Be Cool

At the sweet-smelling University of Cologne, elegant work with the nematode C elegans recently showed (1) that switching the worm temperature to cool activates proteasomes. These tiny barrel-shaped structures, present in all cells, are essential for protein quality control and therefore life.

Protein production is a complex process with a lot of room for error. After transcription, translation and post-translational modifications are completed, over 80% of finished proteins do not meet spec (2-4). If they were to be incorporated into the enzymatic, structural or other cellular processes they were built for, they would cause havoc.

Every cell therefore operates a quality control system to maintain adequate levels of correctly configured proteins. The quality control system is called proteostasis (4).

Proteostasis reduces the overall error rate, but not to zero. Over time, incorrectly coded, malfolded or otherwise damaged protein(s) accumulate and drive, inexorably, towards a threshold of metabolic or structural failure. The affected cell becomes dysfunctional and/or dies, making this process of error accumulation an important contributor to the overall ageing process.

Proteasomes are a critically important part of proteostasis; they are the cell’s recycling bins. Incorrectly formed, damaged or unwanted proteins are identified, tagged (with ubiquitin) and sent to the proteasomes where they are broken down, releasing their amino acid components for reuse.

The process adapts according to need. When damaged proteins accumulate the cell becomes stressed, and responds by inter alia increasing proteasomal activity (5, 6). The boost continues until the percentage of faulty proteins in the cell falls back into the acceptable range. This part of the ageing process is thus controlled, or at least slowed, unless you are unlucky enough to have a gene mutation that codes for part of the proteasome itself.

This leads to proteasome-associated-autoinflammatory-syndrome, chronic inflammation in multiple organs, accelerated ageing and reduced life expectancy. Whether this chronic inflammatory burden can be damped using the usual anti-inflammatory nutrients is unknown, but worth exploring. Omega-3 PUFAs combined with amphiphile polyphenols are likely as good as and certainly safer than the systemic steroids generally used in such cases.

For the majority of people, however, boosting proteasomal activity looks like a useful anti-ageing strategy. Until the recent Köln experiments it was not known if there was a practical (and safe) way of doing this, but that door just opened.

Various neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s and ALS are characterised by the intracellular accumulation of malfolded and thus defective proteins. Transgenic nematodes carrying human disease-coding genes develop a similar problem, but when their temperature was dropped by a few degrees their proteasomes became more active and the protein aggregates disappeared (1).

This might present a way of preventing these diseases from progressing in humans. It might even be a way of turning back the proteomic clocks which, perhaps even more so than the overlapping epigenetic and transcriptomic clocks, influence health and life expectancy (7-9).

Cold exposure works by up-regulating endogenous proteasome activators which would normally be triggered by the accumulation of ‘bad’ proteins (10). The activators open the lid of the barrel structure of the proteasome more widely, allowing more damaged or unwanted proteins to enter the recycling (proteolytic) interior and be broken down (11). They also change proteasomal preference, so that a different spectrum of proteins is broken down (12).

Over-expression of endogenous proteasome activators such as PA28y is linked to an increased risk of malignant cancer (13). This over-expression is likely in response to the cancer cell’s disorderly proteome rather than causative for cancer; but it is probably also a permissive factor, as cancer cells that do not increase proteastasis will tend to self-destruct via apoptosis (14, 15) or some other form of cell death.

The pharma bros are undoubtedly developing PA28y analogues, but you can do it yourself via cold exposure. There may be a slight increase in cancer risk (16), but other pathologies are presumably reduced by a greater extent because moderate cold exposure is linked to an overall increase in life span in worms, flies, mice, hamsters (ie 17, 18) and, possibly, humans.

There is some data – which breaks down at temperature extremes – indicating that humans live slightly longer in the colder regions of the world (19-21). This gradient varies between and within species (22), and the human data is plagued with confounders, but I am tempted to believe in cool because of my own experiences. And if you’re wondering how nutrition fits into all of this, I’ll explain.

In the early 2000’s I spent the better part of a year in Stockholm, hanging around the Karolinska and talking to the academics there. That winter I became aware of an eccentric Swede who walked past the window every day to work, clad only in boots, briefs and a briefcase, even when the outside temperature was minus 10 degrees C.

I knew the work of Pirkko Huttunen, an interesting Finnish researcher who had done pioneering research into brown adipose tissue (BAT) since the early ’80s (i.e., 23, 24). I also knew Nick Dynes Gracey, a medical biochemist who created clothing which up-regulated BAT via cervical cooling (25). Dr Huttunen had shown that a program of cold exposure was only initially uncomfortable (26) but I’m a wimp, and a pharmacologist.

The available science indicated that uncoupling proteins, which degrade the efficiency of mitochondrial ATP synthesis and thus trigger thermogenesis (27), could be induced in white adipose tissue via sympathomimetics, and specifically amphetamines (28). I hadn’t indulged in those since the swinging 60‘s and opted instead for copious black coffee, removing my jacket and jogging across the Karolinska campus four times a day for the first week.

The 2nd week I discarded my sweater, the third week my shirt and by the 4^th week I was swimming in the Mälaren. In January. I was also sleeping under an open window and a single sheet because anything else was too warm, constantly hungry, eating 4-5000 kcalories/day and losing weight. And I felt great.

There are now better nutritional tools than caffeine. Capsiate, a non-pungent alkaloid and analogue of capsaicin, up-regulates the uncoupling proteins and switches white adipose tissue to brown (29, 30). It has poor bioavailability (31), but there is an outstanding molecular engineer in New South Wales who knows how to solve that kind of problem. G’day George!

Fucoxanthin, a carotenoid derived from brown marine algae, has similar effects (32) and so does punicic acid (30), a polyunsaturated fatty acid present in large amounts in pomegranate seed oil.

All of these natural compounds mimic cold exposure and induce thermogenesis, weight loss and metabolic improvement (33). Used singly or in combination they make it easier to live a cooler life, and turn your thermostat down a degree or two. This will cut your energy bills and likely slow your proteasomal clock too.

Proteostasis connects forwards and backwards to inflammation. Poor proteostasis tends to increase chronic inflammatory stress, and chronic inflammation in turn skews proteostasis (34, 35). Taking the usual anti-inflammatory regime and then cooling it should therefore provide additive or supra-additive health benefits, and extend your health- and lifespan significantly.

The health benefits of cold exposure are linked to cold-induced upregulation of thermogenesis and a raised metabolic rate, which is required for increased proteostasis (36) and to maintain body temperature, but don’t overdo it. More (or less, when it comes to temperature) is not better. When cold exposure starts to reduce whole body temperature it impairs immune and nervous function, which is not recommended.

Finally, the pesticide chlorpyrifos was recently banned in the EU and USA as a teratogen but is still used in many parts of the world. Foods containing trace amounts therefore continue to enter the food chain. As this molecule inhibits the browning of adipose tissue (37) it may have contributed to the obesity epidemic, and will also likely inhibit cold-induced health benefits.

If you want to consume less chlorpyriphos, rinsing fruits and vegetables with water is unlikely to be enough. Using a dilute bleach solution is reportedly more effective (38), and paring and peeling is an obvious alternative.

This winter peel off a few your outer layers, and be cool. And exercise, because this will add even more to your health.

Because the accumulation of damaged proteins is so lethal for our cells, they cannot rely on the ubiquitin / proteasome pathway alone and run a parallel system called autophagy. In autophagy, unwanted intra-cellular proteins are packed into special vesicles (not proteasomes), where they are digested by lysosomal enzymes.

Aa autophagy problems are also implicated in the neurodegenerative diseases (39-41), it might be helpful to encourage this process in parallel with cold-induced proteostasis. It’s easy to do.

Autophagy is up-regulated by activating the energy sensor AMP-kinase. Cold exposure up-regulates AMP-kinase in some but perhaps not all tissues (42), so is already boosting autophagy to an extent. Exercise, which up-regulates AMP-K in other tissues therefore likely provides additional benefits (43). For those who won’t or can’t exercise, exercise-mimetics such as ActivAMP (44) offer an alternative.

Heat exposure (heat stress) is a horse of a different colour. It resembles cold exposure in that it increases proteasomal activity (45) (in a general stress response), but it appears to have the reverse effect on autophagy (46). This will make you more prone to laying down fat deposits (46); chubby Bikram yoga practitioners, take note.

Next week: Forty days in the desert; a road-trip across America.

References

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