How dietary restriction slows brain aging and increases lifespan

 Restricting calories is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially in regard to how it protects the brain. Buck scientists have uncovered a role for a gene called OXR1 that is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain aging.

"When people restrict the amount of food that they eat, they typically think it might affect their digestive tract or fat buildup, but not necessarily about how it affects the brain," said Kenneth Wilson, Ph.D., Buck postdoc and first author of the study, published online on January 11, 2024 in Nature Communications. "As it turns out, this is a gene that is important in the brain."

The team additionally demonstrated a detailed cellular mechanism of how dietary restriction can delay aging and slow the progression of neurodegenerative diseases. The work, done in fruit flies and human cells, also identifies potential therapeutic targets to slow aging and age-related neurodegenerative diseases.

"We found a neuron-specific response that mediates the neuroprotection of dietary restriction," said Buck Professor Pankaj Kapahi , Ph.D., co-senior author of the study. "Strategies such as intermittent fasting or caloric restriction, which limit nutrients, may enhance levels of this gene to mediate its protective effects."

"The gene is an important brain resilience factor protecting against aging and neurological diseases," said Buck Professor Lisa Ellerby, Ph.D., co-senior author of the study.

Understanding variability in response to dietary restriction

Members of the team have previously shown mechanisms that improve lifespan and healthspan with dietary restriction, but there is so much variability in response to reduced calories across individuals and different tissues that it is clear there are many yet to be discovered processes in play. This project was started to understand why different people respond to diets in different ways.

The team began by scanning about 200 strains of flies with different genetic backgrounds. The flies were raised with two different diets, either with a normal diet or with dietary restriction, which was only 10% of normal nutrition. Researchers identified five genes which had specific variants that significantly affected longevity under dietary restriction. Of those, two had counterparts in human genetics.

The team chose one gene to explore thoroughly, called "mustard" (mtd) in fruit flies and "Oxidation Resistance 1" (OXR1) in humans and mice. The gene protects cells from oxidative damage, but the mechanism for how this gene functions was unclear. The loss of OXR1 in humans results in severe neurological defects and premature death. In mice, extra OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).

The link between brain aging, neurodegeneration and lifespan

To figure out how a gene that is active in neurons affects overall lifespan, the team did a series of in-depth tests. They found that OXR1 affects a complex called the retromer, which is a set of proteins necessary for recycling cellular proteins and lipids. "The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell," said Wilson. Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restriction, specifically Alzheimer's and Parkinson's diseases.

Overall, their results told the story of how dietary restriction slows brain aging by the action of mtd/OXR1 in maintaining the retromer. "This work shows that the retromer pathway, which is involved in reusing cellular proteins, has a key role in protecting neurons when nutrients are limited," said Kapahi. The team found that mtd/OXR1 preserves retromer function and is necessary for neuronal function, healthy brain aging, and lifespan extension seen with dietary restriction.

"Diet is influencing this gene. By eating less, you are actually enhancing this mechanism of proteins being sorted properly in your cells, because your cells are enhancing the expression of OXR1," said Wilson.

The team also found that boosting mtd in flies caused them to live longer, leading researchers to speculate that in humans excess expression of OXR1 might help extend lifespan. "Our next step is to identify specific compounds that increase the levels of OXR1 during aging to delay brain aging," said Ellerby.

"Hopefully from this we can get more of an idea of why our brains degenerate in the first place," said Wilson.

"Diet impacts all the processes in your body," he said. "I think this work supports efforts to follow a healthy diet, because what you eat is going to affect more than you know."

Journal Reference:

1. Kenneth A. Wilson, Sudipta Bar, Eric B. Dammer, Enrique M. Carrera, Brian A. Hodge, Tyler A. U. Hilsabeck, Joanna Bons, George W. Brownridge, Jennifer N. Beck, Jacob Rose, Melia Granath-Panelo, Christopher S. Nelson, Grace Qi, Akos A. Gerencser, Jianfeng Lan, Alexandra Afenjar, Geetanjali Chawla, Rachel B. Brem, Philippe M. Campeau, Hugo J. Bellen, Birgit Schilling, Nicholas T. Seyfried, Lisa M. Ellerby, Pankaj Kapahi. OXR1 maintains the retromer to delay brain aging under dietary restriction. Nature Communications, 2024; 15 (1) DOI: 10.1038/s41467-023-44343-3

https://www.sciencedaily.com/releases/2024/01/240111162625.htm

Oral Weight-Loss Drug Developer Kallyope Exploring IPO

Kallyope Inc., a US biotech that’s developing oral weight loss drugs, is exploring an initial public offering, according to people familiar with the matter, as the company seeks to capitalize on the investor frenzy around treatments for obesity.

The New York-based company is working with lead underwriter JPMorgan Chase & Co. on a potential listing for this year, said the people, who asked not to be identified because the matter is confidential.

https://www.bloomberg.com/news/articles/2024-01-23/oral-weight-loss-drug-developer-kallyope-is-said-to-explore-ipo

DC CVS closing in February after months of robberies leave shelves bare

 A CVS store in Columbia Heights that has been plagued by robberies is closing its doors after struggling with months of near-constant crime that left shelves empty. 

"We’ve made the difficult decision to close our store at 3031 14th St. NW in Columbia Heights on Feb. 29. All prescriptions will be transferred to the nearby CVS Pharmacy at 1755 Columbia Rd. NW. to ensure patients have uninterrupted access to pharmacy care," said in a statement to FOX 5.  

"Maintaining access to pharmacy services in the communities we serve is an important factor we consider when making store closure decisions. Other factors include local market dynamics, population shifts, a community’s store density, and ensuring there are other geographic access points to meet the needs of the community," the statement continued. 

They add that all employees at the store are being offered "comparable roles" within the company. 

FOX 5 spoke with staff at the Columbia Heights store back in October. They said dozens of kids were regularly going in to steal chips and drinks before school, after school, and late at night.

◀︎▶︎

Image 1 of 4 

▼

CVS store shelves bare after thieves repeatedly target robberies around delivery times, workers say

The employees also said the thieves were aware of when shipments were coming and targeted the store at those times. Some even alleged that street vendors were paying people to steal from the store so they could re-sell the goods. 

Street vendors do line 14th Street selling items like toothbrushes, men and women body wash, car fresheners, and laundry and cleaning supplies but their no evidence of where the goods came from.

A Five Below store in the same plaza as the CVS shut down for good on Jan. 14. 

The Columbia Heights Target has an armed guard at the entrance and a sign warning that minors must be accompanied by an adult.

As crime continues to impact the area, residents are wondering what, if anything, can put a stop to the thefts that are forcing businesses to close their doors.

https://www.fox5dc.com/news/columbia-heights-cvs-to-close-in-february-after-months-of-robberies-leave-shelves-bare

Study questions benefit of new Alzheimer's drug

 Last summer, the U.S. Food and Drug Administration fully approved the first drug shown to slow the progress of Alzheimer's. But new research from the University of Georgia suggests that patients and caregivers may not experience any benefit from the drug in their daily lives.

The drug, Leqembi, became eligible for coverage through Medicare, making it more affordable for the millions of Americans in the early stages of the disease. But experts remained skeptical that the drug provided enough benefit to justify the cost and potential harms of the drug.

A new study from UGA's Mark Ebell systematically reviewed 19 publications with more than 23,000 participants that evaluated eight monoclonal antibodies, including Leqembi. The paper, "Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for Treatment of Alzheimer Disease: A systematic Review and Meta-Analysis," is published in The Annals of Family Medicine.

"We focused very clearly on patient-centered outcomes," said Ebell, who is a physician and professor of epidemiology and biostatistics in UGA's College of Public Health. "We found that even after 18 to 24 months of treatment, the differences in function and cognition between treated and untreated patients were so small that a patient or their caregiver generally wouldn't notice the difference," said Ebell.

"For example, the Mini-Mental State test has 30 possible points, but the difference seen in the studies was less than a third of a point. To be noticeable to a patient or their family, that difference would have to be at least 1 to 3 points."

Ebell and his co-authors examined the drugs' effects on memory and life skills, such as the ability to dress and feed yourself, as well as reported side effects.

Overall, the researchers found that most studies showed that monoclonal antibody drugs led to statistically significant improvements in cognitive function, but none of the drugs showed clinically significant improvements in memory or behaviors.

The study suggests the drug's hefty cost, time burden, and potential side effects, which include brain swelling and brain bleeds, may not be worth the minimal benefit for most patients.

Doctors and patients are being sold the promise of new breakthrough treatment for Alzheimer's, Ebell said. But understanding the potential risks in contrast to limited benefits is critical for patients and their doctors to make informed decisions.

"The potential benefit always has to be weighed against any potential harms," said Ebell. "And it's not by any means a clear-cut choice."

More information: Mark H. Ebell et al, Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis, The Annals of Family Medicine (2024). DOI: 10.1370/afm.3050

https://medicalxpress.com/news/2024-01-benefit-alzheimer-drug.html

Few patients successfully treat their type 2 diabetes through weight loss: study

 A new study finds that very few patients diagnosed with type 2 diabetes are able to achieve normal blood glucose levels through weight loss alone. A team led by Andrea Luk of the Chinese University of Hong Kong, report these findings in the open access journal PLOS Medicine.

Clinical trials suggest that people with type 2 diabetes can control their blood glucose levels without medication if they lose weight and keep it off. However, it is unknown how many patients can achieve remission through weight loss alone under real-world conditions.

In the new study, researchers looked at 37,326 people in Hong Kong who were newly diagnosed with type 2 diabetes to see whether—and low long—patients could control the disease through weight loss.

The researchers discovered that only 6% of people achieved diabetes remission solely through weight loss by about eight years after diagnosis. For people who initially achieved remission, two-thirds had elevated blood glucose levels by three years after diagnosis.

These rates are significantly lower than in clinical trials, where remission occurred in up to 73% of patients at one year post-diagnosis. People with the greatest weight loss in the first year were most likely to have sustained remission.

The study shows that controlling type 2 diabetes through sustained weight loss is possible in real-world settings, but that few patients will achieve normal blood glucose levels through weight management alone, especially over the long-term. One reason for the discrepancy with clinical trials is that trial participants receive intensive lifestyle interventions, including holistic support for dietary changes, physical exercise and mental health.

The researchers conclude that patients should receive early weight management interventions as a way to increase the odds that they will achieve sustained remission. Furthermore, the data suggest that early weight management interventions increase the odds of sustained remission and that sustained lifestyle changes are likely to be paramount.

Luk adds, "Greater weight loss within the first year of diabetes diagnosis was associated with an increased likelihood of achieving diabetes remission. However, the incidence of diabetes remission was low with only 6% of people achieving remission over eight years, and half of those with initial remission returned to hyperglycemia within three years indicating poor sustainability of diabetes remission in real-world setting."

More information: Wu H, Yang A, Lau ESH, Zhang X, Fan B, Ma RCW, et al. (2024) 1-year weight change after diabetes diagnosis and long-term incidence and sustainability of remission of type 2 diabetes in real-world settings in Hong Kong: An observational cohort study, PLoS Medicine (2024). DOI: 10.1371/journal.pmed.1004327

https://medicalxpress.com/news/2024-01-patients-successfully-diabetes-weight-loss.html

Bladder cancer biotech CG Oncology ups share offering by 44% ahead of $289 million IPO

 CG Oncology, a Phase 3 biotech developing an oncolytic immunotherapy for bladder cancer, raised the proposed deal size for its upcoming IPO on Tuesday.

The Irvine, CA-based company now plans to raise $289 million by offering 17 million shares at a price range of $16 to $18. The company had previously filed to offer 11.8 million shares at the same range. At the midpoint, CG Oncology will raise 44% more in proceeds than previously anticipated.

CG Oncology's candidate cretostimogene is initially in development for the treatment of patients with high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) who are unresponsive to Bacillus Calmette Guerin (BCG) therapy, the current standard-of-care for high-risk NMIBC. The company is evaluating cretostimogene as a monotherapy in BOND-003, its ongoing Phase 3 trial in high-risk BCG-unresponsive NMIBC patients, and expects to report topline data by the end of 2024. If successful, CG Oncology believes that this trial could serve as the basis for a Biologics License Application submission to the FDA.

CG Oncology was founded in 2010 and plans to list on the Nasdaq under the symbol CGON. Morgan Stanley, Goldman Sachs, and Cantor Fitzgerald are the joint bookrunners on the deal. It is expected to price during the week of January 22, 2024.

Relevant Profile: CGON

https://www.renaissancecapital.com/IPO-Center/News/102891/Bladder-cancer-biotech-CG-Oncology-ups-share-offering-by-44-percent-ahead-o

Unemployment rises in nearly a third of US states in December

 Unemployment rates increased in 15 U.S. states in December, up by three from the prior month, but was unchanged in the majority of states and the District of Columbia, a report showed on Tuesday.

Nonfarm payroll employment levels, meanwhile, remained essentially unchanged in all states last month from November, according to Bureau of Labor Statistics data. From a year earlier, employment rose in 30 states while remaining essentially unchanged in 20 others and DC.

Massachusetts and Rhode Island experienced a 0.3 percentage point increase in unemployment, the greatest month-over-month rise among states. Minnesota's unemployment rate fell by 0.2 percentage point, the only state to experience a decrease.

Maryland and North Dakota had the lowest jobless rates at 1.9%. Nevada had the highest unemployment rate, remaining unchanged from November's 5.4%.

The national unemployment rate was unchanged at 3.7% in December, the report said. The economy added 216,000 jobs in December, up from November's 173,000 added.

Thirteen states and D.C. have unemployment rates at or above 4%, the highest count since December 2022. That includes three of six key battleground states in this year's presidential election: Michigan, Nevada and Arizona.

Nationally, the jobless rate remains near the lowest levels since the 1960s. That, along with job participation and wage growth are set to be key talking points in President Joe Biden's bid for re-election in what polls suggest will be a rematch with former President Donald Trump.

Biden needs to win the support of workers in swing states like Michigan. Last year he joined striking United Auto Workers members on the picket line in their walkouts against Ford, General Motors and Stellantis, the first for a sitting president, after pressure from Michigan Democrats.

For the week ended Jan. 10, Biden had a lead against Trump by 4 percentage points in the state, according to data compiled by polling analysis site 538.

https://finance.yahoo.com/news/unemployment-rose-nearly-third-u-171106791.html