Posted on Diabetes, Exercise

Researchers shed light on how exercise preserves physical fitness during ageing

Autism and exercise

Proven to protect against a wide array of diseases, exercise may be the most powerful anti-aging intervention known to science. However, while physical activity can improve health during aging, its beneficial effects inevitably decline. The cellular mechanisms underlying the relationship among exercise, fitness and aging remain poorly understood.  

In a paper published in the Proceedings of the National Academy of Sciences, researchers at Joslin Diabetes Center investigated the role of one cellular mechanism in improving physical fitness by exercise training and identified one anti-aging intervention that delayed the declines that occur with aging in the model organism. Together, the scientists’ findings open the door to new strategies for promoting muscle function during aging.  

“Exercise has been widely employed to improve quality of life and to protect against degenerative diseases, and in humans, a long-term exercise regimen reduces overall mortality,” said co-corresponding author T. Keith Blackwell, MD, PhD, a senior investigator and section head of Islet Cell and Regenerative Biology at Joslin. “Our data identify an essential mediator of exercise responsiveness and an entry point for interventions to maintain muscle function during aging.” 

That essential mediator is the cycle of fragmentation and repair of the mitochondria, the specialized structures, or organelles, inside every cell responsible for producing energy. Mitochondrial function is critical to health, and disruption of mitochondrial dynamics  the cycle of repairing dysfunctional mitochondria and restoring the connectivity among the energy-producing organelles — has been linked to the development and progression of chronic, age-related diseases, such as heart disease and type 2 diabetes.  

“As we perceive that our muscles undergo a pattern of fatigue and restoration after an exercise session, they are undergoing this mitochondrial dynamic cycle,” said Blackwell, who is also acting section head of Immunobiology at Joslin. “In this process, muscles manage the aftermath of the metabolic demand of exercise and restore their functional capability.” 

Blackwell and colleagues — including co-corresponding author Julio Cesar Batista Ferreira, PhD, Institute of Biomedical Sciences, University of Sao Paulo — investigated the role of mitochondrial dynamics during exercise in the model organism C. elegans, a simple, well-studied microscopic worm species frequently used in metabolic and aging research. 

Recording wild type C. elegans worms as they swam or crawled, the investigators observed a typical age-related decline in physical fitness over the animals’ 15 days of adulthood. The scientists also showed a significant and progressive shift toward fragmented and/or disorganized mitochondria in the aging animals. For example, they observed in young worms on day 1 of adulthood, a single bout of exercise induced fatigue after one hour. The 60-minute session also caused an increase in mitochondrial fragmentation in the animals’ muscle cells, but a period of 24 hours was sufficient to restore both performance and mitochondrial function.  

In older (day 5 and day 10) worms, the animals’ performance did not return to baseline within 24 hours. Likewise, the older animals’ mitochondria underwent a cycle of fragmentation and repair, but the network reorganization that occurred was reduced compared to that of the younger animals. 

“We determined that a single exercise session induces a cycle of fatigue and physical fitness recovery that is paralleled by a cycle of the mitochondrial network rebuilding,” said first author Juliane Cruz Campos, a postdoctoral fellow at Joslin Diabetes Center. “Aging dampened the extent to which this occurred and induced a parallel decline in physical fitness. That suggested that mitochondrial dynamics might be important for maintaining physical fitness and possibly for physical fitness to be enhanced by a bout of exercise.”  

In a second set of experiments, the scientists allowed wild type worms to swim for one hour per day for 10 consecutive days, starting at the onset of adulthood. The team found that — as in people — the long-term training program significantly improved the animals’ middle-aged fitness at day 10, and mitigated the impairment of mitochondrial dynamics typically seen during aging.  

Finally, the researchers tested known, lifespan-extending interventions for their ability to improve exercise capacity during aging. Worms with increased AMPK — a molecule that is a key regulator of energy during exercise which also promotes remodeling of mitochondrial morphology and metabolism — exhibited improved physical fitness. They also demonstrated maintenance of, but not enhancement of, exercise performance during aging. Worms engineered to lack AMPK exhibited reduced physical fitness during aging as well as impairment of the recovery cycle. They also did not receive the age-delaying benefits of exercise over the course of the lifespan.  

“An important goal of the aging field is to identify interventions that not only extend lifespan but also enhance health and quality of life,” said Blackwell, who is also a professor of genetics at Harvard Medical School. “In aging humans a decline in muscle function and exercise tolerance is a major concern that leads to substantial morbidity. Our data point towards potentially fruitful intervention points for forestalling this decline — most likely along with other aspects of aging. It will be of great interest to determine how mitochondrial network plasticity influences physical fitness along with longevity and aging-associated diseases in humans.” 

Posted on Multiple Sclerosis

Researchers develop a tool to investigate rare, previously inaccessible cells that play a crucial role in multiple sclerosis

Stem cells and multiple sclerosis
Cells and multiple sclerosis


Rare cell types can have an undue influence on human health. Previous research has suggested that a subset of astrocytes—star-shaped cells in the brain and spinal cord—may be responsible for multiple sclerosis (MS), a disease in which the immune system attacks the covering that protects nerves. But finding these rare cells is no easy task—to pinpoint them, investigators need to identify unique surface markers that can distinguish these culprit cells from others. Single-cell RNA sequencing can help find them, even in the absence of distinguishing surface marker, but this technique can become extremely expensive. To address this problem, a team led by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, developed FIND-seq,
which combines nucleic acid cytometry, microfluidics, and droplet sorting to isolate and analyze rare cells of interest based on the expression of mRNA biomarkers detected by digital droplet PCR. Using this method, the team analyzed in great detail a population of astrocytes that drives central nervous system inflammation and neurodegeneration. When used in combination with other tools, FIND-seq identified signaling pathways controlled by the mineralocorticoid receptor NR3C2 and the nuclear receptor corepressor 2 that play important roles in the development of pathogenic astrocytes in mice and humans. In another study, researchers used FIND-seq to identify mechanisms used by HIV to “hide” in immune cells in patients treated with anti-retroviral therapies.

“These findings identify novel targets for therapeutic intervention in neurologic diseases such as MS,” said corresponding author Francisco Quintana, PhD, of the BWH Department of Neurology. The team is working to develop novel small molecules which could be used to target this pathway therapeutically.

Posted on Diabetes

Gut bacteria may play a role in diabetes

One type of bacteria found in the gut may contribute to the development of Type 2 diabetes, while another may protect from the disease, according to early results from an ongoing, prospective study led by investigators at Cedars-Sinai. 

The study, published in the peer-reviewed journal Diabetes, found people with higher levels of a bacterium called Coprococcus tended to have higher insulin sensitivity, while those whose microbiomes had higher levels of the bacterium Flavonifractor tended to have lower insulin sensitivity. 

For years, investigators have sought to understand why people develop diabetes by studying the composition of the microbiome, which is a collection of microorganisms that include fungi, bacteria and viruses that live in the digestive tract. The microbiome is thought to be affected by medications and diet. Studies have also found that people who don’t process insulin properly have lower levels of a certain type of bacteria that produce a type of fatty acid called butyrate. 

Mark Goodarzi, MD, PhD, the director of the Endocrine Genetics Laboratory at Cedars-Sinai, is leading an ongoing study that is following and observing people at risk for diabetes to learn whether those with lower levels of these bacteria develop the disease. 

“The big question we’re hoping to address is: Did the microbiome differences cause the diabetes, or did the diabetes cause the microbiome differences?”said Goodarzi, who is the senior author of the study and principal investigator of the multicenter study called Microbiome and Insulin Longitudinal Evaluation Study (MILES). 

Investigators involved in MILES have been collecting information from participating Black and non-Hispanic white adults between 40 and 80 years of age since 2018. An earlier cohort study from the MILES trial found that birth by cesarean section is associated with a higher risk for developing prediabetes and diabetes.

For the most recent study to come out of this ongoing trial, investigators analyzed data from 352 people without known diabetes who were recruited from the Wake Forest Baptist Health System in Winston-Salem, North Carolina.

Study participants were asked to attend three clinic visits and collect stool samples prior to the visits. Investigators analyzed data collected at the first visit. They conducted genetic sequencing on the stool samples, for example, to study the participants’ microbiomes, and specifically look for bacteria that earlier studies have found to be associated with insulin resistance. Each participant also filled out a diet questionnaire and took an oral glucose tolerance test, which was used to determine ability to process glucose.

Investigators found 28 people had oral glucose tolerance results that met the criteria for diabetes. They also found that 135 people had prediabetes, a condition in which a person’s blood-sugar levels are higher than normal but not high enough to meet the definition of diabetes. 

The research team analyzed associations between 36 butyrate-producing bacteria found in the stool samples and a person’s ability to maintain normal levels of insulin. They controlled for factors that could also contribute to a person’s diabetes risk, such as age, sex, body mass index and race. Coprococcus and related bacteria formed a network of bacteria with beneficial effects on insulin sensitivity. Despite being a producer of butyrate, Flavonifractor was associated with insulin resistance; prior work by others have found higher levels of Flavonifractor in the stool of people with diabetes. 

Investigators are continuing to study samples from patients who participated in this study to learn how insulin production and the composition of the microbiome change over time. They also plan to study how diet may affect the bacterial balance of the microbiome. 

Goodarzi emphasized, however, that it is too early to know how people can change their microbiome to reduce their diabetes risk.

“As far as the idea of taking probiotics, that would really be somewhat experimental,” said Goodarzi, who is also the Eris M. Field Chair in Diabetes Research at Cedars-Sinai. “We need more research to identify the specific bacteria that we need to be modulating to prevent or treat diabetes, but it’s coming, probably in the next five to 10 years.”

Posted on Diabetes, Obesity, Weight Loss

Time-restricted eating reshapes gene expression throughout the body.

Science image


Time-restricted eating reshapes gene expression throughout the body. In this illustration, the Ferris wheel displays the interconnected organ systems working smoothly during time-restricted eating, represented by the clock in the middle CREDIT Salk Institute

Numerous studies have shown the health benefits of time-restricted eating, including an increase in life span in laboratory studies, and practices like intermittent fasting, a hot topic in the wellness industry. However, how it affects the body on the molecular level and how those changes interact across multiple organ systems has not been well understood. Now, Salk scientists show in mice how time-restricted eating influences gene expression across more than 22 regions of the body and brain. Gene expression is the process through which genes are activated and responds to their environment by creating proteins.

The findings, published in Cell Metabolism on January 3, 2023, have implications for many health conditions where time-restricted eating has shown potential benefits, including diabetes, heart disease, hypertension, and cancer.

“We found that there is a system-wide, molecular impact of time-restricted eating in mice,” says Professor Satchidananda Panda, senior author and holder of the Rita and Richard Atkinson Chair at Salk. “Our results open the door for looking more closely at how this nutritional intervention activates genes involved in specific diseases, such as cancer.”

For the study, two groups of mice were fed the same high-calorie diet. One group was given free access to food. The other group was restricted to eating within a feeding window of nine hours each day. After seven weeks, tissue samples were collected from 22 organ groups and the brain at different times of the day or night and analyzed for genetic changes. Samples included tissues from the liver, stomach, lungs, heart, adrenal gland, hypothalamus, different parts of the kidney and intestine, and different areas of the brain.

The authors found that 70 per cent of mouse genes respond to time-restricted eating.

“By changing the timing of food, we were able to change the gene expression not just in the gut or in the liver, but also in thousands of genes in the brain,” says Panda. 

Nearly 40 per cent of genes in the adrenal gland, hypothalamus, and pancreas were affected by time-restricted eating. These organs are essential for hormonal regulation. Hormones coordinate functions in different body and brain parts, and hormonal imbalance is implicated in many diseases, from diabetes to stress disorders. The results offer guidance on how time-restricted eating may help manage these diseases.

Interestingly, not all sections of the digestive tract were affected equally. While genes involved in the upper two portions of the small intestine—the duodenum and jejunum—were activated by time-restricted eating, the ileum, at the lower end of the small intestine, was not. This finding could open a new line of research to study how jobs with shiftwork, which disrupt our 24-hour biological clock (called the circadian rhythm) impact digestive diseases and cancers. Previous research by Panda’s team showed that time-restricted eating improved the health of firefighters, who are typically shifting workers.

The researchers also found that time-restricted eating aligned the circadian rhythms of multiple body organs.

“Circadian rhythms are everywhere in every cell,” says Panda. “We found that time-restricted eating synchronized the circadian rhythms to have two major waves: one during fasting and another just after eating. We suspect this allows the body to coordinate different processes.”

Next, Panda’s team will take a closer look at the effects of time-restricted eating on specific conditions or systems implicated in the study, such as atherosclerosis, which is a hardening of the arteries that is often a precursor to heart disease and stroke, as well as chronic kidney disease.

Posted on Rheumatoid arthritis

A promising drug delivery method could replace injections with pills


For chronic conditions such as rheumatoid arthritis, treatment often involves lifelong injections. Fear of needles, injection-associated infection and pain are responsible for patients skipping doses, which encourages the development of new delivery strategies that combine efficacy with limited side effects to treat patients adequately.

Researchers at Baylor College of Medicine and collaborating institutions have explored a better way of delivering medications that does not require injections but could be as easy as swallowing a pill. The study appears in the Proceedings of the National Academy of Sciences.

“People don’t like to have injections for the rest of their lives,” said co-corresponding author Dr. Christine Beeton, professor of integrative physiology at Baylor. “In the current work, we explored the possibility of using the probiotic bacteria Lactobacillus reuteri as a novel oral drug delivery platform to treat rheumatoid arthritis in an animal model.”

Previous work from the Beeton lab had shown that a peptide, or short protein, derived from sea anemone toxin effectively and safely reduces disease severity in rat models of rheumatoid arthritis and patients with plaque psoriasis. “However, peptide treatment requires repeated injections, reducing patient compliance, and direct oral delivery of the peptide has low efficacy,” Beeton said.

Beeton joined forces with Dr. Robert A. Britton, professor of molecular virology and microbiology and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. The Britton lab has developed the tools and expertise to genetically modify probiotic bacteria to produce and release compounds. In the current study, the team bioengineered the probiotic L. reuteri to secrete peptide ShK-235 derived from sea anemone toxin.

They chose L. reuteri because these bacteria are indigenous to human and other animal guts. It is one of the lactic acid bacteria groups that has long been used as a cell factory in the food industry and is recognized as safe by the U.S. Food and Drug Administration. L. reuteri has an excellent safety profile in infants, children, adults and even in an immunosuppressed population.

“The results are encouraging,” Beeton said. “Daily delivery of these peptide-secreting bacteria, called LrS235, dramatically reduced clinical signs of disease, including joint inflammation, cartilage destruction and bone damage in an animal model of rheumatoid arthritis.”

The researchers followed bacteria LrS235 and the peptide ShK-235 it secretes inside the animal model. They found that after feeding rats live LrS235 that release ShK-235, they could detect ShK-235 into the blood circulation.

“Another reason we chose L. reuteri is that these bacteria do not remain in the gut permanently. They are removed as the gut regularly renews its inner surface layer to which the bacteria attach,” Beeton said. “This opens the possibility for regulating treatment administration.”

More research is needed to bring this novel drug delivery system into the clinic, but the researchers anticipate that it could make treatment easier for patients in the future. “These bacteria could be stored in capsules that can be kept on the kitchen counter,” Beeton said. “A patient could take the capsules when on vacation without the need of refrigeration or carrying needles and continue treatment without the inconvenience of daily injections.”

The findings provide an alternative delivery strategy for peptide-based drugs and suggest that such techniques and principles can be applied to a broader range of drugs and the treatment of chronic inflammatory diseases.