Publisher Health

Why do cells, and by extension humans, age? The answer may have a lot to do with mitochondria, the organelles that supply cells with energy. Though that idea is not new, direct evidence in human cells had been lacking. Until now.
In a study published Jan. 12 in Communications Biology, a team led by Columbia University researchers has discovered that human cells with impaired mitochondria respond by kicking into higher gear and expending more energy. While this adaptation — called hypermetabolism — enhances the cells’ short-term survival, it comes at a high cost: a dramatic increase in the rate at which the cells age.
“The findings were made in cells from patients with rare mitochondrial diseases, yet they may also have relevance for other conditions that affect mitochondria, including neurodegenerative diseases, inflammatory conditions, and infections,” says principal investigator Martin Picard, PhD, associate professor of behavioral medicine (in psychiatry and neurology) at Columbia University Vagelos College of Physicians and Surgeons.
“In addition, hypermetabolism may be a key reason why most cells deteriorate as we get older.”
Hypermetabolic cells age faster
It was generally assumed that mitochondrial defects (which impair the conversion of food sources into usable energy) would force cells to slow their metabolic rate in an effort to conserve energy. However, by analyzing metabolic activity and energy consumption in cells from patients with mitochondrial diseases, the researchers found that cells with impaired mitochondria double their energy expenditure. Moreover, re-analyzing data from hundreds of patients with different mitochondrial diseases showed that mitochondrial defects also increase the energetic cost of living at the whole-body level.

Although this energy boost keeps cells running, it also degrades the cell’s telomeres (caps that protect the ends of our chromosomes) and activates stress responses and inflammation. The net effect accelerates biological aging.
“When cells expend more energy to make proteins and other substances essential for short-term survival, they’re likely stealing resources from processes that ensure long-term survival, like maintaining telomeres,” says Gabriel Sturm, a graduate student and lead author on this study.
Hypermetabolism, fatigue, and aging
This hypermetabolic state could explain why people with mitochondrial diseases experience fatigue and exercise intolerance, among other symptoms. “To make up for the extra energy use in your cells, your body ‘tells’ you not to overexert yourself, to conserve energy. We likely see the same dynamic as people age and their vitality diminishes,” Picard says.
The study doesn’t point to any new remedies for patients with mitochondrial diseases, which are currently not treatable, but it does reinforce the current recommendations for patients to move more. “That may seem counterintuitive, since if you’re more active, you’re going to expend more energy and possibly make your symptoms worse,” Sturm says. “But exercise is known to increase the efficiency of an organism. An individual who runs, for example, uses less energy to sustain basic bodily processes than someone who is not physically active.”
Improving organismal efficiency, which would lower energy use in the cells and improve fatigue and other symptoms, may partially explain the health benefits of exercise in patients with mitochondrial diseases and otherwise healthy people.
In their search for new treatments for mitochondrial diseases, researchers should focus on hypermetabolism, Picard says. “Although mitochondrial defects do impair the ability of cells to produce energy, energy deficiency may not be the primary disease initiator. Our study shows these defects increase energy consumption. To move the needle therapeutically, we may need to target hypermetabolism. We need more research to know if that would work.”
Hypermetabolism is also common to other diseases. If increased cellular energy expenditure plays a causal role in driving the aging process, targeting hypermetabolism may be a way to improve fatigue, improve people’s quality of life, or even to slow biological aging.
The research was supported by grants from the National Institutes of Health (R01AG066828), the Baszucki Brain Research Fund, the J. Willard and Alice S. Marriott Foundation, Muscular Dystrophy Association, Nicholas Nunno Foundation, the JDF Fund for Mitochondrial Research, and the Shuman Mitochondrial Disease Fund.

Epilepsy is present in 4% of the population, and is among the most common brain disorders in children. Modern medicine can prevent most seizure recurrences, but approximately 20% of patients do not respond to treatment.
In these cases, the reason may originate in patches of damaged or abnormal brain tissue known as “malformations of cortical development” (MCD), which results in a diverse group of neurodevelopment disorders. Surgical resection or removal of the patch can cure the seizures, and epilepsy surgery to improve neurological outcomes is now a key part of the modern medical armamentarium, but what causes the patches has largely remained a mystery.
Writing in the January 12, 2023 issue of Nature Genetics, researchers at University of California San Diego School of Medicine and Rady Children’s Institute for Genomic Medicine, collaborating with an international consortium of more than 20 children’s hospitals worldwide, report a significant breakthrough in understanding the genetic causes of MCD.
Members of the Focal Cortical Dysplasia Neurogenetics Consortium investigated 283 brain resections from children across a range of MCD types, with parental consent, looking for potential genetic causes. Because most brain tissue in these children is normal, the scientists focused on mutations present in a small subset of brain cells, a phenomenon termed genetic somatic mosaicism.
“This was a decade-long journey, bringing specialists together from around the world, to recruit patients for this study,” said senior study author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine. “Until recently, most hospitals did not study resected brain tissue for genetic causes. The consortium organized a biobank to store tissue for high-throughput mosaicism analysis.”
Previous research by Gleeson and colleagues had shown that genetic somatic mosaicism in the mTOR signaling pathway was a contributing factor, said co-first author Changuk Chung, PhD, a postdoctoral fellow in the Gleeson lab.

“But most patients remain undiagnosed, which hinders treatment. We tested for hidden mutations, detectable only by greatly expanding the cohort size and improving methods so that the results could be meaningful. We collaborated to solve technical and logistical bottlenecks. The pieces fell into place, but it took 10 years.”
The team conducted intensive genomic discovery using state-of-art somatic mosaic algorithms developed by the National Institutes of Health-sponsored Brain Somatic Mosaicism Network, of which UC San Diego is a member.
“We tried our best to detect mutations in as little as 1 percent of cells,” said co-first author Xiaoxu Yang, PhD, a postdoctoral scholar in Gleeson’s lab. “Initially we failed. To solve these problems, we needed to develop novel artificial intelligence methods to overcome barriers in sensitivity and specificity.”
The team ultimately identified 69 different genes carrying somatic brain mutations, the majority of which have never previously reported in MCD.
“We can draw parallels with the cancer field because these mutations disrupt cellular function and need to be resected,” said co-first author Chung. “However, unlike cancer cells, brain cells mostly do not divide so these cells misbehave by stimulating epileptic seizures. The question that arose was whether the newly found gene mutations were sufficient to cause MCD disease.”
Gleeson said the scientists found that the genes converged on calcium signaling, gene expression and synaptic functions, and noted that when the mutations were introduced into a mouse model, abnormalities similar to those seen in patients were observed. The study authors suggest the findings could be used to improve diagnosis and develop cures for MCD disease.
“The MCD genes in patient brains have demonstrated critical roles during cortical development,” said Gleeson. “These findings could lead to new molecular classifications for MCD, and ultimately to personalized therapies for epilepsy.”

The male reproductive system serves as a hotspot for the emergence of new genes. Perhaps that explains why more new mutations are inherited from fathers than from mothers. It doesn’t, however, clarify why older fathers pass on more mutations than younger ones do. The mechanisms that might underlie these well-documented trends have long remained a mystery. Now, a new study in the journal Nature Ecology & Evolution by Rockefeller University scientists describes why older male fruit flies are more likely to pass mutations onto their offspring, potentially shining a light on inherited-disease risk in humans.
Researchers in Li Zhao’s lab studied mutations that occur during the production of sperm from germline cells, known as spermatogenesis. They found that mutations are common in the testes of both young and old fruit flies, but more abundant in older flies from the outset. Moreover, many of these mutations seem to be removed in younger fruit flies during spermatogenesis by the body’s genomic repair mechanisms — but they fail to be fixed in the testes of older flies.
“We were trying to test whether the older germline is less efficient at mutation repair, or whether the older germline just starts out more mutated,” says first author Evan Witt, a former graduate student in the lab and now a computational biologist at Biomarin Pharmaceuticals. “Our results indicate that it’s actually both. At every stage of spermatogenesis, there are more mutations per RNA molecule in older flies than in younger flies.”
Self-care at the genetic level
Genomes keep themselves tidy using a handful of repair mechanisms. When it comes to testes, they have to work overtime; testes have the highest rate of gene expression of any organ. Moreover, genes that are highly expressed in spermatogenesis tend to have fewer mutations than those that are not. This sounds counterintuitive, but it makes sense: One theory to explain why the testes express so many genes holds that it might be a sort of genomic surveillance mechanism — a way to reveal, and then weed out, problematic mutations.
But when it comes to older sperm, the researchers found, the weed-whacker apparently sputters out. Previous research suggests that a faulty transcription-coupled repair mechanism, which only fixes transcribed genes, could be to blame.

Inherited or new mutations?
To get these results, scientists in the Laboratory of Evolutionary Genetics and Genomics did single-cell sequencing on the RNA from the testes of about 300 fruit flies, roughly half of them young (48 hours old) and half old (25 days old), advancing a line of inquiry they began in 2019. In order to understand whether the mutations they detected were somatic, or inherited from the flies’ parents, or de novo — arising in the individual fly’s germline — they then sequenced the genome of each fly. They were able to document that each mutation was a true original. “We can directly say this mutation was not present in the DNA of that same fly in its somatic cells,” says Witt. “We know that it’s a de novo mutation.”
This unconventional approach — inferring genomic mutations from single-cell RNA sequencing and then comparing them to the genomic data — allowed the researchers to match mutations to the cell type in which they occurred. “It’s a good way to compare mutational load between cell types, because you can follow them throughout spermatogenesis,” Witt says.
The human connection
The next step is to expand the analysis to more age groups of flies and test whether or not this transcription repair mechanism can occur — and if it does, identify the pathways responsible, Witt says. “What genes,” he wonders, “are really driving the difference between old and young flies in terms of mutation repair?”
Because fruit flies have a high reproductive rate, investigating their mutation patterns can offer new insights into the effect of new mutations in human health and evolution, says Zhao.
Witt adds, “It’s largely unknown whether a more mutated male germline is more or less fertile than a less mutated one. There’s not been very much research on it except for at a population level. And if people inherit more mutations from aging fathers, that increases the odds of de novo genetic disorders or certain types of cancers.”

A growing pile of evidence indicates that the tens of trillions of microbes that normally live in our intestines — the so-called gut microbiome — have far-reaching effects on how our bodies function. Members of this microbial community produce vitamins, help us digest food, prevent the overgrowth of harmful bacteria and regulate the immune system, among other benefits. Now, a new study suggests that the gut microbiome also plays a key role in the health of our brains, according to researchers from Washington University School of Medicine in St. Louis.
The study, in mice, found that gut bacteria — partly by producing compounds such as short chain fatty acids — affect the behavior of immune cells throughout the body, including ones in the brain that can damage brain tissue and exacerbate neurodegeneration in conditions such as Alzheimer’s disease. The findings, published Jan. 13 in the journal Science, open up the possibility of reshaping the gut microbiome as a way to prevent or treat neurodegeneration.
“We gave young mice antibiotics for just a week, and we saw a permanent change in their gut microbiomes, their immune responses, and how much neurodegeneration related to a protein called tau they experienced with age,” said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. “What’s exciting is that manipulating the gut microbiome could be a way to have an effect on the brain without putting anything directly into the brain.”
Evidence is accumulating that the gut microbiomes in people with Alzheimer’s disease can differ from those of healthy people. But it isn’t clear whether these differences are the cause or the result of the disease — or both — and what effect altering the microbiome might have on the course of the disease.
To determine whether the gut microbiome may be playing a causal role, the researchers altered the gut microbiomes of mice predisposed to develop Alzheimer’s-like brain damage and cognitive impairment. The mice were genetically modified to express a mutant form of the human brain protein tau, which builds up and causes damage to neurons and atrophy of their brains by 9 months of age. They also carried a variant of the human APOE gene, a major genetic risk factor for Alzheimer’s. People with one copy of the APOE4 variant are three to four times more likely to develop the disease than people with the more common APOE3variant.
Along with Holtzman, the research team included gut microbiome expert and co-author Jeffrey I. Gordon, MD, the Dr. Robert J. Glaser Distinguished University Professor and director of the Edison Family Center for Genome Sciences & Systems Biology; first author Dong-Oh Seo, PhD, an instructor in neurology; and co-author Sangram S. Sisodia, PhD, a professor of neurobiology at the University of Chicago.

When such genetically modified mice were raised under sterile conditions from birth, they did not acquire gut microbiomes, and their brains showed much less damage at 40 weeks of age than the brains of mice harboring normal mouse microbiomes.
When such mice were raised under normal, nonsterile conditions, they developed normal microbiomes. A course of antibiotics at 2 weeks of age, however, permanently changed the composition of bacteria in their microbiomes. For male mice, it also reduced the amount of brain damage evident at 40 weeks of age. The protective effects of the microbiome shifts were more pronounced in male mice carrying the APOE3 variant than in those with the high-risk APOE4variant, possibly because the deleterious effects of APOE4canceled out some of the protection, the researchers said. Antibiotic treatment had no significant effect on neurodegeneration in female mice.
“We already know, from studies of brain tumors, normal brain development and related topics, that immune cells in male and female brains respond very differently to stimuli,” Holtzman said. “So it’s not terribly surprising that when we manipulated the microbiome we saw a sex difference in response, although it is hard to say what exactly this means for men and women living with Alzheimer’s disease and related disorders.”
Further experiments linked three specific short-chain fatty acids — compounds produced by certain types of gut bacteria as products of their metabolism — to neurodegeneration. All three of these fatty acids were scarce in mice with gut microbiomes altered by antibiotic treatment, and undetectable in mice without gut microbiomes.
These short-chain fatty acids appeared to trigger neurodegeneration by activating immune cells in the bloodstream, which in turn somehow activated immune cells in the brain to damage brain tissue. When middle-aged mice without microbiomes were fed the three short-chain fatty acids, their brain immune cells became more reactive, and their brains showed more signs of tau-linked damage.
“This study may offer important insights into how the microbiome influences tau-mediated neurodegeneration, and suggests therapies that alter gut microbes may affect the onset or progression of neurodegenerative disorders,” said Linda McGavern, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which provided some of the funding for the study.
The findings suggest a new approach to preventing and treating neurodegenerative diseases by modifying the gut microbiome with antibiotics, probiotics, specialized diets or other means.
“What I want to know is, if you took mice genetically destined to develop neurodegenerative disease, and you manipulated the microbiome just before the animals start showing signs of damage, could you slow or prevent neurodegeneration?” Holtzman asked. “That would be the equivalent of starting treatment in a person in late middle age who is still cognitively normal but on the verge of developing impairments. If we could start a treatment in these types of genetically sensitized adult animal models before neurodegeneration first becomes apparent, and show that it worked, that could be the kind of thing we could test in people.”

Researchers at La Jolla Institute for Immunology (LJI) have at last uncovered how an enzyme called O-GlcNAc transferase (OGT) keeps cells healthy. Their findings, published in the Proceedings of the National Academies of Sciences, reveals a key aspect of cellular biology and may lead to important medical advances.
“Many diseases are related to OGT function,” says LJI Instructor Xiang Li, Ph.D., who served as first author for the new study. “For example, many studies have shown abnormal OGT function in cancer, diabetes, and cardiovascular disease.”
The new study, spearheaded by Li and co-led by LJI Professor Anjana Rao, Ph.D., and LJI Assistant Professor Samuel Myers, Ph.D., is the first to show that OGT controls cell survival by regulating a critical protein called mTOR.
Cells rely on mTOR to keep their mitochondrial powerhouses working. Without functional mTOR, cells fail at almost all their basic functions, from protein synthesis to cell proliferation. It’s not surprising that mTOR dysfunction is also a hallmark of many diseases.
“OGT is important for every cell in the body,” explains Myers. “Thanks to this research, we now have a model we can use for future studies into what each part of OGT does.”
The one and only OGT
OGT is an enzyme called a transferase. This type of enzyme carries out a job called glycosylation, where sugar molecules are added to recently synthesized proteins. OGT is unique among transferases because it modifies proteins within cells, rather than proteins on the cell surface or secreted proteins.

In fact, OGT’s job of glycosylation is so important that embryonic cells will die without it. But until now, scientists were in the dark as to why.
As Myers explains, the essential nature of OGT is what makes it so hard to study. Scientists usually study enzymes and other proteins by developing cells that lack the genes for those proteins. They generate the new, dysfunctional cells and then investigate how things have gone wrong.
But with OGT, that kind of experiment would be over before it even began. Because there is only one OGT, scientists haven’t been able to delete it or reduce its function without simply killing the very cells they need to study. “We knew OGT was essential for cell survival, but for more than 20 years we didn’t know why,” says Li.
For the new study, Li was able to get around that problem by using an inducible system to delete the OGT gene. He worked with mouse embryonic stem cells and then used an inducible version of a protein known as Cre to delete the gene for OGT. This meant that the cells could grow normally until the scientists decided to activate the process, after which cells that had lost the OGT gene began to stop proliferating and die.
The team found that deleting the gene for OGT led to an abnormal increase in the function of a key enzyme called mTOR that regulates cell metabolism. Deleting the gene for OGT also fueled an essential but potentially dangerous process in cells called mitochondrial oxidative phosphorylation.

Why is mitochondrial oxidative phosphorylation so dangerous? This process in cells is part of a delicate pathway that allows cells to produce ATP (the molecule that powers a cell). ATP can be produced by glycolysis as well as by mitochondrial oxidative phosphorylation, and disturbing this balance can have devastating consequences for cells.
Fortunately, OGT safeguards mTOR activity and mitochondrial fitness by keeping protein synthesis running smoothly and regulating amino acid levels within cells. Importantly, the researchers discovered the same protective role for OGT in CD8+ T cells, which suggests the enzyme works the same way across mammalian cell types, not just in mouse embryonic stem cells.
Researchers to the rescue
Even the dysfunctional cells lacking OGT weren’t doomed forever. The scientists were able to “rescue” the dysfunctional cells using a new cutting-edge technology for gene editing called CRISPR/Cas9.
By asking whether a second gene in the mouse embryonic stem cells would restore the growth of cells lacking OGT, Li found that mTOR and mitochondrial oxidative phosphorylation were hyperactivated in cells lacking OGT, and the cells could be rescued by damping down their function.
This is good news for scientists hoping to learn more about OGT’s role in the body. “Now that we can delete the gene for OGT while keeping cells alive, we can try restoring just pieces of OGT to learn more about how OGT works to keep cells alive,” says Myers.
Li says his new discovery may allow researchers to further study the role of OGT and potentially find therapeutic targets to counteract abnormal activity. “In the future, we hope our research could help shed light on issues related to dysfunctional OGT in cancer and other diseases,” Li says.

Immune checkpoint inhibitors are important medications that boost the immune system’s response against various cancers, but some patients’ cancer cells are unaffected by the drugs or develop resistance during treatment.
Researchers led by a team at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham, and the Broad Institute of MIT and Harvard recently identified an immune evasion gene that is turned on in some of these cells, and they found that silencing the gene enhanced the cells’ susceptibility to immunotherapy.
The gene codes for a protein called TANK-binding kinase 1 (TBK1), a multi-functional enzyme with an established role in coordinating innate immune responses to viruses and other invading pathogens.
In a study published in Nature led by senior authors Russell W. Jenkins, MD, PhD, an investigator in the Center for Cancer Research at MGH and an Assistant Professor of Medicine at Harvard Medical School, and Associate Member of the Broad Institute, and Robert T. Manguso, PhD, also an investigator in the Center for Cancer Research at MGH, Assistant Professor of Medicine at Harvard Medical School, and Associate Member of the Broad Institute, found that deleting the TBK1 gene sensitizes tumors to immune attack.
Also, in mouse models of cancer, treatment with a pharmacologic inhibitor that blocks the activity of the TBK1 protein overcame tumors’ resistance to immunotherapy, without causing weight loss or other signs of systemic toxicity. This strategy also worked in novel patient-based tumor models, including what are called patient-derived organotypic tumor spheroids, or PDOTS, which are “living biopsies” that contain a patient’s own cancer cells and immune cells.
Mechanistically, the team found that blocking TBK1 augments the response to immunotherapy by sensitizing tumor cells to the effects of immune molecules including tumor necrosis factor and interferon.
“It’s counterintuitive that TBK1 loss would enhance immunotherapy, because this protein is generally thought to promote inflammation. Turning it off should make a tumor less sensitive to treatment, not more” says Manguso, who also co-leads the Tumor Immunotherapy Discovery Engine project at Broad. “However, we found that turning off TBK1 reprograms tumor cells’ response to immune signals called cytokines, causing them to die. This latter effect turns out to be critical in this context.”
“Our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy,” says Jenkins. “Our work also provides a framework to evaluate other potential immune evasion targets across multiple model systems using a combination of genetic and pharmacologic tools.”
Additional MGH and Broad Institute co-authors include Yi Sun, Or-yam Revach, Seth Anderson, Emily Kessler, Clara Wolfe, Anne Jenney, Thomas G.R. Davis, Sarah Kim, Amina Fu, Xiang Ma, Jia Gwee, Payal Tiwari, Peter Du, Princy Sindurakar, Jun Tian, Arnav Mehta, Moshe Sade-Feldman, Thomas LaSalle, Tatyana Sharova, Hongyan Xie, William A. Michaud, Rodrigo Saad-Beretta, Kathleen B. Yates, Arvin Iracheta-Vellve, Mack Y. Su, Angelina M. Cicerchia, Martin Q. Rasmussen, Samuel J. Klempner, Dejan Juric, Sara I. Pai, David M. Miller, Jonathan H. Chen, Karin Pelka, Dennie T. Frederick, Debattama R. Sen, David E. Fisher, Ryan B. Corcoran, Nir Hacohen, Keith T. Flaherty, and Genevieve M. Boland.
This work was supported by funding from the National Institute of Health/National Cancer Institute (NIH K08CA226391 (R.W.J.), Melanoma Research Alliance Young Investigator Award Karin Grunebaum Cancer Research Foundation Faculty Research Fellowship (R.W.J.), Termeer Early Career Fellowship in Systems Pharmacology (R.W.J.), and a generous gift from Steven B. And Joan W. Belkin.

Mounting evidence suggests that prolonged sitting — a staple of modern-day life — is hazardous to your health, even if you exercise regularly. Based on these findings, doctors advise all adults to sit less and move more.
But how often do we need to get up from our chairs? And for how long?
Few studies have compared multiple options to come up with the answer most office workers want: What is the least amount of activity needed to counteract the health impact of a workday filled with sitting?
Now a study by Columbia University exercise physiologists has an answer: just five minutes of walking every half hour during periods of prolonged sitting can offset some of the most harmful effects.
The study, led by Keith Diaz, PhD, associate professor of behavioral medicine at Columbia University Vagelos College of Physicians and Surgeons, was published online in Medicine & Science in Sports & Exercise, the journal of the American College of Sports Medicine.
Unlike other studies that test one or two activity options, Diaz’s study tested five different exercise “snacks”: one minute of walking after every 30 minutes of sitting, one minute after 60 minutes; five minutes every 30; five minutes every 60; and no walking.

“If we hadn’t compared multiple options and varied the frequency and duration of the exercise, we would have only been able to provide people with our best guesses of the optimal routine,” Diaz says.
Each of the 11 adults who participated in the study came to Diaz’s laboratory, where participants sat in an ergonomic chair for eight hours, rising only for their prescribed exercise snack of treadmill walking or a bathroom break. Researchers kept an eye on each participant to ensure they did not over- or under-exercise and periodically measured the participants’ blood pressure and blood sugar (key indicators of cardiovascular health). Participants were allowed to work on a laptop, read, and use their phones during the sessions and were provided standardized meals.
The optimal amount of movement, the researchers found, was five minutes of walking every 30 minutes. This was the only amount that significantly lowered both blood sugar and blood pressure. In addition, this walking regimen had a dramatic effect on how the participants responded to large meals, reducing blood sugar spikes by 58% compared with sitting all day.
Taking a walking break every 30 minutes for one minute also provided modest benefits for blood sugar levels throughout the day, while walking every 60 minutes (either for one minute or five minutes) provided no benefit.
All amounts of walking significantly reduced blood pressure by 4 to 5 mmHg compared with sitting all day. “This is a sizeable decrease, comparable to the reduction you would expect from exercising daily for six months,” says Diaz.

The researchers also periodically measured participants’ levels of mood, fatigue, and cognitive performance during the testing. All walking regimens, except walking one minute every hour, led to significant decreases in fatigue and significant improvements in mood. None of the walking regimens influenced cognition.
“The effects on mood and fatigue are important,” Diaz says. “People tend to repeat behaviors that make them feel good and that are enjoyable.”
The Columbia researchers are currently testing 25 different doses of walking on health outcomes and testing a wider variety of people: Participants in the current study were in their 40s, 50s, and 60s, and most did not have diabetes or high blood pressure.
“What we know now is that for optimal health, you need to move regularly at work, in addition to a daily exercise routine,” says Diaz. “While that may sound impractical, our findings show that even small amounts of walking spread through the work day can significantly lower your risk of heart disease and other chronic illnesses.”
More information
Keith Diaz, PhD, is the Florence Irving Associate Professor of Behavioral Medicine in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons and director of the Exercise Testing Laboratory in the Center for Behavioral Cardiovascular Health.
The study is titled “Breaking Up Prolonged Sitting to Improve Cardiometabolic Risk: Dose-Response Analysis of a Randomized Cross-Over Trial.”
The other contributors are Andrea T. Duran(Columbia), Ciaran P. Friel (Feinstein Institutes of Medical Research, Northwell Health), Maria A. Serafini (Columbia), Ipek Ensari(Columbia), and Ying Kuen Cheung(Columbia).
The research was supported by the Robert N. Butler Columbia Aging Center of Columbia University. The authors report no conflicts of interest.

One of the most important classes of human enzymes are protein kinases — signaling molecules that regulate nearly all cellular activities, including growth, cell division, and metabolism. Dysfunction in these cellular pathways can lead to a variety of diseases, particularly cancer.
Identifying the protein kinases involved in cellular dysfunction and cancer development could yield many new drug targets, but for the vast majority of these kinases, scientists don’t have a clear picture of which cellular pathways they are involved in, or what their substrates are.
“We have a lot of sequencing data for cancer genomes, but what we’re missing is the large-scale study of signaling pathway and protein kinase activation states in cancer. If we had that information, we would have a much better idea of how to drug particular tumors,” says Michael Yaffe, who is a David H. Koch Professor of Science at MIT, the director of the MIT Center for Precision Cancer Medicine, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the new study.
Yaffe and other researchers have now created a comprehensive atlas of more than 300 of the protein kinases found in human cells, and identified which proteins they likely target and control. This information could help scientists decipher many cellular signaling pathways, and help them to discover what happens to those pathways when cells become cancerous or are treated with specific drugs.
Lewis Cantley, a professor of cell biology at Harvard Medical School and Dana Farber Cancer Institute, and Benjamin Turk, an associate professor of pharmacology at Yale School of Medicine, are also senior authors of the paper, which appears today in Nature. The paper’s lead authors are Jared Johnson, an instructor in pharmacology at Weill Cornell Medical College, and Tomer Yaron, a graduate student at Weill Cornell Medical College.
“A Rosetta stone”
The human genome includes more than 500 protein kinases, which activate or deactivate other proteins by tagging them with a chemical modification known as a phosphate group. For most of these kinases, the proteins they target are unknown, although research into kinases such as MEK and RAF, which are both involved in cellular pathways that control growth, has led to new cancer drugs that inhibit those kinases.

To identify additional pathways that are dysregulated in cancer cells, researchers rely on phosphoproteomics using mass spectrometry — a technique that separates molecules based on their mass and charge — to discover proteins that are more highly phosphorylated in cancer cells or healthy cells. However, until now, there has been no easy way to interrogate the mass spectrometry data to determine which protein kinases are responsible for phosphorylating those proteins. Because of that, it has remained unknown how those proteins are regulated or misregulated in disease.
“For most of the phosphopeptides that are measured, we don’t know where they fit in a signaling pathway. We don’t have a Rosetta stone that you could use to look at these peptides and say, this is the pathway that the data is telling us about,” Yaffe says. “The reason for this is that for most protein kinases, we don’t know what their substrates are.”
Twenty-five years ago, while a postdoc in Cantley’s lab, Yaffe began studying the role of protein kinases in signaling pathways. Turk joined the lab shortly after, and the three have since spent decades studying these enzymes in their own research groups.
“This is a collaboration that began when Ben and I were in Lew’s lab 25 years ago, and now it’s all finally really coming together, driven in large part by what the lead authors, Jared and Tomer, did,” Yaffe says.
In this study, the researchers analyzed two classes of kinases — serine kinases and threonine kinases, which make up about 85 percent of the protein kinases in the human body — based on what type of structural motif they put phosphate groups onto.

Working with a library of peptides that Cantley and Turk had previously created to search for motifs that kinases interact with, the researchers measured how the peptides interacted with all 303 of the known serine and threonine kinases. Using a computational model to analyze the interactions they observed, the researchers were able to identify the kinases capable of phosphorylating every one of the 90,000 known phosphorylation sites that have been reported in human cells, for those two classes of kinases.
To their surprise, the researchers found that many kinases with very different amino acid sequences have evolved to bind and phosphorylate the same motifs on their substrates. They also showed that about half of the kinases they studied target one of three major classes of motifs, while the remaining half are specific to one of about a dozen smaller classes.
Decoding networks
This new kinase atlas can help researchers identify signaling pathways that differ between normal and cancerous cells, or between treated and untreated cancer cells, Yaffe says.
“This atlas of kinase motifs now lets us decode signaling networks,” he says. “We can look at all those phosphorylated peptides, and we can map them back onto a specific kinase.”
To demonstrate this approach, the researchers analyzed cells treated with an anticancer drug that inhibits a kinase called Plk1, which regulates cell division. When they analyzed the expression of phosphorylated proteins, they found that many of those affected were controlled by Plk1, as they expected. To their surprise, they also discovered that this treatment increased the activity of two kinases that are involved in the cellular response to DNA damage.
Yaffe’s lab is now interested in using this atlas to try to find other dysfunctional signaling pathways that drive cancer development, particularly in certain types of cancer for which no genetic drivers have been found.
“We can now use phosphoproteomics to say, maybe in this patient’s tumor, these pathways are upregulated or these pathways are downregulated,” he says. “It’s likely to identify signaling pathways that drive cancer in conditions where it isn’t obvious what the genetics that drives the cancer are.”
The research was funded by the Leukemia and Lymphoma Society, the National Institutes of Health, Cancer Research UK, the Brain Tumour Charity, the Charles and Marjorie Holloway foundation, the MIT Center for Precision Cancer Medicine, and the Koch Institute Support (core) grant from the National Cancer Institute.

In two studies using nationally representative data from the National Health and Aging Trends Study gathered on thousands of Americans, researchers from the Johns Hopkins University School of Medicine and Bloomberg School of Public Health have significantly added to evidence that social isolation is a substantial risk factor for dementia in community-dwelling (noninstitutionalized) older adults, and identified technology as an effective way to intervene.
Collectively, the studies do not establish a direct cause and effect between dementia and social isolation, defined as lack of social contact and interactions with people on a regular basis. But, the researchers say, the studies strengthen observations that such isolation increases the risk of dementia, and suggest that relatively simple efforts to increase social support of older adults — such as texting and use of email — may reduce that risk. In the United States, an estimated 1 in 4 people over age 65 experience social isolation, according to the National Institute on Aging.
“Social connections matter for our cognitive health, and it is potentially easily modifiable for older adults without the use of medication,” says Thomas Cudjoe, M.D., M.P.H., assistant professor of medicine at the Johns Hopkins University School of Medicine and senior author of both of the new studies.
The first study, described Jan. 11 in the Journal of the American Geriatrics Society, used data collected on a group of 5,022 Medicare beneficiaries for a long-term study known as the National Health and Aging Trends, which began in 2011. All participants were 65 or older, and were asked to complete an annual two-hour, in-person interview to assess cognitive function, health status and overall well-being.
At the initial interview, 23% of the 5,022 participants were socially isolated and showed no signs of dementia. However, by the end of this nine-year study, 21% of the total sample of participants had developed dementia. The researchers concluded that risk of developing dementia over nine years was 27% higher among socially isolated older adults compared with older adults who were not socially isolated.
“Socially isolated older adults have smaller social networks, live alone and have limited participation in social activities,” says Alison Huang, Ph.D., M.P.H., senior research associate at the Johns Hopkins Bloomberg School of Public Health. “One possible explanation is that having fewer opportunities to socialize with others decreases cognitive engagement as well, potentially contributing to increased risk of dementia.”
Interventions to reduce that risk are possible, according to results of the second study, published Dec. 15 in the Journal of the American Geriatrics Society. Specifically, researchers found the use of communications technology such as telephone and email lowered the risk for social isolation.
Researchers for the second study used data from participants in the same National Health and Aging Trends study, and found that more than 70% of people age 65 and up who were not socially isolated at their initial appointment had a working cellphone and/or computer, and regularly used email or texting to initiate and respond to others. Over the four-year research period for this second study, older adults who had access to such technology consistently showed a 31% lower risk for social isolation than the rest of the cohort.
“Basic communications technology is a great tool to combat social isolation,” says Mfon Umoh, M.D., Ph.D., postdoctoral fellow in geriatric medicine at the Johns Hopkins University School of Medicine. “This study shows that access and use of simple technologies are important factors that protect older adults against social isolation, which is associated with significant health risks. This is encouraging because it means simple interventions may be meaningful.”
Social isolation has gained significant attention in the past decade, especially due to restrictions implemented for the COVID-19 pandemic, but more work needs to be done to identify at-risk populations and create tools for providers and caregivers to minimize risk, the researchers say. Future research in this area should focus on increased risks based on biological sex, physical limitations, race and income level.
Other scientists who contributed to this research are Laura Prichett, Cynthia Boyd, David Roth, Tom Cidav, Shang-En Chung, Halima Amjad, and Roland Thorpe of the Johns Hopkins University School of Medicine and Bloomberg School of Public Health.
This research was funded by the Caryl & George Bernstein Human Aging Project, the Johns Hopkins University Center for Innovative Medicine, the National Center for Advancing Translational Sciences, the National Institute on Aging, the Secunda Family Foundation, the Patient-Centered Care for Older Adults with Multiple Chronic Conditions, and the National Institute on Minority Health and Health Disparities.

More than 2,500 genes exhibit significant sex differences in expression in mouse alveolar type II cells (AT2s), important for keeping the lungs functioning, potentially explaining sex biases in the prevalence and severity of lung diseases. In particular, very high numbers of X-linked genes escape transcriptional silencing in lung alveolar type 2 (AT2s) cells, researchers report January 12th in the journal Stem Cell Reports.
“Our study is the first to compare male and female AT2 cells for gene expression, and our findings suggest that there are likely sex differences in lung repair following viral-induced injury,” says co-senior author Montserrat Anguera, an associate professor at the University of Pennsylvania.
Sex differences exist for many lung diseases, but the mechanistic basis for this remains unclear. “We started this project during the beginning of the pandemic, because we were curious about the sex bias with COVID-19 disease, where more older men have increased morbidity, and wondered whether X-chromosome inactivation (XCI) might contribute to this sex bias,” Anguera says. “We realized that the SARS-CoV2 virus first encounters AT2 cells in the lung, and that the virus enters cells through the angiotensin-converting enzyme 2 (Ace2) receptor, which is located on the X chromosome.”
XCI is a process by which one of the copies of the X chromosome is inactivated in female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. XCI prevents female mammals from having twice as many X-chromosome gene products as males, who only possess a single copy of the X chromosome.
In the new study, Anguera and co-senior author Andrew Vaughan, an assistant professor at the University of Pennsylvania, investigated XCI maintenance and sex-specific gene expression profiles using male and female AT2s. The results showed that approximately 68% of expressed X-linked genes in mouse AT2s escape XCI. These genes include Ace2, which serves as the entry point into cells for SARS-CoV-2, but is also involved in lung repair.
There were genome-wide expression differences between male and female AT2s, possibly contributing to sex differences in lung injury and repair in multiple settings. Taken together, the findings demonstrate that AT2 cells have the highest levels of XCI escape for mouse cells reported to date and support a renewed focus on AT2s as a potential contributor to sex-biased differences in lung disease.
In addition, the results showed that AT2 cells, similar to immune cells, do not strictly follow the classic rules of XCI. “We were surprised to find that female AT2 cells lack canonical epigenetic modifications that are typically enriched on the inactive X as a result of XCI. These include the long noncoding RNA Xist and heterochromatic histone modifications H3K27me3 and H2AK119-ubiquitin,” Anguera says. “Because the inactive X in female AT2 cells has fewer epigenetic marks, this enables more gene expression chromosome wide, including the Ace2 gene.”
For now, it remains an open question whether ACE2 escapes XCI in human AT2 cells. to The authors say this is a likely scenario because there are significantly higher numbers of XCI escape genes in human cells compared to mouse cells.
Moving forward, the authors plan to investigate how expression from the inactive X in AT2 cells is affected by SARS-CoV2 infections. They also will continue to study how expression from the X chromosome is regulated in other cell types that do not exhibit conventional XCI maintenance. “Our findings open the door to future work investigating the genetic and epigenetic basis, residing within the X chromosome, of sex differences in immune responses to inhaled viruses,” Anguera says.