Nice job Krister! I created the Agingdoc Podcast to go "deeper" and into interesting places other podcasts do not and was thinking of inviting Joan. But after your excellent podcast, it may not be necessary (or else I may focus on something else) as I think you did exactly that. I always enjoy Joan as a speaker because she is not only a very good physician-scientist, but also one of the best science communicators in geroscience in our field, making aging biology and its relevance to translational medicine clear and accessible to broad audiences. Your questions to her were well formulated, so you two made a great team. -Agingdoc
Perhaps after a few talks/projects... I'm prepping for a few consecutive talks this year and about a year ahead (very crude estimate) in interviews. But when/if I do, among topics I'd consider double-clicking on pharmacokinetics and details of study design. It is seldom appreciated that in rodents ~ 99.9% of rapamycin is protein-bound vs. 75% in humans (and in humans it also enters red blood cells) for example. Modeling is instrumental for best bet dosages to test for different potential indications in humans (it will vary for immune, cardiac, neuro, sarcopenia etc) also high yield. As I discussed with Matt Joan picked an awesome endpoint (my comment to Matt from several months ago, to be released my interview with him); I think there's a big gap yet and would love to see Tornado and other players in this field focus on these; it's unfortunate things take so long, around 2030 (or a tad sooner) optimistically for immune under a best-case scenario with hitting all endpoints, as she noted. @@masteronething
Hi Krister, thank you so much for the podcast. It was live late last night for me to watch, so watching it now. Super excited about it! 🎉You are a great host!
So many. The immune system analysis so well detailed and explained on how it affects people from 75 in winter. I can see that on my going onto 75 yold mother, who 2 years ago use to litteraly jump around, not lying, and this year's winter cold, flu has her down like never before. She s recovering n starting to look at healthy aging options 🤞
Thank you! Seem like the community of self experimenters (which I am joining) needs to identify a set of blood biomarkers which we can use to better assess effects. I'm sure there are immune system markers we could test (I know that Labcorp and Quest in US have immune system markers). Also, Joan's mention of elevated lipids due to mTORC2 suppression might be a gauge that could be used to make sure people don't overshoot dose.
I fully agree! What do you think about using sperm as biomarker. See this post in which I elaborate a little bit on it. twitter.com/KristerKauppi/status/1747881921810510202
@@masteronething worth looking at. I am going to revisit immune system markers as well. I recall a talk and paper by Prof. Jant Lord showed that older people who had exercised consistently for many years had immune system markers that were decades younger, including a thymus that was much young (not as infiltrated with fat as it tends to be). There is also good research suggesting that mild DR slows DNA damage another major contributor to aging, as well as improving autophagy. All of which begs the question - what lifestyle actions can also modulate mTORC1 in a favorable way? And why don't people do them?
Great interview, thanks so much. As others have noted there were some real pearls here. Have others tried using changes in triglycerides and LDL as markers for dosing, ie when they rise, dose should be lowered? I wonder what the significance is of rapamycin concentrating in RBCs. It seems to me the data is clear and overwhelming, as Mannick says, regarding the health benefits of Mtor inhibition. My frustration (understatement) is her prediction of 2030 for drug approval. We already have the drug, it is 50 years old, and well studied with her own clinical trials elegantly demonstrating efficacy. But we must 'wait' for 2030 because of patent runways!! So nuts. I am 76, actively practicing and certainly not waiting another 6 years. No patent protection = no funding= data obstruction = delayed progress. Oh well. Regardless, thanks for a great interview.
Yes, its very frustrating to wait and that most likely Rapamycin will never be FDA approved because there is no patent to earn money on that. Very sad but it's great that Joan Mannick is trying to do her part in this journey. Without her we would not be where we are today.
🎯 Key Takeaways for quick navigation: 00:09 *🧬 Dr. Joan Mannick, CEO of Tornado Therapeutics, is a leading researcher in the field of rapamycin and mTOR, focusing on longevity.* 02:06 *📚 Dr. Mannick's interest in longevity began with the realization that organisms could potentially live much longer than normal, sparked by Cynthia Kenyan's research on lifespan extension in worms.* 04:28 *🌱 Dr. Mannick's journey into the longevity field began with a proposal to study aging biology at Novartis, focusing on targeting mTOR.* 08:29 *🔄 Turning down mTOR to youthful levels or intermittently inhibiting it may promote protective pathways and be beneficial for aging.* 09:09 *🧹 Mammalian Target of Rapamycin (mTOR) inhibition induces autophagy, reduces inflammation, enhances stem cell function, and improves protein quality control, potentially contributing to longevity.* 11:10 *📊 Rapamycin shows consistent longevity benefits across multiple species, suggesting its potential efficacy in humans.* 14:08 *🌋 Rapamycin, discovered on Easter Island, inhibits mTOR, a protein kinase crucial for nutrient sensing and cell growth.* 16:00 *⚠️ Rapamycin's side effects include immune suppression and gastrointestinal issues, prompting research into developing safer mTOR inhibitors.* 20:01 *💡 Tornado Therapeutics aims to develop mTOR inhibitors better than rapamycin, focusing on compounds that selectively target mTORC1 without inhibiting mTORC2.* 22:17 *💼 Dr. Mannick views Tornado Therapeutics' mTOR inhibitor portfolio as a potential game-changer in extending healthspan, driven by strong scientific validation and excitement for its impact.* 25:23 *🦠 Dr. Mannick proposed a unique clinical trial to test whether mTOR inhibitors could improve immune function in aging humans, despite traditionally being associated with immune suppression.* 26:31 *🧬 Joan Mannick proposed using unusual doses of mTOR inhibitors to turn down mTOR without causing immunosuppression.* 27:26 *🐭 Treating old mice with rapamycin for six weeks improved their response to a flu vaccine, inspiring human trials with low or intermittent doses to avoid immunosuppression.* 28:30 *💊 Modeling and simulation, along with expertise from pharmaceutical teams, helped determine safe dosing of mTOR inhibitors to avoid immunosuppression.* 29:25 *🔬 Three different doses of Novartis's rapalogs were tested in a trial, showing improved response to flu vaccination with lower doses without causing harm.* 32:54 *🩺 Aging of the immune system may drive aging of other organ systems, emphasizing the importance of maintaining a healthy immune system for longevity.* 34:03 *💉 Targeting the aging immune system could have therapeutic effects beyond autoimmune diseases, potentially impacting cancer prevention and various pathologies.* 36:31 *🦠 Elderly individuals are more vulnerable to respiratory viruses like influenza, leading to higher mortality rates, emphasizing the importance of strong immune function in old age.* 39:39 *📉 Low doses of mTOR inhibitors reduced total infections, particularly respiratory tract infections, suggesting improved antiviral immunity in older adults.* 41:45 *🧬 RNA analysis revealed upregulation of antiviral pathways in older adults treated with mTOR inhibitors, potentially explaining the reduced respiratory tract infections.* 44:48 *🧪 Failure in a phase three trial doesn't negate the potential benefits of mTOR inhibitors for aging; further research and improved trial designs are needed to clarify their efficacy.* 51:13 *💊 Low doses of certain mTOR inhibitors, such as Torque 1/2 inhibitors, can be safe and effective for aging due to minimal toxicity.* 52:41 *💉 Vaccines are crucial, but not all viruses have effective vaccines; mTOR inhibitors may boost overall immune response and complement vaccines.* 55:21 *💡 Taking mTOR inhibitors for short durations during the winter cold and flu season may enhance antiviral responses with minimal side effects.* 56:27 *📊 The optimal dosing and duration of mTOR inhibitors for boosting immune function are still being studied in controlled trials.* 57:41 *🧬 Biomarkers for immune function, such as antiviral gene upregulation, show promise but need further validation for individual assessment.* 59:28 *💪 mTOR inhibitors like rapalogs show potential for combating sarcopenia, a condition characterized by muscle loss in aging.* 01:02:37 *💊 Tor 101 is a promising rapalog compound that selectively targets Torque 1, potentially offering safer and more effective treatment options for aging-related conditions.* 01:06:40 *🦠 Rhinovirus challenge trials could provide valuable insights into the efficacy of mTOR inhibitors in reducing the severity of viral infections.* 01:08:54 *⏳ Potential approval of mTOR inhibitors for humans could happen around 2030 pending successful clinical trials and regulatory processes.* 01:15:33 *🧬 Autophagy induction varies among different mTOR inhibitors and cell types, with catalytic site inhibitors showing consistent efficacy.* 01:16:39 *💡 Challenges in longevity research include developing drugs for aging-related conditions like sarcopenia and frailty, requiring perseverance and acceptance of failure.* 01:19:07 *💰 Securing funding from seasoned institutional investors is crucial for advancing biotech companies in the longevity field, validating the potential of the industry.* Made with HARPA AI
I like the summary so I don't have to take notes because it's complex you have to hear it two or three times or go over the summary to absorb all of it
Very good interview. How do you reconcile the apparent contradiction between mTOR being hyperactivated with aging (meaning that inhibition of mTOR via rapamycin, protein restriction or plant based diet is health/life span promoting), and the advice from the exercise/muscle scientists that protein restriction is a terrible idea and that the elderly in particular should be eating much more protein, particularly animal protein.
On this comment to Aida I elaborate a little bit my own approach to the topic. www.linkedin.com/feed/update/urn:li:activity:7159481628002529280/?commentUrn=urn%3Ali%3Acomment%3A%28activity%3A7159481628002529280%2C7159488986988593152%29&replyUrn=urn%3Ali%3Acomment%3A%28activity%3A7159481628002529280%2C7159827666408243202%29&dashCommentUrn=urn%3Ali%3Afsd_comment%3A%287159488986988593152%2Curn%3Ali%3Aactivity%3A7159481628002529280%29&dashReplyUrn=urn%3Ali%3Afsd_comment%3A%287159827666408243202%2Curn%3Ali%3Aactivity%3A7159481628002529280%29
In the episode with Ross Pelton he shares a little bit about the discovery on Easter Island. Here is a time clip from that episode. ua-cam.com/video/gW5FreEwRW4/v-deo.html
Yes, metformin inhibits mTOR but most likely not as much as Rapamycin. This could be one reason why Rapamycin works better in lifespan studies compared to Metformin. On this page you get some statistics around that. masteronething.com/lid
Nice job Krister! I created the Agingdoc Podcast to go "deeper" and into interesting places other podcasts do not and was thinking of inviting Joan. But after your excellent podcast, it may not be necessary (or else I may focus on something else) as I think you did exactly that. I always enjoy Joan as a speaker because she is not only a very good physician-scientist, but also one of the best science communicators in geroscience in our field, making aging biology and its relevance to translational medicine clear and accessible to broad audiences. Your questions to her were well formulated, so you two made a great team. -Agingdoc
Big thanks, David! I think you can bring even more to the table if you interview her. You have a much deeper knowledge than me in the area.
Perhaps after a few talks/projects... I'm prepping for a few consecutive talks this year and about a year ahead (very crude estimate) in interviews. But when/if I do, among topics I'd consider double-clicking on pharmacokinetics and details of study design. It is seldom appreciated that in rodents ~ 99.9% of rapamycin is protein-bound vs. 75% in humans (and in humans it also enters red blood cells) for example. Modeling is instrumental for best bet dosages to test for different potential indications in humans (it will vary for immune, cardiac, neuro, sarcopenia etc) also high yield. As I discussed with Matt Joan picked an awesome endpoint (my comment to Matt from several months ago, to be released my interview with him); I think there's a big gap yet and would love to see Tornado and other players in this field focus on these; it's unfortunate things take so long, around 2030 (or a tad sooner) optimistically for immune under a best-case scenario with hitting all endpoints, as she noted. @@masteronething
Thank you Joan for your important work!
Yes, I fully agree! Important work and great passion in the field.
Hi Krister, thank you so much for the podcast. It was live late last night for me to watch, so watching it now. Super excited about it! 🎉You are a great host!
Really glad to hear that you liked it! Curious as I am was it something special that you felt was extra interesting?
So many. The immune system analysis so well detailed and explained on how it affects people from 75 in winter. I can see that on my going onto 75 yold mother, who 2 years ago use to litteraly jump around, not lying, and this year's winter cold, flu has her down like never before. She s recovering n starting to look at healthy aging options 🤞
Thank you! Seem like the community of self experimenters (which I am joining) needs to identify a set of blood biomarkers which we can use to better assess effects. I'm sure there are immune system markers we could test (I know that Labcorp and Quest in US have immune system markers). Also, Joan's mention of elevated lipids due to mTORC2 suppression might be a gauge that could be used to make sure people don't overshoot dose.
I fully agree! What do you think about using sperm as biomarker. See this post in which I elaborate a little bit on it.
twitter.com/KristerKauppi/status/1747881921810510202
@@masteronething worth looking at. I am going to revisit immune system markers as well. I recall a talk and paper by Prof. Jant Lord showed that older people who had exercised consistently for many years had immune system markers that were decades younger, including a thymus that was much young (not as infiltrated with fat as it tends to be). There is also good research suggesting that mild DR slows DNA damage another major contributor to aging, as well as improving autophagy. All of which begs the question - what lifestyle actions can also modulate mTORC1 in a favorable way? And why don't people do them?
@@peterz53 Keep us updated if you find something interesting in the topic!
This is gold! Thank you ever so much!
Big thanks, curious question, was it something you felt was a little bit extra good?
wow - lots of good information that the other speakers sort of gloss over.
Glad to hear that you liked it! Was it something you felt was extra good?
Great interview, thanks so much. As others have noted there were some real pearls here. Have others tried using changes in triglycerides and LDL as markers for dosing, ie when they rise, dose should be lowered? I wonder what the significance is of rapamycin concentrating in RBCs. It seems to me the data is clear and overwhelming, as Mannick says, regarding the health benefits of Mtor inhibition.
My frustration (understatement) is her prediction of 2030 for drug approval. We already have the drug, it is 50 years old, and well studied with her own clinical trials elegantly demonstrating efficacy. But we must 'wait' for 2030 because of patent runways!! So nuts. I am 76, actively practicing and certainly not waiting another 6 years. No patent protection = no funding= data obstruction = delayed progress.
Oh well. Regardless, thanks for a great interview.
Yes, its very frustrating to wait and that most likely Rapamycin will never be FDA approved because there is no patent to earn money on that. Very sad but it's great that Joan Mannick is trying to do her part in this journey. Without her we would not be where we are today.
I have a feeling Tor101 will win the Longevity X prize. Can't wait until Tor101 is tested by the ITP
That would be a great prize for Joan's all hard work 🙏
🎯 Key Takeaways for quick navigation:
00:09 *🧬 Dr. Joan Mannick, CEO of Tornado Therapeutics, is a leading researcher in the field of rapamycin and mTOR, focusing on longevity.*
02:06 *📚 Dr. Mannick's interest in longevity began with the realization that organisms could potentially live much longer than normal, sparked by Cynthia Kenyan's research on lifespan extension in worms.*
04:28 *🌱 Dr. Mannick's journey into the longevity field began with a proposal to study aging biology at Novartis, focusing on targeting mTOR.*
08:29 *🔄 Turning down mTOR to youthful levels or intermittently inhibiting it may promote protective pathways and be beneficial for aging.*
09:09 *🧹 Mammalian Target of Rapamycin (mTOR) inhibition induces autophagy, reduces inflammation, enhances stem cell function, and improves protein quality control, potentially contributing to longevity.*
11:10 *📊 Rapamycin shows consistent longevity benefits across multiple species, suggesting its potential efficacy in humans.*
14:08 *🌋 Rapamycin, discovered on Easter Island, inhibits mTOR, a protein kinase crucial for nutrient sensing and cell growth.*
16:00 *⚠️ Rapamycin's side effects include immune suppression and gastrointestinal issues, prompting research into developing safer mTOR inhibitors.*
20:01 *💡 Tornado Therapeutics aims to develop mTOR inhibitors better than rapamycin, focusing on compounds that selectively target mTORC1 without inhibiting mTORC2.*
22:17 *💼 Dr. Mannick views Tornado Therapeutics' mTOR inhibitor portfolio as a potential game-changer in extending healthspan, driven by strong scientific validation and excitement for its impact.*
25:23 *🦠 Dr. Mannick proposed a unique clinical trial to test whether mTOR inhibitors could improve immune function in aging humans, despite traditionally being associated with immune suppression.*
26:31 *🧬 Joan Mannick proposed using unusual doses of mTOR inhibitors to turn down mTOR without causing immunosuppression.*
27:26 *🐭 Treating old mice with rapamycin for six weeks improved their response to a flu vaccine, inspiring human trials with low or intermittent doses to avoid immunosuppression.*
28:30 *💊 Modeling and simulation, along with expertise from pharmaceutical teams, helped determine safe dosing of mTOR inhibitors to avoid immunosuppression.*
29:25 *🔬 Three different doses of Novartis's rapalogs were tested in a trial, showing improved response to flu vaccination with lower doses without causing harm.*
32:54 *🩺 Aging of the immune system may drive aging of other organ systems, emphasizing the importance of maintaining a healthy immune system for longevity.*
34:03 *💉 Targeting the aging immune system could have therapeutic effects beyond autoimmune diseases, potentially impacting cancer prevention and various pathologies.*
36:31 *🦠 Elderly individuals are more vulnerable to respiratory viruses like influenza, leading to higher mortality rates, emphasizing the importance of strong immune function in old age.*
39:39 *📉 Low doses of mTOR inhibitors reduced total infections, particularly respiratory tract infections, suggesting improved antiviral immunity in older adults.*
41:45 *🧬 RNA analysis revealed upregulation of antiviral pathways in older adults treated with mTOR inhibitors, potentially explaining the reduced respiratory tract infections.*
44:48 *🧪 Failure in a phase three trial doesn't negate the potential benefits of mTOR inhibitors for aging; further research and improved trial designs are needed to clarify their efficacy.*
51:13 *💊 Low doses of certain mTOR inhibitors, such as Torque 1/2 inhibitors, can be safe and effective for aging due to minimal toxicity.*
52:41 *💉 Vaccines are crucial, but not all viruses have effective vaccines; mTOR inhibitors may boost overall immune response and complement vaccines.*
55:21 *💡 Taking mTOR inhibitors for short durations during the winter cold and flu season may enhance antiviral responses with minimal side effects.*
56:27 *📊 The optimal dosing and duration of mTOR inhibitors for boosting immune function are still being studied in controlled trials.*
57:41 *🧬 Biomarkers for immune function, such as antiviral gene upregulation, show promise but need further validation for individual assessment.*
59:28 *💪 mTOR inhibitors like rapalogs show potential for combating sarcopenia, a condition characterized by muscle loss in aging.*
01:02:37 *💊 Tor 101 is a promising rapalog compound that selectively targets Torque 1, potentially offering safer and more effective treatment options for aging-related conditions.*
01:06:40 *🦠 Rhinovirus challenge trials could provide valuable insights into the efficacy of mTOR inhibitors in reducing the severity of viral infections.*
01:08:54 *⏳ Potential approval of mTOR inhibitors for humans could happen around 2030 pending successful clinical trials and regulatory processes.*
01:15:33 *🧬 Autophagy induction varies among different mTOR inhibitors and cell types, with catalytic site inhibitors showing consistent efficacy.*
01:16:39 *💡 Challenges in longevity research include developing drugs for aging-related conditions like sarcopenia and frailty, requiring perseverance and acceptance of failure.*
01:19:07 *💰 Securing funding from seasoned institutional investors is crucial for advancing biotech companies in the longevity field, validating the potential of the industry.*
Made with HARPA AI
Ah, really nice! Great work, Thomas!
I like the summary so I don't have to take notes because it's complex you have to hear it two or three times or go over the summary to absorb all of it
Very good interview. How do you reconcile the apparent contradiction between mTOR being hyperactivated with aging (meaning that inhibition of mTOR via rapamycin, protein restriction or plant based diet is health/life span promoting), and the advice from the exercise/muscle scientists that protein restriction is a terrible idea and that the elderly in particular should be eating much more protein, particularly animal protein.
On this comment to Aida I elaborate a little bit my own approach to the topic.
www.linkedin.com/feed/update/urn:li:activity:7159481628002529280/?commentUrn=urn%3Ali%3Acomment%3A%28activity%3A7159481628002529280%2C7159488986988593152%29&replyUrn=urn%3Ali%3Acomment%3A%28activity%3A7159481628002529280%2C7159827666408243202%29&dashCommentUrn=urn%3Ali%3Afsd_comment%3A%287159488986988593152%2Curn%3Ali%3Aactivity%3A7159481628002529280%29&dashReplyUrn=urn%3Ali%3Afsd_comment%3A%287159827666408243202%2Curn%3Ali%3Aactivity%3A7159481628002529280%29
Wonder if Dr jean knows Harvard guy Marc Lipstich
Curious question, why do you wonder that?
rapaymycin I believe I heard it was first discovered at Easter Island soil.
In the episode with Ross Pelton he shares a little bit about the discovery on Easter Island. Here is a time clip from that episode.
ua-cam.com/video/gW5FreEwRW4/v-deo.html
@@masteronething thanks .I will check it out now
Metformin is a mtor inhibitor.i believe
Yes, metformin inhibits mTOR but most likely not as much as Rapamycin. This could be one reason why Rapamycin works better in lifespan studies compared to Metformin. On this page you get some statistics around that.
masteronething.com/lid
Do you like the idea of taking metformin for quality of life. Has many pathways. Negative possibilities is the kidney
@@andrewfinlay5160 Here are some links that changed my view on Metformin.
twitter.com/KristerKauppi/status/1670296628232593408
Until Fatty acid C15 came along.....
Can you elaborate more on what you mean with this?