Journal Club with Dr. Peter Attia | Effects of Light & Dark on Mental Health & Treatments for Cancer

Dr. Peter Attia, Journal Club (00:00:00)

• Dr. Peter Attia is a medical doctor and world expert in healthspan and lifespan.
• Today's episode is the second in a Journal Club series where Dr. Attia and Dr. Andrew Huberman share and discuss interesting and actionable research papers.

Light, Dark & Mental Health; Retina (00:07:14)

• A study involving over 85,000 people in the UK examined the relationship between light exposure behavior and dark exposure behavior on mental health.
• There is a correlation between day length and mood, with longer days in spring and summer associated with fewer depressive symptoms.
• Seasonal effective disorder (SAD) is a condition where people experience lower mood and affect during shorter days.
• Bright light therapy, typically using 10,000 Lux lamps, is an effective treatment for SAD.
• Light exposure during the day and dark exposure at night have independent and additive effects on mental health.
• Melanopsin retinal ganglion cells in the retina respond to bright light and send signals to the hypothalamus, which controls the circadian clock and affects mood.
• Outdoor sunlight provides much higher Lux levels compared to indoor environments, even brightly lit ones.
• On cloudy days, the total photon energy may be similar to a sunny day, but the lack of visible sunlight affects the circadian clock.
• It's recommended to get 10 minutes of sunlight in the eyes early and late in the day, avoiding sunglasses during these times to maximize light exposure.
• Sunglasses are advisable during the middle of the day to prevent cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.
• The cells in the retina that signal to the circadian clock are located in the bottom two-thirds of the neural retina and are responsible for looking up, gathering light from above.

Outdoor vs. Indoor Light, Cataracts, Sunglasses (00:11:16)

• The circadian clock sums photons, integrating light exposure over time rather than responding to quick changes in light intensity.
• Experiments have shown that bright light can cause these cells to fire action potentials for hours, propagating signals throughout the brain and body.
• Sunlight in the early and late parts of the day, when the sun is low in the sky, poses minimal risk of inducing cataracts.
• Sunglasses are recommended during the middle of the day to protect against cataracts and macular degeneration.
• Large windows that allow direct sunlight can provide sufficient light for the circadian clock, but skylights are even more effective.

Tools: Sunrise & Sunsets, Circadian Rhythm; Midday Light (00:16:17)

• Humans and animals have two cone opsins that respond to short-wavelength (blue) and long-wavelength (orange/red) light.
• These cells compare the contrast between blues and oranges/reds to trigger the existence of those wavelengths of light.
• Low solar angle sunlight at sunrise and in the evening contains enriched blues, oranges, pinks, and reds.
• Viewing low solar angle sunlight in the morning advances the circadian clock, leading to earlier bedtime and wake-up time.
• Viewing low solar angle sunlight in the evening delays the circadian clock, leading to later bedtime and wake-up time.
• These signals average to keep the clock stable and prevent drifting.
• Midday sun contains all wavelengths at equal intensity and is in the circadian dead zone, so it doesn't shift the circadian clock.
• Color vision evolved first for setting the circadian clock, not for pattern vision or aesthetics.
• It's better to get morning light than evening light if you can only do one.
• Retinal sensitivity to light increases as the day goes on, so less light is needed to shift the circadian clock late in the day.
• Afternoon and evening sunlight can partially offset the negative effects of artificial light exposure at night.
• Aim to view low solar angle sunlight early in the day, later in the day, and get as much bright light as possible throughout the day.
• Invest in sunrise and evening simulators or use the 20/20 light bulb for precise color contrast.
• The 20/20 light bulb simulates the contrast of short and long-wavelength light found in low solar angle sunlight and may induce mild euphoria.
• Most SAD lamps only activate one of the relevant mechanisms in the cells and not the most relevant one.
• Future devices like laptops and phones should incorporate these light features.

Tools: Night & Light Exposure; Waking Before Sunrise (00:24:55)

• Dark exposure at night, independent of light exposure during the day, is important for mental health outcomes.
• Some people are more resilient to light effects than others.
• Light exposure to the eyes is what's relevant for circadian rhythm regulation, not the color of one's eyes.
• The best way to wake up if you want to be awake is to turn on as many bright lights as you can indoors.
• If you want to stay asleep or sleepy, keep the lights dim.
• Get outside once the sun is starting to come out.
• In the evening, especially in the winter months, it's important to look West and try and get some sunlight in your eyes.
• Avoid blue blockers in the middle of the day, as they can disrupt circadian rhythms.
• Dim the lights and ideally have lights that are set a little bit lower in your environment in the evening.

Article #1, Light/Dark Exposure & Mental Health (00:31:05)

• The study found that getting a lot of sunlight exposure during the day and getting a lot of dark exposure at night is immensely beneficial for psychiatric health.
• The more time you spend outdoors, the better your mood, sleep, and sleep-wake cycles.
• Avoiding light at night and seeking light during the day may be a simple and effective non-pharmacologic means for broadly improving mental health.
• Wrist-based devices used to measure ambient light are not perfect but can provide valuable information about light exposure patterns.
• The study found that greater light exposure in the day is associated with lower risk for psychiatric disorders, while greater light exposure at night is associated with higher risk for psychiatric disorders and poorer mood.
• Sleep duration and efficiency were determined using accelerometers and self-report.

Odds Ratio, Hazard Ratio (00:38:18)

• Odds ratio: probability of something happening in one group divided by the probability of something happening in another group.
• Hazard ratio: defined over a specific period of time.
• Odds ratio of 2 is 100% and odds ratio of 3 is 200%.

Night vs. Daylight Exposure, Mental Health Disorders (00:45:43)

• More nighttime light exposure is associated with worse mental health symptoms, including major depressive disorder, generalized anxiety disorder, bipolar disorder, PTSD, self-harm, and psychotic symptoms.
• The inverse is true for daytime light exposure, with more daytime light exposure generally associated with reduced symptoms.
• ICU psychosis is a phenomenon where non-psychotic individuals start having psychotic episodes in the hospital due to nighttime light exposure and lack of daytime sunlight.
• It is possible that we are all socially jetlagged due to not getting enough daytime light and getting too much nighttime light.

Major Depression & Light Exposure; Error Bars & Significance (00:51:35)

• Strong correlation between increasing light at night and depression.
• Uncoupled relationship between nighttime light and self-harm in the upper quartile (25% of people with the most nighttime light).
• No significant increase in self-harm at lower levels of light exposure at night, but a 30% greater risk in the fourth quartile.
• Inverse relationship between daytime light and self-harm.
• Psychosis relationship based on daytime light and PTSD relationship based on nighttime light are notable.
• Anxiety and bipolar disorder relationships with light exposure are less impressive.
• Going from the second to third quartile of nighttime light exposure leads to almost a 20% increase in major depressive symptoms.
• Fourth quartile of nighttime light exposure shows a 25% increase in major depressive symptoms.
• Fourth quartile of daytime light exposure leads to a 20% reduction in major depressive disorder.
• Varying lengths of error bars indicate that the study is not overpowered.
• Error bars for self-harm range up to 20% on either side of the mean, while error bars for major depression are around 8-10%.

Prescriptions; Environmental & Artificial Light; Red Lights (01:00:39)

• People with sensitive circadian mood systems may need less daytime light exposure and very little light at night to impact their mood systems negatively.
• Some drugs used to treat bipolar disorder may reduce the sensitivity of the light-sensing circadian apparati, potentially ameliorating some symptoms.
• Certain antidepressants may suppress the ability of daytime light to positively impact the brain's mood systems.
• Darkness for eight hours every night should be considered a treatment for bipolar disorder.
• Avoid bright, extensive light exposure at night.
• Moonlight, candlelight, and campfires are relatively dim compared to densely overcast days and phone screens.
• Phones emit high levels of light, especially when used at maximum intensity.
• The context of light exposure matters. Engaging in stimulating activities on a device with a blue light filter can be more disruptive than watching relaxing content on a device with maximum light.
• Red lights can be used to minimize light exposure at night.

Nighttime Light Exposure; Sleep Trackers & Belief Effects (01:08:14)

• Light exposure at night should ideally be for enjoyable reasons.
• The negative impact of social media may be due to various factors, including screen time, lack of other activities, and content viewed.
• Sleep trackers can have a placebo effect on perceived sleep quality.
• Seeing a bad sleep score may lead to negative expectations and a worse day.
• Sleep trackers can be useful for learning about sleep patterns and making behavioral changes, but they should be used cautiously and not relied upon too heavily.
• Recovery scores and similar metrics are not reliable predictors of performance.
• Serious athletes rely on more traditional methods like heart rate and heart rate variability to predict behavior.

Light Directionality, Phone, Night (01:13:54)

• Reduce nighttime light exposure to improve mood and sleep.
• Brief exposure to bright light at night is less concerning than prolonged exposure.
• The directionality of light matters. Avoid looking directly at bright light sources, especially at night.
• Tilting the phone away from the face when using it at night can reduce light exposure to the eyes.

Light Wavelengths & Sensors; Sunglasses (01:17:21)

• Sunlight includes visible light from 470 nm to 650 nm (blue to orange).
• The study used wrist sensors that detected light from 470 nm to 650 nm (blue and ultraviolet).
• Corrective lenses focus light onto the retina, while windows and windshields scatter and filter light.
• Sunglasses filter out too much light, reducing the total Lux count reaching the retina.
• People differ in their light sensitivity, with darker-eyed individuals generally less sensitive than lighter-eyed individuals.

Hawthorne Effect, Reverse Causality, Genetics (01:20:58)

• The Hawthorne effect refers to the change in behavior when people are being observed.
• Reverse causality occurs when the condition being studied influences the treatment or outcome.
• Obesity and diet soda consumption: the association between diet soda consumption and obesity may be due to reverse causality, with obese individuals choosing diet soda to reduce calorie intake.
• Depression and light exposure: the disruption in light exposure in depressed individuals may be a result of the depression rather than the cause.
• Mendelian randomization could be used to examine the genetic basis of light susceptibility and its link to mental health disorders.
• Manic episodes can lead to increased nighttime light exposure, while dark nighttime exposure is being explored as a treatment for bipolar disorder.

Artificial Sweeteners, Appetite (01:26:26)

• Artificial sweeteners may alter the gut biome and metabolism in susceptible individuals.
• Some people experience increased appetite when consuming diet soda due to the perception of sweetness.
• Artificial sweeteners can impact brain and gut chemistry, potentially affecting metabolism.
• Xylitol and allulose are considered safer sweeteners.
• Stevia, monk fruit, and sucrose should be consumed in moderation.

Natural Light Cycles, Circadian Rhythm & Mental Health (01:31:16)

• Light exposure has a significant impact on mental health.
• Disrupted circadian rhythms are associated with psychiatric conditions, including depression and suicide.
• Positive mood and affect are correlated with healthy circadian behavior.
• Morning sunlight increases the amplitude of the morning cortisol spike, which is beneficial for sleep regulation.
• Following natural light-dark cycles can improve mental health.
• The dose-effect relationship, biological plausibility, and evolutionary conservation support the causal effects of light on mental health.
• Simple light-related behaviors, such as taking coffee on the balcony or removing sunglasses outdoors, can positively impact mental health.
• Getting daytime light exposure and nighttime darkness are independent and additive for mental health benefits.

Article #2, Immune System & Cancer (01:39:53)

• The immune system is remarkable in its ability to detect and eradicate harmful foreign pathogens without attacking the self.
• Autoimmune conditions occur when the immune system mistakenly attacks the self.
• Cancer cells evade the immune system's detection and destruction.

T-Cell Activation; Viruses (01:43:18)

• T-cells recognize and get activated by antigens, which are small peptides of proteins.
• MHC class one receptors present antigens from inside the cell to CD8 T-cells, which then mount an immune response.
• MHC class two receptors present antigens from outside the cell to CD4 T-cells, which help B-cells produce antibodies.
• The immune system's ability to combat viruses is remarkable, and we constantly fight off viral infections without even noticing.
• Our ability to ward off viruses is partly due to prior exposure and partly due to our body's ability to destroy viruses without mounting a significant immune response.

Autoimmunity; Cancer & Immune System Evasion (01:50:41)

• Thymic selection occurs in infancy and teaches T-cells to recognize self, eliminating those that don't.
• Cancer is a genetic disease with mostly somatic mutations that occur during life, not inherited.
• A handful of cancers are derived from inherited mutations, such as Lynch syndrome and hereditary polyposis.
• Cancer cells hijack normal cellular processes and behave differently from non-cancerous cells.
• Cancer cells do not respond to cell cycle signaling and continue to grow uncontrollably.
• Cancer cells have the capacity to metastasize and spread to other parts of the body.
• Cancer cells evade the immune system by secreting factors that suppress immune responses and creating an acidic environment.
• The Warburg effect, where cancer cells undergo glycolysis instead of oxidative phosphorylation, may provide building blocks for cell division and help evade the immune system.
• Some cancers, like Tasmanian devil facial tumors, can be transmitted through physical contact.
• Direct transmission of cancers between organisms is rare, but certain viruses like HPV can increase susceptibility to cancer.

Checkpoint Inhibitors, CTLA-4 (02:00:09)

• 80% of solid organ tumors have antigens recognized by the host's immune system.
• CTLA-4 is a checkpoint inhibitor that acts as the brakes in the immune response.
• Blocking CTLA-4 could unleash the immune system and enhance cancer treatment.

Anti-CTLA-4 Study Drug (Ipilimumab), Melanoma (02:06:45)

• Ipilimumab (anti-CTLA-4 drug) was compared to a peptide vaccine (GP100) in patients with metastatic melanoma.
• The study aimed to determine the impact on median survival and overall survival.
• Patients had progressed through every standard therapy and had no other options.
• Melanoma has a complex staging system based on tumor size, lymph node status, metastases, and lactate dehydrogenase levels.

Patient Population, Randomization, GP100 (02:12:07)

• The study involved 700 patients with advanced melanoma.
• Patients were randomized in a 3:1:1 ratio to receive anti-CTLA-4, anti-CTLA-4 plus GP100, or GP100 alone.
• GP100 is a cancer vaccine that had previously failed to show efficacy in clinical trials.
• The rationale for the 3:1:1 randomization was to increase statistical power and assess the potential efficacy of GP100 in combination with anti-CTLA-4.
• Majority of the patients had ECOG performance status of 0 or 1, indicating minimal to no limitations on their quality of life.
• Most patients had advanced disease with visceral metastasis, high LDH levels, and brain metastases.
• All patients had progressed through standard therapy, including radiation and chemotherapy.
• It is common to use a treatment that failed in clinical trials as a placebo in these types of studies to increase patient enrollment and the probability of novel discovery.

Response Rate (02:18:09)

• The primary outcome of the study was initially set as the best overall response rate, which measures the proportion of patients achieving a partial or complete response.
• A complete response is when all visible cancer vanishes, while a partial response is a 50% reduction in the diameter of every single lesion with no new lesions appearing and no lesions growing.
• The study protocol was amended during the trial to change the primary endpoint to overall survival, which is typically the metric that matters most to patients and researchers.
• The overall survival for metastatic melanoma is generally low, with the exception of patients who respond to high-dose interleukin-2, which can boost the survival rate to 8-10%.
• Approximately a quarter of the patients in the study had already received and progressed through high-dose interleukin-2 treatment.

Overall Survival & Response (02:22:52)

• The Kaplan-Meyer survival curve shows a clear distinction between the placebo group and the two treatment groups.
• The median survival in the placebo group was 6.4 months, while it was 10.1 months in the ntla 4 alone group and 10 months in the anti-la 4 plus GP 100 group.
• 50% of the patients in the control group were dead in 6 months, while 50% of the patients in the treatment groups were dead in 10 months.
• Overall survival has not changed for solid epithelial tumors since 1970, with a 0% survival rate.

Median Survival vs. Overall Survival, Drug Development (02:28:38)

• Median survival is an important metric in cancer therapy, as it measures the time it takes for half of the patients to die.
• Overall survival is the most important metric in cancer therapy, as it measures the time it takes for all of the patients to die.
• Drug companies often focus on extending median survival rather than overall survival, as it is a more easily achievable goal.
• Some drugs that extend median survival by only a few weeks or days are approved by the FDA and can cost tens of thousands of dollars per treatment.
• The societal and patient costs of these drugs can be significant, and the quality of life of patients may be dramatically compromised.

Gender & Dose (02:35:45)

• Subgroup analysis showed that females did not reach significance in risk reduction compared to males.
• Possible explanations include differences in immune response or dosing based on weight, with men receiving higher doses on average.

Adverse Events; Autoimmunity (02:40:32)

• 98.4% of patients in the treatment plus GP 100 group reported some adverse event, 96.7% in the anti-CTLA-4 group alone, and 97% in the placebo group.
• Grade four toxicities were 6.1% in the placebo group, 8.4% in the anti-CTLA-4 group, and 6.8% in the combined group.
• Autoimmune-related events were significantly higher in the treatment groups compared to the placebo group.
• Autoimmunity correlated with response rate, with higher autoimmunity predicting better response.

Pancreatic Cancer; Aging & Immune System Health (02:46:42)

• Pancreatic cancer is often non-survivable and unresectable.
• Surgical removal of the pancreas is no longer the bottleneck as the cancer usually recurs due to micromestasis.
• A possible way to prevent cancer is to stimulate the immune system periodically to eliminate early-stage cancers.
• Keeping the immune system healthy as we age is crucial, and rapamycin might enhance cellular immunity and improve vaccine response.

Melanoma; Lynch Syndrome, Keytruda (02:53:57)

• Melanoma has many more mutations than other cancers, making it more likely to produce antigens recognized as non-self.
• Lynch syndrome is a hereditary mutation that increases cancer risk.
• A patient with Lynch syndrome and pancreatic cancer had a complete regression of his cancer after enrolling in a Keytruda trial.
• The treatment activated his immune system so well that it destroyed his pancreas, resulting in Type 1 diabetes.
• Car T cells are currently mutation-specific, not tissue-specific, but they can selectively target cd19 B cells.
• The correlation between autoimmunity and response to immunotherapy in this study was not analyzed.

Immunotherapy & Cancer Treatment; Melanoma Risk (02:58:43)

• Immunotherapy is a promising treatment for cancer, but there is still room for improvement.
• Engineering T cells to be better recognizers of antigens is a potential way to improve immunotherapy.
• Expanding the number of T cells that recognize the antigen and preventing them from aging too much are key challenges in immunotherapy.
• Avoiding sunburn is the most significant risk factor for melanoma.
• Physical barriers for sunscreen are undisputed, but some sunscreens contain endocrine disruptors.
• Early repeated sunburns may be more of a risk for melanoma than chronic sun exposure.
• The anti-sunscreen establishment is odd, but there is a need for a nuanced discussion about the potential risks of some sunscreens.