During the global pandemic the cytokine storm and its tissue damaging impact via acute inflammation is front and center.
When the immune system is fighting pathogens such as the Covid virus, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection.
Scientists classified IL-6 as a proinflammatory cytokine. But new data is emerging in the world of sports science that muscle damage may not be required to provoke an increase in plasma IL-6 during exercise.
That’s because IL-6 seems to play a dual role. IL-6 is classified as a multi-functional cytokine, which can act as both a pro- and anti-inflammatory cytokine.
Myokines are a type of a chemical messenger in a class called cytokines. Many of the cytokines we already know about are the kind liberated from adipose tissue, your body fat, particularly the truncal fat mass that gives you that apple-shape.
The cytokines produced by muscle tissue, which are known as myokines (“myo” being the Latin root for muscles), have anti-inflammatory effects.
Aerobic exercise provokes a systemic cytokine response, but without triggering pro-inflammatory tumor necrosis factor alpha (TNF-alpha) to fight off an infection
Many of these are inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1 family (IL-1), which are involved in a variety of disease states, including cancer.
Myokines also increase your insulin sensitivity by improving glucose utilization inside your muscles and, acting as chemical messengers, myokines help inhibit the release of inflammatory cytokines produced by body fat.
A burst in myokines was once believed to cause muscle damage.
But now science is discovering that IL-6 activated by exercise, may be necessary to confer some of the benefits of exercise such as improved insulin sensitivity.
Muscle is the seat of insulin sensitivity which is a key to both disease prevention and fat loss. Acute elevation of IL-6 was found to reduce postprandial blood glucose levels and insulin secretion by delaying gastric emptying in men with type 2 diabetes.
Cytokine storm is grabbling headlines. But the myokines produced in muscle tissue may also be an important cytokine, one that helps fight off the unresolved subclinical inflammation tied to chronic disease.
Interleukin 6 (IL-6) may not have been a biomarker that most people were familiar with before the Covid-19 global pandemic.
But IL-6 appears to be an effective marker able to predict upcoming respiratory failure with high accuracy. That’s according to several pre-print (non peer reviewed) and preliminary clinical trial studies.
In 1993 gerontology scientist William Ershler first noted that IL-6 is one of the main signaling pathways that drives aging and chronic morbidity. In the past twelve years, IL-6 has emerged as an important hallmark of aging.
A positive knock-on effect of the pandemic, could be to bring this inflammation marker from the lab bench to the doctor’s office. Downstream of IL-6 measuring levels of C-Reactive protein, is a less expensive blood test.
A dysregulation in levels of C-Reactive protein can signal dysfunction that silently does damage to vital organs like the liver and heart, and or leads to metabolic syndrome.
IL-6 is a cytokine, a large group of proteins that are secreted by specific cells of immune system. Cytokines are a category of signaling molecules that send instructions to various organs in the body that do important things like regulate metabolism. IL-6 regulates immunity, inflammation and the production of blood cells.
Chronic elevation of IL-6 reflects ongoing inflammation and is linked to type 2 diabetes and atherosclerosis.
However medical doctors are trained to test for pathology or specific diseases like fatty liver. So the high sensitivity CRP blood test is not always ordered as part of a patient’s routine bloodwork because results aren’t specific to a particular disease.
But data from the Physicians’ Health Study found that people with elevated CRP were about three times more likely to have a heart attack than those with normal levels.
Covid has brought heartbreak and suffering. But the hope among cardiology experts is a wider use of the hs-CRP test, to improve screening for heart disease in the post pandemic world.
Stem cell injections have stirred the public imagination, as a way to rejuvenate the body.
Mesenchymal stems cells which are found in bone marrow and other tissues are traditionally used in the clinic setting to repair orthopedic injuries such as torn rotator cuffs. Scientists are also now looking at mesenchymal stem cells as a way to treat Acute Respiratory Distress Syndrome (ARDS).
In the case of repairing lung injury, in mice it was observed that tiny bridges (tunneling nanotubes) extend from the MSC to the damaged alveoli and transport a mitochondria, to repair the ATP function of the damaged lung tissue. In other words the stem cell is not repairing the lung by grafting to the lung tissue but rather by repairing the damaged little organelles (the mitochondria) that have lost their ability to transport oxygen and help the patient breath.
Dr. Michael Matthay is leading a University of California, San Francisco clinical trial to see if stem cell therapy can treat Covid-19 symptoms.
According to Dr. Matthay the effects of Mesenchymal stem cells, may be due to two major pathways: a no cell contact pathway, and a cell-to-cell contact dependent pathway:
Paracrine pathways – MSCs appear to release paracrine molecules that reduce injuries. For example, MSCs appear to have beneficial effects on lung injury by releasing interlukin1 antagonist, and anti-microbial peptides (as well as anti-inflammatory and growth factors for tissue repair).
Mitochondrial transfer – It also turns out that other studies suggest a cell contact dependent mechanism. At Columbia University, the team at Dr. Bhattacharya Laboratories observed that MSCs (when given directly into the air space of the lung) appear to attach to the alveolar pathway and deliver mitochondria to the injured alveoli epithelium; these alveoli appear to have mitochondria that’re injured and don’t perform normally. This “mitochondrial transfer” appears to rescue the mitochondria, restore the damage to the alveolus, and allows it to function better by restoring ATP level to normal to allow fluid transfer and surfactant release.
(ARDS) is pulmonary edema, or fluid in the lungs, not due to heart failure. It is a condition that affects 200,000 people/year in the USA with a 30-40% mortality rate. During ARDS, there are many cellular changes with complex pathophysiology making it extremely difficult to treat. Currently, patients are treated by ventilation with low tidal volume and fluid conservative therapy as many pharmacological interventions have failed. Mesenchymal stem cells (MSC), however, may hold promise as a treatment.
MSCs may be doing several therapeutic things at once – secreting signaling or paracrine factors to tell the lung tissue to repair. And making cell-to-cell contact using a tiny tunneling nanotube to transport fresh, healthy mitochondria into a damaged alveoli.
In a clinical trial allogenic (allogenic means from a different donor) bone marrow MSCs were tested on sheep with sever ARDS. Giving human MSCS to sheep with ARDS improved oxygenation, and Pulmonary edema was reduced in sheep treated with high dose of MSCs ten million cells per kilogram.
Sampling plasma in the lungs are planned in Phase 1/11 Trials in humans, to determine if the cytokine or pro-inflammatory levels change.
According to Dr. Matthay secondary endpoints may include oxygenation index, pulmonary dead space, ventilator-free days, mortality, systemic organ failure-free days, and biological markers of efficacy.
Future strategies, may even include giving patients with ARDS paracrine factors and not just the MSCs.
Paracrine signaling is science speak for a signal that is sent at close range between a cell and a nearby cell. By contrast, a chemical signal picked up by the bloodstream and taken to distant sites is called an endocrine signal. Most hormones produced in your body are endocrine signals. For example, hormones produced in the pituitary gland at the base of the brain are carried by the bloodstream to act on the adrenal glands.
Paracrine signaling is a form of cell signaling or cell-to-cell communication in which a cell produces a signal to induce changes in nearby cells, altering the behavior of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action).
Mitochondria contain their own DNA – DNA that is simpler than our DNA but critical to respiration. Respiration depends on a dynamic equilibrium between oxidation and reduction. There are thousands of respiratory chains inside a single mitochondrion.
Since the ATP respiratory chain is embedded inside the wall of the mitochondria, by transferring mitochondria the stem cell restores respiratory function.
A little piece of bacteria inside the stem cell – was observed under electron microscope moving outside and then into the damaged piece of lung sac.
The initiating action signal seems to be coming not from DNA but involves the mitochondrial DNA in distress.
Mitochondria are similar in structure to the bacteria found in common garden soil. And yet mitochondria DNA (despite being simpler in structure than human DNA) can signal to the stem cell to do cell-to-cell contact.
The body has several different types of stem cells :
Embryonic – Embryonic stem cells come from unused embryos and are pluripotent which means that they can turn into more than one type of cell. Embryonic stem cells can develop into more than 200 cell types of the adult body.
Pluripotent – Induced pluripotent stem cells are cells that have been engineered in the lab by converting tissue-specific cells, such as skin cells into cells that behave like embryonic stem cells. iPS cells share many of the same characteristic of embryonic stem cells. The first iPS cells were produced by using viruses to insert extra copies of genes into tissue-specific cells.
Hematopoietictic – blood-forming or hematopoietic stem cells reside in the bone marrow and can give rise to red blood cells, white blood cells and platelets.
Mesenchymal – Mesenchymal stem cells (MSCs) are multipotent stem cells found in bone marrow that are important for making and repairing skeletal tissues, such as cartilage, bone and the fat inside bone marrow.
Mesenchymal stem cells (MSCs) are sometimes called the “injury drugstore”. The body contains these stem cells in a variety of tissues all over the body, constantly repairing injuries.
Only about 0.01% of the cells in the bone marrow are MSCs. Obtaining a mixture of mesenchymal cell types from adult bone marrow, for research, is fairly easy. But isolating the tiny fraction of cells that are MSCs is more complicated.
In a healthy person, MSCs normally reside in the bone marrow in a state of quiescence.
Cellular quiescence is a dormant but reversible cellular state in which stem cells do not proliferate – but instead sit in stand by mode. Adult stem cells can be maintained in this quiescent state, and only get activated upon tissue injury to restore homeostasis. Initially it was believed—based largely on classic studies of hematopoietic SCs (HSCs)—that quiescence was an integral property of all SCs, allowing them to preserve their proliferative potential and limit DNA damage. However, the discovery of highly proliferative SCs in many tissues has challenged this notion (Clevers and Watt, 2018).
Mesenchymal stem cells, are classified as multipotent stem cells, due their capability to transdifferentiate into various lineages that develop from mesoderm. The multipotent stem cells, unlike their cousins the pluripotent stem cells, are theoretically able to differentiate to only one germ layer. (The embryo has three germ layers of cells: ectoderm, mesoderm, and endoderm.)
MSCs can be isolated from a variety of tissues, such as bone marrow, adipose tissue, placenta, umbilical cord, umbilical cord blood, liver, dental and more. MSCs can transdifferentiate to other tissues but it is assumed that most of the benefits come from the factors they secret in the target environment.
Some scientists even want to change the name of MSCs to Medicinal Signaling Cells to more accurately reflect the fact that these cells home in on sites of injury or disease and secrete bioactive factors that are immunomodulatory and regenerative. Possibly the patient’s own tissue-specific stem cells construct the new tissue as stimulated by the bioactive factors secreted by the exogenously supplied MSCs.
Stem cells can divide (keeping a copy of itself, supply of stem cells). And then using a “homing” signal, the body appears to send the stem cell circulating in the blood, like a tiny heat-seeking missile. When tissues are damaged, MSCs are naturally released into circulation, migrate to the site of injury, and secrete molecules to create a microenvironment that promotes regeneration (Chapel et al., 2003, Caplan, 2009).
Originally, it was thought that these stem cells engrafted into the damaged tissue and differentiated into new tissue.
A new hypothesis is that it’s the “signals” (and other growth factors) that MSCs send to the damage tissue that provide beneficial effects. Upon reaching the target tissue, MSCs secrete a variety of factors with powerful immune-modulating effects.
Several laboratories are investigating the hypothesis that adult stem cells exert their therapeutic benefits via the release of biologically active proteins, or paracrine factors.
Mitochondrial DNA may play a significant role in health. Besides regulating ATP and energy production, apoptosis, damaged mitochondria may be signaling micro stem cell rescue missions.
If scientists on the front lines of Covid can figure out how mesenchymal stem can restore damaged lungs it could offer a new treatment for ARDS. And perhaps one day lead to a regenerative medicine treatment to fix damaged mitochondrial function in other diseases.
“I want people to live to be 110 healthy,” says Dr. Valter Longo, founder of Los Angeles-based L-Nutra, a new breed of tele-medicine startup backed by 25 years of scientific research. “It sounds like science fiction,” admits Longo “but it’s not.”
Silicon Valley players like Apple and Google are moving into healthcare. But L-Nutra is a taking a different approach, looking to “flip the script”.
Instead of treating age-related diseases like diabetes, cancer, and Alzheimers one by one, L-Nutra’s goal is to slow aging – and prevent or delay many age-related diseases – in one fell swoop.
Recently science has discovered that two of the most powerful aging pathways in the body are nutrient-sensing.
Which is why top anti-aging drug candidates in some way manipulate pathways that also are tightly wired to levels of protein and sugar in the bloodstream. Rapamycin interacts with mTor, Metformin interacts with the PKA, and NAD is a precursor to Sirtuins (whose levels also rise during fasting).
L-Nutra’s approach is using nutrition, or “nutri-technology”, to produce similar anti-aging effects.
“I think people are underestimating the powerful effects, and that’s both good and bad,” says Dr. Valter Longo.
Nutri-technology: the Biological Equivalent of a Computer Backup and Repair Program The startup holds a patent on the concept “nutri-technology”, manipulating genes in the body via nutrient-sensing pathways to slow aging.
Autophagy (self-eating of damaged components in the cell) could play an important role in slowing the biological age clock. L-Nutra has developed a five-day protocol that works on the body’s nutrient-sensing pathways to flip the autophagy switch “on”.
But unlike caloric restriction, L-Nutra is a pulsing of caloric restriction followed by refeeding. For a healthy person this means being well nourished and eating well except for brief periods of ten to fifteen days throughout year.
L-Nutra’s product the ProLon fasting mimicking diet is a low-calorie plant-based meal plan consisting of soups, snack bars, and sports drinks and provides roughly 30% of your normal caloric intake (1,100 calories on Day 1 and on Days 2-5 750 calories.)
L-Nutra pilot clinical trial data shows a trend that the refeeding phase causes stem cell proliferation .
Bloodwork was used to measure circulating stem cells in L-Nutra’s pilot study. Muscle biopsies from participants are needed to figure out exactly what’s happening in regards to stem cell proliferation. Mesenchymal stem cells appear to play a role in tissues like the liver regrowing, but mechanisms of action aren’t well understood yet.
L Nutra’s origin story all begins with cancer.
Back in 2008, Longo realized cancer genes and aging genes
are connected. His hunch was that the genes that control aging, are the same
genes that get stuck in the on-mode in many cancers.
In a mouse-model clinical trial Longo’s team gave mice a
high dose of chemotherapy. One group of mice was fasted, and one group was fed.
A video shot by his lab shows mice in a fasted state after chemotherapy, moving
about their cage normally. But mice in a fed state who received the same course
of chemotherapy, appear exhausted and just lie down in their cages.
In this pilot study, only 35% of the mice receiving chemo in
a fed state survived.
Cancer cells seem to be hyperactive, and need a microenvironment that will support growth.
Longo’s hypothesis was that if you deprive cancer of glucose and protein with fasting, the rapidly dividing cancer cells (which require more fuel than normal cells) will struggle.
When nutrients are scarce, normal cells go into a slowed down resting mode. But certain types of cancers may lack metabolic flexibility, and can’t switch over to a hunkering down mode that scientists call “quiescence”.
Scientists are also beginning to suspect that autophagy (which occurs during fasting) causes cancer cells to release ATP into the cytoplasm; and this process may trigger the body’s immune cells to move in to kill cancer.
But conducting a clinical trail to test water-only fasting with human cancer patients is not so simple. It took five years to enroll 18 cancer patients in a pilot study.
“It was a disaster,” admits Longo.
“So then we asked people what if we prepared a box of
nutrition [with three meals] for a fasting mimicking diet?,” says Longo. “So
you give the box to patients like medicine. And that’s when everything turned
How Nutri-Technology Works: Cells Have Antennas and Do “Blebbing”
Cells in the body have nutrient-sensing antenna. This tiny
organelle or tube that protrudes outside the cell, called a cilium, gives the
cell information about its surrounding and enables it to respond.
Nutri-technology is about delivering calories to make
fasting safer, but not enough to trigger your cell’s tiny nutrient-sensing
As ProLon Medical Liaison Dr. James Kelley explains the idea
is to tell the body to switch from growth to repair mode. “Growth is good, but
it can also lead to cells dividing more, and to a greater risk of mutations.”
ProLon down regulates three important aging pathways:
Insulin like growth factor (IGF-1) – a protein hormone that is similar to insulin in molecular structure. It is a big gene with a six-part axis of pathways that sends a “go-go” signal to the body to grow. IGF-1 responds to protein (especially animal protein) and drives up mTor. Low levels of IGF-1 are associated with a lower risk of cancer and diabetes.
mTor – or the “protein pathway” is a master regulator of autophagy, or cellular cleanup. mTor is activated by protein (and very strongly by animal protein) and carbohydrates. mTor seems to accelerate aging pathways and prevent the body from turning on tumor suppressing genes.
Protein Kinase A (PKA) – PKA or “the sugar pathway” is switched on by glucose and appears to regulate metabolism. This pathway can activate enzymes and regulate gene expression. If PKA is not controlled, it can lead to hyper-proliferation of cells and contribute and or lead to the development of cancer.
The effects of ProLon appear in the refeeding. “IGF-1 levels come back up after the fast,” which Longo says is an important “Part B” that is missing from caloric restriction.
So why five-days? “Believe me, if we could make the program less than five days, we would,” says medical liaison Dr. Kelley.
“Apoptosis is programmed cell death and begins somewhere around Day Four,” explains medical liaison Dr. James Kelley. “And by Day Five mesenchimal stem cells proliferate.”
On day five early pilot clinical trials show that
mesenchimal stem cells increased by 800%, and go into standby mode.
MSCs can only be created in your body when IGF-1 and mTor
levels are low. MSCs are multipotent stromal cells that are capable of
differentiating into, and contributing to the regeneration of mesenchymal
tissues such as bone, cartilage, fat, tendon, and muscle.
Mesenchymal stem cells have a unique feature, a “homing” mechanism.
Ketogensis is emulsification of fat, or the body using fat for energy. During ketogenesis autophagy occurs, where cells try to scavenger parts from other cells to repair themselves.
Apotosis is an intra-cellular program that causes a cell to
kill itself after damage has occurred. Apotosis is one of the ways that
multicellular organisms protect themselves from cancer.
“During apoptosis a cell decides it’s too damaged to try and
repair itself, and essentially blows itself up,” says Dr. Kelley.
Without food and low mTor hormone levels circulating in the blood, the body goes from a catabolic (growth) to an anabolic (repair) mode and at the five day mark can make mesenchimal stem cells. These stem cells then use a “homing” beacon type of function to move from the bone marrow, to circulate in the blood.
Stem cells (in mouse model studies only) repaired pancreatic beta cells, which are important because they produce insulin in the body.
A biohack for aging in just five days sounds too good to be true.
The startup’s biggest challenge may be market education. ProLon gets confused with calorie restriction, intermittent fasting, and ketogenic diet (technically ProLon is a high-fat medical ketogenic plan).
The average person is not going to pick up a copy of the scientific journal Cell Metabolism and dive into a clinical trial. But they’ll enthusiastically follow the advice from a YouTube video “diet expert” (with no PhD in biochemistry).
ProLon was tested head to head against a keto diet in a
clinical trial involving Multiple Sclerosis (MS) patients. Five days of ProLon produced similar
effects to six months of a ketogenic everyday diet.
Any mention of fasting is usually met with rolled eyeballs. But clients are finding there’s just enough food to get through it.
“We’ve got NFL football players who say yes, I can do this,” says Longo. “We feel good about the efficacy, safety, and compliance.”
With headlines about contestants on the Biggest Loser complaining about regaining all the weight and more, a concern is that fasting (like crash diets) – won’t work. The trick, explains Longo is counter-intuitive:
“We are nourishing the body, while starving it.”
“Most people in our clinical trials have never gone a day
without eating,” according to Longo.
Doctors as Beta Testers
“Eat your own dogfood,” as they say in Silicon Valley. In L-Nutra’s case functional medicine doctors (not a Big Pharma sales rep) recommend ProLon to their patients. And this is often after the doctors themselves have done a fasting mimicking diet (FMD).
“I had a diabetic patient who was trying to quit soda for a year, and couldn’t do it,” an endocrinologist who is also a ProLon client says “After one cycle of ProLon, he quit soda.”
ProLon customers get a one-on-one session with a health coach, to work through any emotional hurdles or questions about how to fast. Facebook Live fasting webinars provide helpful tips from doctors, ProLon’s own team of medical liaison’s, and fitness experts.
L-Nutra is also collaborating with a leading biogerentologist on an app to track biological age based on a blood test and 9 biomarkers.
“We can’t say if this (using ProLon) is reversing aging,” cautions Longo.
But as America faces a diabesity epidemic, Nutri-technology could be a solid science-backed biohack.
Longo’s research team hopes to publish results from a larger human clinical involving several hundred ProLon users, sometime in 2020.
Detecting diseases earlier may come down to tracking how the body is functioning as a whole system.
A new blood test developed by researchers at Yale University includes biomarkers for blood sugar, kidney and liver function, as well as immune and inflammatory markers. These blood measures (which research suggests drive aging pathways) are combined with an algorithm to come up with a biologic age or “phenotypic” age.
Unlike your chronological age, your biological age is the age at which your vital organs are functioning.
“The exciting thing about this research is that these things aren’t set in stone,” says Dr. Morgan Levine. “If we are given the information much earlier in the process, before the patient develops disease – then they can take steps to improve their health before it’s too late.”
Dr. Morgan Levine, today a professor at Yale, first began developing the algorithm as a post-doc at UCLA; she was a fellow in human genetics at the UCLA David Geffen School of Medicine, where she worked with Steve Horvath, Ph.D., to help identify specific DNA methylation sites along the epigenome that are highly correlated with biomarkers of biological age and chronological age.
Levine hopes that this simple blood test could flag if an otherwise healthy person is aging more rapidly than normal. And empower patients to take action sooner, before experiencing symptoms.
This phenotypic age was based on clinical chemistry measures that are routinely ordered by a physician (kidney/liver panel, CBC, lipids, glucose, etc.) and, together, are robust predictors of death and disease.
To create the test, the scientists looked at 42 different clinical measures, such as white blood cell count, glucose and albumin levels, that were recorded for people who took part in two large studies as part of the US National Health and Nutrition Examination Surveys (NHANES). The studies gathered people’s medical and lifestyle details and were linked to death records.
The scientists used information from 10,000 people in the first study, which ran from 1988 to 1994, to identify clinical measures that most strongly predicted life expectancy. From this work, the scientists developed a combined test based on nine biomarkers which they validated in 11,000 people who had taken part in the second study, which ran from 1999 to 2010.
Levine posted details of the research on the online repository, Biorxiv.
The results were quite notable. If a person’s biological age was much higher than their real age, their risk of dying younger shot up. Among 50- to 64-year-olds, a quarter of those ageing fastest died over the next ten years.
This new epigenetic clock, called DNAm PhenoAge, according to the study strongly outperforms previous age clocks in terms of predicting aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer’s disease.
Tracking a patient’s biochemistry like mitochondria function and chronic inflammation is a new approach.
Epigenetics examines how genes are switched on and off by chemical additions to DNA, which alters how the cell “reads” DNA. Levine’s lab is in a sense developing an epigenetic clock that could push medicine to treat aging, instead of siloed diseases separately.
Econometric projections suggest that interventions that achieve even modest slowing of biological aging could reduce burden of disease more than curing all cancer and heart disease combined (1). Interventions to slow the biological processes of aging could prevent or delay many different diseases simultaneously, prolonging healthy years of life
Using Phenotypic Age in Clinical Trials Dr. Valter Longo, a leading aging researcher at the University of Southern California, is collaborating with Levine on developing a smartphone app.
Measuring telomere length, senescent cells, and DNA methlyation are all biomarkers of aging. But according to Longo, blood work is a good indicator of how the body (biochemically speaking) is working.
“For now we don’t have a system that can do anything to address telomere length.”
While he doesn’t believe inflammation causes aging, unresolved chronic inflammation can indicate underlying problems. Trying a cryogenic freeze to slow aging sounds exciting. But what experts in the aging field like Dr. Longo recommend and backed by evidence, is getting a high sensitivity C-Reactive protein blood test.