286‒Journal club with Andrew Huberman: light exposure on mental health & an immunotherapy for cancer

The Stanford sleep lab has shown that waking in the middle of the night to check the time is powerfully disruptive to sleep quality through psychological effects (time checking creates distress about insufficient sleep), independent of light exposure per se.

“we know based on studies from the Stanford sleep lab that if you wake up in the middle of the night looking at what time it is can be very disruptive to your ability to fall back asleep and to your sense the next day it's just a placebo effect but it's a powerful one of how tired you are the next day they've done this where they wake people up in the middle of the night and then they say it's you know 4:00 A.M versus 2: a.m. versus 6 a.m. and people's perceived levels of energy during the day in some ways correlate with what they think how much sleep they think they got”

PTSD symptoms and self-harm show dramatic increases with high nighttime light exposure (Q4 quartile), whereas generalized anxiety shows less impressive relationships, suggesting differential vulnerabilities of psychiatric conditions to light exposure timing.

“the symptomology of PTSD gets far worse with increasing light exposure at night self harm really takes a a leap from being fairly I don't want to say minimal at the second and third quartile so low and let's say medium I'm using some I'm taking some Liberties here but low and medium amounts of of artificial light exposure at night then for people who get quite a lot of nighttime light exposure self harm goes up... anxiety relatively the you know less impressive here and and bipolar disorder didn't seem as strong”

Cancer is a genetic disease in the sense that every cancer has mutations, but most cancer mutations are somatic (acquired during life in specific cells) rather than germline (inherited), so 'cancer is genetic' does not mean 'cancer is inherited.'

“we know that again you know cancer is a genetic disease in the sense that every cancer has genetic mutations um most of those mutations are sematic which means most of those mutations are mutations that occur during the course of our life they're not germline mutations the germline being the uh eggs and sperm right so it's all other cells”

Approximately 20% of treatment-group patients were still alive at 56 months (tail of Kaplan-Meier curve), whereas essentially all placebo-group patients were dead by 44 months, suggesting durable responses in minority of patients.

“people in the placebo group They're All Dead except that one y they're basically all dead at 44 months yep but when I look at the number how long it takes for everyone to be dead in the TR treatment groups it's like 50 looks like 5503 54 months or so well and they're and they're not dead that's the point they're hanging in there right so because you know an extra somebody who um lost both of my uh scientific advisers two of the three the the other one to Suicide... the other uh two to different cancers... an extra 8 to 10 months with your kids or with your spouse or to quote unquote get your Affairs in order is is a big deal”

Median survival for metastatic melanoma increased from 6.4 months (placebo GP100) to 10-10.1 months (anti-CTLA-4 ± GP100), representing approximately 4-month absolute survival extension.

“50% of the patients in the control group were dead in six months 50% of the patients in the treatment group both treatment groups were dead in 10 months so what that means in cancer speak is these drugs extended median Survival by four months... the 10 months was for the anti-la 4 plus GP 100 and 6.4 months for the gp00 alone that's the control and then 10.1 for the ntla 4 alone”

The paper "Day and night light exposure are associated with psychiatric disorders" published in Nature Mental Health examined more than 85,000 UK Biobank participants and used wrist-worn accelerometers with ambient light sensors to measure both daytime and nighttime light exposure

“this paper um which was published in a new Journal I'm really excited about called nature mental health this journal was just launched recently um is entitled day and night light exposure are associated with psychiatric disorders and objective light study and more than 85,000 people”

Approximately 80% of solid organ tumors have antigens that are recognized by the host immune system as foreign, yet these cancers still progress, suggesting the problem is not lack of immune recognition but insufficient T-cell numbers or activity to mount an effective response.

“at least 80% of solid organ tumors and we're going to mostly talk about solid organ tumors because that's where the field of oncology has made very little progress... more than 80% of those cancers have antigens that are recognized by the host's immune system I will state it again because it is so profound 80% at least of those cancers actually generate an antigen meaning a little peptide in that cell gets presented to the T cell and it is recognizable and now the question is why is that not sufficient to induce remission and the short answer is there are not enough te- cells that are able to act and or they are being sufficiently inhibited from acting”

Melanoma historically has more mutations than most solid tumors, making it particularly immunogenic and explaining why early immunotherapy successes (IL-2) and checkpoint inhibitor trials were conducted in melanoma.

“most cancers probably have about 40 mutations in them that's like ballpark 4050 mutations is standard fair for a cancer but melanoma happens to be one of the cancers that has many many more mutations and the more mutations a cancer has the more likelihood that it will produce an antigen that's recognized as non-self and that's why in the early days of immunotherapy the only things that worked were I to against metastatic melanoma and kidney cancer because kidney cancer turned out to also be one of those cancers that for reasons that are not clear produced hundreds of mutations”

Checkpoint inhibitors represent a fundamentally different therapeutic approach than previous cancer immunotherapy: rather than trying to amplify immune response (IL-2 strategy, ~10% response rate), checkpoint inhibitors block inhibitory signals to unleash existing T-cell response.

“and a thought experiment emerged which was what if we block ctla4 what if we block the checkpoint could we unleash the immune system a little bit more and I will say this at the time it was proposed it seemed a bit far-fetched um because of the complexity of the immune system it seemed a little far-fetched that simply blocking the checkpoint would have any effect... prior to this one immunotherapy had found some efficacy which was trying the exact opposite strategy rather than blocking the inhibitor it was throwing more accelerant at the fire which was giving something called interlukin 2”

ECOG performance status 0 (no limitations despite imminent death) and ECOG 1 (some limitations) represented 98% of patients, suggesting that despite 6-month survival expectations, most patients were functionally healthy at enrollment—a sobering testament to cancer's trajectory.

“it kind of amazing when you really consider something I think this speaks to just how devastating this disease is um these are patients who all have like 6 months to live right you know a year Max and yet look at this 58 to 60% of them have no limitation on their quality of life at this very moment that's going to change dramatically”

Virtually all study participants reported some adverse event (96-98%), but only 6-8.4% reported grade 4 (life-threatening) toxicity, similar to placebo rates (~6%), suggesting adverse events partially reflect disease progression rather than pure drug toxicity.

“in the uh treatment plus GP 100 group 98.4% of people reported some event so all but 1.6% in the ntla 4 group alone it was 96.7% so only 3.1% did not but in the placebo group it's 97% so it's important to keep in mind like you know everybody's having some adverse effect okay well let's just limit it to the most severe events well let's just talk about grade four toxicities there were 6.1% of those in the placebo group 8.4% in the anti C4 group and 6.8% in the combined group so not a huge difference in grade four toxicity”

Cancer is evolutionarily clever in that it employs multiple immune evasion strategies: secreting immunosuppressive factors (IL-10, TGF-beta), creating an acidic microenvironment through lactate production that further suppresses immune cells, and other mechanisms that collectively prevent immune activation.

“it basically does a lot of things to trick the immune system so it has its own secretory factors that Tamp down the immune system it grows in an environment because of its nature... it's heavily glycolytic and when something is heavily glycolytic it's going glucose to pyruvate to lactate nonstop there are lots of reasons for that... it's super interesting... glycolysis lowers the surrounding pH because of lactate lactate attracts hydrogen pH goes down and guess what that does to the immune system detracts the immune system so it's also a way to hide from the immune system”

Light from windows that does not directly show the sun does not trigger the circadian photosensitive mechanism effectively, but skylights and light directly visible through windows are more effective because the intrinsically photosensitive retinal ganglion cells reside mainly in the bottom 2/3 of the neural retina and look upward with low resolution

“unless the light is coming directly through the window most of the relevant wavelengths are filtered out in other words if you can't see the sun through the window even if sufficient light is being provided that's insufficient to trigger this phenomenon... windows on your roof which some people do skylights that makes the situation much much better in fact the neurons that in the eye that signal to the circadian clock and these mood centers in the brain reside mainly in the bottom 2third of the neural retina and are responsible for looking up”

The sky at sunrise and sunset is enriched with blue-orange or blue-red color contrast (not midday which is white light), and these color-opponent cells compare blue to orange/red wavelengths, with the subtraction between them triggering the signal for cells to fire to the circadian clock, making sunrise and sunset the times when this wavelength contrast is most potent

“there are two times of day when the sky is enriched with Blues oranges pinks and reds and that's low solar angle sunlight at Sunrise and in the evening these cells are uniquely available to trigger the existence of those wavelengths of light early in the day and in the evening not in the middle of the day so these cells have these two cone photo pigments and they say how much blue light is there how much red light is there or orange light and the subtraction between those two triggers the signal for them to fire this signal off to the circadian clock”

Light is perhaps the most fundamental environmental stimulus for levels of arousal and alertness, which correlate with all sorts of neuromodulator and hormone outputs, making it more foundational than most people recognize.

“I personally am very sensitive to sunlight in the sense that if I don't get enough sunlight I don't feel well after a couple of days um but I'm less sensitive to light exposure at night for instance but I think it is perhaps this is a big statement but is perhaps the most fundamental environmental stimulus for levels of arousal and alertness which correlate with all sorts of you know neuromodulator and hormone outputs”

The study originally planned to measure response rates as primary endpoint but changed to overall survival (OS) during the study, which required regulatory approval but is clinically more meaningful than response rates.

“the primary outcome for this study actually changed in the study now they have to get permission to do that um but the so the original primary endpoint was the best overall response rate... however uh oh I think I said I think it's... but the amendment was made to change the primary endpoint to overall survival”

Sleep trackers and wearable recovery scores are notoriously poor at predicting actual performance, and serious athletes rely on more traditional metrics like morning resting heart rate, heart rate variability, and workout-specific measures rather than recovery scores.

“recovery scores and things like that are just notoriously poor at predicting performance and I think there's a reason that serious athletes would never use things like that um they would tend to rely on the more tried and true methods of predicting Behavior such as heart rate uh maybe heart rate variability but morning resting heart rate probably more predictive than anything else”

People who deliberately get dark exposure at night (absence of light) actually benefit for mental health outcomes even if they aren't getting enough sunlight during the day, and dark exposure acts independently from daytime light in improving psychiatric outcomes

“turns out that dark exposure at night independent of light exposure during the day is important for mental health outcomes now most people think dark exposure how do I think about that well it is dark absence of light it's the absence of light but what this paper really drives home is that people who make it a point to get dark exposure at night aka the absence of light at night actually benefit even if they're not getting enough sunlight during the day”

While blue-light filtering technology has become prevalent (flux on computers, blue-blockers, screen filters), the context of use matters more than the spectral content—what you're doing on the device (social media doom-scrolling vs. entertainment) affects sleep/mood more than whether light is blue-shifted.

“I suspect that that matters somewhat but I think what matters more is the stimulation that may come from those things and what I've come to realize at least in me which means it probably is true in others as well and at least some others is that what I'm doing on my phone matters more than how bright my phone is in other words if I've got the best blue light filter in the world on my phone but I'm doom scrolling social media and getting lit up on email that's way worse for me than if I've got my phone on maximum light and I'm like watching YouTube videos of F1 cars and driving around having fun”

Overall survival is the 'most important metric' in cancer trials but is 'the highest bar' that drugs rarely meet because it represents absolute cure requirement rather than just life extension.

“overall survival is the most important metric and it's the highest bar make no mistake about it and it's certainly not the bar any drug company is ever going to want to talk about for a cancer drug but why not because because they don't none of them work right like we don't have you know like drug they only want to talk about cures they don't want to talk they only want to talk about media and survival they want they only want to talk about extending media and survival”

Some antidepressants may suppress the ability for daytime light to positively impact mood, and while people should not halt medication based on this, understanding which medications affect circadian light sensitivity could inform treatment decisions.

“conversely there's evidence that people who take certain anti-depressants May suppress the ability for daytime light to positively impact the mood systems of the brain now of course we don't want people halting their medication on the basis of that statement alone please don't you know talk to your psychiatrist but if we know one thing for sure it's that if you want a significant outcome and a paper as a scientist give a drug any drug and look at the amount of rapid eye movement sleep or the Circadian cycle pretty much any drug alter Arcadian Rhythm for better or worse”

Afternoon and evening sunlight exposure can partially offset the negative effects of artificial light exposure at night by reducing the amount of melatonin suppression from nighttime light by approximately half

“if you do see afternoon and evening sunlight there's a beautiful study published in science science reports yes science reports two years ago showing that that can partially offset the negative effects of artificial light exposure at night I think of this as your Netflix inoculation and the amount of melatonin suppression from Nighttime light exposure is haved by viewing evening Setting Sun”

Oncology drugs extending median survival by 4-9 weeks or 9 days while costing $40,000-$100,000+ are approved and marketed, illustrating industry incentive to focus on median rather than overall survival.

“there are you know lots of people out there that are on this on this platform I don't need to get on to it but who will say like look it's a real racket in in oncology today where drugs that are extending median Survival by four weeks are being put on the market at a tune of you know $50 to $100,000 per treatment that's not uncommon in oncology uh there was one drug that was approved for pancreatic cancer I believe it extended median Survival by nine days and it cost $40,000 and it's being adverti as significant extend that was a statistical significant Improvement in media and survival”

The recommended light exposure protocol for optimal health involves viewing low solar angle sunlight (sunrise or sunset) in the early part of the day for 10 minutes or so, and another 10 minutes minimum of low solar angle light in later part of day, plus as much sunlight in the eyes as safely possible throughout the day, while minimizing light exposure at night

“I suggest on non cloudy days we'll call them that people get 10 minutes or so of sunlight in their eyes in the early part of the day another 10 minimum in the later part of the day as much sunlight in their eyes as they safely can throughout the day”

In winter months, experiencing darkness upon leaving a clinic or indoor space in the afternoon creates an 'eerie feeling' that may reflect the brain attempting to orient itself in time, and this disorientation is especially problematic for children and correlates with mood disturbance.

“especially in the winter months it's important to look West and try and get some sunlight in your eyes in the evening if you've ever gone into the clinic for instance at 2 o'clock in the afternoon after lunch you know and then in the winter and then come out and it's dark when you're walk into your car it's a kind of eerie feeling that sort of eerie feeling May correlate with the fact that you missed a signal your your brain is trying to orient your brain and body in time”

A phone on maximum light intensity without any filtering produces approximately 500-1000 lux at viewing distance, and cumulative photon exposure is additive over time (lux × duration), so extended phone use at night can deliver substantial circadian-disrupting photon exposure.

“what is your phone if you don't use any sort of uh light mitigating uh Tech on it well distance matters um at the distance we're holding it yeah with so with all the the wavelengths cranked up so no uh there is a nice feature intrinsic to the phone where you can eliminate the blues at night or you know this kind of thing but if you crank it up to maximum light intensity probably something like you know 500 to ,000 Lux now keep in mind though it's additive right so it's over time so Lux is a measure of I think I think it relates back to Candelas it's the amount of light um shown at I think it's like the one meter away and there's a squaring and a falling off of distance we can look it up um these are old measure old school measurements converted to Lux but keep in mind that if you're looking at your phone or tablet at 800 Lux or 500 Lux in the evening and you do that for 2 hours well you're summon quite a lot of photons”

Future cancer immunotherapy advances likely involve engineering T-cells to better recognize antigens, expanding tumor-infiltrating lymphocytes (TILs) and enhancing them, or modifying T-cells to tolerate acidic pH and other tumor microenvironment challenges.

“the Holy Grail is the meaning the next step if you go back to where we start of the discussion is coming up with ways to engineer te- cells to be even better recognizers of antigens and there's many ways to do that one is to direct engineer them another is to find tea cells that have already migrated into tumors those are called tumor infiltrating lymphocytes or till and expanding those and Engineering them to be better and younger”

The health of the immune system is one of the most interesting open questions in longevity, and modulating immunity appropriately as people age may be more important than many current interventions, with rapamycin potentially being one approach to enhance cellular immunity in aging.

“how do you modulate immunity um as you age and to me that's one of the most interesting things about rap ay potentially is that when taken the right way it seems to enhance um cellular immunity which again that that's potentially a really big deal again at least in in short-term human experiments in response to vaccination it's enhancing vaccine response so the question is would that translate into cancer nobody knows could that be one of the reasons why animals treated with rap ayin live longer and get less cancer don't know”

Complete darkness at night (pitch black) probably increases frequency of nighttime injuries from bathroom trips and other necessary nighttime activities, so some dim lighting at night is appropriate despite the paper's recommendations for darkness.

“you don't need Pitch Black in fact pitch black probably just increases the frequency of injury you know I get up in the middle of the night to use the bathroom probably once I think it's normal I go back to sleep you know if it were pitch black I'd probably injure myself so just just dim it down”

A friend with Lynch syndrome developed pancreatic cancer (unresectable) and enrolled in a kit truda (anti-PD1) checkpoint inhibitor trial targeting Lynch syndrome patients who have mismatch-repair mutations and high tumor mutational burden.

“friend of mine got pancreatic cancer and he got um the bad type of pancreatic cancer so this is uh and like the um um adnoc carcinom in the pancreas right so this this is a a non-survivable type of cancer furthermore his was unresectable... so I was going to ask this question later but I'll just ask it now when it comes down to when someone has Lynch syndrome there's one of those few hereditary or germline mutations that results in a huge increase in the risk of cancer he had already had colon cancer at about the age of 40 um and had survived that it was a stage three cancer but he had survived it well now 5 years later had developed uh panc creatic cancer and when he went to see the surgeon um they said yeah we there's nothing we can do like it's too advanced so that's you know to put that in perspective that is a death sentence... there was a study that had come out in the New England Journal of Medicine that had talked about how patients with Lynch syndrome had lots of mutations and so we you know talked with his doctors about the possibility of enrolling him in one of the kit truda trials”

Wearing blue-blocking glasses in the middle of the day is counterproductive and among the worst things one can do for circadian and mood health, whereas wearing blue blockers at night is more defensible, and the priority should be dimming overhead lights at night rather than obsessing about blue light wavelength

“some people are putting blue blockers on in the middle of the day which is the worst thing you could possibly do if you're going to wear blue blockers and I don't think they're necessary but if you're going to wear them you'd want to wear them at night and in the evening you don't need to wear blue blockers you just simply should dim the lights and ideally have lights that are set a little bit lower in your environment”

Red light bulbs or red-light environments in evenings/nighttime are preferable to blue-rich lighting and can support natural circadian patterns without requiring expensive technology.

“some people use red lights you know our friend Rick Ruben friend yeah Rick ruin is uh can we tell a funny story about Rick... he removed all the lighting that existed in that room and replaced it with red light bulbs... in his place he has mostly either no lighting or red lighting so during the day he just goes by ambient light um and then red light in the evening and or candle light”

The Hopkins ICU at the main facility lacked windows, creating particularly poor light environment for patients with brain injury or stroke, and people with head injuries are frequently contacted asking for advice on improving lighting, with recommendation being to place patients near windows.

“I think the the Intensive Care Unit at Hopkins the main one the the main siku didn't have Windows people who who go into the hospital with with a brain injury or or with a stroke or something I get contacted all the time even though I'm not a clinician what should I do for my kid my parent my I always say get them near a window”

Some individuals are more resilient to light effects on mood and circadian rhythm than others—meaning some people can stay up late, get bright light at night, or wear sunglasses all day and maintain good mood and stable sleep, while others are highly sensitive, with genetic polymorphisms potentially underlying this variability

“some people seem more resilient to these light effects than others meaning some people you know also don't suffer from jet lag too much some people can stay up late get a lot of bright light exposure in the middle of the night and during the day they got their sunglasses on all day and they're in a great mood all the time other people are more susceptible these sorts of things and we don't know whether or not gen polymorphisms underly that”

Wrist-worn light sensors have directional limitations because they don't measure light specifically at the eye level, but this limitation can be reconceptualized as an advantage because it better captures ambient light exposure during activities (e.g., conversing under an overhang) rather than only direct sun viewing.

“they had it on the outside of the sleeve but they asked that people just keep it on their dominant hand it's not perfect but in some ways it's kind of nice that it's not perfect we could turn that disadvantage into an advantage by thinking you know when the person is out and about they're not often looking right at the sun you know if you're talking to a colleague under an overhang for instance so it's it's not perfect directionally it's directionally right”

A major question unanswered by this paper is whether there is correlation between autoimmunity incidence/severity and treatment response, given prior evidence that autoimmune reactions predict checkpoint inhibitor efficacy.

“the last thing I'll say about this paper that I found interesting and I I was looking for it and I was surprised they didn't at all comment on if there was any correlation between autoimmunity and response rate um so they obviously acknowledge the autoimmunity in in table three but I would have loved to have seen a statistical analysis that said hey is there any correlation between response rate and autoimmunity but um they they didn't comment to that effect”

Checkpoint inhibitor immunotherapy is the most promising therapeutic approach for solid tumors to date, offering potential for durable responses in minority of patients and conceptual foundation for future developments despite current modest overall survival gains.

“in summary I'll say that the reason I thought this was an interesting paper to present is that I still believe that immunotherapy is probably the most important hope we have for treating cancer and well I think we're still only scratching the surface of it so collectively the overall survival increase for patients with metastatic solid organ tumors is about 8% better than it was 50 years ago and virtually all of that has come from some form of immunotherapy um I think is promising and I think the Holy Grail is the meaning the next step”

While autoimmune organ destruction is severe, survival of checkpoint inhibitor-induced Type 1 diabetes (insulin-dependent) is acceptable tradeoff compared to certain death from metastatic pancreatic cancer.

“so now he is effectively had a pancreatectomy based on his immune system so now he actually has Type 1 diabetes he has no pancreas he injects insulin to deal with that or no no he has to insulin just like some type di you had to pick being alive with type one diabetes yeah of course no comparison but it's just an interesting example of how you know remarkable this treatment was able to work when you could completely unleash the immune system of a person and you eradicate the cancer and the rest of the cells around it”