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In this episode of The Drive podcast, Peter Attia sat down with Dr Matt Kaeberlein for a conversation about the merits of prominent ”anti ageing” drugs. Specifically, they discuss three molecules: NAD, metformin and rapamycin, and the strength of the evidence behind each of them. They also discuss the basics of how we attempt to determine whether a treatment slows ageing, and why studies claiming to show lifespan extension aren’t always as credible as they may first appear.

What follows is a summary of the key points of their conversation. It might be a little hard to follow if you aren’t already versed in some of the topics discussed. If that’s the case, you will find links to some of our previous articles throughout the text. Hopefully, these should provide the context you need to better understand the points being made.

How We Measure Ageing:

Biomarkers of ageing:

• To know if a treatment is slowing ageing, we need ways of measuring it.
• Biomarkers of ageing are measurable variables that can give us an idea of a person’s biological age.
• Unlike many other diseases, ageing does not yet have any great biomarkers.
• The biomarkers that reflect biological age won’t necessarily be the same as the biomarkers that reflect the rate of ageing.
• Not all biomarkers are molecular. Biomarkers such as organ function are harder to measure but are more directly related to health outcomes. These are called functional biomarkers.

Epigenetic clocks:

• Epigenetic clocks can give us an idea of whether a person is ageing more rapidly or more slowly than average by measuring epigenetic modifications – chemical modifications to the DNA or to the molecules that pack the DNA.
• These chemical modifications control gene expression and they change in a predictable way throughout life.
• By comparing epigenetic modifications to chronological age throughout the population, we can make algorithms that take a group of these modifications and use them to estimate what a person’s chronological age should be if they follow the average ageing trajectory for that population.
• If a person’s estimated chronological age is significantly different to their true chronological age, this suggests that they may be biologically older or younger than their chronological age.

Strengths and weaknesses of epigenetic clocks:

• Longitudinal studies in humans suggest that epigenetic clocks correlate with future health outcomes to some extent.
• However, no one has yet shown that reduced epigenetic age at the individual level predicts improved future health or lifespan, either in mice or in humans. Because of this, Matt Kaeberlein is sceptical of whether epigenetic clocks can be more valuable than more tried and tested biomarkers.
• Epigenetic clocks measure just one of the nine suspected hallmarks of ageing, so they aren’t giving us the whole picture.
• We might be able to develop better clocks by combining epigenetic measurements with other biomarkers of ageing, but Matt isn’t sure whether we can do this with our existing biomarkers, or whether we need to discover more.

Important Ideas About Lifespan Extension Studies

Human studies vs non-human studies:

• We are most interested in slowing, preventing or reversing ageing in humans, so studies in humans are the most relevant to our goals.
• Non-human studies are still valuable, but especially when results are consistent across different species, suggesting that the relevant mechanisms of ageing are conserved throughout evolution.
• Non-human studies in pets are valuable because they share our environments.
• Simple organisms like worms and fruit flies are useful because they age quickly and can be used to screen thousands of interventions for anti ageing properties.
• More complex organisms like mice allow us to dig more deeply into the mechanisms of anti-ageing interventions, while also being much more biologically similar to humans.
• Human studies are ideal, but it takes decades to find out whether an intervention is having an impact on ageing.

Problems with studies of lifespan extension:

• Researchers rarely attempt to replicate experiments that extend lifespan in mice.
• When researchers do attempt to replicate these experiments, they are often unable to reproduce the lifespan extension.
• This may be linked to the lifespan of the control group, which can vary quite a lot depending on housing conditions.
• An increase in lifespan is less impressive when the control group is short-lived, because the treatment may simply be ”getting the animals to where they should have been to begin with”.

Comparing NAD, Rapamycin and Metformin

A crash course in NAD:

• NAD is a molecule that is present in all cells and is essential to life. It is required for the production of the ‘cellular fuel’ ATP in the mitochondria, as well as over 500 metabolic reactions.
• NAD can accept an electron from one molecule, becoming NADH, and transfer it to another molecule, which converts it back into NAD. This means that the NAD molecule is not consumed (for a more in-depth explanation of how this all works, see this article).
• NAD is required for the activity of a group of enzymes called sirtuins.

Potential benefits of boosting NAD:

• NAD is necessary for the activity of sirtuins, which control the expression of genes by modifying the DNA’s packaging proteins. Sirtuins are suspected to improve longevity, though there isn’t a lot of strong evidence (yet) that sirtuin activity extends lifespan in organisms other than yeast.
• NAD is critical for the operation of the mitochondria. Mitochondrial dysfunction is considered to be one of the hallmarks of ageing, and leads to the depletion of NAD, which prevents the mitochondria from breaking down glucose to generate ATP (glycolysis).
• NAD is required for the activity of PARPs, which repair DNA. DNA damage is considered to be a hallmark of ageing.

NAD precursors and their evidence:

• NAD itself isn’t absorbed by cells, but cells can absorb some molecules that are then converted into NAD. The most prominent of these are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).
• These supplements are can be taken orally and appear to be safe, but the evidence that they can extend lifespan is limited.
• NAD precursors may be beneficial in diseases in which NAD depletion plays an important role.
• When it comes to treating ageing in general, Matt Kaeberlein notes that while NAD levels may decline throughout life, whether it ever falls low enough for NAD precursors to be beneficial is uncertain.
• Human studies are beginning to show benefits for NAD precursors in certain diseases. For now, these have been mostly small studies with relatively conservative doses.

Rapamycin and Metformin

Metformin and its evidence:

• Metformin is a drug for type II diabetes that also appears to protect against various age-related diseases.
• Metformin has been shown to slightly increase mouse lifespan at low doses, but also greatly shortens their lifespan at higher doses. However, some evidence contradicts this lifespan extension, most notably that from the Interventions Testing Program.
• Lower does metformin also improved health metrics like metabolic function and blood sugar control. Matt Kaeberlein warns against claiming that an intervention increases healthspan when healthspan isn’t something we can quantitatively measure.

• One of the most impressive pieces of human evidence for metformin is that diabetics taking only metformin were more protected against some diseases (such as cancer) than nondiabetics not taking metformin.
• However, Matt Kaeberlein notes that this evidence excludes diabetics who required more than just metformin to maintain their blood sugar. In other words, it’s comparing the healthiest diabetics to nondiabetics, which makes the results a little less impressive.

Rapamycin vs metformin and NAD precursors:

• Rapamycin is an immune system modulating drug, used as an immune suppressant in organ transplant recipients.
• There is convincing data to say that rapamycin extends lifespan in every species it’s been tested in, but we don’t know if this translates to humans.
• The evidence for lifespan extension in animal models is most convincing for rapamycin.
• Rapamycin is the least studied of the three drugs in humans and has the least well understood mechanisms.
• Evidence suggests that rapamycin benefits a wider range of tissues than metformin, which primarily benefits glucose metabolism, and NAD, for which the effects on different tissues are less well understood.

Peter Attia’s risk vs reward ranking:

• When considering whether to take a drug, Peter Attia likes to frame the question in terms of potential reward vs risk.
• In terms of reward, Peter Attia considers rapamycin to have the highest potential reward, while NR and NMN have the lowest. Metformin lies somewhere in between the two, and is likely to have a larger reward in people with insulin resistance.
• In terms of risk, NMN and NR have the lowest risk. Metformin is riskier due to its known side effects. Rapamycin doesn’t appear to have many negative side effects when administered in a pulsatile fashion.
• Peter considers all of these drugs to be relatively low risk when measured up to the potential benefits.

Life is a dangerous thing. We’re all inevitably marching towards death. One has to at least be somewhat prepared to take some risk in order to mitigate the risk of death.

Peter Attia