About TAME: A Metformin Anti-Aging Clinical Trial with Nir Barzilai, M.D.

This video clip is from episode #204 – Centenarians, metformin, and longevity with Nir Barzilai, M.D., originally released on April 25, 2022.

Show Notes

Clinical studies of Metformin

• Peter asks if there are any clean examples of studies that demonstrate gero-protection of Metformin in humans? 
• Nir replies that even the clinical studies are not perfect studies, but there are still enough of clinical studies (or small studies) that provide confidence
  • There are 2 studies of people with mild cognitive impairment that were treated with Metformin with some success
    • In 1, patients were treated for half a year 
    • In another, patients were treated for 1 year, and some of the outcomes have changed
    • There is no different in how they were treated
    • They didn’t have diabetes, so it’s not that they switched to other medications
• If these studies (and other similar studies showing benefit of Metformin) were compelling enough you could argue that we wouldn’t need TAME

 

 The TAME trial (Targeting Aging with Metformin) [1:39:00]

Geroscience and the study of disease

• There are studies for individual diseases of old age but there are no studies agnostic of disease

“We’re targeting aging. We don’t care what disease you have and we don’t care which disease you’re going to get”— Nir Barzilai

• In geroscience we think aging is going to drive your next disease (outlined in the figure below)
  • Therefore it’s the cluster that is going to count; and we’re counting the clusters
  • You get a point for mortality, just like you get a point for a disease

Figure 3. Diseases of old age.  Image credit: American federation for aging research

• Imagine if reduction of cardiovascular disease comes up in the TAME study
  • The FDA will tell us to stop the study because we cannot continue with the placebo
    • This would ruin it for us
    • So the whole problem of the statistics of TAME is to make sure that we’re not getting a significant effect for any disease
    • We’re just focusing on trends, cluster of disease
  • If mortality is significant that will trigger an early end of the study as well
• Peter asks, “So statistically, your biggest mistake here is overpowering the study for mortality and therefore appropriately powering the study for subsets of disease-specific mortality?” 
  • Yes

Details of the TAME trial

• This is a study that is going to look at people who do not have Type II diabetes, who are between the ages of 65-79
  • There are some other exclusion criteria (having cancer in the last year) but it’s not important for this discussion
• These these people are going to be taking statins; they’re going to be taking medication for blood pressure; some of them will be overweight; some of them will be normal weight
  • They don’t want to recruit future centenarians
  • These people need to have something to show their age
    • Such as a walking speed of less than 6 M/sec 
    • They are not exceptionally fit
  • Peter compares it to the patient population that PREDIMED started with
    • This was a primary prevention study for cardiovascular disease that found a statistical significant difference in under 5 years (but expected the study to go for 7 years)
  • You’re looking for people whose risk of death in the next five years is high enough that you’re going to move the needle [with Metformin]
• The risk of this patient group is you may get a negative study, which means there is no difference in all cause mortality or even disease-specific mortality
• And the counterargument might be that you started too late
  • That’s like applying the brakes on a car that’s driving towards a cliff, when it’s only 20 feet from the cliff
• Should this be a longer study where you start this at people when they’re 50 and your 5 year mortality expectation is very low?
  • Peter’s not saying this can be done because it’s a very expensive study
• Nir notes there are 2 arguments here
  • 1) Starting a study at 50 years old where you have to show mortality is going to be a 20-year study
    • This is too expensive
  • We need to start this study when people are starting to accumulate disease in order to have a lot of events
  • Our hypothesis is that the aging part of your biology doesn’t stop working when you’ve had your first disease
    • It’s still going to get your next disease
    • If we think biologically like that, we should be able to intervene quite late, as we do with animals 
  • 2) There are Metformin studies which included elderly people and their results in prevention diabetes were similar to that of younger people
    • The DPP had 20% over the age of 60
  • There are several other studies that tell us that Metformin will still target aging even if you start it later
• Peter notes, if TAME shows a reduction in all cause mortality in older people, this would suggest biologically that there would be a benefit to starting sooner
  • But how soon? 
• Nir clarifies that they are only looking at trends in mortality in TAME (not an endpoint of mortality)
• The primary outcome of TAME is to look at the cluster of cardiovascular disease, cancer, cognitive disease, and mortality
  • Patients get 1 point for each 
  • Peter asks why mortality is given equal weight to disease occurrence, why wouldn’t it be 3 points? 
  • Nir replies that each of these are an outcome, each incurs health spending

 

Selected Links / Related Material

Previous podcasts with Nir Barzali:

• #123 – Joan Mannick, M.D. & Nir Barzilai, M.D.: Rapamycin and metformin—longevity, immune enhancement, and COVID-19 | Host Peter Attia, The Peter Attia Drive Podcast (August 10, 2020) | [0:45]
• #35 – Nir Barzilai, M.D.: How to tame aging | Host Peter Attia, Host Peter Attia, The Peter Attia Drive Podcast (January 7, 2019) | [1:00]

TAME trial website: The TAME Trial: Targeting the Biology of Aging. Ushering a New Era of Interventions | afar (American federation for aging research) | [1:45, 37:00, 1:30:30, 2:05:15] 

TAME trial, clinical data on the role of Metformin in improving longevity: Metformin as a Tool to Target Aging | Cell Metabolism (n Barzilai et al. 2016) | [1:31:30] 

Nir Barzilai’s TED talks:

• How to die young at a very old age | Nir Barzilai | TEDxGramercy (September 30, 2014)
• Nir Barzilai: Can we grow older without growing sicker? | TEDMED (2016) 
• Ageing is a treatable disease | Nir Bazilai | TEDxBeaconStreetSalo (June 9, 2020)
• How to stop, delay and even reverse aging | TEDx Gateway (May 21, 2021) 

Nir Barzilai’s book: Age Later: Health Span, Life Span, and the New Science of Longevity by Nir Barzilai (June 16, 2020)