What I am doing to delay ageing (part I): activating AMPK
Part I: on the role of AMPK in recycling cellular debris
Often referred to as the master energy sensor, you can think of the AMP-activated protein kinase enzyme as the switch that changes your body from storing fat to burning it. Thus, AMPK plays a crucial role in keeping in shape. Can it also affect the process of ageing?
AMPK activates a process known as autophagy. Defective cellular components that accumulate over time, such as misfolded proteins, are decomposed and recycled. As this debris is thought to be implicated in the ageing process, via activating AMPK, we may slow down the pace of ageing. As we age, AMPK signalling generally drops, with its activation compromised. In laboratory experiments of roundworms, boosting AMPK activation clearly boosts longevity. In mankind, our results are also promising, which is why AMPK signalling is increasingly attracting the attention of the pharmaceutical industry.
Obviously, AMPK signalling is boosted when we restrict the quantity of calories entering our bodies. This is why numerous celebrities, including Elon Musk, have endorsed the use of temporary periodic fasting. I don't know about you, but I find restricting the quantity of what I eat to be arduous at the best of times. This is probably why so many dieters end up regaining the weight that they lost temporarily, as they lapse back into their old eating habits. Luckily, a running theme in this series is that I will argue that the quality of calories entering our body, and the composition of our diets, plays a more salient role than quantity. More generally, the totality of our lifestyle choices yield the most important influence on ageing. How does this approach apply to AMPK?
AMPK activation seems to be boosted with aerobic exercise. Here are the key results of one study:
“Seven subjects with type 2 diabetes and eight matched control subjects exercised on a cycle ergometer for 45 min at 70% of maximum workload. Biopsies of vastus lateralis muscle were taken before exercise, after 20 and 45 min of exercise, and at 30 min postexercise. Blood glucose concentrations decreased from 7.6 to 4.77 mmol/l with 45 min of exercise in the diabetic group and did not change in the control group. Exercise significantly increased AMPK alpha2 activity 2.7-fold over basal at 20 min in both groups and remained elevated throughout the protocol, but there was no effect of exercise on AMPK alpha1 activity.”
So mixed results, and a small sample size. Matching per se is also not a panacea for establishing causality. Nonetheless, I find the use of biopsies convincing here, and exercise generally passes the common sense test. AMPK activation is also known to cause mitochondrial biogenesis, and is correlated with obesity, type 2 diabetes, and heart disease, so whatever the doctor recommends to treat those chronic diseases (which usually involves exercise) will likely be a reliable means to improve AMPK signalling too. So I think I'm on safe ground in recommending regular exercise here.
One of the nine “hallmarks of aging” is the loss of mitochondrial functioning. Of course, it is well established that mitochondrial functioning declines with age, so the correlation is there. Dysfunctional mitochondria is likely to be casually linked to accelerated ageing. Hence we have a promising pathway to target. Not only does AMPK activation lead to the creation of new mitochondria, it also removes defective mitochondria via a process called mitophagy. Therefore, this is another pathway of ageing that AMPK is directly implicated in.
Metformin
Metformin, that famous drug used to treat type 2 diabetes, directly boosts AMPK activation. As a drug to decelerate ageing, to say that the results are promising would be an understatement:
“Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR)=0.93, 95%CI 0.88-0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR=0.72, 95%CI 0.65-0.80), insulin (HR=0.68, 95%CI 0.63-0.75) or sulphonylurea (HR=0.80, 95%CI 0.66-0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio=0.94, 95%CI 0.92-0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR=0.76, 95%CI 0.66-0.87) or insulin (HR=0.78, 95%CI 0.73-0.83)”
So should we all be taking it? Not so fast! Not only might it undercut some of the gains from exercise, but lifestyle modifications seem to be more effective. Metformin is also not without its side effects, and of course incurs a monetary cost (whilst lifestyle changes do not, relative to the counterfactual). So once we consider opportunity costs and tail risks, I personally am ambivalent here: if your doctor prescribes it to you it should be taken, otherwise it's not a necessity. ChatGPT appears to agree with me. I have also sought ongoing feedback from ACX readers here. I will also update my priors upon the results of the TAME trial.
AMPK and diet
If pills and supplements are no free lunch, then what should we be eating and avoiding to target this mechanism? First of all, it is clear that we must minimise our intake of saturated fats. Implicated in everything from heart disease to cancer or cognitive decline, it is obvious that saturated fats are amongst the most unhealthy aspects of our diets. Indeed, as a testament to this, saturated fats increase levels of liver fat by a much greater degree than sugar intake or unsaturated fats. In fact, holding calories constant, swapping from a diet high in saturated fats to one high in sugar will decrease levels of liver fat, HDL and non-HDL cholesterol. The high sugar diet was not found to yield any significant effects on those key variables.
Nicotine boosts AMPK activation, which is perhaps why it is associated with weight loss, and why cessation of smoking often contributes to weight gain. Needless to say, I do not recommend taking up smoking! As a former smoker myself, I used vaping as a healthier substitute to manage nicotine cravings. This is not cost-free either; I developed a persistent cough which only subsided when I recently ceased its use. This is probably linked to oxidation, another key accelerator of ageing which I will cover in a future post. Zyn, and other nicotine pouches or gums, might work, although it appears that you have to consume a lot before the benefits become visible.
Vinegars, due to acetic acids, are also known to boost AMPK activation. Alcohol, which is converted into acetic acid when processed in the liver, may boost AMPK activation too, although this process creates a known carcinogen as an intermediate, acetaldehyde. This is why alcohol intake is known to be a major risk factor for cancers of all types, even amongst light drinkers. Unlike alcohol, vinegar is known to promote weight loss and blood sugars, probably via AMPK activation. Moral of the story: do not neglect your salad dressings!
In general, a fibre-rich diet will increase endogenous acetic acid production (and that of other short-chain fatty acids) in our bodies as an output of our microbiome - all the rage in recent years! This likely activates AMPK, which is why a high-fibre diet is positive for weight loss. Legumes and wholegrains are an excellent and tasty source!
How am I boosting AMPK activation?
In summary, from these results, it seems a good idea to try the following. You will notice an emphasis on pragmatism here - I am not advocating that we cut out all saturated fats from our diets (in any case that would likely be impossibl), but rather I highlight a number of incremental yet realistic steps. Over time, these will accumulate to generate substantial changes. You may want to adjust this list depending on your preferences, yet given my utility function, I will try the following:
Reduce meat intake. Meat is heavy in saturated fats, and it is those fats that contribute most to that enticing taste. I am doing this anyhow for ethical reasons, conditional on the fact that I would likely lapse into higher meat eating if I went vegan (as is surprisingly common for vegetarians and vegans). As a general heuristic, I may reserve meat eating for dining out only, and cut it out of home cooking.
Avoid baked goods. Those are notoriously high in saturated fats. I do not consume them that often anyhow - I find that they are subject to incredibly high diminishing returns in taste for me. I also tend to get bored of them swiftly, and find (at least in Britain) that they are often bland in flavour, and leave much to be desired in texture. There are much tastier, more interesting (and healthier!) alternatives out there. For others though, this may be more difficult.
Eat more legumes and wholegrains. This goes without saying! A core staple of Middle-Eastern cuisines and of the Indian subcontinent, my two favourite culinary regions, this should be relatively easy to do.
Consume more salads, using salad dressing as an incentive. This will likely be the hardest step for me, yet I find I enjoy them much more with a dressing, which is convenient given the above. If I focus more on the role of vinegars, an uptake in salad consumption is likely to follow. The acids will boost AMPK, and the salads will positively affect other pathways.
Continue to walk an average of five miles each day at a brisk pace. One of my more eccentric habits, yet one which serves me well. If you are starting out an exercise regime for the first time (or returning to one), I would recommend starting small yet consistently. In the studies I cited, 20 minutes appeared to be sufficient to show some gains.