#175 - Matt Kaeberlein, Ph.D.: The biology of aging, rapamycin, and other interventions that target the aging process
Sep 13, 2021
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Matt Kaeberlein, a renowned expert on aging, discusses groundbreaking research that links aging with chronic inflammation and the immune system. He highlights the potential of rapamycin and other interventions in extending lifespan. Kaeberlein shares insights from his Dog Aging Project, along with the critical importance of biomarkers and epigenetic clocks. They explore the complex relationships between aging, diseases, and nutritional strategies, suggesting that targeting biological aging may offer more significant benefits than merely treating age-related conditions.
Rapamycin shows promise in extending lifespan by targeting chronic inflammation and immune system modifications in aging individuals.
Improving future aging trials involves conceptualizing risks, selecting better endpoints, and collaborating with regulators for trial approval.
Immune function plays a crucial role in aging research, with rapamycin proving to restore immune responses to vaccines in older individuals.
mTOR inhibitors like everolimus demonstrate broad immune enhancement and reduced infection risks in older individuals, contrasting with common misconceptions.
Challenges in phase three aging trials highlight the need for FDA endpoint alignment and risk assessment for successful aging-related intervention studies.
mTOR proteins function in two distinct complexes, mTORC1 and mTORC2, with unique roles in cellular processes like autophagy, metabolism, and translation.
Deep dives
Introduction to Aging Science and Longevity Research
The goal of translating the science of longevity into accessible information is highlighted in the podcast. A broad overview of aging, discussed through the lens of the nine hallmarks of aging, is introduced, along with a contrast between a molecular and functional definition of aging. The podcast engages in a discussion about the importance of understanding functional declines and frailty in aging.
Exploring the Impact of Rapamycin on Aging
The podcast further delves into the effects of rapamycin on aging, emphasizing the detailed research conducted on its rejuvenation potential in aging tissues of mice and possibly in humans. Discussions surrounding interventions focusing on targeting the molecular mechanisms that drive biological changes in aging are presented, shedding light on rapamycin's role in combating chronic inflammation and immune system modifications in aging individuals.
Significance of Immune Function in Longevity Research
The podcast expands on the importance of immune function in aging and longevity research, drawing attention to the immune system's intricate role in physiological responses and age-related changes. Rapamycin's impact on immune modulation in aged physiologies, specifically in restoring immune responses to vaccines in older individuals, is highlighted as an essential aspect of exploring interventions for healthy aging.
Clinical Trials and Future Outlook in Aging Interventions
The podcast explores the progression of clinical trials involving rapalogs and potential combination therapies like RTB101 in targeting aging processes, immune responses, and inflammation. The consideration of drug mechanisms, dosing strategies, and patent life in shaping research designs and outcomes in aging interventions is examined. The podcast underscores the challenges and advancements in studying aging in humans and the promising transition towards a biology-oriented approach to health and longevity.
Impact on Immune Function and Vaccine Response
Everolimus, an mTOR inhibitor, potentially boosts immune function broadly and enhances vaccine response. Notable improvements were observed in vaccine response and reduced risk of upper respiratory tract infections in older individuals receiving mTOR inhibitors, suggesting a broader immune protection mechanism.
Safety and Efficacy of mTOR Inhibitors
Contrary to misconceptions about mTOR inhibitors causing severe side effects, data show minimal adverse events, specifically with rapamycin and everolimus at tested doses. Statins, while commonly used, induce more significant side effects compared to mTOR inhibitors in aging contexts.
Phase Two and Three Clinical Trials on mTOR Inhibitors
Initial successes in phase two trials with mTOR inhibitors led to phase three trials aiming at FDA approval for enhancing vaccine response and immune function in the elderly. However, challenges arose in phase three trials, leading to trial termination and strategic changes.
Need for Reevaluation of Clinical Trial Endpoints
The failure of the phase three trial called for a closer examination of FDA end point requirements and risk assessment in aging-related clinical trials. Discussions on appropriate endpoints and risk levels in aging-related intervention trials are crucial to progress and align FDA criteria with aging research goals.
Eligibility Criteria for the Study Participants
Dogs participating in the study must be at least seven years old and weigh between forty and a hundred pounds to be included. This selection criteria aimed to focus on middle-aged dogs that are likely to exhibit rapid aging in a short time span conducive for observing potential benefits from the treatment.
Mechanisms of mTOR Complexes
mTOR proteins function in two main complexes: mTOR complex one (mTORC1) and mTOR complex two (mTORC2). Both complexes have distinct partner proteins and serve different functions within the cell. mTORC1 is responsive to nutrient levels and regulates processes like autophagy, metabolism, and translation, while mTORC2's functions are still being elucidated.
Exploring the Role of NAD Precursors and Sirtuins in Aging
The discussion delves into the nuances of NAD precursor supplements like NR and NMN and their interactions with sirtuins in aging processes. While there's notable interest in these precursors potentially impacting aging positively, there are varying opinions on their efficacy and biological availability, necessitating further research to understand their true impact on age-related health and longevity.
Matt Kaeberlein is globally recognized for his research on the biology of aging and is a previous guest on The Drive. In this episode, Matt defines aging, the relationship between aging, chronic inflammation, and the immune system, and talks extensively about the most exciting molecules for extending lifespan. He discusses the current state of the literature of testing rapamycin (and rapalogs) in animals and humans, including Matt’s Dog Aging Project, and provides insights into how we can improve future trials by conceptualizing risk, choosing better endpoints, and working with regulators to approve such trials. He also examines the connection between aging and periodontal disease, biomarkers of aging, and epigenetic clocks. Finally, they explore some of the biological pathways involved in aging, including mTOR and its complexes, sirtuins, NAD, and NAD precursors. We discuss:
The various definitions of aging [3:25];
The relationship between disease and the biology of aging [16:15];
Potential for lifespan extension when targeting diseases compared to targeting biological aging [22:45];
Rapamycin as a longevity agent and the challenges of targeting the biology of aging with molecules [32:45];
Human studies using rapalogs for enhanced immune function [39:30];
The role of inflammation in functional declines and diseases of aging [50:45];
Study showing rapalogs may improve the immune response to a vaccine [56:15];
Roadblocks to studying gero-protective molecules in humans [1:01:30];
Potential benefits of rapamycin for age-related diseases—periodontal, reproductive function, and more [1:12:15];
Debating the ideal length and frequency of rapamycin treatment for various indications like inflammation and longevity [1:21:30];
Biomarkers of aging and epigenetic clocks [1:29:15];
Prospects of a test that could calculate biological age [1:37:45];
The Dog Aging Project testing rapamycin in pet dogs [1:42:30];
The role of the mTOR complexes [1:58:30];
mTor inhibitor called Torin2, mitochondrial disease and other potential pathways [2:09:45];
Catalytic inhibitors, sirtuins, and NAD [2:19:15];
