Running Away

Between 2013 and 2020 the USA population increased by 4.5%, and the number of cancer deaths increased by 4.3%^{1, 2}. What is more, most cancers are occurring in progressively younger victims³. Whatever Big Pharma barkers might tell you, the situation is not improving. 

We should focus more on prevention. This may be less lucrative (for some), but it is far better for us. Whereas the side effects of cancer treatment are uniformly harmful, cancer prevention brings multiple health benefits. 

There are many ways of reducing the risk of cancer, and because they work in substantially different ways their protective effects are at least partially additive. 

Avoiding tobacco, hard liquor, processed meats, ultra-processed foods, asbestos, chronic inflammation and excessive UV exposure will take you a long first step away from the oncology department. Losing weight, particularly if you have type 2 diabetes, is hugely protective⁵. And there is more. 

Populations that pre-date or continue to avoid the 20^th / 21^st century lifestyle, which is intrinsically carcinogenic^{3, 4}, have rates of cancer that appear to be as low as 10% of ours^{6, 7}. Nutrition plays a key role here, of course, but levels of physical activity are critically important too.

The ability of physical exercise to reduce the risk of many cancers by between 10 and 30% has been known for years⁸, and a mountain of research has produced insights into how this risk reduction might work. 

Exercise induces transcription factors in the body which act directly on cancer cell metabolism via inter alia AMP-Kinase and MTOR, slowing proliferation and metastasis and inducing apoptosis. Other messengers have an anti-ageing effect on the immune system, restoring effectiveness to key cellular components such as NK cells and improving immunosurveillance in general.

Exercise releases anti-inflammatory myokines, and an anti-inflammatory environment supports immune function and stabilises the extra-cellular matrix, discouraging metastasis. Physical exercise helps some to avoid obesity which is carcinogenic via, among other things, promoting chronic inflammation.

Exercise increases insulin sensitivity^{ie 9} and modulates IGF-1 and other growth factors¹⁰. It may also reduce estrogen levels¹¹ and the amount of estrogen-sensitive tissue in cancer-prone tissues such as the breast¹²; and affect bile chemistry and gut transit time positively also.

There are plenty potentially protective mechanisms to choose from, but how do we know which of these, if any, are important? How much, and what kind of exercise, provides the best protection? And do dietary factors play into this?

One very large USA-based observational study (a half million subjects followed for over 10 years) came up with a road map to cancer risk reduction. The data suggested that it took more than five hours of moderate exercise, plus one hour and 15 minutes of vigorous exercise and at least two sessions of muscle strengthening per week, to achieve what looked like a 56% reduced risk of cancer¹³.

Another major study which followed 22,398 British BioBank participants for an average 6.7 years discovered a very different dose-response curve. The researchers found that a mere 4 to 5 minutes of vigorous (but not high intensity) exercise a day, in one-minute bursts, reduced the overall risk of cancer by 18 per cent and the risk of some specific cancers such as liver, kidney, stomach and bladder cancers, by up to 32 per cent¹⁴.

This pattern was not entirely surprising, as previous research^{ie 15-19} had already found that the risk of these types of cancer were a) more linked to sedentary lifestyle and b) more significantly reduced by increased levels of physical activity than others.

These very different exercise profiles (6-7 hours vs 30 minutes / week) exert rather different metabolic effects, and this should provide clues as to how exercise exerts its chemo-preventive benefits. Let’s start with insulin, which has long been a candidate component in this area.

Insulin resistance is increased by a sedentary lifestyle²⁰, and reduced by exercise^{9, 21}.  It is elevated in many cancer patients^{22, 23}, in whom it is linked to increased mortality^{ie 43}. 

Seen from an evolutionary perspective, it makes sense for cancer cells to cause insulin resistance, because increasing levels of insulin and the insulin-like growth factors (IGF’s) encourage cancer growth and survival (‘success’), at least in the short term²⁵. 

This would explain why cancer cells have found ways of encouraging insulin resistance by more than one route. Some cancers may induce insulin resistance and hyperinsulinaemia directly, by driving or mimicking the production of corticotropin-releasing factors²⁶. Others achieve the same end-result via cross-talk with local adipocytes, recruiting them to produce the adipokine resistin^{27, 28}.

Different exercise regimes reduce insulin sensitivity, and both exercise intensity and duration play a role.

One research team found that High Intensity Interval Training (HIIT) only required 20 to 25 minutes of exercise three times per week to achieve metabolic improvement²⁹. Another group came in with an even lower bid. They reported that 2 weeks of high-intensity training (comprising four to six cycle sprints of 30 s duration at each session, a total session length of 15 min and six sessions per week) improved insulin sensitivity by 23% in young, healthy men³⁰.

This is roughly the duration of exercise that was reported to reduce cancer risk in the BioBank study cited above, but involved a considerably more intense form of activity. So is duration or intensity more important? Or is exercise ‘volume’ (a composite of duration and intensity) the key?

In yet another study, exercising for 170 min/week improved insulin resistance significantly more than a program of 115 min/week, independently of exercise intensity^{28, 29}. The scientists suggested that the theoretical minimal activity to maintain optimal metabolic health is a modest 10–20 km/week of walking or jogging (2,930–4,186 kJ) or other energy expenditure equivalent³⁰.

A Japanese research team looked at the impact of exercise on IGF levels, and showed a significant reduction in free IGF1 on a regime of 60 minutes of low-intensity aerobic exercise / day³².

It is not yet possible to see a clear dose-effect relationship emerging from the noise, because nobody has yet adequately titrated the effects of different volumes of exercise on any one metabolic end-point. Nonetheless, the last two papers suggest that exercise duration may be more important than intensity when it comes to insulin resistance, and are hard to reconcile with the BioBank cancer findings UNLESS the major anti-cancer effect of exercise is not mediated via reduced insulin resistance but via some other mechanism.

NB: Exercise intensity may be more important in addressing metabolic issues³³; which would lead, over time, to reduced GI cancers.

As the optimal amount of exercise needed to reduce cancer risk is not yet resolved, and as the insulin resistance link starts to look less critical (although still likely relevant), let us turn to other possible chemo-protective mechanisms.

From personal experience of 6 decades of sports and athletic activities I am quite sure that a few minutes of exercise is insufficient to alter gut transit or bile chemistry, and from an entry-level appreciation of the body’s multi-layered buffering systems I find it hard to believe that such short bursts of activity modulate the endocrine system in any long-term way.

This brings us back to AMP-Kinase, the energy sensor, AKA the energy master-switch.

When activated (phosphorylated), AMP-K promotes the survival of β cells in the pancreas, and promotes glucose metabolism and uptake. It inhibits insulin resistance and ameliorates diabetic complications³⁴. It also exerts tumor-suppressive and chemo-preventive activity^{35, 36}. 

AMP-K is rapidly activated by vigorous aerobic exercise, at circa 60% of maximal aerobic capacity³⁷, within a time frame that more or less fits the BioBank study results. It is also activated by lower intensity exercise, but this has to be maintained over a very much longer period of time to achieve a similar result³⁸. 

A falling ATP/ADP ratio and glycogen depletion³⁹ triggers the release in muscle of the local energy sensor IL-6^{36, 37}, which activates the systemic energy sensor AMP-K^{40, 41}. Different types of exercise – ie acute, intensive, prolonged – activate different isoforms of AMP-K^42-44, but the clinical implications of these differences are not yet understood.  

Glycogen depletion is also of course caused by calory restriction. Fasting is thus another trigger for AMPK activation⁴⁵, as are a range of phytonutrients^{46, 47} including polyphenols⁴⁸, saponins⁴⁹ and alkaloids⁵⁰, which act as calorie restriction-mimetics⁵¹ and exercise-mimetics⁵². 

Both fasting⁵³ and higher levels of polyphenol consumption⁵⁴ display chemo-preventive properties, which lends tangential support to the idea of exercise reducing cancer risk via AMP-K activation.

AMP-K activation triggers a number of chemo-preventive mechanisms directly.

1. It down-regulates MTOR^{55, 56}, thus reducing cellular proliferation and tumour growth⁵⁵.

2. It promotes mitochondrial biogenesis⁵⁷. This encourages oxidative phosphorylation and inhibits glycolysis⁵⁸, on which many cancer cells depend for ATP synthesis^{ie 59}.

3. It forces cells to down-regulate their intracellular stores of fatty acids⁶⁰, driving both beta oxidation (the primary effect), and their incorporation into cell membranes. If these cells have been fed on HUFA’s such as occur in oily fish, the resulting oxidative stress in cell membranes kills cancer cells via ferroptosis^{61, 62}. Polyphenols like pycnogenol drive ferroptosis via a similar mechanism⁶³, providing another persuasive reason for combining omega 3 HUFA’s and polyphenols in dietary or supplemental form⁶².

4. Intense exercise at a dose of 45 minutes three every other day up-regulates the activity of immunosurveillance cells (specifically CD8+ and NK cells), in a sub-set of individuals with a high genetic risk of acquiring cancer⁶⁴. AMP-K activation plays a key role in enhancing the anti-tumour function of CD8+ cells⁶⁵, and possibly NK cells^{66, 67}.

There is a fifth, somewhat teleological argument or line of evidence. 

AMP-K is very tightly conserved and occurs in almost all eukaryotes where it controls the organism’s metabolic responses to the availability or lack of external energy, whether this is food or sunlight. 

As these responses are critical to survival, AMP-K has acquired multiple binding sites that allow it to be modulated not only by ATP/AMP ratios but also by hormones /cytokines involved in weight and appetite control. These include leptin, adiponectin, ghrelin, thyroid hormones and various endocannabinoids^68-72.

(This is probably putting the cart before the horse. AMP-K likely came first, and higher life forms subsequently developed messenger compounds that could modify its activity). 

During good times the master switch is in the off position, allowing the organism to store energy and grow. When times are lean the switch is activated, initiating a sort of triage. It instructs the organism to maintain those processes essential to survival, slow less essential processes, and stop the routines involved in growth.  This is why exercise, which inevitably shifts you into net negative energy balance, promptly activates the IL-6  AMP-K connection ^{ie 37, 38}. 

As the default mode of single cell organisms has always been proliferation, the evolutionary development of multicellular organisms, eventually including humans, required control mechanisms to prevent unchecked proliferation^{ie 71, 72}. One of these is AMP-K. An original function of AMP-K activation was to stop unnecessary cellular proliferation, which is unaffordable during lean times and is also, in higher lifeforms, a hallmark of cancer. 

As mentioned previously, AMP-K activation up-regulates two different immune cell types that are involved in the identification and killing of cancer cells, namely natural killer cells⁷² and CD8+ T-cells^{65, 74, 75}. So, predictably, does exercise⁷⁶.

In short, exercise appears to be chemo-preventive largely via AMPK-activation. The AMP-K agonist AICAR, which could be regarded as another exercise mimetic, also reliably slows cancer growth and induces cancer cell death⁷⁷. 

Although the exercise / cancer link is starting to look reasonably coherent, and the dangers of the sedentary lifestyle are increasingly well documented⁷⁸, substantial questions remain. 

Why is inactivity so bad for us? The idea that excessive sitting causes health problems seems deeply paradoxical because evolutionary pressures favor energy-minimizing strategies. In an age of food insecurity, wasting calories reduces your chances of survival. 

Maybe it is a question of a trade-off between short-term gains vs longer-term harms. Or maybe it is not sitting that harms us, but the chair. 

Vestigial cultures squat where we lounge; squatting generates constant low level leg muscle activity, but sitting reduces that to near-zero⁷⁸. And as we become less physically active, and less fit, our risks of death not just from cancer but from all causes increase^{79, 80}, in a dose-related manner⁸¹.

So let us re-examine the evolutionary argument.

We evolved on a knife edge. Penalized if we wasted calories, and yet also penalized if we sheltered in place and failed to go out and capture calories, we had to find and occupy that goldilocks zone between starvation and waste. This is where we function best. 

Unfortunately, the current age of food over-security and overload places us in a profoundly unhealthy environment; the combination of calorie excess and low levels of physical activity means that the AMP-K cancer checkpoint is seldom activated. The abnormal nutritional content of our ultra-processed diet creates obesity, inflammation and malnutrition, harming us further.

We were born to run, to fight and/or to flight. 

If you need more reasons to run, consider this. Running not only reduces the risk of early death, it also enhances life. It is, for example, as potent an anti-depressant⁸² and erectile enhancer⁸³ as any pharmaceutical. It is also clearly important for maintaining brain structure and health⁸⁴.

Many questions remain. Why, for example, do so many phytochemicals activate AMP-K? The cannabinoids act by mimicking endocannabinoids^{ie 85}, but why the polyphenols, alkaloids and saponins? Is it because many of these plant defense compounds were ‘designed’ to exert anti-nutrient effects^{ie 86}, before we co-adapted with them? 

Even more baffling are recent findings that being more physically active in youth and early middle age might reduce the risk of a group of the major cancers in later life⁸⁷. Some but not all of these cancers are the ones associated with sedentary lifestyle, and it is unlikely that any of the chemo-preventive mechanisms described above are involved. What is going on here?

If anyone has answers to these questions, I would love to hear from them. 

Finally, there is the exercise paradox. Leisure time activity is good for you, but occupational activity is not. Jobs which involve a good deal of physical work are linked to increased risk of cognitive decline and cardio-vascular disease^{88, 89}. 

The answer to this one may be simpler. Occupations which involve a lot of physical activity are typically jobs with long hours, repetitive tasks, low levels of control and high stress.

That will kill you too, in a wide variety of ways. It can be countered, however, and this will be the subject of next week’s post.

Next week: Horrible bosses, jobs to die for.

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