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Metformin, Gamma Rays or Chocolate?
Brian Hanley   Dec 26, 2015   Ethical Technology  

Is metformin safe? The dose for the metformin aging clinical trial is 1700 mg per day. The mouse study doses from the graphs below are 300 and 100 mg/kg/day. Assuming an average 60 kg person, that’s about 28 mg/kg. This is about one-third to one-tenth the dose that mice got. 

For humans, it’s a fairly stiff dose, but well inside guidelines, so risk of dangerous side effects is low. Metformin induced lactic acidosis cases have been 3 per 100,000 patient years at similar dose rates. Fatality from lactic acidosis has been 1.5 per 100,000 patient years. For this clinical trial, there shouldn’t be problems. But if rolled out to stage 4 (FDA approval) we should expect a few people to die from over-enthusiastic embrace of this drug. Is that epidemiological certainty worth making metformin easily available? I think so. That is about double the death rate for people running marathons. (Curiously, almost all of them die in the last mile.) It’s a bit lower than the 1.77 per 100,000 risk of death while swimming.

There is one disquieting concern with metformin because it kicks up a pathway that produces amyloid. And some indications are that type 2 diabetics using metformin have poorer cognition than those who don’t. Others suggest it might prevent Alzheimer’s, but that is speculation.

Is metformin going to get people to 100 years of age? Here are multiple studies from rats and mice comparing various drugs and environmental interventions. A 20% increase in life span is the outside edge of results for this drug. Metformin results range from 2.27% up to 20.71%, and treated mice from fairly early in life. The median life span extension is 6.87%, which is right between cage enrichment and gamma ray irradiation.

Most people will start taking metformin late. So expecting people to live 120% of normal life span (an extra 14 years or so) is very unlikely. There is little reason to expect a large observable effect. If there is, then it should be in the low single digits. If you are a man, you might see at most 2-3 years more. If you are a woman, perhaps 4.

How does metformin stack up against alternatives?

Gamma ray irradiation extended mouse life span by 6.5%, which is so close to the median for metformin it hardly matters. I like to use gamma irradiation as a benchmark – it gets a person’s attention. These animals were dosed at 0.07 centigray per hour continuously, until they got a dose of 4.5 gray. (They couldn’t dose the mice more than that because they didn’t live long enough. That’s 267 days of continuous, 24x7 gamma radiation.) If some building on earth had that level or radiation, there would be signs all over it. That is a yearly dose of 6.132 Sievert. (Gamma rays have a one-to-one correspondence with Sieverts, the measure of biological effect, so the numbers are the same here.) To give you a sense for how much that is, it is 14 times the inner evacuation zone at Chernobyl, in the first year after that accident. It is 122 times the NRC nuclear worker limit per year.

This is a special mouse strain, AKR/J, which gets leukemia/lymphoma at about a 90% rate. So, it could be argued that the sick mice were helped by radiation treatments, but generally, these kinds of mice are chosen because they get sick more easily, not less, when exposed to carcinogens. There is also a 2006 paper from Taiwan that showed radically lower cancer incidence in people who lived in apartments that irradiated them with gamma rays at levels up to nearly double the NRC’s nuclear worker limit of 50 mSv. Since the overall lifetime risk of getting cancer is about 1 in 2 for men and 1 in 3 for women, if continuous irradiation cuts cancer rate dramatically, that should translate into a significant gain in life span.

Chocolate may have as large an overall effect as metformin. Acticoa, a Swiss product, improved cognition and increased life span by 11%. Similarly to metformin, this chocolate product shows some cancer prevention activity. So you can probably get similar results from the right chocolate preparation as from metformin.

Which is better? That’s really hard to say. Metformin is a good thing to try. It’s a foot in the door for a new class of treatments in a new category the FDA has never reviewed before, and that’s good. But it’s not the only game in town, not by a long shot.

Image #1: Brian Hanley creation
Image #2: The green line

Brian Hanley is the founder of Butterfly Sciences, a company developing gene therapies for aging. He has a range of papers in biosciences, economics, policy and terrorism, in addition to a recent text on radiation treatment. He obtained his PhD in microbiology with honors from UC Davis, has a bachelors degree in computer science, is a multiple entrepreneur and guest lectured for years to the MBA program at Santa Clara University.

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