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.
甲福明如何与其它可选项抗衡？How does metformin stack up against alternatives?
伽马射线照射的小鼠寿命延长了6.5%，这是如此接近甲福明的中值。我喜欢用γ辐照作为基准，它比较引人注目。这些动物在0.07 cGy/h（厘戈瑞/小时）的持续辐照下，直到他们得到一个4.5Gy的累积剂量。（他们无法对小鼠辐照更多的剂量，因为他们没有活足够长的时间。那是连续267天，24 x7的伽马辐射）。如果地球上的某个建筑物正好有那样的辐射水平，它会有迹象。这是一个6.132西弗特的年剂量。(伽马射线与西弗特一一对应，生物效应的测量，所以这里的数字是相同的)。给你一个多少的概念，这是切尔诺贝利那次事故后第一年内部疏散区的14倍，是NRC核工人每年上限的122倍。
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 of 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.
这是一个特殊的鼠系，AKR / J，得白血病/淋巴瘤的机率约为90%。所以，认为辐射治疗帮助了病鼠，但是一般来说，这些老鼠之所以被选择，是因为他们更容易生病，而不是更少生病，当暴露于致癌物时。还有来自台湾的2006年的一篇论文显示，住在伽马射线辐照水平两倍于NRC的核工人50 mSv的极限的公寓里的人们的非常低的癌症发病率。因为人一生中患癌症的风险是，男性是2个中有1个，女性是3个中有1个。,如果连续辐照大大削减了癌症发病率，这应该转化为寿命的显著提高。
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.