18 replies to this topic

[Mind]

It has been 11 years since the LongeCity Now podcast last hosted Dr. Bill Andrews of Sierra Sciences, one of the leading proponents of the telomere theory of (primary) aging.

 

Here is the previous podcast: http://www.longecity...ndrews_2013.mp3

 

Sierra Sciences Website.

 

Some things I was wondering about.

 

What is the state of telomere research within and outside of Sierra Sciences?

 

What is holding back progress? (probably funding)

 

What is the status of the drug momelotinib?

 

Please post any questions you have for Dr. Bill Andrews. The podcast will occur within the next 1 to 2 weeks.

[QuestforLife]

Why has the telomere theory of ageing fallen out of fashion? 

 

You’ve had a long career Dr Andrews, are you still as enthused as ever about finding powerful telomerase activators to extend human health and life span, or are you looking to retire and hand the reins to someone else?

 

You have a robotic assay for detecting telomerase gene activation; how much does it cost to assay a single chemical and how long does it take? 

 

Do you think CRISPR might be a viable strategy for reactivating the human telomerase gene?

 

You are very fit and healthy, but if your health started to deteriorate, would you risk telomerase gene therapy?

 

[Mind]

I apologize for not getting the very good questions - above - into the interview. I forgot to check back here.

 

Otherwise, the interview was good and has a lot of information that touches on some of the points raised above.

 

In the first few minutes we discuss why the development of telomere therapy has been slow. In the middle there is discussion of telomere lengthening products and biomarker testing. In the last few minutes BIll talks about other mechanisms of aging and what he does to stay so young-looking and healthy.

 

https://www.longecit...aim_andrews.mp3

Edited by Mind, 21 November 2024 - 04:52 PM.

[QuestforLife]

Really great interview, thanks!

[Mind]

Bill highlights a potential problem with current biomarker testing which an interesting concern. I think the best way to counter the problem of bias is to do a variety of tests from different companies.

[QuestforLife]

I also think that telomere tests (in particular) are quite limited. So even if you think telomeres are fundamental to ageing (I do), telomere testing is still of limited usefulness. Lifelength are the best, as they measure a lot of telomeres, so you can get a median, mean and length of the 20% (short telomeres). But someone should fund Bill to develop one of his alternatives for measuring telomeres. That would offer a relative quick turnaround on the investment.

[Castiel]

Bill said he tested resveratrol, iirc.  But resveratrol lengthens telomers indirectly through sirt4, not by activating telomerase itself, afaik.  And it doesn't even do this if not in the presence of certain amino acids, think it was tryptophan or leucine.   Though could be mistaken one of the aminos is associated with turkeys.  It also needs nad+.  So you need resveratrol+aminos+nad+ to see telomere lengthening.

 

It could easily fail any screening if it is testing just for direct activation of telomerase, or fails to include the complementary molecules.

 

There is a research paper showing doubling of telomere length, iirc, and also not just that but cells went from near senescent decayed in appearance to youthful looking cells in the microscope.   It was in vitro, and it was after more than 24 hour of exposure to resveratrol.

 

It is conceivable pterostilbene might do similar, but may also have similar dependence on aminos and nad+ given structural similarity.

 

It would be interesting to see if this can be replicated in vivo.  Missed there was going to be an interview this time, but would be nice to get a comment from Bill Andrews on this research.

 

The following is the paper I'm referencing.

Eva Latorre, Vishal C. Birar, Angela N. Sheerin, J. Charles C. Jeynes, Amy Hooper, Helen R. Dawe, David Melzer, Lynne S. Cox, Richard G. A. Faragher, Elizabeth L. Ostler, Lorna W. Harries. Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biology, 2017; 18

Edited by Castiel, 23 November 2024 - 11:24 AM.

[QuestforLife]

The whole SIRT4 telomerase link has never been replicated. It was a single paper from 2015.

 

Latest work indicates that SIRT1 increases telomerase localisation to the nucleus so likely there is some important link between sirtuins and telomeres/telomerase. But not necessarily anything to do with increasing telomerase itself.

 

Regarding the splicing factor work, I do remember that they made lots of resveratrol-like molecules and showed the telomere extending effect was nothing to do with sirtuins. 

Splicing factors are able to change the form of the protein into a more active one. This is probably highly significant for life extension; I have commented elsewhere on how you can do this to P53 to express telomerase and how this might be better than the current gene therapy approaches.

[QuestforLife]

Bill is only interested in expression of the telomerase gene RNA, because without that there can be no telomerase. 

 

A lot of papers claim things like 40% increase in telomerase protein, or telomerase activity, but this % is an increase on near 0 activity, so is highly inaccurate. I think Bill has the right idea. But I also still think there may be other ways to make a small amount of telomerase more efficient at doing its job in the nucleus. 

[Castiel]

Bill is only interested in expression of the telomerase gene RNA, because without that there can be no telomerase. 

 

A lot of papers claim things like 40% increase in telomerase protein, or telomerase activity, but this % is an increase on near 0 activity, so is highly inaccurate. I think Bill has the right idea. But I also still think there may be other ways to make a small amount of telomerase more efficient at doing its job in the nucleus. 

 

Either by splicing factors, or sirtuins.  Whatever the mechanism, the splicing factor paper showed iirc vast increase of telomere length to near youthful level or something to that effect in human cells in vitro.  It reversed aged phenotype and restored youthful phenotype in human cells.

"c Telomere length was quantified by qPCR relative to the 36B4 endogenous control and normalised to telomere length in vehicle-only controls, younger passage cells (PD25) and in cells treated with compounds 1–6."

 

This hasn't been replicated in vivo.  And might be difficult, given 24+h exposure to resveratrol, might not be easy to replicate in vivo given liver quickly gets rid of resveratrol.

[QuestforLife]

Bill sometimes tests compounds he doesn't even know what they are, if that's what he's paid to do - I'm pretty sure I read one of the patent applications years ago for a nutraceutical mix Bill tested and there was some small effect on telomerase from resveratrol.

The point is splicing factors- or whatever - lengthen telomeres by activating telomerase, so should show up in Bill's assay. The only thing that wouldn't, would be if the telomeres were lengthened by ALT methods, like some cancer cells do.

Edited by QuestforLife, 25 November 2024 - 06:08 PM.

[Castiel]

Bill sometimes tests compounds he doesn't even know what they are, if that's what he's paid to do - I'm pretty sure I read one of the patent applications years ago for a nutraceutical mix Bill tested and there was some small effect on telomerase from resveratrol.

The point is splicing factors- or whatever - lengthen telomeres by activating telomerase, so should show up in Bill's assay. The only thing that wouldn't, would be if the telomeres were lengthened by ALT methods, like some cancer cells do.

 

but there are questions for example of time.  This splicing factor had 24+Hour exposure, iirc.  It is possible some compounds can take some time to do their thing, especially the more indirect their method of action is.  Also at least for sirtuins resveratrol requires presence of certain aminos to activate these, also needs nad+.  It is unknown if its effects on splicing factors is through sirtuins.

Edited by Castiel, 25 November 2024 - 06:22 PM.

[QuestforLife]

but there are questions for example of time.  This splicing factor had 24+Hour exposure, iirc.  It is possible some compounds can take some time to do their thing, especially the more indirect their method of action is.  Also at least for sirtuins resveratrol requires presence of certain aminos to activate these, also needs nad+.  It is unknown if its effects on splicing factors is through sirtuins.

 

Well I'd assume any assay would test different concentrations of compounds. Of course there are subtleties: I think in the splicing paper they grew the cell cultures to replicative  senescence first, which might respond differently to healthy cell cultures. But now it is a different argument over which is the most representative system. And certainly maintaining 5uM of resveratrol for 24 hours in a senescent cell culture is not something that is ever going to happen in the body.

 

Perhaps Lorna Harries company has come up with something better since, though if they have, they are keeping it a secret. 

 

https://www.senisca.com/

[Mind]

Bill said he tested resveratrol, iirc.  But resveratrol lengthens telomers indirectly through sirt4, not by activating telomerase itself, afaik.  And it doesn't even do this if not in the presence of certain amino acids, think it was tryptophan or leucine.   Though could be mistaken one of the aminos is associated with turkeys.  It also needs nad+.  So you need resveratrol+aminos+nad+ to see telomere lengthening.

 

It could easily fail any screening if it is testing just for direct activation of telomerase, or fails to include the complementary molecules.

 

There is a research paper showing doubling of telomere length, iirc, and also not just that but cells went from near senescent decayed in appearance to youthful looking cells in the microscope.   It was in vitro, and it was after more than 24 hour of exposure to resveratrol.

 

It is conceivable pterostilbene might do similar, but may also have similar dependence on aminos and nad+ given structural similarity.

 

It would be interesting to see if this can be replicated in vivo.  Missed there was going to be an interview this time, but would be nice to get a comment from Bill Andrews on this research.

 

The following is the paper I'm referencing.

Eva Latorre, Vishal C. Birar, Angela N. Sheerin, J. Charles C. Jeynes, Amy Hooper, Helen R. Dawe, David Melzer, Lynne S. Cox, Richard G. A. Faragher, Elizabeth L. Ostler, Lorna W. Harries. Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biology, 2017; 18

 

Bill's Response

 

We were unable to reproduce the telomere lengthening data with Resveratrol. We have tested Resveratrol 1000’s of times in the last 15+ years. That’s because we actually always use Resveratrol, as a toxicity control in all our screening, along with ginger and ginseng. Any chemicals that are as toxic as Resveratrol, ginger, and ginseng are discarded. The study referred to in the comments DID NOT look at telomerase activity. Why not??? It usually tells me that they tested for telomerase activity  and saw none. So why did the telomeres appear to get longer??? It could be that Reseveratrol killed the cells with short telomeres. There is no way to tell with so little details provided. Bottomline, the lab is not a telomere lab and many explanations could exist as to why they got unusual data.  Plus, we have never gotten the same results even though we have tested it on multiple cell lines. 

 

Why has the telomere theory of ageing fallen out of fashion? 

 

You’ve had a long career Dr Andrews, are you still as enthused as ever about finding powerful telomerase activators to extend human health and life span, or are you looking to retire and hand the reins to someone else?

 

You have a robotic assay for detecting telomerase gene activation; how much does it cost to assay a single chemical and how long does it take? 

 

Do you think CRISPR might be a viable strategy for reactivating the human telomerase gene?

 

You are very fit and healthy, but if your health started to deteriorate, would you risk telomerase gene therapy?

 

Bill's Responses

 

Not sure what "telomere theory of ageing fallen out of fashion” means. It’s just becoming more and more undisputed. I’ve invested a lot of time speaking at key conferences clearing up the confusion promoted by hearsay. Every lab working with human cells knows that every normal (non-cancer or non-primordial germ cell) human cell line they work with has a Hayflick limit. And the only way to overcome the Hayflick limit is to lengthen telomeres with telomerase. That’s a fact, not a theory.

No matter what else we do to cure aging, human lifespan and health span can never exceed 125 years without solving the telomere shortening problem. And none of us ever get close to 125 because of poor lifestyle choices and poor genetics that accelerate the rate of telomere shortening. Again, that's a fact, not a theory because of the Hayflick Limit. 

The progress to find ways to “really” reverse telomere shortening are stalled due to insufficient funding. Also, false claims regarding some products claiming to reverse telomere shortening are causing disillusionment because no one is passing the Betty White Test (see the first 4 minutes of https://youtu.be/tiLCZFYxiB8).

Retire???? My motto is “Cure Aging or Die Trying”.

It costs us about $5,000 to test one microtiter plate of chemicals, peptides, or nutraceuticals. And that is not including the price of obtaining the chemical, peptide, or nutraceutical being tested. One microtiter plate will hold 20 samples at most considering that we test everything in quadruplicate and have controls. So, if someone asks us to test one sample it costs us $5,000/sample. If someone asks us to test 20 samples it costs us $250/sample. We spend $1-2 million per month to test samples. 

CRISPr would be great if anyone could figure out a way to deliver the CRISPr machinery to all (or most) of the cells. Believe me, we have been working on that since the 1980’s with CRISPr’s predecessor, and equal, Zinc Fingers. 

I’ve been part of too many “First in Human” clinical studies, to know that there are always unexpected results, that get fixed later, to risk telomerase gene therapy if my only problem was deterioration of my fitness and health. But if I was told that I had 6 months to live because of an aging related disease I would be first in line for telomerase gene therapy at doses that we have determined to be efficacious, in vitro, at Sierra Sciences. There’s no point in doing a dose considered to be safe if it is unlikely to be efficacious. But I believe I that I know how to make even high doses safe. I just need funding to do the pre-clinical and clinical studies to test my ideas for making it safe. By the way, I would do my pre-clinical studies with Pygmy Marmosets, not mice.  I just need funding.

 

 

[QuestforLife]

Thanks Mind, some very interesting answers. Just shows that if you speak with a bench scientist who knows his stuff, a lot of myths that would otherwise be argued over for years, can be quickly cleared up. 

 

And very glad Bill is not retiring!

[dlewis1453]

Very interesting Mind, thanks for sharing Bill's responses! It is frustrating to see money being wasted on pointless endeavors when a relatively small investment in an expert scientist like Bill could lead to big breakthroughs. 

[Castiel]

Thanks mind! I was wondering but this can wait for some far off future contact, no immediate reply needed, has Bill heard of the cancer immune mice?

https://www.huffpost...nt-di_b_5472369

This might explain how all ageless animals do not die of cancer despite active telomerase and live for centuries without dying of cancer.

 

Since cancer immunity is conferrable through cell therapy, I suspect, there is a possibility that if a mouse was somehow made to activate telomerase and was also cancer immune it might break longevity records.   Could potentially win the methuselah mouse price.

[Castiel]

Also regards the telomerase resveratrol paper, iirc, I think I heard one of the authors say in a video that cells with too much genetic damage remain senescent and do not rejuvenate upon telomere lengthening.   It seems that only cells with reasonable levels of dna damage rejuvenate.   If I'm recalling correctly that suggests that resveratrol did lengthen telomeres.

 

will review the video, but I believe this is the video talking about the paper where the author mentions that cells with too much damage do not rejuvenate despite long telomeres, only cells with moderate or little damage rejuvenate.

 

edit

going over the video which i'd forgotten about, the author says they spent a lot of time making sure the resveratrol and similar molecules were not acting as senolytics killing cells

Edited by Castiel, 07 December 2024 - 05:43 AM.

[QuestforLife]

We were unable to reproduce the telomere lengthening data with Resveratrol. We have tested Resveratrol 1000’s of times in the last 15+ years. That’s because we actually always use Resveratrol, as a toxicity control in all our screening, along with ginger and ginseng. Any chemicals that are as toxic as Resveratrol, ginger, and ginseng are discarded. The study referred to in the comments DID NOT look at telomerase activity. Why not??? It usually tells me that they tested for telomerase activity  and saw none. So why did the telomeres appear to get longer??? It could be that Reseveratrol killed the cells with short telomeres. There is no way to tell with so little details provided. Bottomline, the lab is not a telomere lab and many explanations could exist as to why they got unusual data.  Plus, we have never gotten the same results even though we have tested it on multiple cell lines.

 

 

It is absolutely fascinating to see Bill being so outspoken like this. In the past he has always refused to reveal various nutraceuticals he said were toxic. It is a sign that he is getting fed up with all the BS that he is speaking so candidly now. 

 

He is also right to be so bullish on the telomere theory of ageing. It is just hard to see it (that more and more scientists are accepting its underlying importance) because as longevity has become more mainstream there is more an more BS. Basically more noise so it is harder to see the signal. As more and more anti-ageing approaches fail, we'll eventually see people coming back to telomerase and telomeres. 

Edited by QuestforLife, 09 December 2024 - 10:42 AM.