If you like concrete answers and absolutes, longevity is not a fun sandbox to play in. There are surprisingly few things that researchers can agree on when it comes to improving healthspan and lifespan in relatively healthy individuals. However, exercise is generally accepted as one of the few tools that can reliably extend healthspan. (Biting my tongue on a rant of what the definition of “exercise” really is…)
Relatively intense physical exercise is inversely associated with immobility, several cancers, cardiovascular disease, and premature mortality. The proxies for exercise’s benefits we typically see in the literature are improved insulin sensitivity, increased skeletal muscle size, and increased cardiorespiratory fitness, or CRF for short.
So, when an article comes out in the New York Times saying there’s a drug out there that may blunt the health benefits of exercise in healthy older adults, it probably gives one pause. When that drug turns out to be metformin, a candidate for extending healthspan (and is often used off-label for this purpose), it probably gives one a WTF? moment.
If you ask researchers in the longevity field what are the most intriguing interventions for slowing aging and/or increasing healthspan, aside from nutritional manipulation and rapamycin (and aforementioned exercise), a common answer is the chronic use of metformin. So, it’s probably not unreasonable to assume that combining metformin and exercise may produce better results than employing either approach alone. However, a 2019 study casts doubts on this assumption.
Researchers split 53 participants in their early-60s, who had no chronic disease but at least one risk factor for, or a family history of, type 2 diabetes (T2DM), and put them all on an aerobic exercise training (AET) regimen for 12 weeks. One group received metformin (titrated up to 2,000 mg/d in most cases; 1,000 mg twice daily) while the other got a placebo. The AET consisted of 3x/wk of 45-minute sessions at about 85% of their max heart rate on a treadmill, elliptical, or exercise bike.
In a nutshell, the study showed that metformin diminished improvements in skeletal muscle mitochondrial respiration, CRF, and whole-body insulin sensitivity after AET. The investigators suggested that metformin prevented an increase in skeletal muscle mitochondrial respiration without affecting protein synthesis. This wasn’t the first study to show that metformin can lower the exercise-induced improvements in CRF and insulin sensitivity in people without diabetes, as a 2010 and 2012 study had similar findings. Not only that, there are preliminary findings that metformin may inhibit skeletal muscle mass gains in response to resistance training in the elderly.
If we take these findings at face value, what the heck is going on here? Metformin is somehow interfering with adaptations to exercise. Allow me to speculate for a moment. Metformin is known to be anti-inflammatory and reduces reactive oxygen species (ROS) and oxidative stress. All good things, right?
From a “chronic” perspective, sure, which may partly explain its benefits in a chronic disease like T2DM that’s related to chronic inflammation and oxidative stress (as is aging: inflammaging, anyone?). However, from an “acute” perspective, exercise is also pro-inflammatory and ROS-promoting. These are part of a signaling network involved in the exercise-induced adaptations discussed above. Remember the story of antioxidants and the exercise-induced effects of exercise?
Something similar might be going on with metformin and exercise. ROS, cytokines, and myokines, for example, are involved in the adaptation process. If metformin is blunting these signals, it’s interfering with the adaptation. The perceived stress in the body may be artificially attenuated by the drug and therefore the compensatory response is, too. I will save you from all of the gory details in this email, but I may elaborate on the mechanisms and biochemistry down the road.
So, if you’re a relatively healthy person that exercises regularly and takes metformin as an anti-aging drug, should you continue taking metformin? I don’t think there’s a black and white answer at this point and it depends on how you personally respond. In the most recent study, there was a high amount of variability in the metformin group in their response to exercise-induced adaptations. For me, in response to these papers, along with my personal experience of seeing slightly higher lactate levels during zone 2 training(suggesting, perhaps, less mitochondrial efficiency), I’ve reduced my dose of metformin and only take it in the evening in an effort to reduce the amount of metformin in my system when I’m awake and exercising.
Maybe there’s an optimal dosing, timing, and scheduling of metformin, fasting, nutritional makeup, and exercise that’s superior to placebo. Maybe not. And it depends on your makeup and your individual response. As they say in the sports world, that’s why they play the game. While it can be frustrating not having the answers, to paraphrase Richard Feynman, there’s a pleasure in finding things out.