Scientists at Weill Cornell Medicine in New York say that stress-induced circadian clock disruptions may influence weight gain.

A study published in June showed that mice with artificially increased stress levels and interrupted hormone releases experienced an increase in fat cell growth. Its results appear in Cell Reports.

The second study, published in August, found that fat cell precursors commit to becoming fat cells only within a few hours at night. This work appears in the Proceedings of the National Academies of Sciences (PNAS).

Mary Teruel, PhD, associate professor of biochemistry at Weill Cornell Medicine, was the senior author of both studies.

A lot of forces are working against a healthy metabolism when we are out of circadian rhythm, Dr. Teruel said in a press release. The more we understand, the more likely we will be able to do something about it.

In the Cell Reports study, Dr. Teruel and her team implanted pellets with glucocorticoids, a type of stress-related hormone, in mice. This was to mimic the effects of chronic stress or Cushings disease.

Cushings disease triggers elevated levels of cortisol, the bodys stress hormone.

The pellets released glucocorticoids under the skin of the mice at a steady rate over three weeks. The researchers also observed control mice with typical daily stress hormone fluctuations.

Although all the mice ate the same healthy diet, the mice with pellets ended up weighing over 9% more than the control mice.

The researchers observed whether the weight gain was from fat expansion and found that the brown and white fat of the pellet mice had more than doubled. Their insulin levels spiked as well.

To the teams surprise, the metabolic disturbances kept blood glucose levels low. Further, the disruptions prevented fat from accumulating in the blood or liver.

When the researchers removed the pellets, these changes reversed immediately.

Dr. Teruel explained to MNT: We saw this in our paper, basically, once we stopped flattening the corticoids, [the mice] started reversing [the fat mass gain] and the hyperinsulinemia went away so that increased insulin that seems to be causing the fat mass gains that went away when the restored rhythm.

She added that this study indicates that chronic stress can make weight gain more likely, even with a healthy, low fat diet.

If you stress the animals at the wrong time, it has a dramatic effect. The mice arent eating differently, but a big shift in metabolism causes weight gain, Dr. Teruel said in the release.

Dr. Teruels research team hopes that their findings lead to developing drugs that could help reset circadian rhythms to help people with obesity.

We dont know enough [yet], but one would think cortisol receptor antagonists or [] things that restore the cortisol rhythms would probably help a lot.

Dr. Mary Teruel

Experts understand that flaws in circadian clock genes can alter cell differentiation in fat, immune, skin, and muscle cells.

The PNAS study revealed that even though differentiation happens over a few days, differentiation commitment happens within only a few hours. The findings also show that daily bursts of cell differentiation seem to be limited to evening phases when people are normally resting.

The decision to become a fat cell happens rapidly over 4 hours. It is like a switch, Dr. Teruel said.

Medical News Today discussed this with Dr. Mir Ali, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California.

Dr. Ali explained how fat cells come to be: Fat cells form from [an] adipocyte progenitor cell or a type of cell that has not differentiated into its final form. The form it takes [to become] a fat cell depends on the hormonal and chemical stimulation it receives.

In the study, Dr. Teruel and her partners used fluorescent markers to observe daily fluctuations of fat cell production.

The researchers attached a red fluorescent protein to a protein that regulates circadian clock genes. They also attached a yellow fluorescent protein to peroxisome proliferator-activated receptor gamma (PPARG), a protein that controls fat cell production.

They discovered that during the rest period of the day, a certain circadian protein CCAAT enhancer binding protein alpha induces a rapid increase in the protein that regulates fat cell production.

The researchers also found that when PPARG levels hit a certain threshold, individual fat precursor cells irreversibly commit to differentiate within only a few hours, which is much faster than the rest phase and the overall multiday differentiation process.

Dr. Teruel and her team believe that working with this time window may open therapeutic strategies to use timed treatment relative to the [circadian] clock to promote tissue regeneration.

Dr. Ali said: These studies are interesting in that they show the timing and length of stimulation affect the formation and growth of fat cells. The implications of this are that if we can find a way to safely influence the cell to grow or not grow, it may affect obesity in humans.

However, he believed that more extensive research is needed to make the studies findings applicable to humans.

Dr. Teruel told MNT that she and her co-authors were just trying to work on basic mechanisms [] Right now, we need to show this is really a mechanism that happens []

The researchers do plan to replicate the studies with people. We are looking at protein ribbons and humans using saliva samples, Dr. Teruel shared with MNT. Were planning to do those kinds of experiments.

Their main objective, she said, is to figure out ways to restore circadian [rhythms].

Dr. Teruel mentioned that currently known strategies, such as meditation and regular sleep in the dark may help.

She expressed hope that there could be some pharmacological ways [to] fix this in the future as well.

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Stress can throw off circadian rhythms and lead to weight gain - Medical News Today

August 16, 2022

Without a steady supply of oxygen from the blood, processes leading to cell death in mammals begin within minutes. Recent studies have shown that cells can still recover even hours after interrupting blood flow. But such recovery has so far only been demonstrated in isolated organs.

An NIH-funded team of researchers led by Dr. Nenad Sestan at Yale School of Medicine developed a system to promote cellular recovery and preserve tissue integrity in the intact body after loss of blood flow. The system, called OrganEx, is based on the teams previous work restoring circulation and cell function in a pig brain that was removed after the animals death.

OrganEx uses a device like the heart-lung machines that take over the functions of the heart and lungs during surgery. The device pumps a mix of the pigs own blood and a protective fluid throughout the bodys blood vessels in a process called perfusion. This fluid contains oxygen and a synthetic form of hemoglobinthe oxygen-carrying protein in red blood cells. It also contains electrolytes and compounds designed to protect cells and prevent blood clots.

The researchers tested OrganEx in pigs undergoing cardiac arrest. Perfusion of pigs began one hour after cardiac arrest and continued for another six hours. Results appeared in Nature on August 3, 2022.

OrganEx was able to circulate the fluid throughout the body and deliver adequate oxygen to tissues. It also prevented electrolyte imbalances that normally occur when blood flow stops. The researchers compared OrganEx with a conventional heart-lung perfusion machine that pumped the pigs own blood back through its body.

OrganEx perfusion for six hours preserved cell and tissue integrity and reduced cell death in various organs. These included the brain, heart, liver, and kidneys. In the brain, OrganEx preserved all three major cell types: neurons, astrocytes, and microglia. Cells in the heart, liver, and kidneys had less damage than corresponding cells after treatment with the standard device.

The researchers also found signs of restored organ function in the perfused pigs. They observed glucose uptake in brain, heart, and kidneys. They found electrical activity and contraction in the heart, and protein synthesis in the liver and brain. Several organs activated genes associated with cellular repair processes and preventing cell death.

These findings suggest the potential for organs to recover up to an hour after blood flow stops. OrganEx technology could leverage this potential to prolong the life of human donor organs. This could make more organs available for transplants. It might also help damaged organs to recover following heart attacks or strokes. Yet the researchers stress that further research will be needed. It remains to be seen how much organ function can be recovered and how long it can be maintained. Because of the ethical implications of brain recovery after death, this and future work will continue to require rigorous ethical review.

There are numerous potential applications of this exciting new technology, says study co-author Dr. Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics.However, we need to maintain careful oversight of all future studies, particularly any that include perfusion of the brain.

by Brian Doctrow, Ph.D.

References:Cellular recovery after prolonged warm ischaemia of the whole body. Andrijevic D, Vrselja Z, Lysyy T, Zhang S, Skarica M, Spajic A, Dellal D, Thorn SL, Duckrow RB, Ma S, Duy PQ, Isiktas AU, Liang D, Li M, Kim SK, Daniele SG, Banu K, Perincheri S, Menon MC, Huttner A, Sheth KN, Gobeske KT, Tietjen GT, Zaveri HP, Latham SR, Sinusas AJ,Sestan N. Nature. 2022 Aug 3. doi: 10.1038/s41586-022-05016-1. Online ahead of print. PMID:35922506.

Funding:NIHs National Institute of Mental Health (NIMH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Schmidt Futures.

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Restoring cell and organ function after the heart stops - National Institutes of Health (.gov)

Family, friends and positive attitudes helped Katherine Haug through months of failed attempts at ridding her body of cancer. Then a passionate doctor with an experimental treatment gave the wife, mother and grandmother a big reason to smile.

Last November, Manali Kamdar, MD, informed the longtime Buena Vista resident that her cancer was in remission. Go live your life, and Ill see you in a year, Kamdar told her. The news was profound, not just for the people standing in Kamdars office that fall day, but for the thousands of patients who will find themselves on Haugs path in the future.

Did you know: Patients at the University of Colorado Anschutz Medical Campus have access to potentially life-saving therapies often years before the treatments are approved for general use? At any given time, 1,400-plus active clinical trials are taking place on campus, transforming healthcare. Find research studies here.

This is not just about me. Its not just about Ron, Haug said of her husband of 47 years. Its about everybody.

Haug was diagnosed with large B-cell lymphoma (LBCL) in January 2019, when scans showed two large masses, one in her spleen and one in the parietal peritoneum, the tissue that lines the abdominal wall. The standard immunochemotherapy treatment (R-CHOP), which succeeds nearly 60% of the time, failed.

The tumor in the peritoneal area disappeared after the second R-CHOP treatment, said Haug, who had six rounds in total. But the one in the spleen was the one that was kind of cranky and didnt want to go away.

Her oncologist near her Buena Vista home of 40 years sent Haug down the mountain to Kamdar at the University of Colorado Anschutz Medical Campus. There, Haug found herself with an option:

She could undergo the standard and often-brutal second-line treatment of intensive chemotherapy followed by stem-cell transplant. Or she could roll the dice and join a randomized clinical trial comparing that therapy to lisocabtagene maraleucel (liso-cel), an investigational chimeric antigen receptor (CAR) T-cell therapy.

Haug decided to gamble.

Although she had never heard of CAR T-cell therapy, a rising star in cancer research deemed the 2018 Advance of the Year by the American Society for Clinical Oncology, Haug sensed Kamdars excitement about the treatment, which was not yet an option for patients in Haugs situation. She joined the study, deciding, among other reasons, to be part of something bigger than myself.

Today, thanks in part to Haug and the 183 other participants in the global phase-3 trial that involved 47 sites, the liso-cel CAR T-cell therapy is now approved as a second-line treatment for relapsed or refractory large B cell lymphoma (LBCL).

To Kamdar, lead author of the study published in June in The Lancet, approval represents a win for patients and for science.

Without the CAR T-cell option, nearly 70% of patients like Haug who failed R-CHOP would succumb to their disease, said Kamdar, an associate professor of hematology at the University of Colorado School of Medicine and a member of the CU Cancer Center. Its amazing to see how quickly we are moving forward in advancing patient care and improving patient outcomes.

In the most recent assessments of the ongoing randomized study called TRANSFORM, survival rates were significantly higher in the CAR T group compared with the standard therapy group. Median event-free survival was 10.1 months versus 2.3 months, and median progression-free survival (disease doesnt get worse) was 14.8 months versus 5.7 months.

Potential CAR T-cell therapy side effects can include cytokine release syndrome, an over-aggressive immune system response that causes fever, nausea, fatigue and body aches. Neurological issues, such as speech problems, tremors, delirium and seizures, also can occur. But of the CAR T-related toxicities seen in the study, all were low-grade and completely reversible, said Kamdar, clinical director of lymphoma services.

The breakthrough outpatient therapy also involves less time in the hospital than the traditional stem-cell transplant a winning point for Haug. I told Dr. Kamdar, I cant sit for 15 days in the hospital.

The dice rolled in Haugs favor, and she was randomly assigned to the trial's CAR T arm. After undergoing tests for study approval, she and her husband packed up and traveled over 140 miles to Aurora to begin the therapy.

The process begins with leukapheresis, where blood is drawn via a large, centrifuge-like machine that extracts T cells before returning the remaining blood to the patient. Thats about four hours and 20 minutes laying with your arm straight out, and you cant move, Haug said. It wasnt painful. It was just one of those things.

A nurse monitors injection of the genetically modified CAR T cells.

Cells are then modified in the lab where they are genetically engineered to become fighter cells, and millions of copies are created. Then they are injected back into the patient, and an observation period begins. The couple had to be near the hospital for 30 days, made easy by the nonprofit Brents Place program, Haug said. They give you a place to stay, and it was within walking distance of the hospital.

Patients are carefully monitored during that month for progress and side effects. I was fortunate, Haug said. My numbers just got better and better, and I never experienced any significant side effects.

The Haugs, who recently moved to Kansas to be closer to family, are grateful for finding Kamdar and the trial.

Shes obviously very good at what she does, but yet shes very human, Haug said. She wants it to work, and she wants it to work for everybody, not just me. And I think that attitude bears a lot of merit. Going through cancer, you have to have, I think, not only a good sense of humor but great confidence in who you are going to. If you dont, you need to find somebody else.

I cant thank her enough, Ron Haug said of Kamdar, adding that hes proud of his wife for taking part in the trial that can make cancer treatment a little easier on other patients in the future. The Haugs also hope the Food and Drug Administration approval will make CAR T-cell therapy more accessible and affordable for everyone.

That would make me feel like maybe I accomplished something good in my life, Katherine Haug said, to which her husband quickly responded: You did.

As the therapy highlighted in this article exemplifies, doctors at CU Anschutz continually pursue new treatments that save lives without debilitating their patients. Patient Katherine Haug offered other top strategies for staying as mentally and physically healthy as possible during a cancer journey.

We laughed a lot, with each other and at each other, she said of her and her main supporter: husband Ron Haug.

One time, a family member looked horrified after saying: Well, Id better get out of your hair, when Haug was bald from chemotherapy. No need to get out of my hair; I dont have any! she responded, busting out laughing, along with her husband.

You do have to have a real positive aura around you because otherwise it would be too hard, said Haug, who even cut ties with toxic friends after being diagnosed.

The Haugs found and relied on support all along, from friends, family (especially their daughter) and nurses, who overwhelmed her husband, he said, with their kindness and compassion.

"You have to keep your body moving," Haug said, adding that a friend and breast-cancer survivor shared the advice with her when she was diagnosed. "No matter how bad you feel, try to at least go for a walk," her friend told her.

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Rolling the Dice: Gamble Pays Off For Cancer Patient in CAR T-Cell Clinical Trial - University of Colorado Anschutz Medical Campus

image:The new study shows that boosting neurogenesis increases the number of newly formed neurons involved in storing and retrieving memories (arrows) in the hippocampus of mice with AD. view more

Credit: 2022 Mishra et al. Originally published in Journal of Experimental Medicine. https://doi.org/10.1084/jem.20220391

Researchers at the University of Illinois Chicago have discovered that increasing the production of new neurons in mice with Alzheimers disease (AD) rescues the animals memory defects. The study, to be published August 19 in the Journal of Experimental Medicine (JEM), shows that new neurons can incorporate into the neural circuits that store memories and restore their normal function, suggesting that boosting neuron production could be a viable strategy to treat AD patients.

New neurons are produced from neural stem cells via a process known as neurogenesis. Previous studies have shown that neurogenesis is impaired in both AD patients and laboratory mice carrying genetic mutations linked to AD, particularly in a region of the brain called the hippocampus that is crucial for memory acquisition and retrieval.

However, the role of newly formed neurons in memory formation, and whether defects in neurogenesis contribute to the cognitive impairments associated with AD, is unclear, says Professor Orly Lazarov of the Department of Anatomy and Cell Biology in the University of Illinois Chicago College of Medicine.

In the new JEM study, Lazarov and colleagues boosted neurogenesis in AD mice by genetically enhancing the survival of neuronal stem cells. The researchers deleted Bax, a gene that plays a major role in neuronal stem cell death, ultimately leading to the maturation of more new neurons. Increasing the production of new neurons in this way restored the animals performance in two different tests measuring spatial recognition and contextual memory.

By fluorescently labeling neurons activated during memory acquisition and retrieval, the researchers determined that, in the brains of healthy mice, the neural circuits involved in storing memories include many newly formed neurons alongside older, more mature neurons. These memory-stowing circuits contain fewer new neurons in AD mice, but the integration of newly formed neurons was restored when neurogenesis was increased.

Further analyses of the neurons forming the memory-storing circuits revealed that boosting neurogenesis also increases the number of dendritic spines, which are structures in synapses known to be critical for memory formation, and restores a normal pattern of neuronal gene expression.

Lazarov and colleagues confirmed the importance of newly formed neurons for memory formation by specifically inactivating them in the brains of AD mice. This reversed the benefits of boosting neurogenesis, preventing any improvement in the animals memory.

Our study is the first to show that impairments in hippocampal neurogenesis play a role in the memory deficits associated with AD by decreasing the availability of immature neurons for memory formation, Lazarov says. Taken together, our results suggest that augmenting neurogenesis may be of therapeutic value in AD patients.

Mishra et al. 2022. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20220391?PR

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About Journal of Experimental Medicine

Journal of Experimental Medicine (JEM) publishes peer-reviewed research on immunology, cancer biology, stem cell biology, microbial pathogenesis, vascular biology, and neurobiology. All editorial decisions on research manuscripts are made through collaborative consultation between professional scientific editors and the academic editorial board. Established in 1896, JEM is published by Rockefeller University Press, a department of The Rockefeller University in New York. For more information, visit jem.org.

Visit our Newsroom, and sign up for a weekly preview of articles to be published. Embargoed media alerts are for journalists only.

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Journal of Experimental Medicine

Experimental study

Animals

Augmenting neurogenesis rescues memory impairments in Alzheimers disease by restoring the memory-storing neurons

19-Aug-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Boosting neuron formation restores memory in mice with Alzheimer's disease - EurekAlert

The image shows an irradiated Drosophila embryo, where p53 activity (green) is reduced in neuronal precursors (red). All nuclei are labeled in blue.

John Abrams, Ph.D.

DALLAS August 18, 2022 A gene thats well known for its role in turning on tumor-suppressing genes when cells become stressed also keeps potential tumor-driving genes turned off, UTSouthwestern researchers report in a new study. The findings, published in Developmental Cell, provide new insight into the gene, known as p53, which is mutated in most human cancers.

"If we truly want to understand how cells move from normal to malignant states, understanding p53 and what happens when it becomes disabled is critical, said study leader John Abrams, Ph.D., Professor of Cell Biology and a member of theHarold C. Simmons Comprehensive Cancer Center at UTSW. Our study suggests that when this gene becomes mutated, certain genes and programs that should otherwise be silent become reactivated.

The p53 gene has long been a focus of cancer research because of how often its mutated in malignant tumors, covering more than half of all human cancers. Studies over the past several decades have shown that this gene appears to activate a variety of downstream genes when cells become stressed from factors that damage their DNA, such as genotoxic chemicals or ionizing radiation. These genes subsequently kick off a cascade that stops genes from proliferating a hallmark of cancer by causing cells to go into an inactive stage called senescence or inducing a type of cellular suicide called apoptosis.

Mutations that disable p53 prevent this cascade, allowing cells to begin multiplying out of control. However, explained Dr. Abrams, when researchers individually disabled cellular programs known to be activated by p53, the gene appeared to still suppress tumor development, suggesting that stress-induced gene activation isnt its only job. Previous research by the Abrams labshowed that p53 can also suppress gene activity but how it accomplishes both activation and suppression wasnt understood.

The new study builds on a2020 report from the Abrams lab. Together, the two papers suggest that beyond turning on genes when cells are stressed, p53 appears to have a second role in which it acts directly on other genes to keep them turned off. Notably, these include many not currently known to contribute to cancer, such as transposons, or jumping genes DNA sequences that can move around the genome and genes associated with meiosis, a type of cell division that halves the number of chromosomes to produce sperm and eggs.

Further experiments in the new study showed that p53 accomplishes simultaneous gene activation and inactivation by producing a set of different proteins, or isoforms. By individually deleting specific p53 protein isoforms in their model system the quintessential lab model Drosophila melanogaster, or fruit fly Dr. Abrams and his colleagues demonstrated that previously silent gene programs became activated.

Dr. Abrams said the work has two important implications for developing new cancer treatments. First, ongoing efforts to discover drugs that can replace p53 activity when it becomes impaired by mutations should not only focus on p53s role as a gene activator but also replicate its role as a gene silencer. Secondly, genes that healthy p53 keeps inactivated may play currently unrecognized roles in promoting cancer, Dr. Abrams explained. His lab is currently investigating whether transposons that become reactivated when p53 is disabled could function as oncogenes, making them potential targets for cancer therapies.

Other researchers who contributed to this research include Annika Wylie, Amanda E. Jones, and Simanti Das of UTSW; and Wan-Jin Lu of Stanford University School of Medicine.

This study was supported by grants from the National Institutes of Health (5T32CA124334, R01GM115682, R01CA222579), the Cancer Prevention and Research Institute of Texas (RP160157, RP170086), and the SCCC Translational Pilot Program.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in more than 80 specialtiesto more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

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UTSW study finds p53 gene plays second role in suppressing genes tied to cancer - UT Southwestern

A randomized, double blind human clinical trial conducted by researchers at Baylor College of Medicine reveals that supplementation with GlyNAC a combination of glycine and N-acetylcysteine improves many age-associated defects in older humans and powerfully promotes healthy aging. This is relevant because until now, there have been no solutions toward improving many of these age-related declines in people.Published in the Journalof Gerontology: Medical Sciences, the study shows that older humans taking GlyNAC for 16-weeks improved many characteristic defects of aging. This includes oxidative stress, glutathione deficiency and multiple aging hallmarks affecting mitochondrial dysfunction, mitophagy, inflammation, insulin resistance, endothelial dysfunction, genomic damage, stem cell fatigue and cellular senescence. These were associated with improvements in muscle strength, gait speed, exercise capacity, waist circumference and blood pressure.

This is the first randomized clinical trial of GlyNAC supplementation in older humans, and it found that a wide variety of age-associated abnormalities improved in older adults supplemented with GlyNAC, while no improvements were seen in those receiving placebo, said corresponding author Dr. Rajagopal Sekhar, professor of medicine - endocrinology, diabetes and metabolism at Baylor.

The improvements in oxidative stress, glutathione levels and mitochondrial function in the muscle tissue of older humans taking GlyNAC were similar to the improvements in organs such as the heart, liver and kidneys of aged mice supplemented with GlyNAC as reported in the researchers recent publication. Taken together, the results of these studies show that GlyNAC supplementation can improve these defects in many different organs of the body. GlyNAC supplementation in aging mice increased their length of life mice by 24%, said Sekhar. Gait speed is reported to be associated with survival in older humans. Our randomized clinical trial found a significant improvement in gait speed in older humans supplemented with GlyNAC. This raises the interesting question of whether GlyNAC supplementation could have implications for survival in people.For the last 20 years, Sekhar has been studying natural aging in humans and animal models to understand why age-related declines occur and how to correct them. His work brings mitochondria, known as the batteries of the cell, as well as free radicals and glutathione to discussions about how they are connected. Sekhars work and discoveries could also help explain why we age and how to improve health while aging.

Mitochondria dysfunction, oxidative stress and aging

Mitochondria generate energy needed for supporting cellular functions. Therefore, normal mitochondrial function is critically important for a healthy life. Sekhar believes that improving the health of malfunctioning mitochondria in aging is the key to healthy aging. Energy supports life and mitochondria provide energy. I believe that mitochondrial health is vitally important to our well-being, and maintaining mitochondrial health as we age should be a high priority in our efforts to improve overall health, said Sekhar.

However, the ability of mitochondria to work well declines as we age. How to improve the ability of these failing mitochondria to work is not well understood, and therefore no solutions have been available. Sekhars group discovered earlier that supplementing GlyNAC in aged mice corrected malfunctioning mitochondria. However, to definitively determine whether GlyNAC supplementation benefited people, a placebo-controlled randomized clinical trial was required.

Sekhar and his team conducted and completed such a randomized clinical trial which found that older people have widespread mitochondrial damage and other age-associated defects compared to young people. After 16-weeks of GlyNAC supplementation, mitochondrial function of older people improve toward levels found in young people. This was accompanied by improvements in multiple additional outcomes as reported in the publication. Analysis of the molecular data from the trial suggests that the GlyNAC supplementation is able to fill cells with younger and more efficient mitochondria. Collectively these exciting new discoveries hold great promise for improving our mitochondrial and general health as we age, Sekhar said.

A second vital benefit offered by supplementing GlyNAC is that it also helps protect the body from an important problem called oxidative stress. Oxidative stress is caused by high levels of toxic waste products known as reactive oxygen species or free-radicals. Oxidative stress can damage our cells, membranes, lipids, proteins and DNA, and is very common in aging. Glutathione is a natural antioxidant. Glutathione is made every day inside our cells and it works by protecting cells from harmful oxidative stress. However, in older people, glutathione levels are very low and the harmful oxidative stress is very high. GlyNAC supplementation corrects glutathione deficiency and lowers oxidative stress in older humans back to youthful levels, thereby solving both problems.

Sekhar believes that the restoration of mitochondrial health and correction of oxidative stress with GlyNAC supplementation are two powerful reasons which help explain why so many other age-related defects improve. It also accounts for the wide spectrum of health benefits.

Taking GlyNAC is not the same as taking glutathione: Introducing the Power of 3

It is really important to understand that this trial supplemented GlyNAC, and did not supplement glutathione, says Sekhar. This is because our body does not get its glutathione from food, but the body has to make its own glutathione every day. All our organs maintain different levels of glutathione in a delicate balance that favors health. Too little glutathione cannot fight the harmful oxidative stress, and too much glutathione could lead to harmful reductive stress, said Sekhar. This is why GlyNAC is a natural solution for correcting glutathione deficiency, because it provides the raw materials to help cells to make their own glutathione in just the right amount. We have seen that this repeatedly in all our prior studies supplementing GlyNAC, including this trial.

One of the intriguing questions from this trial is why so many improvements occur toward promoting health. We believe that this is due to the combined effort of three separate components glycine, cysteine (from NAC) and glutathione, and not just due to glutathione itself. Glycine and cysteine are both very important for cellular health on their own, and GlyNAC provides both. Glycine and cysteine are building blocks to form glutathione, which also has health benefits. We believe that the improvements in this trial and in our previous studies are the result of the combined effects of glycine and NAC and glutathione, and we refer to this combination as the Power of 3, said Sekhar.

GlyNAC improves several aging hallmarks in agingThe population of older adults is expected to exceed 2.1 billion by 2050, according to the World Health Organization. This predicted increase in the older human population will result in a rise of the need for healthcare and will intensify the stress on healthcare systems around the world. To understand what causes unhealthy aging, scientific research has identified nine aging hallmarks that represent specific defects that are believed to contribute to health decline while aging.

It is believed that correcting aging hallmarks could help people age in a healthier way, Sekhar said. However, we do not fully understand why these aging hallmarks occur in the first place, and therefore there have been no proven solutions via human randomized clinical trials to improve or correct aging hallmarks in aging humans.

The aging hallmarks that improved are mitochondrial dysfunction, altered intercellular communication, nutrient sensing, loss of proteostasis, genomic instability, cellular senescence and stem cell fatigue. The study participants were instructed not to change their usual diet or physical activity; therefore, nothing changed except for the GlyNAC supplementation. This tells us that benefits were due to GlyNAC supplementation. But we were really surprised to see so many aging hallmarks improve. This level of improvement offers clues as to how and why these aging hallmarks may be connected to one another, says Sekhar.

GlyNAC improves muscle strength in aging

GlyNAC supplementation improved muscle strength in the upper and lower extremity and a trend toward increased exercise capacity. These findings could have additional implications for improving the health of older humans, especially in terms of being able to be more physically active, said Sekhar.

This study was effort intensive and took many years to complete. I take this opportunity to thank all my co-investigators, nursing staff, and everyone who helped with this trial. I especially thank all the trial participants who volunteered to participate in this research, Sekhar said.

Sekhar led the study team consisting of Premranjan Kumar, Chun Liu, James Suliburk, Jean W. Hsu, Raja Muthupillai, Farook Jahoor, Charles G. Minard and George E. Taffet, all at Baylor College of Medicine. For this trial, Sekhar received funding support from the National Institutes of Health/National Institute of Aging, and philanthropic support from the McNair Medical Institute at the Robert and Janice McNair Foundation in Houston, TX.

Baylor College of Medicine holds a patent on GlyNAC, which has been licensed to Nestl Health Science. GlyNAC is marketed in the United States by Nestl Health Science under the nameCelltrientTM Cellular Protect. Nestl Health Science did not provide financial or material support for this research work.

As he moves forward, Sekhar plans to expand on his work to understand more about the health benefits of GlyNAC supplementation on cells, tissues and organs of the body. He plans on seeking funding to conduct larger clinical trials in more typical older humans to increase our understanding of how GlyNAC could improve health in aging. Additionally, as reported in their previously published exploratory study, Sekhars group found that GlyNAC supplementation in older humans could improve memory and cognition. He has studied this further in aged mice and found that GlyNAC supplementation appears to correct multiple age-related declines directly in the brain, and was associated with improvements in memory and brain health a report on these emerging new and exciting findings is in development.

The Journals of Gerontology Series A

Randomized controlled/clinical trial

People

Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial

17-Aug-2022

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GlyNAC supplementation reverses mitochondrial dysfunction, oxidative stress and aging hallmarks to boost strength and promote health in aging humans -...

BOSTON Researchers at Massachusetts General Hospital (MGH), published a new paper in Cell Reports Medicine demonstrating the protective potential of multiple doses of the Bacillus Calmette-Guerin (BCG) vaccine against COVID-19 and other infectious diseases.

In a double-blind, placebo-controlled study of patients with type 1 diabetes conducted at the start of the pandemic (before COVID-specific vaccines were available), the researchers found that 12.5% of placebo-treated individuals and 1% of BCG-treated individuals met criteria for confirmed COVID-19, yielding a vaccine effectiveness of 92%.

The BCG-vaccinated group also displayed protective effects against other infectious diseases, including fewer symptoms, lesser severity and fewer infectious disease events per patient. No BCG-related systemic adverse events occurred.

BCGs broad-based infection protection suggests that, in addition to COVID-19, may potentially provide protection against new SARS-CoV-2 variants and other pathogens.

The researchers are hoping the results will spur a larger scale study of the effects of the BCG vaccine in patients with type 1 diabetes, considered among the most vulnerable groups to COVID-19.

The BCG vaccine is an avirulent tuberculosis strainMycobacterium bovishistorically given to protect against tuberculosis and, since its introduction in 1921, has been the most widely administered vaccine in the history of medicine.

Considered to be extremely safe, BCG is on the World Health Organizations List of Essential Medicines and is given to roughly 100 million children per year globally. BCG is also one of the most affordable medicines, costing less than a dollar a dose in many parts of the world.

Multiple studies have shown that adults with type 1 diabetes who are diagnosed with COVID-19 are at increased risk of severe illness.

We found that three doses of BCG administered prior to the start of the pandemic prevented infection and limited severe symptoms from COVID-19 and other infectious diseases.

Unlike the antigen-specific vaccines currently in use to prevent COVID-19, BCGs mechanism of action is not limited to a specific virus or infection, says Denise Faustman, MD, PhD, director of theImmunobiology Laboratoryat Massachusetts General Hospital.

The participants in the COVID trial had previously enrolled in a clinical trial testing the effectiveness of the BCG vaccine for type 1 diabetes. Participants in the test group had received multiple vaccinations prior to the onset of the pandemic in early 2020.

This data set is unique and exciting because the patients were all vaccinated with multiple doses of BCG prior to the onset of the epidemic. Prior to the trial they had no known exposure to tuberculosis or prior BCG vaccination. This eliminates the major confounding factors that have limited other trials.

The results support the idea that BCG needs time to have a clinical effect, but its effects may then be very lasting and durable saysHazel Dockrell, London School of Hygiene & Tropical Medicine, an infectious diseases expert who was not officially involved in the study.

The 144 adult type diabetics (96 BGC treated and 48 placebo) analyzed in the COVID-19 trial were part of an ongoing Phase IIb clinical trial testing BCG as a treatment for adults with established type 1 diabetes. Patients were followed for COVID-19 related outcomes for 15 months.

Outcomes for the COVID-19 trial included: COVID-19 infection rate, COVID-19 related symptoms, reduction overall infections disease and SARS-CoV-2 antibody-level presence and intensity. The type 1 diabetes outcomes were not unblinded as part of this study and will be unblinded at the completion of the trial in 2023.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. TheMass General Research Instituteconducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #5 in theU.S. News & World Reportlist of Americas Best Hospitals.

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Randomized controlled/clinical trial

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Multiple BCG vaccinations for prevention of COVID-19 and other infectious diseases in Type 1 diabetes

15-Aug-2022

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Multiple shots of the BCG vaccine protect type 1 diabetics from COVID-19 - EurekAlert