In this episode, Matt and Brian Kennedy delve into the potential benefits and side effects of interventions like Rapamycin, the role of biomarkers, and optimal approaches to enhancing healthspan and cognitive function. Together they highlight the challenges of supplement use, aging research methodologies, and regulatory hurdles like the FDA’s stance on aging. They address emerging ideas such as leveraging AI for aging research, the importance of lifestyle factors like diet and sleep, and the need for actionable biomarkers. The session is a candid exchange of expert opinions, tackling scientific controversies and practical strategies for healthy aging.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

mTOR inhibition improves immune function in the elderly - PubMed

Matt addresses the question about optimal clinical study design for evaluating the efficacy of a putative gerotherapeutic intervention with the example of Joan Mannick’s everolimus trial on immune health and functioning. Joan’s trial was a randomized, double-blind, placebo-controlled trial involving generally healthy, elderly individuals taking various doses of rapamycin (0.5 mg/day and 20 mg/week) and evaluated antibody response to the influenza vaccine four weeks post-vaccination, a marker of immune function that typically declines with age. Participants demonstrated a statistically significant improvement in antibody response compared to placebo.

Nonlinear dynamics of multi-omics profiles during human aging | Nature Aging

Does the rate of aging change across an individual’s life course ? Matt and Brian discuss the limitations in interpreting the study evaluating multi-omic biological aging signatures suggesting individuals go through two accelerated phases of aging in their life, one in their 40’s and the other in their 60’s. Researchers conducted a comprehensive analysis of over 135,000 molecular profiles across 108 adults aged 25 to 75. They examined a wide array of molecules, including metabolites, lipids, proteins, and transcripts, to identify patterns of change associated with aging. Their findings suggest that the human body undergoes dramatic molecular shifts in the 5th and 7th decades of life, challenging the traditional view of a steady age-related decline over time. Further, authors suggest that timing longevity interventions according to these anticipated changes may improve healthy aging outcomes. Matt and Brian conclude that the study has too many limitations to conclude anything about an individual’s rate of aging based on how the clock was developed (cross-sectional, retrospective study on a small and specific population), the limitations of proteomic data used as a surrogate for aging, and the lack of supporting data of external factors that may have influenced these changes.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults - PubMed

Matt addresses the question of optimal dose and regimen of rapamycin for healthy aging by highlighting that the existing clinical literature in normative aging individuals is limited, but there is a growing body of real world data in which most individuals are taking 6 mg per week based on initial studies by Joan Mannick demonstrating improvements in immune health with a similar regimen. This study evaluated off-label rapamycin use in 333 adults taking rapamycin from anywhere between 1 month and several years. The findings suggested that rapamycin can be used safely in normative aging adults over extended periods, with over one-third of users self-reporting positive health outcomes and preliminary signals of decreased severity of COVID-19 symptoms for individuals taking rapamycin. Randomized controlled trials are needed to provide more clarity on optimal dose and regimen for improving various healthspan metrics.

Rapamycin and Alzheimer’s disease: Time for a clinical trial? - PMC

This perspective article coauthored by Matt discusses the potential of rapamycin as a therapeutic intervention for Alzheimer's disease (AD). The authors highlight rapamycin’s promise in various animal models of neurodegeneration and aging, including mouse models of Alzheimer's disease and cognitive decline through its effects on enhancing autophagy, reducing protein aggregation, and modulating inflammatory responses. Clinical trials focused on individuals with neurodegenerative disease and cognitive decline are overdue as promising preclinical data and rapamycin's established safety profile in humans justifies its evaluation in a clinical setting.

Attenuation of age-elevated blood factors by repositioning plasmapheresis: A novel perspective and approach - ScienceDirect

The biological aging process is associated with increased levels of certain plasma factors that impair tissue function, drive inflammation and alter inter-organ communication. These factors contribute to the decline in regenerative capacity and overall health. TPE, commonly known as plasmapheresis, involves the removal and replacement of plasma. This perspective piece reviews existing literature and presents a novel perspective on using therapeutic plasma exchange (TPE) to dilute and reduce the concentration of systemic, age-elevated deleterious factors in the bloodstream. Within preclinical studies, attenuating these harmful factors with TPE restores youthful signaling pathways, enhances tissue function, and promotes systemic rejuvenation.