Is Metformin an Anti-aging Drug?

As we age, we all lose sensitivity to insulin and begin, gradually or rapidly, to poison our bodies with excess sugar in the blood. This happens to almost everyone, and it is only when the symptom is particularly severe that it is diagnosed as (type 2) diabetes. Metformin is a drug that has been used to treat diabetes for 50 years, but it is only recently that epidemiologists have begun to notice that patients on metformin have lower rates of cancer and heart disease. Of course, cancer and heart disease were elevated to begin with in diabetics. But the question has been asked: will metformin provide a benefit for “normal” aging, and lower cancer risk for people who are not diagnosed with diabetes?

Vladimir Anisimov from University of Glasgow has proposed that it’s time to test metformin for its anti-cancer and life extension potential for non-diabetics. He is a biostatistician, an epidemiologist and not a physiologist. But a good part of the reason to think that this might work comes from theory.

Metformin and Caloric Restriction

The only intervention that is known to consistently extend life span across many different species is caloric restriction. Animals seem to be widely adapted to stabilize their populations by suppressing death from aging under conditions of starvation (and raising the internally-programmed death rate when there is plenty of food). How does the individual metabolism detect when it is starving? The signal comes mainly from the insulin metabolism. The body responds to chronically elevated insulin by decreasing sensitivity to insulin, and raising insulin levels yet further in a positive feedback loop that cascades toward death. Metformin interrupts this cycle in a manner similar to lowered food intake. Since most people don’t tolerate chronic hunger very well, a drug that offers the benefits of a lean diet without having to cut calories would be highly prized. Such a drug is called a caloric restriction mimetic, and there is some reason to believe that is what metformin does. (Many people taking metformin experience actual weight loss as well.)

The health benefits of metformin for diabetics are striking, and are not shared by other drugs that treat only the diabetes. Metformin cuts cancer rates by 37%.  But cancer is already elevated in diabetics. If the reduction in cancer had been to values below the rates in non-diabetics, then metformin for non-diabetics would seem to be a slam dunk. But in reality this sizable benefit brings cancer rates down just about to their level in non-diabetics, but not further. So the benefits for non-diabetics remain speculative.

Life extension in rats and mice

Over the years, there have been many studies of metformin’s effects on mice and rats. Most show some life extension, and the best result increased life span by 38%. Metformin seems to work better for mice than rats, and better for females than males.  Here is a table (from Anisimov) summarizing results in rodents.

STRAIN	SEX	TREATMENT	NO. OF ANIMALS	LIFE SPAN, DAYS			REFERENCES
				MEAN	LAST 10% OF SURVIVORS	MAXIMUM
Mouse
C3H/Sn	Female	Control	30	450 ± 23.4	631 ± 11.4	643	[67]
		Phenformin	24	545 ± 39.2 (+21.1%)	810 ± 0 * (+28.4%)	810 (+26%)
FVB/N	Female	Control	34	264 ± 3.5	297 ± 7.3	311	[68]
		Metformin	32	285 ± 5.2 (+8.0%)	336 ± 2.7 (+13.1%)*	340 (+16.2%)
FVB/N	Female	Control	15	285 ± 12	396 ± 0	396	[69]
		Metformin	20	304 ± 10	352 ± 7	359
SHR	Female	Control	50	388 ± 29.2	727 ± 22.5	814	[70]
		Metformin	50	535 ± 31.9* (+37.9%)	878 ± 6.6* (+20.8%)	898 (+10.3%)
NMRI	Female	Control	50	346 ± 11.9	480 ± 9.2	511	[71]
		Diabenol	50	369 ± 12.9	504 ± 6.4* (+5.9%)	518
129/Sv	Male	Control	41	662 ± 27.7	951 ± 32.3	1029	[72]
		Metformin	46	573 ± 26.5 (-13.4%)*	931 ± 30.4	1044
129/Sv	Female	Control	47	706 ± 20.8	910 ± 8.9	930
		Metformin	48	742 ± 16.3 (+5.1%)	913 ± 19.2	966 (+3.9%)
Rat
LIO	Female	Control	41	652 ± 27.3	885 ± 11.3	919	[1,73]
		Phenformin	44	652 ± 28.7	974 ± 16.2** (+10.1%)	1009 (+9.8%)
	Female	Control	74	687 ± 19.2	925 ± 22.5	1054	[74]
		Buformin	42	737 ± 26.4 (+7.3%)	1036± 38.9* (+12%)	1112 (+5.5%)
Fischer-344	Male	Control	31	796 ± 170	1039 ± 29.6	1065	[75]
		Metformin	40	815 ± 186	1061 ± 2.5	1062

The difference with control is significant: * – p < 0.05 ; ** p < 0.01 (Student’s test)
(Phenformin and buformin are chemical sisters of metformin. Metformin is prescribed for people because it has the lowest rate of complications and side effects.)

Mechanism for protection against cancer

There is also “test tube” evidence for metformin’s effect on cancer: Cancer cells are supposed to detect that they are diseased  and eliminate themselves harmlessly and promptly via a mechanism called apoptosis. Cancer can’t become cancer until this mechanism is suppressed, mutated away so that the cancer cells don’t automatically commit suicide.   In lab studies of cell cultures, cancer cells respond to metformin by restoring the apoptosis mechanism that was suppressed when they became cancerous in the first place.  Metformin shrinks tumors by inducing cancer cells to commit suicide.  On this basis, metformin is just beginning to be tried as a treatment for cancer patients, with first application to breast cancer.

Side-effects

Complications and risks from metformin are unusual, but they do exist. The main one is called lactic acidosis – a rare but serious disease that is almost unknown outside metformin patients. A conscientious doctor who prescribes metformin will counsel the patient to be alert to the symptoms.

Research study would be most beneficial – but who will pay the bill?

For those who are overweight in middle age or pre-diabetic, there is much to recommend metformin. But are there benefits for middle-aged people who are not in this category? The only way to know for sure is through double-blind clinical trials with at least several thousands of patients. But who will fund such a study? Metformin is a cheap, generic prescription, decades out of patent. There is no company with the motivation to invest in it.

Even if such a study is begun, it will require ten years at best before we know anything.  In the meantime, a few avid life extensionists are taking the chance and asking their doctors for a prescription, or even self-medicating through on-line pharmacies.  Perhaps we will learn from their experience.