The Literature Review 2024 Lookback

Some Key Literature Review Studies from Year 14

This is a bit of a long newsletter. That is intentional. This will be a repository for some of the best research for us to look back on from time to time this coming year to solidify the learning moving forward.

1) Time restricted eating patterns are known to help physiology and metabolism by initiating a pause in the action of mTOR and muscle synthesis as well as inducing autophagy. Autophagy is critical to the clearance of broken or damaged cells following injury or disease. How does circadian biology play into this reality? From Cell Metabolism: "Circadian disruptions impact nearly all people with Alzheimer’s disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Ab42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression." (Whitaker et. al. 2023) This continues a long list of research papers telling us that eating often and with large volumes, especially at night, is not good for cellular metabolism and especially for cellular regeneration. Circadian biology is at the root of cellular function as would be expected based on the diurnal rhythms of historical human activity. When we sleep we are expected to repair and regenerate which occurs when the sun goes down. Digesting consumed foods is a sunlight based activity and should remain so. Adults should aim to stop eating by 6 pm and resume eating between 8 am and 12 noon to open pathways that are beneficial for longevity.

2) In an excellent paper by Dr. Harlan and colleagues, we see a group looking at how to modify ultra processed foods to remain tasty for consumption but also healthy. The lead author is Dr. Rob Lustig, a pioneering Pediatric Endocrinologist from UCSF and upcoming podcast guest. From the paper: "Ultraprocessed food is established as a metabolic disruptor acting to increase adiposity, reduce mitochondrial efficiency, drive insulin resistance, alter growth, and contribute to human morbidity and mortality. Consumer packaged goods (CPG) companies are beginning to understand the detrimental impact of the food they market, and have employed substitution strategies to reduce salt, sugar, and fat. However, the harms of ultraprocessed foods are far more complex than any single component, and are not ameliorated by such simple substitutions." (Harlan et. al. 2023)

The group has three stated goals: 1) protect the liver, 2) feed the gut, 3) support the brain. These are all of the aspects of health that we have discussed for years on the podcast and in this newsletter. His group has dedicated themselves to meeting the companies at a place where they can produce food that is healthful and cost effective. An admirable desire for sure. This article is absolutely worth a full read. The paper goes on to cover 5 misconceptions of insulin resistance and chronic disease: 1) chronic disease is the inevitable result of the aging process. 2) the rise in prevalence and severity of obesity is self-determined due to an increased prevalence of the vices of gluttony and sloth. 3) obesity and chronic disease are the same phenomenon. 4) most clinicians mistakenly attribute the growing rise of non-communicable diseases (NCDs) to fat depots which are outwardly noticeable. 5) the cause of chronic disease is the quantity of the food consumed according to the metric of “calories.” (Harlan et. al. 2023)

Ultraprocessed foods are causing mitochondrial dysfunction and disease through multiple pathways: macronutrient and micronutrient composition, fiber, food additives, toxins, heat exposure, and packaging (mostly due to plastics as endocrine disruptors). These are the levers to pull on for all of us. Whole food in its original or close to original form will have the best macro and micro nutrient profile. Vegetables and fruits are our fiber source. Synthetic food additives and emulsifiers are not to be consumed. Plastics and chemicals in food, water and air are to be avoided. These are simple truths to promote health.

3) What is happening to the gut microbiome when non caloric sweeteners like aspartame are consumed. The authors looked specifically in the duodenum of the small intestine where post acid hydrolyzed food is mixed with bile and pancreatic enzymes before entering the jejunum and remainder of the small intestine. This Cell study compared aspartame, non aspartame non caloric sweeteners and a control on the microbiome of the duodemum. They noted that both non caloric sweeteners and asparatame reduced biodiversity and also increased the proportion of gram negative rods like e coli and klebsiella. (Hosseini et. al. 2022)

Prevention remains the key - children first.

The key to this study is two fold: 1) weakened biodiversity is a proxy marker for leaky gut and inflammation over time, i.e. not good. 2) the rise in gram negative rods is a main driver of lipopolysaccharide release into the systemic circulation due to a concentration gradient and the associated leaky gut. The LPS in the blood stream is a direct trigger of toll like receptor activation, immune activation subsequently and mobilization of lipoproteins including LDL and HDL to clear the LPS. The end result is elevated LDL levels which are Apo B containing and a direct link to cardiovascular disease.

4) More on nanoplastics (NP) - It turns out that the nanoplastics can activate the innate immune system via the NLRP3 inflammasome. This leads to localized inflammation and resolution of the NP in that area. the problem arises in my mind when the NP's are persistent and found in a human with high NLRP3 activity at baseline due to fructose ingestion and processed foods. (Alijagic et. al. 2023) I am struck by the beauty of the NLRP3 inflammasome system during baseline historical exposome surveillance, inflammation and resolution. It is an elegant system that seems to be at the center of much that we look at including covid, preeclampsia, ASD and much more. Now usher in the emerging research on nano plastics infiltrating all biological tissues at such tiny sizes leading to bioaccumulation and chronic innate immune activation, apoptosis and cellular senescence. I am continually intrigued by the fructose ( or starch via polyol pathway) to uric acid to NLRP3 activation globally as a gasoline source for reducing cellular/mitochondrial resistance to these disparate toxicities as they are emerging and increasing over time. Almost like a Patrice Cani style low level (NLRP3 induced) endotoxemia via refined carbohydrates and toxins working in concert to overwhelm the system over time. This recent PNAS paper by Qian et. al. is quite disturbing as they found 100000 nanoparticles per liter of drinking water in the context of this frontiers paper is a solid mess.

5) In a translational model, sulphurophane increases mitochondrial biogenesis which is a critical factor in age related mental function, especially memory. (Shimizu S. et. al. 2022) The sources of sulphurophane are broccoli, broccolini, sprouts, greens, brussel sprouts, cabbage and other similar leafy vegetables. Sulphurophane is very important for increasing the action of NRF2 as well as being an antioxidant that neutralizes mitochondrial free radicals.

Nrf2 is an activator of our cellular defenses which means that it is intimately involved in our species longevity. Nrf2 is at the center of the science of environmentally derived oxidative stress and the human mechanisms cells use to counter it. (Houghton et. al. 2016) Sulphurophane is the most potent plant chemical with the capacity to activate Nrf2 inducing gene transcription regulating much of any cell's defenses. Thus, it behooves us to pull on this lever for cellular solvency and long term health. Now we can add this new mechanistic data to our understanding of its use. Memory and mental health over our lifespan is enhanced by the consumption of these plant based foods.

6) Acid suppressing medicines are now firmly associated with the development of food allergies and sensitivities. From a news article in AAAAI, they note a 6X increase in the development of food allergies in infants that used proton pump inhibitors. "We found that early exposure to acid-suppressive medications was associated with a 5-6 times higher risk of food allergy and anaphylaxis, with similar trends observed for antimicrobials,” said primary author Julia Tanzo while working with co-author Mohamad Chaaban, MD." (AAAAI)

For me this research still begs the question of chicken or egg. I believe that this data set is the second problem. The primary issue is that these children have symptoms that push a provider to use a PPI without understanding the root cause. The issue here is that these children have intestinal dysbiosis from inherited/transferred microbiomes leading to very early 3-4 weeks of age milk protein intolerance that presents as reflux, colic, congestion, bloody diarrhea and eczema. These children will improve the reflux and colic concerns with the PPI medicine without addressing the root dysfunction. Thus, the persistent intestinal dysbiosis and food intolerance will drive further inflammation in the gut leading to antigen presentation that we see as more food intolerances and true food IgE mediated allergies. If the root cause is not addressed, the problem will NOT go away. You are just kicking the can down the road to a worse outcome.

7) How is the development of allergy induced by exposure to advanced glycation end products? First, what are AGEs? AGEs are proteins and fats that are cross linked to glucose during a metabolic process in the body triggered by high volume sugar intake. Think hemoglobin A1C. They can also occur while grilling, frying or toasting foods. They are highly associated with ultra processed foods. Here is a good image for you to review. I think of this mostly from the perspective that high volume sugar laden beverages promote these AGEs which trigger AGE receptors leading to oxidation and inflammation. This is a direct cause of cellular aging and mitochondrial damage. In this new study they looked at the effect of these AGEs on gut cells.

The study results: "Human enterocytes exposed to AGEs showed alteration in gut barrier, AGE receptor expression, reactive oxygen species production, and autophagy, with increased transepithelial passage of food antigens. Small intestine organ cultures exposed to AGEs showed an increase of CD25+ cells and proliferating crypt enterocytes. PBMCs exposed to AGEs showed alteration in proliferation rate, AGE receptor activation, release of inflammatory and TH2 cytokines, and mitochondrial metabolism. Significant higher dietary AGE intake and skin accumulation were observed children with FA compared with age-matched healthy controls).(Paparo et. al. 2023)

8) Women's brains change during pregnancy as per a new study. The authors looked at brain changes before and after birth as well as with or without a vaginal delivery route. Their study findings noted transient changes in some brain regions as well as permanent changes in other brain regions that turn on self-reflection and empathy for others. The default mode network (DMN) turns on when we are not task oriented, i.e. day dreaming. This area is up regulated which would propose that its enhancement is for the maternal child bond strengthening. The study notes that the DMN does not ever regain prepregnancy size positing that this change is permanent and necessary. This, to me, reinforces the evolutionary need of the DMN to help foster mother child attachment which is critical to species survival.(Paternina-Die et. al. 2024)

You may ask why a reduction in the DMN size would correlate with more DMN activity? The answer lies in selective neuronal pruning to emphasize certain important pathways while other less important pathways are pruned. This happens at many different stages of life while we sleep to enhance necessary memories and down play unimportant ones. The brain is very adept at selective pruning for species benefit. Mothers and their children will selectively prune certain neuronal pathways for a collaborative attachment and loving bond.

My question is this, what blocks this from happening in certain poorly attached/bonded mother child dyads? I suspect that maternal trauma is at the root. TBD.

9) We know that vaccines in infancy and childhood elicit different immune reactions with some having robust and long lasting immunity and others little to no action. In Dr. Pichichero's recent article, he notes that "Among the early life determinants of vaccine responses, ...there are modifiable factors involving development of the infant microbiota and metabolome: antibiotic exposure, breast versus formula feeding, and Caesarian section versus vaginal delivery of newborns." How our intestinal microbiota serve as natural adjuvants for vaccine responses and how microbiota-derived metabolites influence vaccine responses are discussed in his review. If a child fails to develop a good cellular immune response to vaccinations, they are at significant risk for infectious disease that can be life threatening.

He writes:

"To cope, the neonatal immune system moves through a gradual maturation process from one shifted towards immune tolerance, with a prominent role of regulatory T (Treg) cells and anti-inflammatory predominance towards immune responsivity and pro-inflammatory predominance. The maturation occurs at different rates in different children affected by development of a nascent microbiota. During this period, there is a high risk of contracting infections, which are sometimes treated with antibiotics that may influence vaccine responsiveness as well."

The article goes on to add layers of evidence that modern choices are driving poor vaccine .

In my mind, here are the key players:

1) the maternal intestinal microbiome - which becomes the infants to start

2) time of day vaccines are given

3) antibiotic use at birth or soon after

4) form of milk - breast or formula

5) endocrine disrupting chemical exposure for pregnant women and the infant

6) maternal and infant vitamin D status

7) not enough animal bacterial exposure after birth

8) poor nutrient status from dietary choices

9) toxin exposure through air, water and food

10) circadian biology/sleep

10) From Nature: "The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function, metabolism and nutritional state. Here, we show that a peripheral immune insult powerfully activates the body-brain axis to regulate immune responses. We demonstrate that pro- and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-to-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords exceptional neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuro-immune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock." (Jin et. al. 2024)

This continues to add layers of data on how powerful the peripheral immune system is at sensing and transmitting danger signals to the brain via the vagus nerve and the brain stem. This bidirectional feedback system is at the heart of most chronic diseases of aging. Again, this highlights Dr. Porges work a few weeks ago in the newsletter and podcast #69.

As a human species, we must heed the warning signs of disease. Stress that is chronic and unremitting is a root cause of immunoneuroendocrinological disease.

11) Exercise and muscle use have distinct immune based repair and hypertrophy mechanisms. The act of using muscles for activity triggers an inflammatory response that is specifically geared toward inflammation and repair which leads to hypertrophy and improved function. From Cell metabolism: "interleukin (IL)-6, the prototypical exercise-induced cytokine, or “exerkine,” promotes increased numbers of natural killer (NK) cells and dendritic cells (DCs), but not monocytes or T cells, in blood after acute biking exercise, without altering catecholamine responses. During recovery, the total number of blood immunocytes returns to pre-exercise values within hours; however, after intense or long-duration (>2 h) exercise, the numbers of lymphocytes, including NK and T cells, drop below pre-exercise levels for several hours up to multiple days. This biphasic response of peripheral-blood immunocytes to exercise is proportional to exercise load (duration × intensity) and is sensitive to the age, sex, and training history of the organism as well as to the mode and frequency of exercise." (Langston et. a.l. 2024)

The drop in circulating immunokines is related to the fact that they enter the muscle tissue to perform the healing and growth process. The harder that you exercise the more the immunokines need to enter the muscle tissue.

Langston goes on:"In the early phase of exercise-induced stress responses, there is a concurrent reduction in physical performance. This impairment is underpinned by temporary biochemical and biophysical changes, such as depletion of tissue glycogen stores and alterations in muscle ultrastructure, including loss of intermediate myofilaments. However, temporary reductions in these properties are followed by supercompensation, characterized by an increase in biochemical and biophysical properties to a level above the previous set points. Such supercompensation buffers against future perturbations in these properties and augments performance in subsequent bouts of a similar type and load as the first."

Here in lies the key to mammalian adaptation over time. Recurrent use and muscle challenge adapts to increased future needs. At the heart of this process is the immune system sensing muscle cell injury by damage associated molecular pattern receptors seeing cell debris like ATP, DNA and cell wall debris triggering a local lymphocyte response to heal and grow the muscle tissue.

This is the amazing repeated pattern throughout human bioevolution. The immune system plays a central role in all facets of life and death. More on this topic when we look at Klotho next week.

At the end of the day, know this, if you choose to do one thing for your health, choose exercise. Your immune system will thank you.

If you are a young or an older gentleman, join F3 and get fit with friends every day.

12) Does vitamin D affect the deposition of muscle? From Research Square: "Obesity occurs because the body stores surplus calories as fat rather than as muscle. Fat secretes a hormone, leptin, that modulates energy balance at the brain. Changes in fat mass are mirrored by changes in serum leptin. Elevated leptin prompts the brain to decrease appetite and increase energy expenditure. In obesity, however, impaired leptin sensitivity mutes these leptin-mediated changes. We have limited understanding of what controls leptin production by fat or leptin sensitivity in the brain. Muscle produces a hormone, myostatin, that plays a role in muscle analogous to the one that leptin plays in fat. Absent myostatin leads to increased muscle mass and strength. As with leptin, we also do not know what controls myostatin production or sensitivity. Although fat mass and muscle mass are closely linked, the interplay between leptin and myostatin remains obscure. Here we describe an interplay linked thru vitamin D. Conventionally, it is thought that vitamin D improves strength via trophic effects at the muscle. However, we find here that high dose dietary vitamin D allocates excess calories to muscle and linear growth instead of storage as fat. Vitamin D mediates this allocation by decreasing myostatin production and increasing leptin production and sensitivity. That is, high dose vitamin D improves integration of organismal energy balance. Obesity, aging and other chronic inflammatory diseases are associated with increased fat mass and decreased muscle mass and function (e.g. sarcopenia). Our work provides a physiologic framework for how high-dose vitamin D would increase allocation of calories to muscle instead of fat in these pathologies. Additionally, our work reveals a novel link between the myostatin and leptin signaling whereby myostatin conveys energy needs to modulate leptin effects on calorie allocation. This result provides evidence to update the conventional model of energy stores sensing to a new model of energy balance sensing. In our proposed model, integration of leptin and myostatin signaling allows control of body composition independent of weight. Furthermore, our work reveals how physiologic seasonal variation in vitamin D may be important in controlling season-specific metabolism and calorie allocation to fat in winter and muscle and growth in summer." (Roizen J. et. al. 2024)

Latham and colleagues noted in a review paper in Frontiers Physiology that vitamin D taken in the diet increases mitochondrial function and muscle regeneration. From the paper:" VDR expression is strongly upregulated following injury, particularly in central nuclei and SCs in animal models of muscle injury. Mechanistic studies provide some insight into the possible role of vitamin D activity in injured muscle. In vitro and in vivo rodent studies show that vitamin D mitigates reactive oxygen species (ROS) production, augments antioxidant capacity, and prevents oxidative stress, a common antagonist in muscle damage. Additionally, VDR knockdown results in decreased mitochondrial oxidative capacity and ATP production, suggesting that vitamin D is crucial for mitochondrial oxidative phosphorylation capacity; an important driver of muscle regeneration. " (Latham et. al. 2021)

These are key studies that show us the many effects of vitamin D on metabolism through muscle growth and function.

I just cannot imagine why vitamin D is not the poster child for natural living. The sun is your friend for many reasons, but especially for the production of skin derived vitamin D. Get in the sun for appropriate volumes of time based on your skin tone. Do not burn your skin ever.

13) Fasting is super important! Every culture on earth fasts during religious and secular ceremony in order to have clarity of mind and body. This is unlikely to be a mistake or coincidence as it relates to mental and physical health. In the Journal Cell Immunity, Dr. Delconte and colleagues noted that fasting offers these immune enhancements: 1) NK cell-mediated anti-tumor immunity, 2) metabolic reprogramming of splenic NK cells, 3) Fasting-induced fatty acid oxidation improves the NK cell anti-tumor response, 4) fasting redistributes NK cells to the bone marrow for reprogramming. (Delconte et. al. 2024)

What this data says makes intuitive sense. Obesity is heavily associated with all cause cancer. Thus, the over fed state equals more cancer. The converse would state that the less fed state favors immune health that is anticancer. Fasting forces the body to look for building blocks of cells in your current tissue. It will preferentially break down old and worn down tissue. This has a metabolic and immune effect based on the data to date. Immunologically, the system shifts into a reduced inflammation and anti cancer phenotype.

14) Does sleep affect the intestinal microbiome in children? From Nature: "Investigating the characteristics of the gut flora in children who go to bed early versus late. The study sample consisted of 88 healthy children aged 2–14 years, with an equal number of boys and girls. The researchers collected faecal samples from all participants and sequenced the genome of their gut flora. Findings indicate that beta diversity was statistically significant at the genus level for both the early and late sleeper groups. Furthermore, alpha diversity indicators, exhibited higher values at the genus level. The differences observed in terms of species diversity, abundance, and metabolic pathways offer potential avenues for implementing pharmacological interventions aimed at addressing sleep disorders in children." (Mao et. al. 2024)

What this study shows us is that children who go to bed earlier have increase bacterial diversity in their gut as well as certain keystone species abundance like Akkermansia mucinophilia. The cause and effect is a stretch that sleep alone is the reason. The early sleepers are likely in families that stress health including sleep, diet, avoidance of toxins etc. However, we know that poor sleep is a net negative on immunometabolic function.

Take home: earlier sleep meeting a child's total sleep needs is very important.

15) In a Nature Communications study from 2021 we see Dr. Jones and team investigating the role of fructose in inflammation at the cellular level, revealing how it reprograms glutamine metabolism to intensify inflammatory responses. When the body is exposed to lipopolysaccharides (LPS), which mimics intestinal bacterial overgrowth or a systemic bacterial infection, fructose primes cells to utilize glutamine more aggressively, diverting it toward pathways that sustain oxidative (i.e. aerobic with oxygen) metabolism and drive up total body inflammation.

From the article:"Here, we investigate how activated human monocytes and mouse macrophages respond metabolically and functionally to fructose exposure. We demonstrate that mononuclear phagocytes from both species are metabolically plastic in engaging in the metabolism of an alternative carbon source and reprogram the cellular pathways to favour oxidative metabolism. Although able to rewire their metabolic pathways upon exposure to fructose, the cells are left metabolically inflexible and vulnerable to further metabolic challenge. Importantly, we show that fructose exposure ex vivo promotes elevated cytokine production in both human and mouse mononuclear phagocytes and that a high fructose diet promotes an inflammatory phenotype in vivo, attributing pathophysiological relevance to our findings."(Jones et. al. 2021)

For clinicians, this research reinforces concerns about high-fructose diets, especially regarding chronic inflammatory conditions. Fructose doesn't just lead to metabolic disturbances but acts as a trigger, supporting inflammation on a cellular level. This study underscores the need for dietary guidance focused on reducing excess fructose intake, especially in patients struggling with inflammatory conditions, as minimizing fructose could reduce the biochemical substrates that fuel inflammation. GLP1 agonists will not stop this problem. It is a problem of input through and through.

Dr. M