Finally cold
The fascinating reality of physiological plasticity
Pottery hand made craft by young girl in Tunis village in Fayoum Egypt, 24 February 2017. Ahmed Kassem.
May I celebrate this? I think I can. Here is what: this is the first year in many decades that I haven’t suffered from the heat almost every day from mid-spring to mid-fall. I’ve been heat intolerant all my life, I’ve had heat exhaustion and heat stress episodes, and even two episodes of hyperthermia in the past. The wider air-conditioned urban environment in the US was one reason I favored living here instead of Brazil. In some of these heat-induced episodes, my body got covered in skin eruptions. In others, I had respiratory distress. I’m one of the few percent unlucky people who are extremely sensitive and don’t do well in the heat. I’m great during the winter.
The reason I am not suffering from heat is that my sensitivity and intolerance decreased substantially. A couple of weeks ago I realized it was already May and I hadn’t had one night of sleep interrupted by feeling hot and sweating too much. Most years, at this time, it would be happening every night.
At first, we thought it was an intermittent fever - never good. Antonio told me to take Tylenol. I said I would, but I didn’t, as I often don’t, because Tylenol makes me feel uncomfortable. It messes with my thermoregulation and makes me feel “artificially or weirdly hot”. The fact is that I like feeling colder.
I did nothing about the potential intermittent fever and enjoyed the better sleep without associating it with feeling colder until I realized I was always colder than I used to be at the same ambient temperatures.
And then I did intentionally observe the thermostat several times a day, confirming my hypothesis that I had become less sensitive to heat. At temperatures that months before I would be freaking out, stripping off my clothes, and cranking up the AC, I am ok. Sometimes I put on a sleeveless shirt when it gets a little too warm.
If it is not a fever, why am I feeling colder? The phenomenon is called adaptive thermogenesis. It refers to the body's ability to adjust heat production (thermoregulation) in response to different stimuli, including cold exposure and diet. My body did so in response to diet.
Adaptive thermogenesis is a form of physiological plasticity (aka physiological adaptation and phenotypic plasticity), which is the ability of an organism to alter its physiological functions in response to environmental conditions. Physiological or phenotypic plasticity includes muscle growth from exercise, increased lung capacity at high altitudes, tanning from sun exposure, immunological responses to infection and chronic disease, as well as nutritional state.
In the case of adaptive thermogenesis, there is a change in resting metabolic rate that is greater than would be predicted from changes in lean body mass and fat mass alone during periods of energy imbalance. To accomplish that, certain molecular pathways are activated, particularly in brown and beige adipocyte mitochondria.
My reading of the literature is that there has been a lot of new research in the past couple of years, most of which is not yet integrated into consensual models and hypotheses. Several mechanisms and molecular pathways have been proposed, with interest in developing pharmaceuticals, including hormones (like thyroid hormone and beta-adrenergic agonists), transcription factors (like NRF-1 and NRF-2), and enzymes (like COX-2), but how they work as parts of an integrated system of regulation is poorly understood.
When we talk about adaptive thermogenesis in the context of a prolonged energy deficit, or chronic calorie restriction (CR), we are referring to the greater-than-expected reduction in energy expenditure “independent of concomitant loss of metabolically active body mass”. That means we are spending less energy, or using it more efficiently, regardless of how much or whether we lost body mass, as a response to calorie restriction.
That’s what happened as I kept going with my CR diet. Several responses, including weight loss, seem to be associated with the magnitude of adaptive thermogenesis.
What I learned about long-term CR with adequate nutrition in ‘lean and weight-stable healthy humans” made me a fan. I learned that it is associated with a sustained reduction in core body temperature, similar to that found in CR for rodents and monkeys, about which there is much more research. It is thought that this is due to CR itself, and not leanness or weight loss, and may be involved in slowing the rate of aging. So I followed the literature to see what else was linked to “sustained (chronic) calorie restriction” and “adaptive thermogenesis”.
I learned that long-term CR “with adequate protein and micronutrient intake in lean and weight-stable healthy humans” is associated with a sustained reduction in serum T(3) concentration, as well as that of 2 biomarkers of longevity (fasting insulin level and body temperature). CR has also been found to have direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV (heart rate variation) indexes in CR individuals are similar to those of individuals 20 years younger.
Different organs and tissues seem to respond differently to CR. In skeletal muscle, CR induces dramatic changes in the transcriptional profile that resemble those of younger individuals, as seen with HRV. These changes are based on three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation.
Because of this, CR is a known prophylactic intervention against sarcopenia (the pathological loss of muscle mass). Aging and CR behave in opposite ways concerning gene regulation in muscle: CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively.
How exactly calorie restriction influences core body temperature is still unclear. The signaling molecules and their receptors participating in it include hypothalamic neuropeptides regulating feeding (appetite) but also energy expenditure via modulation of thermogenesis.
What matters to me and to many other patients right now is that in older adults, lower basal body temperature appears to be associated with healthy aging in the absence of excessive adiposity, and calorie restriction seems to deliver it.
Mechanisms not only for lowering body temperature but for most or all of CR’s physiological outcomes are still controversial. As I pointed out, this seems to be the blooming of a recent research interest in different disciplines, marked by several new impactful findings and some heated controversy. For example, some authors claim that sustained mitochondrial biogenesis is essential to maintain calorie restriction-induced beige adipocytes, which have been shown to be strongly associated with extracellular remodeling in adipose tissue, decrease in adipose tissue inflammation, and improved systemic metabolic homeostasis. A prevalent mechanistic hypothesis explaining this effect suggests that protein degradation, including mitochondrial autophagy, is increased with CR, removing damaged proteins and improving cellular fitness. At steady state, increased catabolism must be balanced by increasing mitochondrial biogenesis and protein synthesis. Another research group, however, reported that their findings contradict that hypothesis and provide evidence that cellular fitness is accompanied by reduced global protein synthetic burden. That’s a major controversy with serious implications for money-sensitive issues, such as drug development.
Core body temperature is a long-established determinant of longevity across species. There is evidence demonstrating that reducing Tb increases lifespan and that lowered Tb contributes to the antiaging effects of calorie restriction. Most of the studies about this were done with invertebrates, and we are a bit far from understanding how it works in humans. The mechanisms involved in the relationship between temperature and longevity also appear to be less direct than once thought with neuroendocrine processes possibly mediating complex physiological responses to temperature changes.
Even with these gaps in clinical evidence, calorie restriction has presented itself as a powerful, but simple, dietary modulation that extends both life- and health-span in model organisms. Calorie restriction offers all these benefits and has little to no negative side effects. Moreover, CR addresses incurable conditions affecting millions (certainly a good billion) for which the available treatments can be unaffordable and inefficient. Why, then, isn’t it more widely prescribed and used?
The literature offers me five classes of reasons: the lack of conclusive human studies, challenges with adherence and sustainability, potential risks and side effects, ethical and practical considerations, and the need for further research. The arguments for each one vary in consistency: risks and side effects are almost all limited to what is considered extreme calorie restriction, or CR to less than the person’s BMR (basal metabolic rate); the evidence is just starting to emerge, so there isn’t enough accumulated data, but that didn’t prevent other treatments to urgent public health issues from being adopted in the past, especially if there are no contraindications. The problem is that eating restriction is now considered a taboo subject in the communication with obese and overweight subjects, or in the context of weight loss conversations. For the past two decades, this particular conversation has been heavily influenced by a new movement known as “fat liberation”. This is a primarily American phenomenon among a young, white, female, middle-class population that became well known for its leaders being mostly fashion influencers promoting the acceptance of extremely fat bodies (over 300 lbs in women). I believe this is less of an ethical problem, as argued by some, and more of a political one where the interests of fat liberation clash against the interests of millions of aging and chronically ill individuals. It seems to me unjustified that the concerns of these leaders should hinder the prescription of CR in other scenarios, particularly in aging and non-transmissible diseases.
From what I gather, psychological and social-behavioral limitations are the key obstacles to wide adoption of CR as a treatment option. This also has an important political component: as long as the 12 trillion dollar food industry is the major force shaping our eating environment - from the food itself to its presentation infrastructure -, there is no way to curb behavioral resistance. It is built into the industrial food system: we live in a carefully designed obesogenic environment with the most powerful eating “cues” everywhere, all the time. This food system requires and manufactures societal-level overeating/automatic eating behaviors so that every individual being triggered thousands of times in a day consumes these industrial products at the rate required by the industry.
The food industry-based industrial food system taps into a sophisticated and carefully regulated architecture of food harvesting, foraging, choosing, and consuming in humans. Our species has evolved selecting generalist, omnivorous, opportunistic strategies of survival. “Satiety” is not optimized in it. In our several million years of evolutionary history since, say, australopithecus, we are very well adapted to relative scarcity and intermittent availability of food.
Maybe because of this, this “self-organized” diet of mine feels like coming home. I don’t know how to explain this other than a general sense of appropriateness. I still respond to cues like anyone - smells and visuals of food that doesn’t fit the meal I’m about to eat.
Calorie restriction, whether continuous or achieved through different fasting strategies, is not for everyone, though. I think it requires a high threshold level of motivation to even try it. Self-restraint always requires a justification, nobody exerts it for fun, and unless the person is left with few other choices, they are not going to choose CR. It is particularly difficult when sharing spaces and meals with other people, a situation that provides too many eating cues to resist.
I am obviously very motivated. As I wrote before, I’ll eat dog shit with paprika and a pinch of mint if there is even a remote chance that it will decrease my pain.
CR is working for me. I’m happy eating my fiber-rich, seed-heavy meals. I cook them. I season them to my taste. They make sense to me. Even more than the modest pleasure of enjoying them, feeling cooler and more comfortable in my skin makes a lot of sense. Regardless of how much corroborating evidence CR receives as an approach to chronic diseases and aging in the short term, I think it passed the test for me. It looks like something worth keeping and improving.
I like my new cool comfort. I don’t miss feeling constantly hot, panicking when entering a warm environment or passing out from heat. I feel so much better now that it’s almost as if CR fixed an old problem instead of being a side effect that deviates from normal function. Almost as if it’s really the right thing to do.