#207 – AMA #35: “Anti-Aging” Drugs — NAD+, metformin, & rapamycin

In this “Ask Me Anything” (AMA) episode, Peter is joined by special guest, Dr. Matt Kaeberlein. Together they answer many questions around the field of aging with an emphasis on three specific molecules—NAD, metformin, and rapamycin—and their purported geroprotective qualities. They first discuss aging biomarkers and epigenetic clocks before breaking down the advantages and limitations of the most common experimental models being used today to study aging and pharmacological possibilities for extending lifespan. Next they dive deep into NAD and the much-hyped NAD precursors, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). They compare data from NAD precursors to studies on metformin and rapamycin, assessing how they stack up against each other and using the comparison as an opportunity to illustrate how to make sense of new experimental data and make smart decisions about how to approach future research.

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We discuss:

• Logic behind comparing NAD precursors to rapamycin and metformin [3:40];
• Aging biomarkers: current state, usefulness, and future promise [7:00];
• Epigenetic clocks: definition, use case, and limitations [14:45];
• Advantages and limitations of studying aging in non-humans and the strengths and weaknesses of different model systems [26:30];
• Aging studies: importance of control lifespans and the problems with reproducibility [34:15];
• Intro to NAD, potential role in aging, relationship to sirtuins, and more [48:15];
• NAD precursors (NR and NMN): current data [1:10:00];
• Human studies with NAD precursors [1:25:45];
• Comparing NAD lifespan data to data from metformin and rapamycin [1:28:30];
• Defining a “clean drug” and a “dirty drug” [1:38:00];
• Reason for the lack of rapamycin studies in humans compared to NAD and metformin [1:41:00];
• Ranking the geroprotective molecules in terms of risk and reward [1:48:00]; and
• More.

Logic behind comparing NAD precursors to rapamycin and metformin [3:40]

The team has been collecting a ton of questions around the science of aging—specifically about three geroprotective molecules: NAD, rapamycin, metformin

*Previous podcasts on related topics:

• Matt Kaeberlein (#10, #175)
• Steve Austad
• Nir Barzilai (#35, #204)
• Joan Mannick
• David Sinclair (#27, #70)
• Lloyd Klickstein
• David Sabatini

The rationale

• Initially, the idea was to exclusively discuss NAD and its precursors
• However, Matt felt strongly that we needed to look at rapamycin and metformin
• The reason being that those three molecules often get talked about together in the field and by people who are following the field as certainly three of the leading candidates for geroprotectors
• There’s a lot of value in a compare and contrast in order to take a look at the current state of the data so that you can really understand what is the evidence for each of these classes of molecules
  • Including some of the challenges as we think about moving from the laboratory into the real world, into the clinic in terms of testing them

Aging biomarkers: current state, usefulness, and future promise [7:00]

Are there any biomarkers of aging that we can look at when we look at these molecules?

• When you contrast aging with a field like lipidology, you can see how much more challenging aging is, relatively speaking
• For instance, if your objective is to lower ApoB, because ApoB plays a causative role in atherosclerotic cardiovascular disease, you have the perfect biomarker
• But when it comes to this field of aging, it really is difficult

The two sides of thinking…

• Some people who will argue that we have remarkable biomarkers for aging
• Others argue that we don’t really have any good biomarkers for aging

Where does Matt come down on this?

• One of the things that you have to consider is, what do you want a biomarker to do?
• Note that we’re talking about biomarkers of biological aging
• “What I think you really want is something you can measure that is predictive at either the individual or the population level of future health outcomes, mortality, certainly, but also functional outcomes, disease risk, things like that” says Matt
• On one level we absolutely have biomarkers
• For instance, we can look at two people who are the same chronological age and humans are actually pretty good at estimating who’s in better health
• We’ve evolved to do that so the thinking is that there must be some underlying molecular, biochemical signatures that we can find that are predictive of that
• Trying to find these molecular biomarkers of aging has been going on since the 1980s and it’s still a work in progress

Biomarker candidates

• We do have some candidates now
• There are people in the field who are very optimistic, possibly overly optimistic, about how well those candidates work
• It’s also an interesting time because we’re starting to see commercialization of these so-called aging clocks that are being sold to the general public
• Matt does feel like we are closer than we were 15 or 20 years ago, however, we’re still a ways off from the ultimate goal—having something that you can measure that in a predictive way, at either the individual or the population level, really tells you with any level of precision, what the biological aging trajectory is

The idea of blood-based biomarkers

• Peter says it would be really valuable if we had blood-based biomarkers where you could do interventions for a short period of time
• And if in fact those interventions would, if continued, lead to better lifespan, they would show up
  • For example, if you took an individual and you calorie restricted them for three months, took them down to 70% of their weight maintenance caloric intake, you would like to think that there would be some set of biomarkers that would suggest an improvement in their lifespan

What does Matt think about that idea?

• From a pragmatic perspective and a usefulness perspective, that’s exactly what we want
• But it remains a complicated question—it’s one thing to hypothesize that there are going to be molecular biomarkers that reflect biological age, but those are not necessarily going to be the same biomarkers that reflect rate of aging
• A short-term read-out almost has to reflect rate of aging, or even potentially, a reversal of biological aging
• And those may not actually be the same markers for each of those classes

“I certainly believe that there will be signatures of intervention responses that are predictive of efficacy, I’m not sure that it’s going to be the same as the signatures of biological age.” says Matt

Looking back…

• When Matt was first starting in this field 15-20 years ago, if you had asked him then whether caloric restriction is slowing aging or reversing aging, he would’ve answered their slowing aging by decreasing the rate of decline or damage accumulation
• What’s been really exciting over the last 10 years is the observation that at least some of these interventions reverse many of the molecular changes that go along with aging, and in many cases, the functional changes that go along with aging.

Functional biomarkers

• Matt says he’s a big fan of functional biomarkers (i.e., organ function, tissue function)
• It’s harder to do in  people than it is in laboratory animals 
• Matt feels that functional biomarkers are telling us something fundamental about future health outcomes that you can almost take to the bank
• I.e., if you can make somebody’s heart function better, their brain function better, you got to feel pretty good about that
• If you can make multiple organs and tissues function better with the same intervention, you can probably make a case that you are in fact modulating some underlying biology of aging, as opposed to only the biology of that tissue and organ

“What gives me great confidence that we’re moving in the right direction with a patient, it’s when basically when all of those functional things improve.” —Matt Kaeberlein

• If VO2 max improves, muscle mass improves, strength improves, cardiovascular efficiency improves, phenotypic markers of disease improve (i.e., glucose disposal, insulin signaling, ApoB, lipid markers, inflammatory markers)
  • some of those are things you measure in blood,
  • some of those are things that you measure non-invasively, 
  • some of those things are imaging related
• “But until someone comes up with better tools, this is basically how I think about this problem.” says Matt

Epigenetic clocks: definition, use case, and limitations [14:45]

What are epigenetic clocks, how they work, and what they’re aspiring to do?

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