Your Cells Have Antennas: Cilia’s Role in Health

We tend to think of our cells as big blobby things.

But floating around the inside of our cells, is cell cycle machinery constantly regulating growth and repair signals.

One organelle called the lysosome acts like a tiny garbage can, a small membrane bound sac containing highly acidic degradative enzymes inside the cytoplasm. Lysosomes can inform the rest of the cell of its intracellular and extracellular milieu, and trigger pathways to help the cell adapt to emerging conditions.

Outfitted with pervasive sensing cilia and microtubules, the lysosome organelles are constantly sensing the microenvironment.

Now science is discovering that far from being passive, these lysosome organelles appear to signal inside out to the surface of the cell.

In the high tech world of Silicon Valley “pervasive sensing” is a familiar concept, and driving force behind today’s trends in automation as well as the Internet of Things (IoT). Robots equipped with sensors on the factory floor can for example send signals, alerting technicians that a damaged part needs repair.

The body may also come equipped with the biological equivalent of pervasive sensing equipment.

Sitting on the cell’s surface, microscopic cilia are tiny pervasive sensors that sense growth factors and nutrients. By activating an important growth pathway called the mechanistic target of rapamycin (mTOR), these tiny microtubule signals tell the cell when to get big, and divide.

A central regulator of human metabolism and physiology, the mTOR pathway is considered to be a major axis involved in aging. mTOR helps regulate the liver, muscle, adipose tissue, and the brain, and is dysregulated in diseases such as diabetes and certain cancers.

mTOR works closely with lysosomes, the small vesicles that help our cells take out the trash. Signals travel between the mTOR growth axis and our cells via a mechanism or signaling pathway involving microtubules and cilia.

In lungs epithelial cells in the airway are ciliated with multiple motile cilia. Motile cilia make a swishing motion to move fluid or clear debris. The presence of cilia in the respiratory track is critical for normal lung function, and alterations in these motile cilia contribute to the development of pathologies such as chronic bronchitis, or Acute Respiratory Distress Syndrome (ARDS).

But there’s also another type of cilia called immobile cilium. While we may be less familiar with these cilia their signals may be important. According to Dr. Jon Lieff, author of “The Secret Language of Cells”, although first observed in 1887 these primary or immobile cilia have been difficult to study because they are ten thousand times smaller than a human cell.

Scientists believe that these immobile cilia sit on the surface of cells, and can act as nutrient-sensing antennas. When amino acids and sugars are present in the blood stream, the cilia senses the exterior environment and knows that it is safe for the cell to divide. If nutrients are scarce, the cilia can signal to the cell to switch into a quiescent mode, stop dividing and growing, and instead focus on repair.

Inside the cell, the lysosome serves as a platform to assemble signaling hubs, on its surface. An aging pathway, the hormone axis mTORC1 uses the lysosome garbage can as a docking station, to lock on to and activate growth.

If sufficiently low levels of growth signals are present, and if mTOR is deactivated and undocked, the lysosome will signal to the cell to “switch on” autophagy or self-eating. In this quiescent or standby mode, autophagy is used to repair damaged components like misfolded proteins or defective mitochondria.

The mechanistic target of rapamycin (mTOR) pathway regulates cell growth and enlargement, and has been found to be aberrant in a wide variety of malignancies.  

Scientists are now learning that more than acting as a passive blobby garbage can, the lysosome is more like a command center mTOR docking station sending signals to the cells’ surface antennae. Acting as a central processing unit of the cell, the lysosome triggers microtubules to grow.

Nutrients (proteins and sugars) are players in delivering a “go-no go” signal to the mTOR complex to be activated, and dock onto the lysosome. This cell cycle machinery can be observed in a video of fluorescent died lysosomes that move from the cytoplasm onto the lysosome or garbage can membrane wall.     

When nutrients are scarce, autophagy delivers cytoplasmic cargo to lysosomes rather than extracellular cargo. Generally, surplus organelles, damaged organelles, protein aggregates, and free bacteria that escape phagosomes are targeted for autophagy.

In a catabolic state (when nutrients are scarce) mTOR will undock itself from the lysosome’s outer membrane. mTOR is deactivated by sensing a lack of amino acids such as leucine in the bloodstream.

Once dismissed as garbage cans, these tiny organelle lysosomes appear to be integrating extracellular signaling important to healthy cell cycle, and metabolism.

Autophagy, ketogenic diets, and measuring telomeres has grabbed headlines as a way to maintain health.

But the lysosome acting as a central processing unit coordinating healthy cilia signals may play an underlying role, regulated by nutrition.

Something as innocuous as protein and type of protein consumed in the diet could control when mTOR finds the “off” switch, to signal the body to switch to repair.

“Pile on the protein” is popular nutrition advice given to patients.

Eating to maintain muscle keeps the body strong and yet the molecular science cells a different story.

Scientists studying the mTOR complex point out that nutrient-sensing cilia vital to regulating homeostasis appear to be highly attuned to levels of protein in the bloodstream. Acting as tiny antennae cilia signals are constantly sensing the microenvironment and use nutrition (especially certain proteins) as an”on” and “off” switch for repair.

Like motile cilia in the lung that constantly clear out debris, these immobile cilia appear to be active players in health. How to keep cell cycle machinery working and protein’s role, may warrant further investigation.

       

Even Without Steroids, Cancer Patients Experience Less Chemo Side Effects on Fasting Mimicking Diet

In 1971 President Nixon declared a “War on Cancer”, and signed the National Cancer Act on December 23, 1971. Since the early 70s the focus in cancer research has been on drug development, as well as early preventative screenings.

But a somewhat eyebrow raising trend in cancer treatment, is exploring ways to treat certain cancers by combining standard of care therapies and nutritional intervention. Based on decades of aging research, nutritional pathways in the body are used in a targeted way to impact the cancer patient microenvironment and oncogenes. Early human pilot studies are testing whether a few days of fasting with food, followed by refeeding can make chemotherapy more targeted and less toxic.

A recent study investigated whether the fasting mimicking diet (FMD) influenced the toxicity or effectiveness of chemotherapy in women with early-stage breast cancer. The fasting mimicking diet is a four-day meal replacement designed to provide vital nutrients. The FMD triggers the body to switch from an anabolic (growth state) to catabolic (repair state) metabolism, and for cells to enter into a protected state.

The authors of the randomized controlled study assigned 131 women with stage II/III breast cancer to receive either a low calorie fasting mimicking diet or their regular diet three days before and throughout neoadjuvant chemotherapy.

Chemotherapy administered to shrink a tumor prior to surgery is known as neoadjuvant chemotherapy.

Researchers observed that women on the FMD were more likely to experience a 90 to 100 percent tumor cell loss as compared to women on a regular diet. Patients on the FMD had less DNA damage in T-lymphocytes from chemotherapy than those on the regular diet.

A fasting-mimicking diet (FMD) combined with chemotherapy resulted in a 300-400% increase in the chance of killing 90-100% of cancer cells in women with breast cancer. DNA damage in T-cells was less in patients who received the FMD with chemotherapy.

Interestingly, a steroid Dexamethasone was not given to the FMD group. But there was no difference in toxicity between both groups.

Dexamethasone is an antiemetic drug, belonging to a class of drugs that is effective against vomiting and nausea. Antimetics are typically used to treat motion sickness and the side effects of general anaesthetics and chemotherapy directed against cancer. Administering steroids is a standard practice to help chemotherapy patients stave off naseau and handle chemo side effects.

According to the study: “This suggests that the FMD may obviate the need for dexamethasone in the prevention of the side effects of chemotherapy. Importantly, DNA damage in T-lymphocytes was less in patients who received the FMD in combination with chemotherapy compared to those receiving chemotherapy while on a regular diet, suggesting that the FMD protected these cells against the induction of DNA damage by chemotherapy.”

Steroids like dexamethasone are routinely given to cancer patients directly following chemotherapy, but also can trigger serious spikes in insulin.

Typical cancer dietary guidelines encourage chemo patients to consume a high protein diet to combat malnutrition or muscle wasting.

Only normal weight patients were involved in this study to guard against cachexia or muscle wasting. Fasting faces the challenge of going against nutritional guidelines in cancer therapy that are deeply entrenched. And patient compliance in this study was problematic, indicating that patients may need to be followed carefully or supported by a dietician in future larger mult-site studies still in the planning stage.

For now, this cutting edge pilot trial suggests that for certain cancers at least new nutritional, and even steroid administration options, could be on the horizon.



Why This Chemotherapy Ward Includes a Gym

Putting a gym in a chemo ward at first blush, may sound out there.

But in a groundbreaking move, at the Edith Cowan University Cancer Clinic in Perth, Australia researchers located the gym (exercise medicine care clinic) directly next to the chemotherapy suites.

On chemo or radiation days, patients book into the exercise clinic and then go directly from hospital to workout.

And patients aren’t doing just gentle walking, but intense short bursts of weight lifting or jumping, following radiation or chemotherapy. Each cancer patient meets with an exercise physiologist to go through exercises, specifically customized to their tumor or cancer type.

One of the ideas behind exercise medicine for cancer patients is based on tumorogenisis. Tumors grow rapidly, sometimes developing pockets with no functional blood vessels.

By increasing blood flow to tumors, exercise is thought to help drive chemo into the tumors. Working out might also make it easier for our own immune system, to move in and destroy cancer cells.

Typically a cancer patient will lose 10% to 15% of lean body mass during chemo or radiation treatment.

Exercise as medicine had previously been used only after chemotherapy to rehabilitate patients. Oncologists were wary about asking patients to workout directly before or after chemo and radiation treatments.

But science is now learning that precision exercise can help the body maintain muscle, if highly personalized to the cancer, tumor type, and stage of treatment.

“What’s quite astounding is that a patient [with stage three breast cancer] increased her muscle mass during chemotherapy,” explains Professor Robert Newton of Edith Cowan University.

“Bodyweight squats or step ups can have a very large impact on the body,” says Newton. Even ten minutes of intense effort counts and could help make chemotherapy treatment targeted in two important steps:

Step One: Stimulate Immunosurveillance

Science has known that among our white blood cells killer T-Cells are hunting down and killing cancer cells floating around in the body. T-Cells are immunotherapy anti-cancer medicine as evidenced in this microscopic video showing a T-cell in action, hunting down a cancer cell.

According to Professor Newton dovetailing off the way immunosurveillance seems to kill cancer, exercise for cancer patients aims at recruiting the help of the Natural Killer (NK) cell.

Natural killer (NK) cells are the most responsive immune cells to exercise, and seem to mobilize during physical exertion. Exercise-dependent mobilization of NK cells might improve NK recruitment and infiltration in solid tumors.

Step Two: Increase blood flow to Hypoxic Tumors

Tumor cells divide rapidly, and this can create a messy blood supply system with areas of hypoxia. Hypoxia, or low oxygen condition, is a normal physiological response to certain body stressors such as high altitudes. Tumor cell hypoxia results from an imbalance between the oxygen supply available and the oxygen consumption of the rapidly dividing cells.

 “One of the biggest issues with improving delivery of chemotherapy to solid tumors is that only about half of the blood vessels are functional and mature enough to deliver the drugs,” explains Keri Schadler, Ph.D., an expert in cancer tumors at MD Anderson.

By increasing blood flow in the body, the hypothesis is that precision exercise can help get chemotherapy to the places that need it most. Chemo is a blunt instrument, but exercise administered by an exercise physiologist in coordination with the oncologist is precisely tailored. And cytokines or other growth factors released by exercise may help the body’s natural immunosurveillance system find tumors.

Although the exact mechanisms aren’t well understood, early clinical trial data indicates that exercise is doing more than helping cancer patients ward off nausea. Pilot studies in Australia and Sweden and a few early clinical trials are just beginning in the U.S.

Recently Newton told Australia’s ABC news radio, other than in Australia and Sweden, cancer management is behind where the research is.

The problem according to Professor Newton is the way oncologists are currently prescribing exercise to their patients. What type of cancer and where tumors are located matters. He sees little benefit from telling a cancer patient to simply “get out there and move”.

Diluting Plasma Slows Aging, New Mouse Study Suggests

University of California, Berkeley researchers have recently published a mouse model study that shows age-reversing effects can be achieved by diluting the blood plasma of old mice.

In 2005, University of California, Berkeley, researchers made a surprising discovery by stitching together a young and and old mouse like conjoined twins. Sharing blood and organs between the mice, scientists rejuvenated tissues and reverse the signs of aging in the old mice.

This conjoined twin mouse model study led to the idea that young blood contains special proteins, which deliver a ‘fountain of youth’ effect. And biohackers got the idea that getting transfusions from young donors aka “blood boys” could slow aging.

Problem is mouse studies are not a strong signal and exploratory. A follow on mouse model study conducted by the same research team, now shows simply diluting the blood plasma of old mice achieves age reversing effects.

Here’s how parabiosis became a thing:

Early 2000s – Senior researcher and professor of bioengineering Irina Conboy and Michael Conboy have a hunch that our body’s ability to regenerate damaged tissue remains with us into old age in the form of stem cells. But that somehow these cells get turned off through changes in our biochemistry as we age.

2005 – Conboy lab publishes study showing that making conjoined twins from the old mouse and a young mouse reversed many signs of aging in the older mouse. Many researchers seized on the idea that specific proteins in young blood could be the key to unlocking the body’s latent regeneration abilities.

2016 – a second follow-up study finds young blood does not reverse aging in old mice. Tissue health and repair dramatically decline in young mice when half of their blood is replaced with blood from old mice.

The study suggests to Irina Conboy that young blood by itself will not work as effective medicine. Rather the idea that emerges is that inhibitors in old blood could be a target to reverse aging.

In this 2016 study, Conboy and colleagues developed an experimental technique to exchange blood between mice without joining them so that scientists can control blood circulation and conduct precise measurements on how old mice respond to young blood, and vice versa.

In the new system, mice are connected and disconnected at will, removing the influence of shared organs or of any adaptation to being joined. One of the more surprising discoveries of this study was the very quick (within 24 hours) onset of the effects of blood on the health and repair of multiple tissues, including muscle, liver and brain.

June, 2020 – A new study finds that diluting blood in old mice by replacing half of the plasma with a saline and albumin mixture was able to reverse aging in the brain, liver, and muscle.

In a press release statement Irina Conboy, a professor of bioengineering at UC Berkeley who is the first author of the 2005 mouse-conjoined twins paper and senior author of the new study explains the results:

“There are two main interpretations of our original experiments: The first is that, in the mouse joining experiments, rejuvenation was due to young blood and young proteins or factors that become diminished with aging. But an equally possible alternative is that, with age, you have an elevation of certain proteins in the blood that become detrimental, and these were removed or neutralized by the young partners.”

In the years since the exploratory 2005 study, scientists have spent millions to investigate the potential medical properties of youthful blood with enterprises emerging to infuse old people with young blood.

“What we showed in 2005 was evidence that aging is reversible and is not set in stone,” Irena Conboy said in a UC Berkeley press release. “Under no circumstances were we saying that infusions of young blood into elderly is medicine.”

What the Hack? 5 Popular Biohacks vs. Science

Biohacking is taking off. Fueled by tweets from the likes of entrepreneur Jack Dorsey, there’s something appealing about the self-experimenting scientist nerd.

“Hackathons” have been a pastime for tech geeks for years. Software engineers fix bugs and come up with new ideas in hackathons that stretch through the night.

Today this fix-it nerd approach to hacking software code, is applied to our own biology by broscience and biohackers (who sometimes hold degrees in biochemistry).

And Covid has led to a renewed interest in ways to boost the immune system.

The voice of science may be getting drowned out by the sheer volume of health influencers in social media. And it’s getting harder to distinguish signal from the noise.

Scientists and biohackers are driven by a shared sense of curiosity and a desire to help people feel better. But both camps do not disseminate information in the same way.

Scientists run clinical trials. The average cost of phase 1, 2, and 3 clinical trials across therapeutic areas is 4, 13, and 20 million respectively. Pivotal studies cost a median of $41,117 per patient.

Science also follows the credo that “correlation does not imply causation” in regards to observational or epidemiological studies. The randomized, double-blind placebo control is the gold standard for designing an experiment or testing a new drug. If a clinical trial involves only a small number of patients the data is considered as a pilot study (or weak signal), and other labs will try to repeat and validate the results. And those results will be peer-reviewed before publication in a science journal.

Biohackers on the other hand are self-experimenters, and will share “N of 1” data from their own personal self-experiments. An N of 1 trial is a clinical trial in which a single patient is the entire trial. Results are blast out on social media and sometimes linked to product promotions.

In the biohacker realm, a boost to the immune system is sometimes discussed as a productivity or work hack.

Hackers in the early days of Silicon Valley learned about something by building, and trying to make things and seeing what happens. The biohacker hands on approach worked well for building computer keyboards and hardware. Scientists on the other hand work on the body that as a complex system has multiple sites of action. When a drug is working at one site, it is working and doing things all over the body. Side effects are caused by a drug working on multiple sites of action.

But the general public that hears an idea that’s been popularized by biohackers, probably doesn’t know about potential side effects. Scientific research is published in journals that the average Joe Q. Public doesn’t read. How does science get out there on the airwaves?

Increasingly, media-savvy scientists are also creating apps, giving TED talks, and doing Facebook Lives. But still the demands of research, the pressure to publish, and the expense and difficulty of designing a good clinical trials, means less time to post YouTube videos.

With Covid and a higher volume of non-peer reviewed preprints and Twitter spreading science faster than ever on social media, this issue may be coming to a head.

Here’s five simple ideas about health scientists worry we may be getting wrong:

ONE – Free Radical Damage is Bad

The idea “free radicals bad, antioxidants good” is everywhere. But in the past ten years, several scientists are calling into question the Free Radical Theory of Aging which was first proposed in the 1950s.

What’s less well recognized is that the body has its own antioxidant system, which is more powerful than any pill.

Somewhat counterintuitively, free radical damage from exercise is beneficial because it causes helpful adaptations like an increase in muscle strength and mitochondria growth.

According to sports science research, Reactive Oxygen Species (ROS) and oxidative damage, are a normal part of biology and something that cells in the body are equipped to neutralize. Besides causing wrinkles, Reactive Oxygen Species (ROS) are key signaling molecules that trigger muscles to grow. 

Exercise triggers an antioxidant system that exists in the body’s cells, blood, and organs. And when it comes to antioxidant supplements – timing matters.

Emerging research suggests that taking antioxidants (in particular Vitamin E) right before or after training may blunt some of the benefits of working out, like mitochondria biogenesis.

Mitochondria are the powerhouses in your muscles that mop up glucose and are important to insulin sensitivity and preventing diabetes. There is some conflicting evidence and more trials are underway. But for now, experts in exercise physiology advise athletes to proceed with caution.

For elite athletes, taking a mega-dose of Vitamin E and C before or right after training may in fact be doing more harm than good.

TWO – High Protein Intake Can Accelerate a Key Aging Pathway

Biohackers talk about the benefits that come from getting into ketosis from mental clarity to getting six-pack abs.

But high protein diets may also increase levels of an important aging biomarker called insulin like growth factor or IGF-1 levels in humans.

The master axis the mammalian target of rapamycin mTOR pathway is a primary aging pathway that senses amino acid concentrations and regulates cell growth, and integrates other pathways including insulin. mTOR plays a key role in metabolism, and important roles in the function of tissues including liver, muscle, and the brain. It is dysregulated in many human diseases such as diabetes, obesity and certain cancers.

IGF-1 is a blood test used in the clinical setting as a biomarker relevant to preventing age-related diseases like diabetes, cancer, and Alzheimers.

Going on a high animal protein, keto diet may result in six pack abs. But given the science, keto dieters may also want to get bloodwork done.

THREE – Dark Chocolate Doesn’t Contain Exogenous Antioxidants

An important protective pathway called Nfr2, enhances the body’s antioxidant defense. A wide variety of bioactive nutrients in a whole food diet are capable of activating Nrf2 signaling pathways. One of the biggest benefits of Nrf2 is how it protects against inflammation.

Exercise, sleep, and a high nourishment diet appear to keep this antioxidant system working optimally.

Bioactive nutrients in a whole food diet can activate Nrf2 signaling pathways. Nrf2 pathways protect your cells from stressors. The pathway appears to play an important role as a master regulator of more than 200 protective genes that shield your cells against toxins and harmful agents.

Ultimately food does not deliver an exogenous dose of antioxidants.

Consuming a high quality diet activates a variety of signaling pathways in the body’s antioxidant system, and this in turn helps to switch on protective genes.

So consuming dark chocolate is a healthy choice, but not because the chocolate itself contains antioxidants. The bioactive nutrients or polyphenols in the chocolate activate the body’s Nrf2 signaling pathway to help protect cells from stressors.

FOUR – Some Circadian Clocks Are Run by Eating Window

Biochemical clocks exist in tissues throughout the body. And a cutting edge field of science called chronobiology, is now discovering that how the circadian clocks in our organs, tissues, and cells are tuned matters.

Today we know that there is a decline in circadian rhythms with age, concomitant with declines in the overall metabolic tissues homeostasis and changes in the feeding behavior of aged organisms. This disruption of the relationship between the clock and the nutrient sensing networks might underlie age-related diseases.

According to Dr. Satchin Panda, an expert in circadian clock research, when the timing systems in the human body are desynchronized, essential organs are compromised, reducing the potency of the immune system.

A recent breakthrough in Panda’s lab suggests that a primary time cue may not only be light, but glucose – and this happens in the circadian clocks in the liver and pancreas.

When we start the liver clock (by taking our first sip or bite of the day) appears to have effects on glucose, lipid and oxidative pathways and immune system rejuvenation and repair.

Eating in an eight hour (or even 10-12 hour window) may tune the circadian liver clock to significantly improve immune system health.

Panda’s lab is currently running a 9,000 patient clinical trial using an app called mycircadian.org to test this drug-free, cost-effective, lifestyle choice as a way to prevent insulin resistance and other disease risk factors.

According to several early clinical studies in humans, your liver has a circadian clock that is switched on and regulate thousands of genes.

“There is a [circadian] clock in the liver. Forget about light or dark,” says Panda. “What we have to be more careful about is when we eat and when we fast.”

In other words, researchers are learning that beyond jet lag, there’s also metabolic jet lag. More and larger human clinical trials are needed.

But for now, “metabolic jet lag” appears to play a more important role in immune system health than was previously thought.

FIVE – Your Stem Cells Have a Built-in “Homing Beacon”

The picture of regenerative medicine portrayed on blogosphere is that rejuvenating stem cells requires painful needle, a lot of money, and or a potential trip to a clinic outside the US.

Science is now focusing on a different angle.

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 found in bone marrow. These are not to be confused with haematopoietic (blood) stem cells that are also found in bone marrow and make our blood.

Everyone has these stem cells inside our bone marrow, which are in stand by mode or quiescence.

What is less well understood or talked about in the broscience is that injecting a needle into damaged tissue isn’t the only way to direct stem cells to the site of damage.

Stem cells appear to operate like heat-seeking missiles, equipped with a “homing beacon”.

It was once thought that the decline in mesenchymal stem cells as we age was a given.

But now science is learning that the microenvironment that your stem cells are in can have a dramatic impact on their ability to grow, proliferate and repair damaged tissue. Stem cells can be impacted by diet, exercise and taking mediations.

In the world of biohacking getting a stem cell injection is portrayed as a way to slow aging. But science is now learning that nutrition may be able to trigger stem cells out of quiescence to rejuvenate the boy.

Scientists at USC in a mouse model study observed an 800% increase in the proliferation of

Clinical trials in humans using muscle tissue biopsies are hoping to validate the study and find out how stem cells proliferation or differentiation works as triggered by changes in nutrition.

At the very least, science is learning that nutrition (or pulsing a five-day low calorie period with refeeding) may produce more powerful effects on stem cells than previously understood.

While more studies are needed, science is learning that nutrition and manipulating nutrient-sending aging pathways (no needle required) appears to have positive effects on stem cell health.

Covid as a health crisis is also providing scientists with an inflection point. People under quarantine have time to stop and evaluate their health. But with today’s rise of biohacker culture, getting valid science from the lab bench to the pop culture milieu for wellness – might take a revolution.