Longevity Interventions: A Deep Dive into NAD, Rapamycin, and Dr. Peter Attia's Healthspan Strategies

This episode features Dr. Peter Attia, a renowned expert in healthspan and lifespan, discussing various approaches to longevity. The primary focus is on the NAD pathway, exploring molecules like NR, NMN, and direct NAD infusions. Huberman and Attia compare the existing research and clinical literature on their efficacy, delivery routes, and whether they personally incorporate these supplements into their regimens, providing a nuanced perspective on their potential benefits for extending health and life.

The discussion also contrasts Huberman's initial framework for longevity (dos and don'ts, caloric/mTOR regulation, specific pathways, and the 'kitchen sink' approach) with Attia's more structured categorization. Attia's framework emphasizes essential behavioral interventions (eating, sleeping, moving correctly), exogenous molecules targeting specific disease processes (e.g., Metformin, SGLT2 inhibitors), and geroprotective molecules that target the fundamental hallmarks of aging (e.g., rapamycin). This provides a comprehensive lens through which to evaluate different longevity strategies.

A significant portion of the conversation is dedicated to rapamycin, which Dr. Attia personally takes. He details his dosage and the common side effect of aphthous ulcers, which he paradoxically views as a biomarker of the drug's activity. Attia highlights rapamycin's mechanism of action, including mTOR inhibition, autophagy stimulation, and senescent cell suppression. His conviction in rapamycin stems from robust experimental data showing uniform life extension across various organisms, a finding he notes is unique to rapamycin and caloric restriction. The ongoing Dog Aging Study, led by Matt Kaeberlein, is presented as a crucial upcoming readout for further validating rapamycin's potential in higher-order mammals.

Finally, the episode delves into the fundamental biology of NAD, explaining its ubiquitous role as a co-factor in hundreds of cellular pathways, primarily as an electron shuttle, and its tight regulation within the body. A smaller but critical function involves its consumption as a substrate by sirtuins for DNA repair, which is where the initial interest in NAD for longevity began. The discussion uses the example of the Clotho gene, where both loss-of-function and gain-of-function experiments demonstrated its necessity and sufficiency for extended lifespan, setting a high bar for the kind of evidence required to confidently label a molecule or gene as a true longevity intervention.

Dr. Attia is one of the world's most trusted voices on the topics of healthspan and lifespan and with good reason he is known to systematically review the research literature the clinical trials and he maintains an avid clinical practice.

NAD is again one of the most ubiquitous molecules in the body and most of what it does and I mean most meaning like somewhere between five and 600 Pathways of it utilize NAD as a co-actor meaning that it's not consumed in a chemical reaction but rather it serves as an electron shutle.

There are only two interventions full stop that have ever extended life across those four categories of UK chariots caloric restriction and rap ay.

So now for you and I to live longer we basically have to delay the onset of cardiovascular disease cerebrovascular disease cancer neurodegenerative disease dementing diseases and metabolic diseases.

I take eight milligrams once a week for as long as I can tolerate it but that I usually have to take breaks why is that I get these vicious apus ulcers uh little mouth sores canker Source yes about 10% of people get them hm it's paradoxically the only biomarker we probably have.

My conviction around mtor is far more based on the experimental data something that is actually sorely lacking in the NAD story which we'll discuss.

If you knock out that Gene you kill an animal very quickly now that doesn't mean it's a longevity Gene you have to do the other experiment to your point you have to overexpress that Gene and ask the question do you live longer and sure enough when they overexpressed that same gene that they had just knocked out and killed the mouse the thing was living 15 to 20% longer.

We have these Central things that everybody would agree Define what an aging phenotype is and can we use exogenous molecules to target those specifically.

The model you choose matters right and and sort of you you you know in an Ideal World you want to use a mouse model that is um you know not inbred that is more closely related to the what we care about which is ourselves.

If that piece isn't working it's very difficult to regulate the first bucket because the first bucket takes so much work so if you can't regulate yourself it's very difficult to regulate the the dos and don'ts but even absent just length of Life stuff it impacts quality of life which is this idea of Health span as well.