Jet Lag
Jet Lag&WhyItMatters
It isn't just tiredness. On a cellular level, jet lag is a state of internal desynchronisation, and for frequent travellers, the long-term stakes are higher than most realise.
In about a month from now I'll set off from Sydney and fly over 10,000 miles to Cannes, France. I feel it's necessary to rather quickly clarify that I will (only minimally unfortunately) be there for work, not vacation.
Nonetheless, I will be trading in winter in Australia for summer in France for a week. Yes, beaches for beaches, sun for sun. What will change upon arrival in Cannes, however, is the time zone, and along with it the Beast of the Burden of travel: jet lag.
Because of these upcoming travels, and an increasing body of literature suggesting a re-analysis of how we think about jet lag in the space of longevity, I figured now may be a good time to talk about all things jet lag. I'll spend this newsletter discussing how jet lag fundamentally operates as well as its relevancy to the space of longevity. The jet lag focus won't end here; expect more newsletters to come on this topic!
Jet Lag: Physiologically Explained
In the most rudimentary terms, jet lag is the result of circadian misalignment caused by crossing time zones too quickly for the body's circadian system to adjust. Your circadian system is simply a 'body clock,' regulating sleep cycles, wakefulness, hormones, and other physiological processes. When we are not traveling, circadian rhythms are incredibly helpful in keeping us in a consistent pattern of wakefulness and rest, and help space out our days.
This breaks down, however, when we rapidly cross timezones with modern advances; evolution clearly didn't account for this, and therefore if you were to land in London on a redeye from New York, there is a misalignment between what your circadian system perceives the time to be and what the time actually is.
In short, jet lag itself really isn't a sensation of tiredness, but, rather, of misalignment.
"Jet lag itself really isn't a sensation of tiredness, it's a sensation of misalignment."
- Dr. Adam BrownThe Feedback Loop
At the most basic molecular level, the circadian system is built from interlocking gene feedback loops in which proteins like CLOCK gene and BMAL1 activate the expression of PER genes and CRY genes, which then accumulate and inhibit their own production. This creates a self-sustaining ~24-hour oscillation in gene expression across cells. This transcription-translational loop has a well-defined orchestrator: the suprachiasmatic nucleus (SCN). Located in the hypothalamus, the SCN is a dense cluster of neurons that is considered the master oscillator that coordinates daily rhythms. The SCN synchronizes its activity to light from the retina.
The ~24-Hour Molecular Feedback Loop
Based directly on Adam's text: CLOCK and BMAL1 activate PER and CRY gene expression. PER/CRY proteins then accumulate and inhibit their own activators, closing the loop at ~24 hours. The SCN (suprachiasmatic nucleus), synchronised to light via the retina, acts as the master orchestrator of this system.
However, there exists a lag between when the SCN receives new environmental input from a new time zone and when so-called peripheral clocks - those that control local organ activity such as metabolism, detoxification, and repair - fully adjust to this new schedule. The lag comes about because while the SCN is directly adjusted to a new time zone by light exposure, peripheral clocks rely more heavily on downstream signals such as feeding timing, hormonal rhythms, and temperature cycles, which adjust more slowly. During this lag interval, there is a phase difference between the two clocks - between orchestrator and, say, lead saxophone (of which my intern Eli insists he was for his elementary school band) - where different systems can be temporarily out of phase with one another, meaning they "agree" on different internal times. This internal desynchronisation is what jet lag, fundamentally, reflects.
The previous two paragraphs are dense; no need to fully grasp the molecular and physiological mechanics. What is important to understand, however, is that the fundamental misalignment on the cellular level produces system-wide, physiological effects that manifest into what we call jet lag.
Directly reset by light from the retina. Rapidly adapts to the new time zone, often within 1–2 days of consistent light exposure.
Adapts quicklyDepend on feeding rhythms, hormones, and temperature. Lag behind the SCN by days, creating system-wide internal disagreement.
Slow to adjustWhat jet lag looks like internally
The SCN adapts quickly to a new time zone via light. Peripheral organ clocks, driven by meals, hormones, and temperature, lag behind by days. The gap between them is what jet lag is.
"Dr. Adam, this is a longevity newsletter. If jet lag is temporary, why feature it?"
Definitionally and symptomatically, jet lag is an acute event. Most of us see jet lag as temporarily problematic; after a few days of adjusting to a new time zone, all our jet lag woes fade away, and we feel pretty much back to normal. Now, behaviorally and symptomatically, this may feel true; but on a physiological level, especially for those of you who are frequent travelers, there are significant long term consequences for repeated jet lag exposure.
There is, unfortunately, a lack of academic literature that explicitly studies the impact of jet lag on long-term human disease risk. There is, however, a plethora of academic literature that is written about circadian misalignment - the key physiological driver of what we perceive as jet lag.
Now, you're free to take that as you will. From my perspective, however, as demonstrated by the lengthy discussion in the previous section, jet lag is circadian misalignment. So while not explicitly studying the effects of jet lag, these studies analyze the root cause of such, which is enough to convince me that chronic jet lag may indeed have long-term effects. Circadian disruption has been well studied in three major risk categories, all of which appear to pose threats to long-term health. These risk categories are: Cardiometabolic diseases, Neurocognitive diseases, and Cancer.
Each of these risk categories has been the subject of extensive research examining the effects of circadian misalignment, both in humans and in laboratory animals. Again, the following studies (barring one!) aren't explicitly testing jet lag, rather circadian misalignment, which I hope, as per the previous section, is abundantly clear as the underlying cause of jet lag.
Three Risk Categories
Tap each category to expand the research.
A 2014 human observational trial examined what the effects circadian misalignment were on cardiometabolic disease. The study, published by the ADA (American Diabetes Association), enrolled 26 healthy adults, where participants underwent identical sleep restriction (~5 hours/night), but one group had a stable sleep schedule, while the other experienced repeated 8.5-hour phase shifts, mimicking shift work or jet lag conditions. Importantly, total sleep time and diet were carefully matched between groups, an attempt to, as well as possible, isolate circadian misalignment as the key independent variable.
The study found that circadian misalignment amplified insulin resistance, with a larger decrease in sensitivity than in the circadian alignment group which represented sleep restriction alone. In addition, systemic inflammation increased and to a greater extent in the circadian misalignment cohort.
Results like these were similarly found in a 2009 paper from researchers at Brigham and Women's Hospital and Harvard, who also induced experimental circadian misalignment on a human study cohort and monitored a number of vitals and biomarkers related to cardiometabolic health. Their study demonstrated broad cardiometabolic consequences; three stood out to me. First, blood glucose and insulin levels rose when study participants were in a state of circadian misalignment as compared to their baseline levels. Physiologically, this is indicative of, as also demonstrated by the previous paper, a decrease in insulin sensitivity. This may sound unremarkable, but reducing insulin sensitivity results in overproduction of insulin by our bodies and chronically elevated blood sugar levels, eventually leading to type 2 diabetes (T2D). In fact, reduced insulin sensitivity is a hallmark of T2D, and can manifest into broader cardiovascular diseases and chronic obesity. Second, mean arterial pressure rose by 3% when participants were in the CM stage. This may sound insignificant, but even a small elevation like this kept over a long period of time can have chronic effects on the integrity of our bodies' vasculature. Lastly, 3 of 8 patients who had sufficient glucose response data recorded developed post-meal glucose responses that fell within the prediabetic range, despite being healthy young adults! Taken together, these findings suggest that circadian misalignment can rapidly impair multiple systems involved in metabolic and cardiovascular health, even in otherwise healthy individuals.
↑ Insulin resistance +3% arterial pressure ↑ Inflammation markersEffects of chronic circadian misalignment don't stop at the cardiometabolic level. The literature on CM and neurocognition is admittedly less extensive; nevertheless, a 2015 longitudinal study looked at the cognitive performance of shift workers in France who had experienced chronic CM as a result of their work schedules. They employed a huge study cohort (over 3,000 participants!) of both shift workers and controls who would not have been exposed to chronic CM. The study measured their cognitive function with tests of memory and processing speed at baseline and then again 5 and 10 years later. Across the board, shift workers had greater decreases in cognitive performance than non-shift workers, particularly in memory and processing speed. Further, there was a dose-response relationship between shift work exposure time and cognitive performance deficits, such that workers with more than 10 years of shift work exposure had the largest decrease in cognitive capability.
This is a really impressive and important finding. This was not a state-induction, but rather one that just observed individuals who, by nature of their job, find themselves chronically in a state of CM. It reinforces the idea that while the acute brain fog normally associated with jet lag is certainly real, there is an entirely separate dimension to the cognitive impact that chronic circadian misalignment may have chronically. This study concluded that the cognitive disadvantage associated with long-term shift work was approximately as large as the disadvantage normally associated with being 6.5 years older. In short, this is a meaningful impact, and one that cannot be understated, nor conflated with the acute neurocognitive effects, as it reflects a persistent, long-term decline in cognitive function associated with chronic circadian disruption.
10-year longitudinal study 3,000+ participants ≈6.5 years cognitive agingMost patients I talk to can at least rationalize the link between jet lag and the two aforementioned risks; cancer, while seemingly in a more indirect relationship with CM, may also be associated with an elevated risk due to chronic disruption. While not yet examined in humans, a 2004 study with mice attempted to observe a link between jet lag and cancer. Researchers implanted tumors manifesting cells into mice, and then split them into a control group and a group that induced a state of jet lag - ie. CM - and then monitored, among other things, gene expression of clock-like cells and tumor growth. Their findings were, to say the least, interesting; they observed an elevation in tumor growth and reduction in survival following cancer onset among the jet lag-induced mice compared to the controls. How might this be mechanistically explained, you may ask? Well, the circadian system exhibits some control over cell cycle and immune system regulation. With a misalignment to the internal timing system of these mice, tumors grew more aggressively, suggesting that circadian integrity plays an important role in preventing cancer progression.
This, at least I feel, was likely the most shocking correlate between CM and a disease risk. It feels weird, and maybe even implausible, that something acute - such as jet lag - that disrupts the body's circadian rhythm may contribute to such a profound, chronic, and life-altering disease such as cancer. Fundamentally it's of my opinion that this link lends itself very well to this newsletter's overarching idea that the bodily and physiological mechanisms that jet lag impacts, chief among them circadian rhythm, have wide-reaching effects on other biological functions, many of which are tied to complex disease processes such as type 2 diabetes, cognitive decline, and even cancer.
I'd like to reiterate that this study was done in mice - not humans. There are certainly multiple inferential steps being taken to draw a connection here. I want to be clear that this is not an insinuation that jet lag, point blank, causes cancer. Instead this study should serve to help us understand a plausible biological mechanism linking circadian misalignment and cancer, demonstrate how chronic circadian disruption can accelerate tumor progression in an animal model, and remind us that the circadian system plays a fundamental role in regulating processes that are intimately tied to cancer development and progression. It's important that we do not overextrapolate these findings and jump to rash conclusions, however fluid and easy that jump may feel.
Animal model only ↑ Tumour growth rate ↓ Survival post-onsetIf reading through that felt overwhelming, then that makes two of us. That was an informational dump, albeit a necessary one. For much of my life, even through my medical training and even as I became more involved in the longevity space, I thought about jet lag almost exclusively in its acute form.
What these above studies should collectively accomplish, above all, is that (a) I was wrong for doing so, and (b) an understanding and recognition that jet lag is both an acute and chronic effector. This is a reframing of jet lag that feels necessary and one that I hope will be helpful in creating a new lens by which we see travel and time zone adjustments as an opportunity to employ strategies for jet lag reduction.
Because I'm a longevity physician, I tend to think more on the level of chronicity, and thus find the above highlighted risks vital to both recognize, and think about how to address and mitigate the effects that jet lag has on each of our individual longevity profiles. More on this to come.
