Take metformin OR exercise, but don't do both
That's my (slightly clickbaity) summary of this article, which I am sure will reverberate in the haging and healthspan scientific community. To be clear, the inclusion criteria for this (BMI ≥ 25 and ≤ 47 kg/m^2, not diagnosed with Type 2 diabetes (T2D), not currently engaged in > 150 min/wk of exercise, with additional risk factors for metabolic syndrome) filtered out healthy or morbidly obese populations, so these results have to be confirmed in a broader context. All links in the comments.
Still, the study, led by Steven Malin of Rutgers University, is showing some concerning results for at least two reasons:
1️⃣ Doctors have long advised their patients at risk of metabolic syndrome to take metformin, one of the most prescribed T2D drugs, AND exercise. "Researchers tracked how well participants’ blood vessels responded to insulin, a sign of vascular health that also helps regulate blood sugar after meals. Exercise alone improved this vascular insulin sensitivity, allowing blood to flow more efficiently and helping muscle tissues absorb glucose. But when metformin entered the mix, those improvements shrank. The drug also dampened gains in aerobic fitness and reduced positive changes in inflammation and fasting glucose."
2️⃣ Metformin is kind of a pre-GLP-1 miracle drug with all sorts of benefits, some proven clinically (e.g., Polycystic Ovary Syndrome (PCOS)), some under investigation (anti-aging with large trials, cancer prevention, cardiovascular protection, neuro-protection/lowers dementia risk). If metformin is shown to blunt the vascular benefits of exercising in a broader population, that puts a dent in the potential. But that was to be expected. Almost by virtue of affecting multiple aging "pathways", metformin exhibits polypharmacological effects (AMPK, mTOR, NF-κB signaling, and more) that interact, and must strike a delicate balance, with the infinite complexity of biology. Metformin activates AMP-activated protein kinase (AMPK), a master regulator of energy balance, by inhibiting mitochondrial complex I, which leads to improved glucose and lipid metabolism, reduced inflammation, and enhanced autophagy... but also reduced mitochondrial activity. "Those same mitochondria are responsible for adapting to exercise, building endurance, muscle, and cardiovascular health. In effect, the drug may be hindering the body’s ability to strengthen itself through training."
Understanding all of metformin's mechanisms of action remains an open research domain.
Eric Verdin, Alex Zhavoronkov, Jordan Shlain, MD, John Battelle, Nir Barzilai, Adam Gries, Alex Colville, David Barzilai MD, David A. Sinclair A.O., Ph.D., Brian Kennedy, Sergey Jakimov, Mehmood Khan, Hevolution Foundation
https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgaf551/8276136
https://scienceblog.com/when-exercise-stops-working-how-metformin-blocks-the-bodys-gains/
Your immune system doesn't just wear out with age, it actively reprograms itself, starting in middle age (mid-50s), well before you'd be considered "elderly.
A team lead by Claire Gustafson, Ph.D., Peter Skene (both at the Allen Institute for Immunology) and Jane Buckner, MD (Benaroya Research Institute) tracked the immune systems of healthy adults (ages 25-65+) over 2 years, analyzing millions of immune cells and their responses to flu vaccines (Multi-omic profiling reveals age-related immune dynamics in healthy adults), all links in the comments. It also comes with a great playground to explore the data (image below is from the website), my only issue with it being that they (like everyone else) are still using the misleading UMAP algorithm for visualization.
They found that:
➡️ T cells (immune cells that help coordinate defense responses) shift toward a "Type 2" pattern as you age, which causes your body to produce less effective antibodies against vaccines you've had many times before
➡️ Importantly, this isn't caused by inflammation or chronic infections: it seems to be a "natural" aging process (although other latent causes might still be identified).
The downstream clinical applications? Here are some thoughts.
1️⃣ Better Vaccines for Older Adults. Vaccines could be redesigned specifically for how older immune systems work and boosters could be timed better based on these immune changes. Vaccine formulations could also counteract the Type 2 bias.
2️⃣ Early Detection & Prevention. The "RNA Age Metric" the authors developed could identify people whose immune systems are aging faster than expected and are at risk for weak vaccine responses, certain autoimmune diseases (they found similar changes in people who later developed rheumatoid arthritis), and infections.
3️⃣ Targeted Interventions. Specific molecules (like GATA3 and IL-4) seem to be driving these changes, suggesting possible targets for future therapies
4️⃣ Understanding Disease Risk. These findings explain why older adults are more susceptible to certain infections. They help explain why some autoimmune diseases develop in middle age.
Jane Metcalfe, Jordan Shlain, MD, Eric Verdin, John Battelle