In the Future, Could Exercise Come in a Pill?

As we get older exercise helps keep our bodies working properly. And a protein encoded by the mitochondrial genome could also be an important player. That’s according to researchers looking at mitochondrial medicine, or whether it’s possible to develop a pill that could someday mimic some of the beneficial effects of exercise.

We tend to think of mitochondria as the cell’s energy producing powerhouses.

But a new study published in Nature Communications, suggests that aging is regulated by genes encoded in the mitochondrial genome. Mitochondria possess their own genome, possessing only 13 protein-coding genes. And although only a small mouse model and human pilot study, the data adds to a growing number of findings describing beneficial effects of MOTS-c, a mitochondrial-derived peptide that is known to mimic the effects of exercise.

“Mitochondria are known as the cell’s energy source, but they are also hubs that coordinate and fine-tune metabolism by actively communicating to the rest of the body,” said Changhan David Lee, assistant professor at the USC Leonard Davis School of Gerontology and corresponding author of the study.

Maintaining muscle mass in middle age could be doing a lot more than keeping our gait and posture healthy.

“This discovery sheds new light on mitochondria and positions them as active regulators of metabolism,” said Changhan Lee, assistant professor at USC Davis and lead author of the study.

In a small human pilot study, researchers at the University of Southern California (USC) found that exercise induces mtDNA-encoded MOTS-c expression. In muscle cells, levels of MOTS-c significantly increased nearly 12-fold after exercise and remained partially elevated after a four-hour rest, while MOTS-c levels in blood plasma also increased by approximately 50% during and after exercise and then returned to baseline after the rest period.

In mice MOTS-c treatment significantly improved physical performance, regulated skeletal muscle metabolism and gene expression, and enhanced adaptation to metabolic stress.

Scientists have known that mitochondria tend to produce large amounts of free radicals when muscles contract. However, this study sheds light on how the mitochondrial genome also acts as a source for instructions that can regulate physical capacity.

A “mitokine” is a mitochondrial hormone. When muscles contract during exercise mitokines called MOTs-c are produced. Mitochondrial-encoded MOTS-c instructs proteins to interact with the nuclear genome and plays an important role in regulating cell metabolism and stress responses.

MOTS-c treatment enhanced physical performance by improving whole body energy metabolism, in part, by promoting adaptive responses to exercise-related stress conditions (e.g. metabolic imbalance and heat shock) in skeletal muscle.

MOTS-c protein treatment may play a role as a signaling molecule that can repair free radical damage to muscle tissue. According to Changhan David Lee this ability of MOTS-c treatment to repair damage may be relevant as muscle cells do not divide as frequently as other organs like the liver, and in the elderly or frail patient tend to accumulate damage and lose function.

Mitochondrial Medicine in a Brief Timeline:

1967 – The adaptive response of muscle mitochondrial content to regularly performed exercise (i.e. training) was first convincingly demonstrated by John Holloszy in 1967. Exercise in combination with high intensity intervals, could produce a remarkable 100% increase in the level of oxidative enzymes per gram of muscle. High intensity aerobic exercise in short bursts, led to the most convincing changes in mitochondrial content.

2015 – Changhan Lee, who, along with Pinchas Cohen, professor of gerontology, medicine and biological sciences and dean of the USC Leonard Davis School, first described the evolutionarily conserved protein MOTS-c and its effects on metabolism. Subsequent studies showed how mitochondrial-encoded MOTS-c instructs proteins to interact with the nuclear genome and plays roles in regulating cell metabolism and stress responses.

2020 – A new study shows MOTS-c in humans acts as an exercise-induced mitochondrial-encoded regulator of muscle homeostasis and potentially age-dependent physical decline. MOTS-c protein treatment in aged mice appears to reverse insulin resistance, opening the door to research into an exercise mimetic pill to combat cachexia.

Meanwhile, other researchers are investigating FDA-approved diabetes drug metformin as a possible anti-aging pill. However, unlike MOTS-c recent evidence indicates that adding metformin to exercise antagonizes the exercise-induced improvement in insulin sensitivity and cardiorespiratory fitness.

This early data suggests that MOTS-c could someday act as an exercise mimetic, to treat insulin resistance-induced skeletal muscle atrophy in the elderly or patients unable to exercise.

However as this was a mouse study primarily, whether MOTS-c mitochondria protein effects will translate to humans requires further study.

Your Cells Have Antennas: What It Could Mean to Aging

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 as a sort of microscopic garbage can. A small membrane bound sac containing highly acidic degradative enzymes the lysosome resides inside the interior walls of the cell, the cytoplasm. Lysosomes 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 (before the production line needs to be halted).

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 one of the body’s key growth pathways’s 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 even 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.

Cilia exist throughout the body and in the 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 lungs aren’t the only organs that require cilia.

Our body also contains another type of cilia called immobile cilium.

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, one regulated by nutrition.

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

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

Maintaining muscle and mitochondria function as we age is important. But the latest research on how the body’s cell cycle machinery works opens the door to not piling on, but instead using protein in on/off bursts.

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 including specific amino acids (and sugars) as an”on” and “off” switch for repair.

Like motile cilia in the lung that constantly clear out debris, immobile cilia appear to be play an equally active role in health.

What this emerging science on immobile cilia’s role seems to suggest is that constant levels of high protein in the diet, at the molecular level may push cell signals too hard. The mTOR aging pathway and nutrient-sensing cilia, both respond to brief pulses of low protein as a signal for vital cell repair.


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 pilot trial suggests that (for certain cancers) new nutritional as well as 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.”