Drugs that tamp down inflammation in the brain could slow cognitive decline | Hacker News Reader

Drugs that tamp down inflammation in the brain could slow cognitive decline

news.berkeley.edu

148 pointschris199378 comments

Alternatively, you can quite dramatically reduce inflammation in the brain via some simple lifestyle modifications (cutting out sugar, intermittent fasting):

Mattson, Mark P., Keelin Moehl, Nathaniel Ghena, Maggie Schmaedick, and Aiwu Cheng. “Intermittent Metabolic Switching, Neuroplasticity and Brain Health.” Nature Reviews. Neuroscience 19, no. 2 (February 2018): 63–80. https://doi.org/10.1038/nrn.2017.156.

Pinto, Alessandro, Alessio Bonucci, Elisa Maggi, Mariangela Corsi, and Rita Businaro. “Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer’s Disease.” Antioxidants 7, no. 5 (April 28, 2018). https://doi.org/10.3390/antiox7050063.

Gao, Yuanqing, Maximilian Bielohuby, Thomas Fleming, Gernot F. Grabner, Ewout Foppen, Wagner Bernhard, Mara Guzmán-Ruiz, et al. “Dietary Sugars, Not Lipids, Drive Hypothalamic Inflammation.” Molecular Metabolism 6, no. 8 (June 20, 2017): 897–908. https://doi.org/10.1016/j.molmet.2017.06.008.

White, Hayden, Karthik Venkatesh, and Bala Venkatesh. “Systematic Review of the Use of Ketones in the Management of Acute and Chronic Neurological Disorders.” Journal of Neurology and Neuroscience 08, no. 02 (2017). https://doi.org/10.21767/2171-6625.1000188.

Alirezaei, Mehrdad, Christopher C. Kemball, Claudia T. Flynn, Malcolm R. Wood, J. Lindsay Whitton, and William B. Kiosses. “Short-Term Fasting Induces Profound Neuronal Autophagy.” Autophagy 6, no. 6 (August 16, 2010): 702–10. https://doi.org/10.4161/auto.6.6.12376.

Mattson, Mark P. “Energy Intake, Meal Frequency, and Health: A Neurobiological Perspective.” Annual Review of Nutrition 25 (2005): 237–60. https://doi.org/10.1146/annurev.nutr.25.050304.092526.

This incidentally also reduces system-wide inflammation among other benefits as well:

Houtman, Judith, Kiara Freitag, Niclas Gimber, Jan Schmoranzer, Frank L. Heppner, and Marina Jendrach. “Beclin1‐driven Autophagy Modulates the Inflammatory Response of Microglia via NLRP3.” The EMBO Journal, January 7, 2019, e99430. https://doi.org/10.15252/embj.201899430.

Camell, Christina, Emily Goldberg, and Vishwa Deep Dixit. “Regulation of Nlrp3 Inflammasome by Dietary Metabolites.” Seminars in Immunology 27, no. 5 (September 2015): 334–42. https://doi.org/10.1016/j.smim.2015.10.004.

Yamanashi, Takehiko, Masaaki Iwata, Naho Kamiya, Kyohei Tsunetomi, Naofumi Kajitani, Nodoka Wada, Takahiro Iitsuka, et al. “Beta-Hydroxybutyrate, an Endogenic NLRP3 Inflammasome Inhibitor, Attenuates Stress-Induced Behavioral and Inflammatory Responses.” Scientific Reports 7, no. 1 (August 9, 2017): 7677. https://doi.org/10.1038/s41598-017-08055-1.

Youm, Yun-Hee, Kim Y. Nguyen, Ryan W. Grant, Emily L. Goldberg, Monica Bodogai, Dongin Kim, Dominic D’Agostino, et al. “Ketone Body β-Hydroxybutyrate Blocks the NLRP3 Inflammasome-Mediated Inflammatory Disease.” Nature Medicine 21, no. 3 (March 2015): 263–69. https://doi.org/10.1038/nm.3804.

Marín‐Aguilar, Fabiola, Ana V. Lechuga‐Vieco, Elísabet Alcocer‐Gómez, Beatriz Castejón‐Vega, Javier Lucas, Carlos Garrido, Alejandro Peralta‐Garcia, et al. “NLRP3 Inflammasome Suppression Improves Longevity and Prevents Cardiac Aging in Male Mice.” Aging Cell 0, no. 0 (n.d.): e13050. https://doi.org/10.1111/acel.13050.

Xiao, Yichen, Wenna Xu, and Wenru Su. “NLRP3 Inflammasome: A Likely Target for the Treatment of Allergic Diseases.” Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology 48, no. 9 (2018): 1080–91. https://doi.org/10.1111/cea.13190.

Bugyei-Twum, Antoinette, Armin Abadeh, Kerri Thai, Yanling Zhang, Melissa Mitchell, Golam Kabir, and Kim A. Connelly. “Suppression of NLRP3 Inflammasome Activation Ameliorates Chronic Kidney Disease-Induced Cardiac Fibrosis and Diastolic Dysfunction.” Scientific Reports 6 (December 21, 2016). https://doi.org/10.1038/srep39551.

Have any of these studies been reproduced?

The body of work, while still emergent, is fairly robust IMO if that's what you're asking. I've cherry picked just a few out of hundreds of papers in my personal archive related to this topic, but if you have an interest you can easily check Pubmed or Researchgate to both follow the citation chain and get a sense of which research teams are publishing and working on what aspects (sadly there's no tool to do that automatically, although it seems like that might be a cool thing to build).

Eight of those studies have been published only in the past 3 years. Until I see a pattern of repeated results, I'm going to file these under "pop science." "Keto is the shizzle, let's get our pubz!" Let's see what happens as others work on repro over the next 10+ years.

TIL the benefits of eating less refined carbs and intermittent fasting is still up for debate to some folks.

Add salt, fat, coffee, wine, eggs, and about a dozen other things researchers can’t agree on. nutrition research is hella sketchy

The only fat that is really problematic is trans fats, and those are pretty much banned most places now. Fats, from particularly protein sources, contain more bioavailable micronutrients than fruits and vegetables.

The top papers I included are purposefully recent as they are recent reviews on an emerging area of research.

Having read a lot of papers this year, my conclusion btw is actually that recent papers are much better than older papers. One, newer papers allow you to spelunk through older papers in the citation chain (all peer reviewed work has substantive reference lists), and two, and state of understanding of basic human biology is miniscule and for emerging topics (like chronic inflammation, or human metabolism) our understanding has changed enormously due to recent discoveries (at a much improving rate).

As an FYI, the inflammasome wasn't even discovered until 2002 [1] so you can basically be guaranteed that any prior research is going to be missing some key context. This is repeated for many pathways and processes that we take for granted (and a lot of it has barely filtered out to clinical practice much less pop culture) and will this will be repeating itself for quite some time, since we're still discovering so many new things that turn our understanding of biology on its head (just a handful of examples off the top of my head: role of microbiota (the wild west!), vagus nerve communication, autophagy, epigenetics, circadian clocks, and yes, most of ketone metabolism, particularly BHB as a signaling molecule).

[1] https://en.wikipedia.org/wiki/Inflammasome#History

The keto diet is a low fiber high saturated fat intake diet. The effects of low fiber consumption and high intake of saturated fat are well established, and they certainly aren't inflammation reducers. Also, fasting is not without risks.

Keto is a low carb high fat diet. With keto you can have as much fibre as you like as long as it's not paired with carbs.

> With keto you can have as much fibre as you like as long as it's not paired with carbs.

Plants, which are extremely high in carbs, are where fiber comes from.

High intake of saturated fat is associated with heart disease.

There are a ton of low carb vegetables, you should google it.

As mentioned, plenty (maybe even most!) vegetables are not very high in digestible carbs - certainly not the ones that are high in fiber and nutrients (you can probably skip the potatoes unless you're on a mono-diet). But this is where I think you really need to reconsider where you're getting you're data from...

> High intake of saturated fat is associated with heart disease.

First off, associations, especially in nutritional epidemiology, is trash:

Ioannidis, John P. A. “The Challenge of Reforming Nutritional Epidemiologic Research.” JAMA, August 23, 2018. https://doi.org/10.1001/jama.2018.11025.

Archer, Edward, Carl J. Lavie, and James O. Hill. “The Failure to Measure Dietary Intake Engendered a Fictional Discourse on Diet-Disease Relations.” Frontiers in Nutrition 5 (November 13, 2018). https://doi.org/10.3389/fnut.2018.00105.

Archer, Edward, Michael L. Marlow, and Carl J. Lavie. “Controversy and Debate: Memory-Based Methods Paper 1: The Fatal Flaws of Food Frequency Questionnaires and Other Memory-Based Dietary Assessment Methods.” Journal of Clinical Epidemiology 104 (December 2018): 113–24. https://doi.org/10.1016/j.jclinepi.2018.08.003.

I don't think people realize just how bad the quality of data is in these sort of survey studies. IMO anything w/ an HR/OR of <2 should probably be outright ignored, if not taken with a big salt block before using as a hypothesis for an interventional trial.

But more interestingly, is how nutritional myths can sustain after it's been overturned. It turns out that on meta-analysis (n=347747), again keeping in mind how we should treat observational studies, the HR between eating the highest and lowest saturated fat consumption is... exactly 1.0.

Siri-Tarino, Patty W, Qi Sun, Frank B Hu, and Ronald M Krauss. “Meta-Analysis of Prospective Cohort Studies Evaluating the Association of Saturated Fat with Cardiovascular Disease.” The American Journal of Clinical Nutrition 91, no. 3 (March 1, 2010): 535–46. https://doi.org/10.3945/ajcn.2009.27725.

Lets see what some other teams say. This analysis uses the GRADE approach for evidence analysis:

"Saturated fats are not associated with all cause mortality, CVD, CHD, ischemic stroke, or type 2 diabetes, but the evidence is heterogeneous with methodological limitations."

Souza, Russell J. de, Andrew Mente, Adriana Maroleanu, Adrian I. Cozma, Vanessa Ha, Teruko Kishibe, Elizabeth Uleryk, et al. “Intake of Saturated and Trans Unsaturated Fatty Acids and Risk of All Cause Mortality, Cardiovascular Disease, and Type 2 Diabetes: Systematic Review and Meta-Analysis of Observational Studies.” BMJ 351 (August 12, 2015). https://doi.org/10.1136/bmj.h3978.

There have still been plenty of studies so lets focus on adequately controlled RCTs, the highest evidence we might have:

"When pooling results from only the adequately controlled trials there was no effect for major CHD events (RR = 1.06, CI = 0.86–1.31), total CHD events (RR = 1.02, CI = 0.84–1.23), CHD mortality (RR = 1.13, CI = 0.91–1.40) and total mortality (RR = 1.07, CI = 0.90–1.26). Whereas, the pooled results from all trials, including the inadequately controlled trials, suggested that replacing SFA with mostly n-6 PUFA would significantly reduce the risk of total CHD events (RR = 0.80, CI = 0.65–0.98, P = 0.03), but not major CHD events (RR = 0.87, CI = 0.70–1.07), CHD mortality (RR = 0.90, CI = 0.70–1.17) and total mortality (RR = 1.00, CI = 0.90–1.10).

Conclusion

Available evidence from adequately controlled randomised controlled trials suggest replacing SFA with mostly n-6 PUFA is unlikely to reduce CHD events, CHD mortality or total mortality. The suggestion of benefits reported in earlier meta-analyses is due to the inclusion of inadequately controlled trials. These findings have implications for current dietary recommendations."

Hamley, Steven. “The Effect of Replacing Saturated Fat with Mostly N-6 Polyunsaturated Fat on Coronary Heart Disease: A Meta-Analysis of Randomised Controlled Trials.” Nutrition Journal 16 (May 19, 2017). https://doi.org/10.1186/s12937-017-0254-5.

This isn't the only RCT meta-analysis confirming this. Here's one w/ n=62421 from another team:

"The current available evidence found no significant difference in all-cause mortality or CHD mortality, resulting from the dietary fat interventions. RCT evidence currently available does not support the current dietary fat guidelines. The evidence per se lacks generalisability for population-wide guidelines."

Harcombe, Zoë, Julien S. Baker, James J. DiNicolantonio, Fergal Grace, and Bruce Davies. “Evidence from Randomised Controlled Trials Does Not Support Current Dietary Fat Guidelines: A Systematic Review and Meta-Analysis.” Open Heart 3, no. 2 (August 1, 2016): e000409. https://doi.org/10.1136/openhrt-2016-000409.

So how did this come to be in the first place? Harcombe et al have done a ton of interesting research on this topic, which I'll include for those wanting to dive into the history of the topic (I'm personally a bit bored by the whole lipid heart stuff; turns out that MetS is a 10X greater risk factor, and also if you get a CAC scan every 5 years and keep a 0 score, you're CHD risk is basically nil) :

Harcombe, Zoë, Julien S. Baker, Stephen Mark Cooper, Bruce Davies, Nicholas Sculthorpe, James J. DiNicolantonio, and Fergal Grace. “Evidence from Randomised Controlled Trials Did Not Support the Introduction of Dietary Fat Guidelines in 1977 and 1983: A Systematic Review and Meta-Analysis.” Open Heart 2, no. 1 (January 1, 2015): e000196. https://doi.org/10.1136/openhrt-2014-000196.

Harcombe, Zoë, Julien S. Baker, and Bruce Davies. “Evidence from Prospective Cohort Studies Did Not Support the Introduction of Dietary Fat Guidelines in 1977 and 1983: A Systematic Review.” British Journal of Sports Medicine 51, no. 24 (December 2017): 1737–42. https://doi.org/10.1136/bjsports-2016-096409.

Harcombe, Zoë. “Dietary Fat Guidelines Have No Evidence Base: Where next for Public Health Nutritional Advice?” Br J Sports Med 51, no. 10 (May 1, 2017): 769–74. https://doi.org/10.1136/bjsports-2016-096734.

Harcombe, Zoe. “US Dietary Guidelines: Is Saturated Fat a Nutrient of Concern?” British Journal of Sports Medicine 53, no. 22 (November 1, 2019): 1393–96. https://doi.org/10.1136/bjsports-2018-099420.

Oh, just in case anyone wants to dive into the best risk factors I found (and I've done a lot of digging on risk factors) for avoiding heart disease:

Reverse prediabetes (HR: 0.44):

Vistisen, Dorte, Mika Kivimäki, Leigh Perreault, Adam Hulman, Daniel R. Witte, Eric J. Brunner, Adam Tabák, Marit E. Jørgensen, and Kristine Færch. “Reversion from Prediabetes to Normoglycaemia and Risk of Cardiovascular Disease and Mortality: The Whitehall II Cohort Study.” Diabetologia, May 23, 2019. https://doi.org/10.1007/s00125-019-4895-0.

Maintain a CAC=0 (HR: 0.41):

Blaha Michael J., Cainzos-Achirica Miguel, Greenland Philip, McEvoy John W., Blankstein Ron, Budoff Matthew J., Dardari Zeina, et al. “Role of Coronary Artery Calcium Score of Zero and Other Negative Risk Markers for Cardiovascular Disease.” Circulation 133, no. 9 (March 1, 2016): 849–58. https://doi.org/10.1161/CIRCULATIONAHA.115.018524.

And a few interesting final thoughts on etiology (and circling back to the original topic of inflammation):

Malhotra, Aseem, Rita F. Redberg, and Pascal Meier. “Saturated Fat Does Not Clog the Arteries: Coronary Heart Disease Is a Chronic Inflammatory Condition, the Risk of Which Can Be Effectively Reduced from Healthy Lifestyle Interventions.” Br J Sports Med 51, no. 15 (August 1, 2017): 1111–12. https://doi.org/10.1136/bjsports-2016-097285.

Tsoupras, Alexandros, Ronan Lordan, and Ioannis Zabetakis. “Inflammation, Not Cholesterol, Is a Cause of Chronic Disease.” Nutrients 10, no. 5 (May 12, 2018). https://doi.org/10.3390/nu10050604.

(Cholesterol is a whole different can of worms than saturated fat (I'll leave that as an exercise to the reader), but cholesterol is also a terrible marker. "Most major heart attacks occur in people with normal cholesterol": https://www.sciencedaily.com/releases/2017/04/170412105837.h...)

> associations, especially in nutritional epidemiology, is trash: > I think you really need to reconsider where you're getting you're data from...

I'm going to go with established medical science on this one.

> Most medical, scientific, heart-health, governmental, and professional authorities agree that saturated fat is a significant risk factor for cardiovascular disease, including the World Health Organization,[1] the Food and Nutrition Board of the National Academy of Medicine,[2] the Academy of Nutrition and Dietetics,[3] the Dietitians of Canada,[3] the Association of UK Dietitians,[4] the American Heart Association,[5] the British Heart Foundation,[6] the Heart and Stroke Foundation of Canada,[7] the World Heart Federation,[8] the British National Health Service,[9] the United States Food and Drug Administration,[10] and the European Food Safety Authority.[11] All of these organizations recommend restricting consumption of saturated fats to reduce that risk.

https://en.wikipedia.org/wiki/Saturated_fat_and_cardiovascul...

Actually, I think it's an important distinction that your citation aren't on "established medical science", but rather nutritional guidelines, which are consensus statements at best (but since their first introduction in 1980 have as much political as scientific policy).

They have bent to scientific evidence, but very slowly. The 2015 US Dietary guideline revision quietly removed both dietary cholesterol and total fat consumption [1]:

"In the new DGAC report, one widely noticed revision was the dropping of dietary cholesterol as a “nutrient of concern.” This surprised the public, but is concordant with scientific evidence demonstrating no appreciable relationship between dietary cholesterol and serum cholesterol1 or clinical cardiovascular events in general populations.2 The DGAC should be commended for this evidence-based change.

A far less noticed, but more momentous, change was the new absence of any limitation on total fat consumption. The DGAC neither listed total fat as a nutrient of concern, nor proposed any limitation on its consumption. Rather, they concluded, “Reducing total fat (replacing total fat with overall carbohydrates) does not lower CVD risk Dietary advice should put the emphasis on optimizing types of dietary fat and not reducing total fat.”"

Even at their best, guidelines will trail what the scientific evidence shows by years. I don't see how what you've posted reflects "established medical science" at all, unless you have recent evidence that shows saturated fat intake as being harmful. Here's a recent direct critique on btw on why the WHO guidelines are wrong for saturated fat limits specifically:

Astrup, Arne, Hanne CS Bertram, Jean-Philippe Bonjour, Lisette CP de Groot, Marcia C. de Oliveira Otto, Emma L. Feeney, Manohar L. Garg, et al. “WHO Draft Guidelines on Dietary Saturated and Trans Fatty Acids: Time for a New Approach?” BMJ 366 (July 3, 2019): l4137. https://doi.org/10.1136/bmj.l4137.

For those wanting to learn more about how nutritional guidelines are made and their impact, this short history is a good introduction: https://www.nutritioncoalition.us/dietary-guidelines-for-ame...

And here are some more peer-reviewed critiques on how nutrition guidelines should be improved:

Bero, Lisa A., Susan L. Norris, and Mark A. Lawrence. “Making Nutrition Guidelines Fit for Purpose.” BMJ 365 (April 16, 2019). https://doi.org/10.1136/bmj.l1579.

Johnston, Bradley C., Pablo Alonso-Coello, Malgorzata M. Bala, Dena Zeraatkar, Montserrat Rabassa, Claudia Valli, Catherine Marshall, et al. “Methods for Trustworthy Nutritional Recommendations NutriRECS (Nutritional Recommendations and Accessible Evidence Summaries Composed of Systematic Reviews): A Protocol.” BMC Medical Research Methodology 18, no. 1 (December 5, 2018): 162. https://doi.org/10.1186/s12874-018-0621-8.

Magni, Paolo, Dennis M Bier, Sergio Pecorelli, Carlo Agostoni, Arne Astrup, Furio Brighenti, Robert Cook, et al. “Perspective: Improving Nutritional Guidelines for Sustainable Health Policies: Current Status and Perspectives.” Advances in Nutrition 8, no. 4 (July 6, 2017): 532–45. https://doi.org/10.3945/an.116.014738.

Fogelholm, Mikael. “Nutrition Recommendations and Science: Next Parallel Steps.” Journal of the Science of Food and Agriculture 96, no. 4 (March 15, 2016): 1059–63. https://doi.org/10.1002/jsfa.7479.

Teicholz, Nina. “The Scientific Report Guiding the US Dietary Guidelines: Is It Scientific?” BMJ 351 (September 23, 2015). https://doi.org/10.1136/bmj.h4962.

Archer, Edward, Gregory Pavela, and Carl J Lavie. “The Inadmissibility of ‘What We Eat In America’ (WWEIA) and NHANES Dietary Data in Nutrition & Obesity Research and the Scientific Formulation of National Dietary Guidelines.” Mayo Clinic Proceedings 90, no. 7 (July 2015): 911–26. https://doi.org/10.1016/j.mayocp.2015.04.009.

[1] Mozaffarian, Dariush, and David S. Ludwig. “The 2015 US Dietary Guidelines – Ending the 35% Limit on Total Dietary Fat.” JAMA 313, no. 24 (June 23, 2015): 2421–22. https://doi.org/10.1001/jama.2015.5941.

In general, carbs / sugar paired with fiber are healthy. Sugar without fiber is unhealthy. Fiber is always healthy.

>>>Fiber is always healthy

Fiber is indigestible, provides no nutritional value. It just passes through. The only thing its good for is being the scaffolding to make a nice turd.

No, fiber supports the microbiome in the gut, which is nowadays understood as being really important for overall health.

https://www.nytimes.com/2018/01/01/science/food-fiber-microb...

Keto has a concept of "net carbs". The calculation is: All carbs, minus fiber, minus sugar alcohols (most sugar alcohols are not metabolized or bioavailable). Keto doesn't restrict the subtracted types of carbs.

> cutting out sugar

I'll assume you mean refined sugar here. I'd expect the benefits of eating fresh fruit and sugar-containing vegetables to outweigh most of the harm done by their sugar content.

By eating the whole fruit, you're consuming the fiber, which changes how your body metabolizes the sugar (more slowly), as opposed to say, drinking a glass of apple juice.

The sugar itself between fruits and refined sugars contained in processed foods isn't all that different. Apples contain fructose, glucose, and sucrose, but in different ratios compared to table sugar. The more important factor is the quantity of sugar you're consuming.

But we don't even need to eat sweet fruits. If you look at your plate size as a constraint, then fruit carries an opportunity cost. You're adding sweet fruit in place of something else which could add more nutritional value in that same space. If you do eat fruit, then eat something which isn't sweet (tomato for example.)

Very few vegetables (starchy tubers are the main exception) contain much sugars (and specifically fructose, which is uniquely bad for your liver), so I think it's worth separating out fruit vs vegetables, but yes, there's also a very different metabolic response to acellular sugars (the best review I've seen on the subject is actually a talk given by Gabor Erdosi: https://www.youtube.com/watch?v=8rcfvRGZsDs), but I'd also say that the harm is contextual. If you're metabolically flexible, or if you're actively replenishing muscle or liver glycogen, your body comp is where you want it, and your insulin sensitivity/glucose disposal is good, then yeah, sure, have some fruit if you want. If you're like the majority of American adults though, then it's probably not doing you any favors.

* 2013–2014 NHANES Data shows 70.2% of US adults are overweight or obese. [1] 37.7% being obese. Note, that this percentage is reported at 39.8% in 2015-2016 (using the same NHANES data). [2]

* The NIH estimates that "Between 30 and 40 percent of adults in the United States have NAFLD." [3]

* The CDC says: "An estimated 33.9% of U.S. adults ... had prediabetes in 2015" and "Nearly half (48.3%) of adults aged 65 years or older had prediabetes." (only 1/3 are "aware" of this). Another 9.4% of the population is estimated to be diabetic. [4] That means well over half of American adults are pre-diabetic or diabetic, and that number is only going up.

It's important to recognize that diabetes is only the endpoint and it is usually preceded with Metabolic Syndrome markers. Here's a recent analysis of 2009-2016 NHANES data: https://www.liebertpub.com/doi/10.1089/met.2018.0105

* 80.1% of Americans had at least one marker of MetS by ATP III criteria

* Using more restrictive (calculated in the study) cutoffs gave a result of 12.2% of American adults in "optimal metabolic health"

Sadly, what's notably missing from all of this is measurement of fasting insulin - almost no one gets this measured (and I've both had personal experience and tons of stories from friends where Doctor's will actively fight back when requesting to have your FI tested) - it's been know for decades that hyperinsulemia and insulin resistance (best calculated by HOMA or HOMA2, indices which require FG and FI to calculate) will precede hyperglycemia by years or decades (subclinical diabetes). The insulin assay costs $8 direct-to-consumer pricing in the US when added onto standard FG/A1c testing. (FI is also required to calculate your NAFLD LFS, the best index for diagnosing NAFLD.)

To me, what was sort of shocking/amazing to me after doing my own research is how negligently ignorant GPs/clinicians are about literally the most common disease that's killing their patients.

Based on what I've learned this year, I have some (pretty well-founded IMO) opinions now, but I'm actually not all that interested in these Nutrition Wars arguments (the quality of the research is very poor and population-level dietary policy has honestly been such a disaster, but almost impossible to turn around due to institutional momentum/regulatory capture) but so much of metabolic health is contextual and bio-individual. I'd rather people pick some good surrogate markers they can track sequentially and then make controlled lifestyle modifications and see what actually helps them. Everyone should just do more of what works for them, and do less of what doesn't and worry less about what "experts" say on the matter.

[1] https://www.niddk.nih.gov/health-information/health-statisti...

[2] https://www.cdc.gov/nchs/data/databriefs/db288.pdf

[3] https://www.niddk.nih.gov/health-information/liver-disease/n...

[4] https://www.cdc.gov/diabetes/data/statistics-report/prevalen...

Wouldn't it be better and more effective to treat the cause of the inflammation instead?

Maybe, but what's the plan to do that?

Occasional fasting, diet, exercise, sleep, positive relationships.

Not eating inflammatory foods. Severely limit sugar, carbohydrates. Not eating as much. Enough sleep.

That's a misunderstanding of the article, it says that the issue is due to the leaky blood brain barrier. The chemicals for inflammation in the body aren't inherently bad, they're just not designed to be in the brain. Decreasing the source of that inflammation could help but it's not the issue being discussed here.

From the perspective of a non-biologist reader only seeing popular articles, the past ten years have been completely bewildering. Nutrition has seemingly been boiled down to a couple of magic totems that are always simplistically either good or bad.

Antioxidants are good.

Inflammation is bad.

Telomeres are good.

Carbs are bad.

All the "bad" things get associated with each other and anti-associated with the good things. Carbs have less antioxidants, which prevent inflammation, which shortens telomeres. Everything is associated in a completely mysterious way to "the gut". Carbs are bad. Why? The gut. We read this in more words and nod sagely. It gives me the feeling of reading a children's picture book.

Biology isn't supposed to be this simple. If inflammation were always bad, our bodies wouldn't have evolved to do it. I'm not saying the science is wrong, I'm sure it's well thought out, but something is getting severely oversimplified in the leap to popular articles, to the point that I don't trust any nutrition advice based on the pop science. Does anybody know of a better source?

> Biology isn't supposed to be this simple.

I don't this new understanding implies biology is simple, but it looks like we had previously understood the urban, Western diet's consumption levels of sugar and simple carbs as "normal" when in reality it wreaks havoc in seemingly everyone's system.

We now have enough data to think critically about our diet so it's almost like Nutrition is a whole new field of study that is being discovered.

Carbs aren’t bad and protein isn’t some miracle. First I’ve heard of proteins being a source of antioxidants if carbs can’t be their source. Really colorful things like the skin of blueberries tend to be the highest sources of antioxidants, vitamins, and minerals. Also is there some dietary source of telomeres? Slightly sarcastic there...

“How not to die” really combined a lot of knowledge, including dietary knowledge, into one place. Netflix’s “the game changers” was cool, too.

I spend/spent a lot of time on nutritional information sites like the SELF or nutritional value org site. I research ingredients and recipes that way to make dietary choices. It’s the pretty “boring”, uncontested data in the dietary mine field.

General trends include Whole foods tend to have the highest concentrations of nutrients per calorie. Stay away from processed foods like white sugar, white flour, etc.

There's a huge difference between the acute inflammatory response (obviously good and necessary for life) and chronic inflammation (very bad).

The biology is hideously complex and not well understood. This past year I've gone through thousands of paper and feel like I'm just getting a real handle on how little is known. Mechanisms (not to mention downstream effects) for some of the most widely and commonly used medications are practically medical mysteries and new metabolic pathways are discovered basically daily.

Luckily almost all of the peer-reviewed primary literature is indexed on PubMed, and you can use ResearchGate, Altmetric, etc to help prioritize your research. Once you start reading you'll see that there's tons of conflict and disagreement.

If you're looking for something a step up from pop journalism (which is terribad), you can start with sites like Examine or Health Line which at least give proper citations, but in the end, I suspect you're just going to need to do your own spelunking and come to your own conclusions because the quality of life-sciences research is quite frankly... uneven at best. Nutritional research is particularly bad.

Chronic inflammation is definitely turning out to be a topic of great interest lately. Here's some starting points (you can follow the citation chain if you actually care):

Pahwa, Roma, and Ishwarlal Jialal. “Chronic Inflammation.” In StatPearls. Treasure Island (FL): StatPearls Publishing, 2019. http://www.ncbi.nlm.nih.gov/books/NBK493173/.

Lawrence, Toby, and Derek W Gilroy. “Chronic Inflammation: A Failure of Resolution?” International Journal of Experimental Pathology 88, no. 2 (April 2007): 85–94. https://doi.org/10.1111/j.1365-2613.2006.00507.x.

Freire, Marcelo O., and Thomas E. Van Dyke. “Natural Resolution of Inflammation.” Periodontology 2000 63, no. 1 (October 2013): 149–64. https://doi.org/10.1111/prd.12034.

Hunter, Philip. “The Inflammation Theory of Disease.” EMBO Reports 13, no. 11 (November 2012): 968–70. https://doi.org/10.1038/embor.2012.142.

Straub, Rainer H., and Carsten Schradin. “Chronic Inflammatory Systemic Diseases.” Evolution, Medicine, and Public Health 2016, no. 1 (January 27, 2016): 37–51. https://doi.org/10.1093/emph/eow001.

Murakami, Masaaki, and Toshio Hirano. “The Molecular Mechanisms of Chronic Inflammation Development.” Frontiers in Immunology 3 (November 15, 2012). https://doi.org/10.3389/fimmu.2012.00323.

Minihane, Anne M., Sophie Vinoy, Wendy R. Russell, Athanasia Baka, Helen M. Roche, Kieran M. Tuohy, Jessica L. Teeling, et al. “Low-Grade Inflammation, Diet Composition and Health: Current Research Evidence and Its Translation.” The British Journal of Nutrition 114, no. 7 (October 14, 2015): 999–1012. https://doi.org/10.1017/S0007114515002093.

>>Biology isn't supposed to be this simple. If inflammation were always bad, our bodies wouldn't have evolved to do it.

People think that they can "hack" the body and live to 4000 years. What if biology is pretty simple: some things are good, some bad, but even if you do all the "good things," unexpected things will happen and either way you'll die one day. Find a mate to pass your genes, raise your kids and start saying your goodbye! The fact that we now live some 30-40 years after our kids are grown, is a bonus, but that doesn't mean that it is unlimited.

> Find a mate to pass your genes, raise your kids

What about those who are not fortunate enough to have kids or pass on genes like gays?

adopt, raise, long life. Or just live. My post wasn't meant to include everyone or exclude a specific group. (they are some who can't have kids for example, or refuse to...etc.etc. But in general we want to pass down our genes)

This is exactly the problem. In general the society expects us to pass on our genes by default. And those unfortunate feel that if they can’t pass on their genes there is something wrong with them.

What you said, is irrelevant to the main discussion (biology.) Whether not passing down your genes is good or bad for the person or society is a different discussion.

The good versus bad narrative is also determined by the source/reader's orientation:

Western medicine is corrupt and bad; natural solutions are wholesome and good.

Natural medicine is anti-science and bad; western medicine = science and good.

Each side is engaged in a turf war with the other. IMO, there are pros and cons to each, but the dogmatism clouds adherents to the potential of the enemy's understanding and solutions. That potential seems to be inflated and premature in the case of natural medicine, and sometimes deceived via bias by money-interests in the case of western medicine. Pursuing natural treatments to the exclusion of western treatments can prevent a person from using something that has proven effect; pursuing western treatments to the exclusion of natural treatments can be signing on to destructive side effects.

That’s a common narrative, but science can explain what’s going on just fine.

Natural Medicine does seem to get people to change various behaviors. Several friends went through a bizarre homeopathic stage. I kept quiet because they where told the ‘magic pills’ only worked if they took care of their general heath better such as getting more sleep, and so they would comply.

I don’t think the placebo effect + lifestyle changes warrants calling these things an alternative, but it does explain why they can stick around. Sadly, some people are willing to just sell the magic pills without the advice that makes them useful.

Retraction Watch says "hello".

I have no idea what you mean by that.

Inflammation is like scorched earth. You hurt yourself to hurt your enemy more. Best not to be in a position where you have to do it.

> magic totems that are always simplistically either good or bad.

I read a book on nutrition (forgot which) that started out with these helpful definitions:

  unhealthy - food we statistically eat too much of

  healthy - food we statistically should eat more

Food that is unhealthy is almost never plain "bad". In small quantities it is probably even "good". It's just that most people have too much of it in their everyday diet.

Can someone please fix block quote on mobile?

> Nutrition has

-> Always been like this.

As a very smart bio professor once said to me: the half-life of a nutrition paper is about 2 years.

Antioxidants aren't necessarily good. Like most anything, consuming too much can cause health problems.

Easy to see when comparing diet with life expectation throughout the world.

Carbs bad, fat actually alright.

> Carbs bad

But Japan.

I'm in there currently.

I somehow do not see the high carb stuff.

"Antioxidants are good."

Ingested antioxidants have no pathway to the cell interior where they might act to "counter oxidation".

Further, if there were it would probably be quite negative as the oxidation and free radical production, etc., is very likely an essential cell signaling mechanism - namely, a signal that it is time for that cell to undergo apoptosis.

Which is to say, those cells are poorly performing and need to be culled. They should commit cellular "suicide". If you found a way to keep them alive it would be to your freat detriment.

I encourage everyone to read _Power, Sex, Suicide_ by Nick Lane:

https://en.wikipedia.org/wiki/Power,_Sex,_Suicide

... which is a very enjoyable and enlightening look at these mechanisms. His book _Oxygen_ is also quite good.

No, you are right. It is not so black and white, and it is a double-edged sword.

> Antioxidants are good.

Not necessarily. They could promote cancer growth[1][2] and are not inherently good for you[3][4].

[1] https://www.cancer.gov/news-events/cancer-currents-blog/2015...

[2] https://www.nature.com/articles/475043a

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094884/

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292009/ (see: "Harmful Effects of Antioxidants")

---

But yeah... antioxidants are not necessarily good. Or consider this: if you have an autoimmune disorder, you gotta be careful with immunomodulatory agents that are supposed to "boost" your immune system. What might be healthy for people without autoimmune disorders might be lethal for you. Here is an eye-opening article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130893/

Aside from the drugs mentioned, read "Why We Sleep" by Matthew Walker and all the natural hormonal drugs that happen when one consistently sleeps.

Matthew Walker's "Why We Sleep" Is Riddled with Scientific and Factual Errors https://guzey.com/books/why-we-sleep/

Not that fast. Unfortunately, "Why We Sleep" appears to be rather controversial.

[1] https://guzey.com/books/why-we-sleep/

[2] https://www.wired.com/story/stop-obsessing-over-sleepyour-br...

Maybe, but we do sleep for roughly 1/3rd of our life. Something might be in there.

"I study sleep. While some of walker's claims may be hyperbolic, I think they are within reason and justified by the important message he is trying to convey. Too many people have begun to forego sleep in their health choices, and he has helped raise awareness of sleep's role in our health.

Many of these criticisms are quite unfair or misunderstanding the science."

https://www.reddit.com/r/slatestarcodex/comments/dwtr0m/matt...

Inflammation in all parts of the body seem to be problematic and the source of all kinds of disease and other sorts of deficiencies. What sorts of studies and preventative treatments are leading this field?

From all my readings, some natural preventative strategies seem to be: not eating sugar or long chain complex carbohydrates and sleeping consistently a full night of sleep (removing alcohol or caffeine cited multiple times seems to help).

Sleep (and related, circadian health) are some super interesting topics of emerging research. For those that like books, there are two recent ones written by researchers in the field. Matthew Walker's Why We Sleep, and Satchin Panda's Circadian Code that are pretty breezy reads. (there are YouTube interviews and TED talks as well):

For those that prefer more succinct reviews and want to spelunk citations, these are a couple good starting points:

Potter, Gregory D. M., Debra J. Skene, Josephine Arendt, Janet E. Cade, Peter J. Grant, and Laura J. Hardie. “Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences, and Countermeasures.” Endocrine Reviews 37, no. 6 (December 2016): 584–608. https://doi.org/10.1210/er.2016-1083.

Manoogian, Emily NC, and Satchidananda Panda. “Circadian Rhythms, Time-Restricted Feeding, and Healthy Aging.” Ageing Research Reviews 39 (October 2017): 59–67. https://doi.org/10.1016/j.arr.2016.12.006.

What actually is inflammation?

I've been a casual reader about it.

It seems to be the healing process, but it can go overboard and be counter productive.

Drugs are the only cause of psychological and physical affect of the inflammation in the brain

Stress, injury, etc

Chronic inflammation appears to be caused by persistent self-stimulation -- eating for comfort or pleasure, not getting enough sleep, chain-smoking, getting high, etc, without respite. So it's not really a biological problem. It's a widespread personal problem with complex biological consequences.

can you expand this concept?

Not much because it's quite nebulous. It does seem to make scientific sense that the body would reduce such defences to bare essentials like inflammation and blood clotting during crisis in order to save energy. These systems would normally come fully back online during 'rest and digest' periods when the short-term crisis is over. Why do people enjoy chronic activation of the sympathetic nervous system? I think it's a form of distraction: a way of avoiding boredom or the contemplation of painful memories and personal problems. This is common sense for many people but it obviously isn't being addressed by the harder biological and medical journals because they don't like to talk about subjective experiences. Presumably because they require objectivity and they think of subjectivity as being the opposite. But this is itself a misconception:

https://twitter.com/DavidDeutschOxf/status/11746303659123261...

thanks. in the end, I think your view is quite interesting. thanks for sharing.

A pleasure!

Can you cite your sources for that claim?

No, it's just the way it seems to me.

Even if chronic inflammation was caused by self-stimulation, that still makes it a biological problem. Maybe you meant it wasn't an inherent, biological part of aging? If that's what you meant, then I still don't agree.

IMHO, the biggest contributor to chronic inflammation is the Standard American Diet (lots of grains and refined foods) combined with a lack of exercise. These things have a greater, compounding effect with age. You can't exactly tell an 80 year old woman to start running or lift weights on a daily basis.

OK, but only in the sense that a car crash is a mechanical problem (there may be repairs to make).

>lots of grains and refined foods

i.e. rather tasty! I don't think we can escape from motives here: they select what type of diet we prefer given the choice. The market caters to that.

> i.e. rather tasty!

Most people don't find refined foods tasty. In blind taste tests, people vastly prefer the old McDonalds fries back when they used actual potatoes and fried them in lard. Then the American Government said it was illegal to use lard for "health reasons" and they need to use vegetable oil instead. As it turns out, vegetable oils are considerably more pro-inflammatory than lard and, as a result, are extremely unhealthy compared to lard.

> OK, but only in the sense that a car crash is a mechanical problem (there may be repairs to make).

You're making a category error. Self-stimulating activities and inflammation are orthogonal. Mechanical problems don't always cause accidents and accidents aren't always the result of mechanical problems. Similarly, not all self-stimulating activities contribute to chronic inflammation. Eating better will absolutely help decrease chronic inflammation, but smoking pot is anti-inflammatory.

PS: are you a bear or ilk? Feel free to email me if you don't want to answer publicly.

> back when they used actual potatoes

What are they using now?

I don't know but they taste like potatoes with some kind of added coating.

Thank you. Good examples. Yes, some substances cause more inflammation than others. The tar in cigarette smoke more so than vaping vapour. Vegetable oil more than lard or beef dripping. Yes, it gets worse with age.

However, people don't prefer substances that cause more inflammation because they cause more inflammation, rather people prefer things that they find more pleasurable. This might include not having to switch restaurants and consuming things that are cheaper.

This is not inconsistent with the idea that chronic pleasure-seeking without respite causes chronic inflammation, e.g. if we indulge gluttonous impulses by eating sufficient amounts of chips fried in lard with mountains of blueberries for pudding then we're going to acquire the same problem.

>Self-stimulating activities and inflammation are orthogonal. Mechanical problems don't always cause accidents and accidents aren't always the result of mechanical problems.

I guess I'm claiming that they aren't. That car accidents aren't usually caused by mechanical faults was my point.

>smoking pot is anti-inflammatory

On the face of it this does look like a good counter-example. I might have to do some reading! It could be that cannabis relieves mental stress by a different route and this outweighs the effects of the 'high' (is there a high?)

>PS: are you a bear or ilk?

No, I'm not a joiner but I'm sympathetic to those guys. Discovered!

Let me add that I don't think that the inflammation problem is unsolvable. I'm a firm believer that everything good can ultimately be felt to be good, to the point where no discipline is required to purse it.

Even supposing that were true, it's arbitrary to place fallible biological systems of motivation and reward into the "personal problem" category, as if they were not part of the same overall biological system.

If a computer program crashes would you investigate the problem by opening the case and testing the chips inside with a voltmeter? My motivation in labelling the problem as I did is to show where I think it truly lies and thus make it easier to solve. Metabolism is notoriously complicated.

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