<div>Lloyd Klickstein is the Chief Science Officer at resTORbio, a biopharmaceutical company that develops medications to target the biology of aging. In this episode, Lloyd discusses his company's clinical application of rapamycin and its derivatives. He also elucidates details of his 2014 paper—a paper that greatly influenced Peter's perspective of rapamycin in the context of longevity. Peter and Lloyd go on to discuss the dose-dependent effect of rapamycin on immune function and compare rapamycin, fasting, and caloric restriction.</div> <div> </div> <div>We discuss:</div> <div> <ul> <li>His background and decision to leave academia for translational medicine [6:15];</li> <li>Translational medicine—bridging the gap between basic science and clinical medicine [10:30];</li> <li>What prompted Lloyd to focus on mTOR inhibition? [18:00];</li> <li>Defining mTOR, TORC1, and TORC2, and the consequences of inhibiting them with rapamycin [21:30];</li> <li>Dose-dependent impact of rapamycin on immune function, mTOR inhibition, and toxicity [42:15];</li> <li>Lloyd's 2014 experiment—mTOR inhibition improves immune function in the elderly [53:00];</li> <li>Insights into autophagy, antigen presentation, and the pleiotropic benefits of a rapalog, and how it compares to fasting [1:13:00];</li> <li>Lloyd's 2018 experiment—TORC1 inhibition enhances immune function and reduces infections in the elderly [1:18:45];</li> <li>Creation of resTORbio, subsequent studies, and takeaways about dosing, TORC2 inhibition, and tissue selectivity [1:29:00];</li> <li>Comparing the longevity effect of rapamycin, fasting, and caloric restriction [1:40:00];</li> <li>Excitement around RTB101—resTORbio's mTOR inhibiting molecule [1:47:00];</li> <li>Identifying rapalogs selective for TORC1 [1:56:15];</li> <li>Treating depression with ketamine, an activator of mTOR [2:00:00];</li> <li>Epigenetic clocks, rapalogs, and metformin [2:03:30]; and</li> <li>More.</li> </ul> <p>Learn more: <a href="https://peterattiamd.com/">https://peterattiamd.com/</a><br /> <br /> Show notes page for this episode: <a href="https://peterattiamd.com/LloydKlickstein">https://peterattiamd.com/LloydKlickstein</a><br /> <br /> Subscribe to receive exclusive subscriber-only content: <a href="https://peterattiamd.com/subscribe/">https://peterattiamd.com/subscribe/</a><br /> <br /> Sign up to receive Peter's email newsletter: <a href="https://peterattiamd.com/newsletter/">https://peterattiamd.com/newsletter/</a><br /> <br /> Connect with Peter on <a href="http://Facebook.com/PeterAttiaMD"><u>Faceboo</u></a><u>k</u> | <a href="http://Twitter.com/PeterAttiaMD"><u>Twitter</u></a> | <a href="http://Instagram.com/PeterAttiaMD"><u>Instagram</u></a>.</p> </div>
Actionable Insights
1. Optimize Rapamycin Dosing Strategy
To maximize benefits and minimize side effects of rapamycin or its analogs, consider intermittent dosing rather than continuous administration. This approach helps avoid undesirable mTORC2 inhibition and allows cellular organelles to recover from trough-driven toxicities.
2. Rapamycin Boosts Elderly Immunity
For individuals aged 65 and older, low-dose, intermittent rapamycin (Everolimus 0.5mg daily or 5mg weekly) can significantly improve the immune response to flu vaccination and reduce the incidence of respiratory tract infections. This effect is observed after a washout period, suggesting an indirect, lasting benefit on immune function.
3. Rapamycin Effects Are Temporary
The immune-enhancing benefits of intermittent rapamycin dosing in the elderly do not persist for an entire year. Therefore, periodic re-dosing may be necessary to maintain improved immune function.
For perfectly healthy individuals without diabetes or pre-diabetes, there is currently no clear evidence of a longevity benefit from taking metformin. It may also pose risks as a weak mitochondrial toxin, potentially dwarfing any perceived benefit.
5. DHEA Supplementation Lacks Benefit
Despite DHEA levels decreasing substantially with age, multiple studies on DHEA replacement have shown no clinical benefit for longevity or overall health.
6. Older Adults Impaired Fasting Response
In older individuals, the body’s ability to suppress mTOR activity in response to fasting appears to be impaired compared to younger individuals. This suggests older adults may not experience the same metabolic benefits from fasting alone.
7. RTB101 Reduces Elderly Infections
For individuals aged 65 and older, especially those with asthma or diabetes, 10 milligrams of RTB101 taken once daily for 16 weeks during cold and flu season can decrease the incidence of respiratory tract infections. This is believed to occur by upregulating antiviral gene expression, but it did not show benefit for smokers or those with COPD.
8. Ketamine for Severe Depression
Intravenous ketamine can act as a rapid and highly effective treatment for patients suffering from severe, recalcitrant major depression. Its effects can be observed within minutes to hours, offering a significant and swift impact.
9. Rapamycin Common Side Effect
Mouth ulcerations are a common and fairly specific side effect of rapamycin and its analogs. The incidence of these ulcers varies based on the specific dose and frequency of the drug.