in vivo, I’m talking about even human cells in a Petri dish. I like to call that in vivo, most people call that in vitro. So we finally after 10 years, and we’d done just about everything we can, we never published any of our work ’cause our focus wasn’t publishing, but a lot of people in the last 20 years, 10, 15 years, have published papers reproducing our results. But my team knows that that’s not gonna get anywhere because it’s not gonna actually work in a normal human cell in a body. 

We finally just decided, okay, so we’ve done everything, we can’t imagine anything else to try. We haven’t figured out what other telomerase promoters regulated, nobody else has. And I came up with a thought that, well, maybe there’s multiple repressors. And when there’s multiple repressors, you can’t use the standard technologies to derepress to see that the gene turns on because you have to derepress several at the same time. And how do you find several of ’em if to find one of ’em, you have to do press all of them? So we decided to do it the hard way, okay? And we’re obsessed with this goal so if we have to do it the hard way, let’s go for it. 

So we developed an assay that everybody else had said was impossible. And that was a high throughput screening assay that used real-time PCR to detect telomerase mRNA. And even though mRNA is so low in even cancer cells, the level of the mRNA for telomerase is so low, it’s something like one mRNA per cell, it’s so low that PCR was thought not to be practical. 

But I have some pretty good people here and we developed a really good, powerful real-time PCR assay that we can do in . It’s still a trade secret, we didn’t publish it or patent it, nobody else has figured it out, if they have, they sure aren’t using it. But we were able to screen like 500,000 different chemicals, including a lot of natural products, in this assay without knowing what the repressor is, without knowing how the gene was regulated. But we ended up finding 900 different chemicals that actually did turn on the telomerase gene. 

Not to the level that we see in cancer cells. And we picked HeLa cells as a standard to go with because HeLa, the ones from Henrietta Lack, those were the cells that we had determined when I was still at Geron Corporation produced the lowest amount of mRNA, telomerase mRNA, but were still immortal. So we decided, okay, that must be the amount that we need to get to to make a normal human, a non-cancer cell, immortal. So the highest we’ve gotten is 16% of that. So we have gotten chemicals that induce telomerase to that level. We still don’t know how they work, but we know that they, we’ve done a lot of studies on toxicity and things like that and they’re not causing any side effects. Well, some are, but the ones that we’re pursuing aren’t, don’t cause any side effects.

Joseph M. Raffaele, M.D.

What’s 16%, you hear about the trap assay as what you use to sort of figure out whether something’s turning on telomerase or not and you talk about one-fold, two-fold, three-fold increase. A HeLa cell will be how many fold?

William Andrews, PhD

You can’t because it’s dividing by zero. So when you get really good at measuring telomerase activity, you find out that there really isn’t any mRNA or any telomerase activity in endothelial cells or fibroblast cells at all. And so when we do our PCR tests and stuff like that, we have to go through many, many CT’s, units of measurement in PCR, before we actually see anything from a normal human cell. And we just figured that’s zero, that means there’s zero mRNA. So we can’t really say a fold increase, but we can say how much fold are we away from getting to what HeLa is? So 16% is about what one-sixth or one-eight of what HeLa is. 

So if we can increase, if we can find some way to increase it eightfold more we could. Now let’s go back to this idea that there’s multiple repressors. Well, we’re planning to now try to do a synergy study, to try, let’s say maybe some of the repressors that we have found attack one of the repressors, some attack another repressor and some attack a third repressor. And maybe we might find that mixing them will attack all three repressors and we’ll get to 100% HeLa or even higher. That experiment hasn’t been done mostly because of the lack of funding. 

But we’re geared up to do that, it’s just a very expensive experiment to do. Literally, when we were identifying the first 900 chemicals before we even got a chance to start talking about doing synergy, we were spending a million dollars a month on the screening. And then lots of things happened, the global financial crisis, the Tokyo earthquake, the pandemic, COVID pandemic, all these things started interfering with our ability to be able to do this research. But that’s still what I’m trying to do. And I’m trying to find some way of bringing in funding to do that without losing control of the science. One of the big problems, one thing I learned when I did have investors and I used to only own 17% of the company, I found that I had very little control over the science. Some of the investors were outstanding, but many of them would completely take over our strategy meetings and get our scientists geared towards other things. And then there was even talk when I used to complain about it, that they were gonna fire me and replace me with somebody else. 

And it’s like, that would end my life ’cause I’m so obsessed with this. And so finally, I was able to buy out all my investors so I own 100% of the company now. But I don’t want to bring in more investors that are gonna have control. So I’m trying to find funding without losing control, but I’ve got some great opportunities for investors to make a ton of money off of marketing the discoveries if they just let me focus on the science. So I’m hoping something will turn up soon and we can get back onto this. But I think when we do get the funding that we need, we will be able to make some, get a lot of these questions answered. Does telomerase cure aging? Does telomerase cause cancer? All these things, we’ll be able to answer very straightforwardly. Right now, they’re just all hearsay.

Joseph M. Raffaele, M.D.

People are looking at, I mean obviously you hear sort of the thought from the gerontology community, and it’s perfectly valid, that trying to cure individual diseases will only add about seven years to the average life span, but if you cure aging, obviously you’re gonna add decades to it. But there is work going on looking at, well there’s lots and lots of observational studies looking at the role of telomeres or any other association of telomere length with cardiovascular disease, dementia, osteoporosis, of course, cancer in the opposite direction, short telomeres increase. 

And some of that’s probably through affecting the aging process, but some of it’s maybe more direct to the pathology for those particular diseases. There’s some research, a lot of research in cardiovascular disease. What’s your thoughts about sort of that area and clinicians trying to keep telomeres longer in their patients to stave off some of these chronic diseases, particularly Alzheimer’s and cardiovascular disease?

William Andrews, PhD

Well, I get misunderstood a lot. I think it’s because I’m not a semantics expert, but when I say curing aging, I’m talking about curing Alzheimer’s, curing cardiovascular disease, curing osteoporosis, curing multiple sclerosis and all the demyelinating related disorders and things like that, because I believe that telomere shortening plays a critical role in almost every disease we’ve ever heard of. In fact, I am totally unaware of any disease that’s ever been discovered that there hasn’t been now a scientific, peer reviewed publication, showing that telomeres played a role in inducing that disease. 

So I believe that lengthening telomeres is going to correct many, many diseases, and I especially target Alzheimer’s and cardiovascular disease. As I mentioned before, we do have a telomerase gene therapy that we’re trying to get clinical studies underway with. I think it’s gonna have a delivery problem. We’re not going to be able to get all the cells, but it still might help. 

But the big problem with it is it costs like a million dollars to treat one patient once. And even though it’s great proof of concept, it’s not gonna be something that is gonna be readily available to everybody and so it’s not my priority. But I do have clinical studies designed, protocols designed, and you’re involved in some of them actually, to treat Alzheimer’s, that’s our main one to treat cardiomyopathy, critical limb ischemia, demyelinating disorders, idiopathic pulmonary fibrosis, which is actually something you promoted that we focus on and many other diseases. 

I mean the list is mind-boggling. But these things are super expensive and it’s, like I am in contact with the FDA and stuff, I’m forgetting the guy’s name, there’s a guy at the FDA, I want to say Don Fink but I don’t think it’s him, that he’s very on board, but the big problem with aging, and I agree with the FDA totally on this, is that you can’t measure it. And even though people are constantly saying they have markers of aging, they really aren’t markers of aging, they’re just markers of the markers.

Joseph M. Raffaele, M.D.

Well yeah, I mean, there’s the TAME trial that they’re looking at right now, and that’s sort of not aging per se, it’s multi-morbidity markers, clusters of diseases and when they have onset. But I guess the DNA methylation clocks are kind of interesting as markers and there’s a lot of buzz about them. It is an area I actually did want to talk to you about which is for a long time measuring telomeres was sort of a biomarker that you looked at. And I’ve been measuring telomeres in my practice for 15 years now. The R-square with aging, with chronological age isn’t that great, but then along came these clocks that were R-squared with chronological age is like .95, .98. 

Then, there was the TRIIM trial that was published with where they looked at growth hormone, DHEA and Metformin, very small, but because Steve Horvath’s clock was used and he saw like a two year of aging, would you expect someone who was treated with, let’s say Ron DePinho’s mice, I mean, it would’ve been interesting if they’d used Horvath clock on DePinho’s mice, and I wish somebody would do that experiment, it wouldn’t be that expensive to do, where that would validate that as a marker if you saw a real significant reversal of DNA methylation. ‘Cause you see that when you do the Yamanaka factors, the epigenetic clocks get reversed as well. Would you say that that’s, of course being a clinician, I’d be like, the lungs got to work better, the muscles got to work better, the brain’s got to work better too, but as a short-term marker, would you accept that?

William Andrews, PhD

Yeah no, I actually, I openly say that I think DNA methylation on DNA is a better marker of aging than telomere length measurement, only because telomere length measurements are very difficult to do. I believe that telomeres, telomere lengths are probably controlling the methylation. And one of the studies that I would love to do, and some people have already done some studies that really suggests this is true, at least in vitro, in human cells in a Petri dish, let telomeres shorten and relengthen ’em, let ’em shorten and relengthen ’em and see if that corresponds with a changing back and forth of the methylation pattern.

Joseph M. Raffaele, M.D.

I bet you it will, yeah.

William Andrews, PhD

What might even be better than DNA methylation is the glycosylation.

Joseph M. Raffaele, M.D.

Gordon Lao’s stuff.

William Andrews, PhD

What did you call it?

Joseph M. Raffaele, M.D.

Oh you’re talking about glycosylation, you’re talking about the glycome or are you talking about hemoglobin A1c glycosylation?

William Andrews, PhD

I’m forgetting the name of the guy, Gordon Laos.

Joseph M. Raffaele, M.D.

Gordon Laos.

William Andrews, PhD

Yeah, I think he’s brilliant. I think he’s what he’s gotten onto is amazing. I think again though, I think that that’s probably controlled by telomeres.

Joseph M. Raffaele, M.D.

Oh that’s interesting. Have you talked to Gordon about that?

William Andrews, PhD

Oh yeah, yeah. Gordon and I have become good friends ever since I first heard him talk and was just impressed ’cause what I look at is how good are people at doing critical meta-analysis of scientific peer-reviewed studies and building theories out of that. And Gordon is just amazing at that and so are a lot of other people. And I kind of like to work with them, that’s one of the reasons I like to work with you too. So getting all this stuff put together is I think putting a model together, and a lot of these people agree with the idea that telomeres are probably controlling the methylation and glycosylation and things, but the markers for aging, like glycosylation, glycosylation might be a better marker for aging than methylation, I can’t really say yet. But I know that telomere length measurement is so difficult to do so many people do it incorrectly. There is at least one company that I recommend people go to.

Joseph M. Raffaele, M.D.

You can say the company.

William Andrews, PhD

It’s a Life Length. Definitely, if you’re gonna get your telomere length measured I think Life Length is really the only place you should be going.

Joseph M. Raffaele, M.D.

Not Repeat Diagnostics?

William Andrews, PhD

Repeat Diagnostics would be okay except that they don’t really measure the percent of telomeres that are short.

Joseph M. Raffaele, M.D.

Yeah, I mean that is a differentiation between the companies, but my question about the percent short telomeres is when we first did that study with, the precursor to Life Length and Maria Blasco’s lab and we measured the percent, it was the bottom three percent or something like that or three kilobases and below. They’re reporting out 20% percentile. And when we did, remember we did the telomere workshop at A4M and we had that cohort of people? The 20th percentile had almost like a R-squared of .7 correlation with the median. So I wasn’t getting the same information, it wasn’t extra information.

William Andrews, PhD

I don’t know why they switched to the 20% or just doing I thought it was two and a half kilobase pairs that they were going, but maybe it was three kilobase pairs.

Joseph M. Raffaele, M.D.

It was much shorter. 20th percentile just doesn’t add that much information. That’s my concern about it. I know that the theory, and you’ve talked about it before, is that it’s the critically short telomere that causes the problem, but I don’t know that we’re getting that measurement. That’s my only issue.

William Andrews, PhD

I think measuring the critically short telomere gives a better correlation with aging and disease than the average. But I think it’s only because the average is so hard to measure. So the percent of critically short telomeres correlates with the average, but it’s easier to measure the percentage of the short telomeres. Now I’m not exactly certain why Repeat Diagnostics doesn’t measure or doesn’t report to percent of tumors that are short, but they’re actually looking at whole cells. So they’re looking at the average telomere length per cell as the cell goes through their flow cytometer where as Life Length has the ability to look at each telomere individually and measure it. But I’ve noticed lately, they’re actually look, they’re reporting actually average cells too. So I think technologies need to be improved even more. 

We actually have two protocols here that we’re trying to develop right now that look at not just percent of short telomeres, but look at each individual telomeres and also identify which chromosome it’s on. And we also, essentially doing high throughput sequencing of telomeres, long range sequencing of telomeres. ‘Cause nobody’s really looked at this, but actually one paper right now has come out on this, we don’t know that telomeres are all TTA-GGG all the way through. 

There are probably regions that might be different and they might be correlated with disease. And so it’d be good to start finding out. So I think the ultimate would be when we can actually get technique, and we’re working on this right now even though it’s gonna be unaffordable as a personalized medicine kind of thing, it’ll be great for research, we’re working on trying to make it so that we can sequence every telomere and know what the whole sequence is, what chromosome it came from, what its length is, and then be able to correlate it with all kinds of diseases in very computer intensive algorithms that compare diseases. 

That’s gonna give us a lot of information. Again, funding is the issue. We’ve been trying to raise funding to do this for quite some time. And even the long range sequencers are more expensive than people want to invest in. I do believe that telomere length measurement can be the best thing in the future, but right now I’m thinking DNA methylation and glycosylation are probably the best place to go. And believe me, Repeat Diagnostics is a very, very good company. I definitely believe in their company. I just don’t, I wish they would provide the percent of the short telomeres. I think that information would be very valuable if it’s presented correctly. And that’s why I, I’m not certain that, it might be a cost thing, it might be in order to make it affordable, Life Length has to go with different methods, otherwise they won’t get any clients to get their telomeres measured.

Joseph M. Raffaele, M.D.

I think the main reason probably is with them is that they’re more focused on the telomere biology disorders and bone marrow transplant stuff where they’re looking just at really short telomeres, people with telomeres in the bottom one percentile, under five, under 4KB, so the percent shortage doesn’t really make a difference. It’s do you have a telomere biology disorder or not? And the mean telomere length that they report out is pretty good for that, they have good percentiles on that. I send lots of samples to them, other doctors do, but I think their focus is on that. 

I mean I was thinking about asking Geraldine Ober to come on and talk about it, but I’m not sure they’re that interested in it. That’s my thinking about it. So I wanted to shift gears just a little bit. We were talking about telomere length and telomerase, but there are other, these other sort of, and I want to get your take on it, these non-canonical activities of telomerase, in the mitochondria, you talk about it shuttling into the mitochondria and the beneficial effects that it has. What’s your take on the importance of that role of telomerase?

William Andrews, PhD

Personally, I haven’t seen any studies that really convinced me that that’s for real. It’s something that I want to take on when we get more funding is I want to look at that more critically, but it’s almost like irrelevant as long as long as our cells aren’t producing any telomerase to begin with.

Joseph M. Raffaele, M.D.

Well I mean that’s a very good point there. So I’m just thinking back to the study out of DePinho’s lab that I think Sahin did where he showed that there was increased mitochondrial biogenesis through the PGC-1 alpha and beta and that’s, is that through telomerase tracking into it?

William Andrews, PhD

No, that was probably due to changes in gene expression on the main chromosomes that were affected ’cause remember most of the proteins in the mitochondria are encoded by the chromosomes, not the mitochondrial DNA. And so that was probably an effect of gene expression on the main chromosomes, which was causing energy levels. I can’t remember the name of the genes right now. I remember they had the letter E in it. I can’t remember the details of those, but yeah, I think that telomere length does have a big effect on mitochondria health. That data that I’m not convinced about is that telomerase, if it does get inside mitochondria, is it actually doing something there, is it just completely irrelevant?

Joseph M. Raffaele, M.D.

What would it be doing?

William Andrews, PhD

There’s no end. Mitochondria DNA’s circular. The question is does telomerase have other activities besides lengthening telomeres? And that I haven’t seen any convincing data of. And from an evolutionary perspective, there’s a lot of reasons to suspect, there’s a lot of things that happen in the cell just because why not? It doesn’t do anything. There’s nothing to cause it to be there, nothing to cause it not to be there, it just is there and it is completely irrelevant. So a lot of these things haven’t been addressed really, as far as the why does it look like telomerase actually gets inside of the mitochondria? And I would think there’d be a lot more studies out now if that was actually reproducible by a lot of labs. But I can’t say that the data that is published right now is wrong until, I’d like to get my hands on that myself and look at that.

Joseph M. Raffaele, M.D.

And the mechanism through which telomere shortening changes gene expression, is that through that, what’s the term that they use? Telomere gene expression change at a distance, I forget what it’s called, I’m blanking on it right now.

William Andrews, PhD

Cancer sequences or?

Joseph M. Raffaele, M.D.

No, it has to do with the way, when the t-loop gets smaller, it changes the way in which it touches the DNA, like 10 megabases proximal to the telomere. And so just even a small amount of shortening can change gene expression and that’s why it’s, I’ve always thought that the theory of it’s not only important not to have critically short telomeres, but to have exactly the right telomeres that you started out with. If that mechanism is affecting gene expression even with a small change in telomere length, then is it important to maintain your telomeres at a certain level? Not so much as like, like you can let them go down to as long as they don’t get below a certain length. But we know the aging process starts, you start seeing aspects of it in the mid 20’s, late 20’s. So is it, you talk about gene expression, DNA methylation sort of picking up the changes in aging and that’s somehow controlled by telomere length. Is it through that way in which the slight change in telomere length changes gene expression?

William Andrews, PhD

Well, a lot of what you just said sounded like the theories I’ve proposed, okay, which haven’t been generally accepted by a lot of people.

Joseph M. Raffaele, M.D.

I’ve read some papers. I can’t cite them right now, but I have some read some papers where they do talk about that and showed some data.

William Andrews, PhD

Woody Wright and Jerry Shay did publish some papers showing that they could affect gene expression and if they shortened and lengthened the telomeres that gene went up and down and there was a position effect.

Joseph M. Raffaele, M.D.

Yeah the telomere position effect, that’s what it is.

William Andrews, PhD

TPE, yeah. I definitely believe in TPE, telomere position effect. But I think of the telomere as like a magic wand. Like I remember when I was in the early ’70s studying molecular biology for the first time in a textbook written by Bruce Alberts, where he talked about, he gave a really good explanation with a lot of papers explaining why genes can be regulated by other elements that are a long ways away, these enhancer sequences that can be 100,000 bases away, but still affect the gene expression of that gene that’s 100,000 bases upstream of it. And the DNA folds over and transcription factors bind to the enhancer and bind to the promoter and then these things come together and turn the gene on. So I think of the telomere, and the telomere actually does have a lot of similarity to transcription factor sites. And TRF-I and TRF-II which bind telomeres do have a lot of similarity to transcription factors.

Joseph M. Raffaele, M.D.

Oh really?

William Andrews, PhD

I think the telomeres are actually working like enhancer sequences and that they fold over and essentially touch genes turning them on and turning off just like a magic wand. But the shorter the telomere gets, the less likely it is to reach the genes that are further away.

Joseph M. Raffaele, M.D.

And it might change gene expression in some other genes that you don’t necessarily, is not in the salubrious direction potentially.

William Andrews, PhD

Right, indirectly yeah, those genes, one thing that I noticed is that a lot of like zinc finger transcription factors, their genes are located near the telomeres. So the telomeres are folding over touching these genes, turning them on and off, these are going over activating or repressing other genes. So there is a theory that I propose a lot. I’ve got some hypotheses to do testing and things like that, but again, it’s when can we do it, how do we do it, things like that, it’s funding and priorities. But I do believe that the length of the telomere is affecting gene expression and really the only paper so far is Woody Wright and Jerry Shay’s paper, which was really good, showing that they could lengthen this telomere position effect. 

The gene was DUX, d-u-x, the DUX gene where they show that they could control its expression just by changing the length of the telomeres or its position relative to the telomeres. And I believe a lot of genes are regulated like that, we just don’t know yet. But you know, people seem to forget about Bruce Alberts textbooks back then, which showed that this phenomenon already exists, there’s a precedence for it. Why wouldn’t telomeres be doing this? People want to envision some type of chromosomes or chromatin molecules, histones moving along the chromosomes regulating things, and there’s no precedence for that really. There is precedence for histones moving along chromosomes, but not long distances that are needed to actually have an effect on gene expression. So who knows? It’s all still research.

But what I really like about telomere biology is there’s so many good theories that explain everything about everything. And I say it’s the only theory of aging that can do that. You can’t say that some of the other things, like like methylation is affecting telomere length, but you can say to telomere length is affecting methylation. And so telomeres, I compare this to searching for the source of the Nile a lot, I call it searching for the source of aging. What is the ultimate source of it? Is like methylation a symptom of aging or is it a cause of aging? I call it both. I call it a symptom and cause. But I think telomeres could be the cause of aging and other things are symptoms and then indirect causes.

Joseph M. Raffaele, M.D.

So it’s the most upstream you believe of them. But I mean, actually just getting back to the methylation, potentially methylation around the telomerase gene could affect telomere length, so it could work both ways potentially.

William Andrews, PhD

Cancers, yes.

Joseph M. Raffaele, M.D.

Yeah. So I think that’s the whole idea behind a sea change in approach to Alzheimer’s disease is in focusing on the glial cells and their caretaker role and their role in keeping the neurons healthy so that they don’t start producing a lot of beta-amyloid rather than focusing on removing beta-amyloid. And when you’re talking about curing aging, I mean I think there’s a difference between curing aging when I think about it, which is someone’s old, like an old DePinho mouse, and then fixing them, as opposed to preventing aging, where you keep them in the healthy state and the aging process just doesn’t happen. For me, it seems like it would be easier to do that with Alzheimer’s than, prevent it than to cure it, particularly if you’re able to keep those cells doing their job indefinitely, then, and I think that’s, I guess where we should start looking earlier on.

William Andrews, PhD

But to get a clinical study to use telomerase to prevent Alzheimer’s is gonna be next to impossible relative to doing a clinical study to actually treat Alzheimer’s.

Joseph M. Raffaele, M.D.

Well so that’s where the biomarkers, the models, the fMRI and some of the new techniques that they have, I was talking to Tom Dowd about looking at the retinal epithelial cells and how they can be a signal for early changes that could precede Alzheimer’s disease and getting validated biomarkers that yeah, in order to fully validate it, then you’d have to follow those biomarkers for a long time, but it’s probably worth taking a flyer on it potentially and then it may work in slowing down Alzheimer’s in early Alzheimer’s as well, potentially. 

So you might be able to do it that way. And that’s where the TAME trial is probably important ’cause it’s gonna start to focus on looking at the aging process and hopefully when it finally gets underway, COVID put the kibosh on that too, they’ll then start to think about things differently. I mean, it’s all about the biomarkers. I mean, that’s what I’ve always been involved in because no one’s gonna make a career waiting for 25 years to see if you prevent a disease.

William Andrews, PhD

And that’s one of the reasons why I want to focus on reversing the disease because you can see reversal of the disease a lot faster than you can see the prevention of disease.

Joseph M. Raffaele, M.D.

Absolutely true.

William Andrews, PhD

But it’s like when I was talking about getting, it’s hard to get a clinical study for those, I’m talking about getting approval from the FDA to treat somebody with something like a telomerase inducer, ’cause the fear is of it causing cancer and stuff like that. Now, some of the other things like the TAME study and things like that with Metformin and things, those are different, those things have already shown, people aren’t really saying these are gonna cause potential health problems. So getting a study there I think is a good idea and I strongly support ’em and encourage ’em. I take my Metformin everyday and I’ve been taking it for 10 years because I believe that it’s something, but I don’t believe it’s the end-all. I think the end-all’s gonna be lengthening telomeres.

Joseph M. Raffaele, M.D.

Yeah. So, I mean look, it’s been fantastic talking to you. I mean is there any kind of parting thoughts you’d like to leave? I mean, I think about the future of telomere biology and, and aging or just yourself?

William Andrews, PhD

I mean I can’t think of anything. There’s so much that I could talk about. If we had another hour, I’d love to talk about like what is aging, what causes aging, why do we age? My background in evolution gives me a unique perspective on that. But it’s a long, there’s YouTube videos where I spend a lot of time talking about those kinds of things, but it’s really, it really doesn’t help us come up with the cure for aging by looking at those things. And so my focus is on trying to come up with something that’s gonna kind of cure aging, and again, semantics, my definition of cure aging means preventing Alzheimer’s, things like that. So cure aging has just become a coin phrase for my company. And in fact, my father, those are the words my father said to me when I was 10 years old when he said, why don’t you grow up and become a doctor and find a cure for aging.

Joseph M. Raffaele, M.D.

I read that on Wikipedia and I was like, did that really happen or is that just a great story?

William Andrews, PhD

That’s true, I’ll never forget. I remember where I was, what I was doing. I was obsessed with science and medicine and I wanted a telescope for Christmas and my parents got me a really crappy telescope and I cried about it. They went out and bought me a nice eight inch reflector telescope from a garage sale. And that night I was out on the front lawn of our house, finding craters in the moon, moons of Saturn, rings of Saturn, moons of Jupiter, things like that. And my father just came out and said to me, “Bill, since you’re so interested in science and medicine, when you grow up, you should become a doctor and find a cure for aging.” And he was serious about this. And then he said, “I don’t know why nobody’s done this yet.” 

My father wasn’t a scientist, he just did not like the whole idea that he was aging. He thought maybe his son because his son was so obsessed with science and medicine, his son would be the person that’s gonna come up with the solution. So I got hooked on it. All through schools, even in elementary school, junior high school, everything like that, people would get sick of me talking about curing aging. In high school or college, I did experiments with fruit flies in the early 1970s to try to cure aging. 

I wish I knew Mike Rose at the time because, oh and we should’ve mentioned Mike Fossel, ’cause we were talking about Alzheimer’s, Mike Fossel and his company Telocyte has got a program underway to try to use telomerase induction to treat Alzheimer’s. And I just want to mention it just to help him get support to get this thing underway. But Mike Rose, I ended up meeting Mike Rose in early 1960s. In fact, Mike Rose and I started a company together called Methuselah Research, MRX. And it was like the next day I learned about telomeres. So I walked away from the company and brought my father in, and my father took over as the president. My father and I were like best friends because we were both so obsessed with aging, my entire life, this is what we talked about all the time. So when Mike Rose and I and Harvey Sabor started this company called MRX and I suddenly wanted to go work on telomeres instead, I brought my father in and he became the president and worked with Mike Rose and Harvey Sabor and made some significant progress, but again, funding was always the issue. 

But Mike’s what the plan was to apply everything ’cause Mike was leading, and still is leading expert in the world on extending lifespan in fruit flies, even though I’d worked on it before, I did nothing like, in fact, he probably worked on it before I did, I just didn’t know he was doing work on it. But the work I did was nothing compared to the work that Mike Rose did. And when I met and talked with Mike Rose, we talked about let’s apply everything Mike Rose had learned in fruit flies, let’s apply that to mice, with Harvey Sabor, who was working on mice colonies. And that was the whole focus of MRX.

Joseph M. Raffaele, M.D.

But you were gonna do that, just breed older mice and see if you could have the same longevity effect? He had a very significant effect, but it was-

William Andrews, PhD

It was a lot of work. It was a lot of work, but it was a lot more work than fruit flies, but all it needed was a bunch of money in a big warehouse where you could have lots of mice and breeding and stuff like that. And then, when you got longer living mice, then find out what changed, what genes were selected for? That was the whole plan.

Joseph M. Raffaele, M.D.

Somebody should still do that, right, exactly.

William Andrews, PhD

But the funding, somebody’s gotta-

Joseph M. Raffaele, M.D.

I think there’s been a sea change just in the last couple years in interest in funding aging. And then just recently with Bezos $270 million creation of that company paying the scientists a million dollars a year. So I think it’s gonna happen.

William Andrews, PhD

All over the news raving about the greatest salaries they have now. Well, that’s not the issue. Curing aging is supposed to be the important things. Now I’m concerned about the Yamanaka factor. We’ve been working a lot with the Yamanaka factors and I collaborate a lot with-

Joseph M. Raffaele, M.D.

Michael West.

William Andrews, PhD

And he and I, we’ve done a lot of work together on Yamanaka factors, published and things like that. The Yamanaka factors are really a dedifferentiating technique, not a rejuvenation technique. And I compare it to like does turning a butterfly back into a caterpillar make it younger or does turning a frog back into a tadpole, does that make it younger? It just dedifferentiated it, it didn’t make it younger. And I’m afraid that that’s what’s gonna happen with the Yamanaka factors. And I’m concerned that these billionaires might’ve been misled into thinking that this is gonna actually be a cure for aging, and maybe it will be, okay. I mean it’s like let’s get it tested. But I’m just feeling that I hope the investors know that this is really a discovery research, not an actual application to try to get it done. But again, I can’t even say that ’cause it might just work.

Joseph M. Raffaele, M.D.

What happens to telomere length? Does it get reset with Yamanaka factors?

William Andrews, PhD

No, when the Yamanaka factors get induced, when you with four Yamanaka factors, telomerase gets turned on and telomeres get longer. We’ve done a lot of research here, and we’ve presented posters and stuff like that, trying different combinations, like one Yamanaka factor, two, all different combinations. So what is it, four different factorial different ways of treating things and trying to find some combination that turned on telomerase without dedifferentiating.

Joseph M. Raffaele, M.D.

Right that would be-

William Andrews, PhD

And it never happened. The only time we could get telomerase induced was when all four Yamanaka factors were added. And it’s like this partial reprogramming, this whole idea of partial reprogramming. I don’t know if that’s gonna really do anything ’cause it’s still gonna cause dedifferentiating. It’s gonna cause telomerase to get induced and make telomeres get longer, but it’s, we got to figure out a way to turn on telomerase without dedifferentiating our cells, except we want to do differentiate senescent cells into non-senescent cells and that’s the only thing we want to do. And that’s been successfully done by Jerry, again, I mentioned their names a lot, Jerry Shay and Woody Wright. They’ve done experiments where in vitro they’ve been able to turn senescent cells into non-senescent cells just by lengthening the telomeres. But it’s again, we could talk for hours if you wanted to.

Joseph M. Raffaele, M.D.

Well, we may have you back for a redux if possible. We could talk about aging, per say, ’cause I think you do have to really understand why aging occurs to buy into why it would make things a lot better if you can stop aging. Some people are like, well, that’s not really gonna do it and that doesn’t make that much sense. And so if you really understand the biology behind why aging comes, and there’s a pretty good I think consensus on that in gerontology communities, then I think it makes looking at diseases of aging differently.

William Andrews, PhD

Nobody knows, nobody knows what causes aging, nobody knows why we age. They’re all theories.

Joseph M. Raffaele, M.D.

Right, well yeah, but I mean there is some consensus on the idea that it comes in through the back door. I mean there are some people that still think that it might be actually programmed. I forget which camp you’re in, but many people think that it’s a trade-off of resources versus the environment. So why are there species with negative negligible senescence? Because they don’t have a lot of predators, the field mouse is gonna get eaten so there’s no reason to invest in keeping his body in good shape. That kind of stuff is pretty well agreed upon I think. The molecular mechanisms of it are less so.

William Andrews, PhD

Everything you’re saying is making me hope that you invited me back so we can have a discussion on it. All right, good.

Joseph M. Raffaele, M.D.

We’ll have that discussion. Yeah, I’ll have you back. Very good. Well, it’s been a pleasure Bill and we’ll talk soon.