Longer Life In A Bottle?

It’s a new year and it’s time for a better you. How timely therefore is the recent approval of the well-publicized TAME trial? Have you not borne witness to the media frenzy, rife with phrases such as “anti-aging” and “life-extension”? TAME stands for “targeting aging with metformin.” Metformin is a diabetic drug that’s been around for 60-plus years. The one your grandma takes? You got it.

If you’re skeptical, that’s only natural. Odds are, however, that as biomedical technology improves, allowing us to probe deeper into the pathways underpinning the aging process, various interventions (be they genetic or purely biochemical) will be spawned that will slow down or potentially reverse the aging process. And there is already ample data to suggest that metformin, a time-tested generic drug (to the chagrin of Big Pharma), has anti-aging and potentially life-extending properties. If you’re still in doubt, then Google “Metformin + Life Extension.” The number of citations touting the salubrious effects of the drug is astounding. It not only improves one’s metabolic profile by enhancing insulin sensitivity and lowering circulating insulin, but also by virtue, reduces the formation of AGEs (the pun is uncanny), or advanced glycation end-products, that wreak havoc on the vascular endothelium and dramatically accelerate the atherosclerotic process. And what kills more Americans than any other disease hands down? Vascular diseases such as heart attack and stroke. There is truth to the adage, “You’re only as old as your arteries.”

Yes, it is likely that metformin tempers the atherogenic (plaque-forming) process. But its effects are undoubtedly far more wide-ranging as described in a 2014 study published in Diabetes, Obesity and Metabolism. Scientists compared mortality in diabetic individuals treated with metformin or sulphonylurea monotherapy and matched non-diabetic controls. And guess what? The diabetics on metformin lived longer than even their non-diabetic patient-matched counterparts.  And the study was massive, following 78,241 subjects over a five and a half year period. Specifically, adjusted mean survival time was 15 percent lower in matched individuals without diabetes relative to diabetics on metformin monotherapy.

What is going on here? Can people with type 2 diabetes live longer than those without by virtue of a drug effect? Diabetics classically succumb to the effects of accelerated aging, manifested as premature development of cancer, atherosclerotic heart disease, Alzheimer’s dementia, or any number of age-related diseases. So metformin’s substantial actions more than negate the untoward metabolic effects of elevated glucose levels and secondarily insulin. How does it accomplish this? That is unclear.

Remember, though, that metformin increases one’s insulin sensitivity and, by virtue, lowers circulating levels of the inflammatory hormone insulin. Put simply, less inflammation means a longer life. Excess insulin is one of our nation’s biggest risk factors for disease. Secondly, by reducing mTOR pathway throughout (like the anti-rejection drug rapamycin), metformin reduces circulating levels of “growth factors” that accelerate not only the atherosclerotic processes but oncogenic (cancer-forming) ones as well.

A testament to this is the observation that survival was better with metformin even in those people who did not receive cardiac prophylactic medications at baseline. Clearly metformin served as the cardio-protectant in this large patient cohort. How? In addition to its capacity to inhibit hepatic gluconeogenesis (glucose release from the liver), the actions of metformin are intimately related to its actions on adenosine mono-phosphate kinase (AMPK), an enzymatic “master switch” integral to cellular energy regulation, hormone expression, and protein synthesis.

Metformin upregulates AMP kinase and drives lipolysis (fat-burning) in a similar way that occurs during the fasted state. From a bio-evolutionary standpoint, the presence of famine induces a metabolic shift: We call upon our fat stores for energy (ATP) production, right? By increasing the expression of AMPK, metformin mimics the effects of caloric restriction, the only proven life-extending strategy in mammalian models.

This begs the question: Can metformin exert similar life-extending effects in those of us with normal serum insulin levels? There is no “indication” for metformin in the normal population, certainly not as a protective or preventive medication. Speaking from experience, most physicians shudder at the thought of such an off-label indication for metformin, but all of this recent data cannot be ignored.

Pharmaceutical companies have zero interest in sponsoring trials (such as TAME) for medicines that potentially have a preventive role for the population at large. Why? Unfortunately, there is money in disease, not health. If fewer people were sick, there would be fewer people to whom their medications could be peddled.

Our advice? Discuss the info with your doctor. Don’t wait for the data from the TAME trial prior to your doing so either. Inform your doctor of the available study data (likely he or she will be unaware of it). Heck, take this issue of Iron Man to your next physician’s visit. Metformin has a fairly benign side-effect profile and is usually well tolerated. In fact, one of the often-noted “side effects” is fat loss. (We bet that piqued your interest.) Lowered circulating insulin levels are typically associated with fat loss, right? Think Atkins Diet. Metformin is also cardio-protective, chemopreventive (in the context of cancer), thought to thwart the progress of neurodegenerative diseases such as Alzheimer’s dementia, and it is inexpensive as well. In fact, Publix pharmacy offers a 30-day supply of metformin for free to select insured patients presenting with a prescription. The drug with potentially the most global impact is free. Oh, the irony…  IM

Bannister CA, Holden SE, Jenkins-Jones S et al.  Can people with type 2 diabetes live longer than those without?  A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obesity and Metabolism 2014; DOI: 10.1111/dom.12354 [Epub ahead of print].

Osborn, Brett A. Get Serious, A Neurosurgeon’s Guide to Optimal Health and Fitness. Bothell, WA: Book Publisher’s Network, 2014. Print.