Prompt Cast
Clinical Application of Rapamycin and Rapalogs in Immunology and Rheumatology
TLDR Lloyd Klickstein discusses the clinical application of rapamycin and rapalogs, highlighting their effects on TORC1 and TORC2, immune system modulation, and potential benefits in altering lymphocyte biology. The study explores different doses and schedules of RAD001, showing efficacy in reducing respiratory tract infections and improving immunologic function over time.
Timestamped Summary
00:00
Lloyd Klickstein, M.D., Ph.D., discusses the clinical application of rapamycin and rapalogs, focusing on the turning point study from December 2014 and subsequent developments in the field.
06:36
Science and medicine run in Lloyd Klickstein's family, leading him to focus on immunology and rheumatology, driven by the people he met and worked with.
14:39
Lloyd Klickstein worked on translational programs at Novartis focusing on regenerative medicine concepts in musculoskeletal biology to increase bone density and muscle strength.
22:47
MTOR is a highly conserved signaling pathway that integrates various signals to determine cell growth based on available resources, with its presence on lysosomes likely linked to evolutionary origins of nutrient intake mechanisms.
31:09
Rapamycin inhibits the TORC1 complex effectively for certain downstream pathways, such as phosphorylation of S6 kinase, while being less effective for others like ULK1 activation, making it a strong inhibitor of new protein synthesis and a modest activator of autophagy.
39:28
Rapamycin's effects on TORC2 downregulation and immune system modulation were initially puzzling but eventually led to the discovery of its potential benefits in altering lymphocyte biology.
47:17
Sustained inhibition of TORC1 by rapamycin can lead to toxicity, particularly in the kidney, but drug-free periods may allow for organelle recovery.
55:13
The study design involved testing different doses of RAD001 to assess vaccine response and toxicity levels in older adults.
01:02:56
Adverse effects were consistent across different doses of RAD001, with mouth ulceration being a notable side effect observed in the study.
01:10:18
The study observed a decrease in PD1 levels on lymphocytes in the drug treatment group compared to placebo, potentially indicating a reduction in lymphocyte exhaustion.
01:18:20
Negative studies on methylation clock unwinding have been conducted in various species, including mice and humans, with concerns raised about the lack of publication of such studies, leading to discussions on the potential expansion of drug indications based on study outcomes.
01:26:08
Patients in a study showed improved immunologic function over a six-week treatment period, with the drug's effects waning after a year, leading to further exploration of dosing intervals and the creation of a new compound that decreased respiratory tract infections.
01:34:23
Drug design involves targeting specific tissues or enzymes, with the aim of hitting the desired tissue or cell type to achieve the intended effects, such as upregulating interferon-stimulated antiviral gene responses.
01:42:35
Older animals may lose the ability to respond to environmental reductions in nutrients, impacting their mTOR activity and suggesting potential implications for aging in humans.
01:50:03
The study discussed different doses and schedules of a drug targeting mTOR inhibition, showing efficacy in reducing respiratory tract infections across different patient populations.
01:57:25
The compound discussed in the paper selectively binds to FKBP12, possibly influencing mTOR inhibition through downstream signaling mechanisms, leading to complex interactions that are not yet fully understood.
02:05:35
Aging is viewed as a biological process influenced by changes in gene expression, with DNA methylation potentially playing a causal role in gene expression changes associated with aging.
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Health & Fitness
