The process of aging is often related to the onset of neurological symptoms such as cognitive decline, memory loss or mood disorders such as depression. Previous studies have shown that the growth factor GDF11, a protein found in blood, has a beneficial effect on olfactory perception and on the generation of new cells in the brains of aged mice. However, the mechanism of action of GDF11 in the brain has remained unknown.
Researchers from the Institut Pasteur, CNRS and Inserm have discovered that long-term administration of the GDF11 protein to aged mice improves their memory and significantly reduces behavioral disturbances related to depression, allowing them to return to a behavior similar to that seen in younger mice. The results of this study were published in the journalNature Agingon February 2, 2023.
The scientists conducted further studies in different aged mouse models or mouse models with depression-like behavioral disorders and in vitro neuronal cultures, which enabled them to identify the molecular mechanism of action of GDF11. They discovered that administration of GDF11 activates the natural process of intracellular cleaning, called "autophagy," in the brain and the elimination of senescent cells. The GDF11 protein thus indirectly increases cell turnover in the hippocampus and restores neuronal activity.
To better understand the link between depressive disorders and the GDF11 protein in humans, scientists from the Institut Pasteur, CNRS and Inserm, in collaboration with scientists from McMaster University, quantified the protein in the blood serum of an international cohort of young patients with major depressive disorder. They observed that GDF11 levels are significantly lower in these patients. Moreover, by measuring the levels of this protein at different stages, the scientists observed a fluctuation in the level depending on the depressive state.
"This work provides clinical evidence linking low blood levels of GDF11 to mood disorders in patients with depression," said Lida Katsimpardi, a researcher in the Institut Pasteur's Perception and Memory Unit, affiliated with Inserm at the Institut Necker-Enfants Malades, and co-last author of the study. "In the future, this molecule could be used as a biomarker to diagnose depressive episodes. It could also serve as a therapeutic molecule for the treatment of cognitive and affective disorders," she concludes.
More information: Carine Moigneu et al, Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy, Nature Aging (2023). DOI: 10.1038/s43587-022-00352-3
New evidence released today from a study of 31,245 patients already taking statin therapy indicates that inflammation may be a more powerful predictor of risk of future cardiovascular events—such as heart attack and stroke—than "bad" cholesterol.
Treatments that aggressively lower vascular inflammation need to be incorporated into daily practice if doctors are to maximizepatient outcomes, according to the study's corresponding author, Paul Ridker, MD, a preventive cardiologist at Brigham and Women's Hospital, a founding member of the Mass General Brigham health care system. Ridker presented the findings at the American College of Cardiology meeting in New Orleans. Results are published simultaneously inThe Lancet.
"The new data should be a wake-up call for preventive cardiologists and their patients," said Ridker. "Virtually all patients with or at risk for atherosclerotic disease are appropriately treated with aggressive statin therapy. Yet, in our study of patients already taking a statin, hsCRP—a measure of residual inflammatory risk—was a more powerful determinant of having a future heart attack or dying from cardiovascular disease than was LDL-cholesterol—a measure of residual cholesterol risk. The data are a powerful demonstration that to beat heart disease, we need to lower both cholesterol and inflammation, not just cholesterol alone."
Once a patient is on statin therapy, cardiologists typically describe two conditions: "residual cholesterol risk," which can be further reduced with additional lipid-lowering therapy, and "residual inflammatory risk," which can be further reduced with certain drugs that impact vascular inflammation. Whether clinicians should choose to focus on further lowering cholesterol or inflammation has been uncertain and controversial.
Ridker and colleagues examined data from three recently conducted clinical trials (PROMINENT, REDUCE-IT and STRENGTH) of patients with or at high risk for atherosclerotic disease to understand the relative importance of "residual inflammatory risk" as compared to "residual cholesterol risk" among contemporary statin-treated patients.
All patients were receiving aggressive guideline directed medical care including statins, usually at high doses. But cardiovascular event rates in all three trials approached 10 percent at five years. In all three trials, blood levels of high-sensitivity C-reactive protein (hs-CRP, a measure of vascular inflammation) were significantly associated with major adverse cardiovascular events (MACE), cardiovascular mortality and all-cause mortality.
Moreover, the researchers report that hs-CRP was a more potent predictor of future cardiovascular risk than LDL-cholesterol. For example, among aggressively treated patients already on higher intensity statins, the risks of cardiovascular death and all-cause mortality were more than twice as high among those with the highest levels of CRP when compared to those with the highest levels of cholesterol, differences that were highly statistically significant.
The data have immediate implications for patient care today and for future research, according to the authors.
"There is no doubt that lower is better for LDL-cholesterol and we need to aggressively reduce cholesterol whenever possible. But if cardiologists want to eliminate cardiovascular disease, they clearly must target inflammation as well," Ridker said.
Inflammation inhibition has been found in several clinical trials to reduce cardiovascular risk, yet uptake of anti-inflammatory therapy in daily practice has been limited. This has been particularly true for colchicine, an inexpensive anti-inflammatory therapy that reduced cardiovascular event rates in two major randomized trials with a benefit at least as large as that associated with much more expensive cholesterol-lowering drugs. Ridker notes the importance of weighing the potential benefits of anti-inflammatory agents, in addition to statin therapy and lifestyle modifications, to lower cardiovascular risk.
"Beyond statins and consideration of anti-inflammatory agents, physicians should not lose sight of diet, exercise, and smoking cessation, all of which lower vascular inflammation and save lives," Ridker said.
More information: Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials, The Lancet (2023). DOI: 10.1016/S0140-6736(23)00215-5
For people with alcohol use disorder (AUD), there is a constant, vicious cycle between changes to the brain and changes to behavior. AUD can alter signaling pathways in the brain; in turn, those changes can exacerbate drinking.
Now, scientists at Scripps Research have uncovered new details about the immune system's role in this cycle. They reported in the journal Brain, Behavior and Immunityon Feb. 28, 2023, that the immunesignaling moleculeinterleukin 1β (IL-1β) is present at higher levels in the brains of mice withalcohol dependence. In addition, the IL-1β pathway takes on a different role in these animals, causing inflammation in critical areas of the brain known to be involved in decision-making.
"These inflammatory changes to the brain could explain some of the risky decision-making and impulsivity we see in people with alcohol use disorder," says senior author Marisa Roberto, Ph.D., the Schimmel Family Chair of Molecular Medicine and a professor of neuroscience at Scripps Research. "In addition, our findings are incredibly exciting because they suggest a potential way to treat alcohol use disorder with existing anti-inflammatory drugs targeting the IL-1β pathway."
AUD is characterized by uncontrolled and compulsive drinking, and it encompasses a range of conditions including alcohol abuse, dependence and binge drinking. Researchers have previously discovered numerous links between the immune system and AUD—many of them centered around IL-1β. People with certain mutations in the gene that codes for the IL-1β molecule, for instance, are more prone to developing AUD. In addition, autopsies of people who had AUD have found higher levels of IL-1β in the brain.
"We suspected that IL-1β was playing a role in AUD, but the exact mechanisms in the brain have been unclear," says first author Florence Varodayan, Ph.D., an assistant professor at Binghamton University and former postdoctoral fellow in the Roberto lab.
In the new study, Roberto, Varodayan and their colleagues compared alcohol-dependent mice with animals drinking moderate or no alcohol at all. They discovered that the alcohol-dependent group had about twice as much IL-1β in the medial prefrontal cortex (mPFC), a part of the brain that plays a role in regulating emotions and behaviors.
The team then went on to show that IL-1β signaling in the alcohol-dependent group was not only increased, but also fundamentally different. In mice that had not been exposed to alcohol, as well as in mice that had drunk moderate amounts of alcohol, IL-1β activated an anti-inflammatory signaling pathway. In turn, this lowered levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), a signaling molecule known to regulate neural activity in the brain.
However, in alcohol-dependent mice, IL-1β instead activated pro-inflammatory signaling and boosted levels of GABA, likely contributing to some of the changes in brain activity associated with AUD. Notably, these changes in IL-1β signaling in the alcohol-dependent mice persisted even during alcohol withdrawal.
Drugs that block the activity of IL-1β are already approved by the U.S. Food and Drug Administration to treat rheumatoid arthritis and other inflammatory conditions. More work is needed to determine whether these existing drugs could have utility in treating AUD.
"We plan to follow up on this study with more work on exactly how targeting specific components of the IL-1β pathway might be useful in treating alcohol use disorder," says Roberto.
More information: F.P. Varodayan et al, Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice, Brain, Behavior, and Immunity (2023). DOI: 10.1016/j.bbi.2023.02.020
On an August evening in 2021, 24-year-old Dandre Johnson was gunned down as he stood on a South Bronx street. Seventeen-year-oldTyree Malonewas arrested and charged with the murder of Johnson.
Malone was no stranger to the criminal justice system or to guns.
According to reporting in The Post, Malone had at least three prior gun possession arrests within the previous year.
So why was this young and dangerous offender still on the streets?
Because that is the result the New York state Legislature wanted.
In 2017, with enthusiastic support from Gov. Andrew Cuomo, the Legislature passed the now infamous“Raise the Age” law that radically changed the scope of criminal and juvenile justice in New York.
Cuomo proudly announced, “At a time when President Trump and this federal government are taking us backward, New York is moving forward with bold criminal justice reform. By raising the age of criminal responsibility, New York is putting an end to an injustice that falls disproportionately on people of color and once again proving that we are the progressive beacon for the nation. In New York, we will never stop fighting for a more equal and more just society for all.”
Tyree Malone had at least three prior gun possession arrests within the previous year.
Unfortunately, not for Dandre Johnson.
Prior to the passage of RTA, most juvenile crime cases were heard by the state’s Family Court as juvenile delinquency cases.
Youth aged 7-15 years were tried before Family Court judges in “quasi criminal” proceedings that do not, legally, result in criminal “convictions” but are deemed “adjudications” of delinquency.
During the spiking crime wave in the 1970s, state law was amended to allow certain serious crimes like murder, rape, serious assaults and armed robbery to be handled in the criminal courts for 14- and 15-year-olds.
Those youth, designated “Juvenile Offenders,” are deemed criminally responsible and could be sentenced to incarceration in secure facilities specifically designed for teens.
Meanwhile, 16- and 17-year-old offenders were subject to the jurisdiction of the criminal courts for all crimes.
Innocent bystander Kyhara Tay, 11, was fatally shot during the incident.NYPD
Child advocacy groups and progressive politicians have long been lobbying to raise the age of criminal responsibility to 18 years and send all youth to the Family Court.
These advocates argued that adolescent brains had not yet fully developed and, therefore, young offenders should not be held criminally responsible for most crimes.
They further averred that only one other state besides New York treated 16- and 17-year-olds as criminal defendants.
The RTA law creates a new category of juvenile criminal, as well as a new court part: 16- and 17-year-olds arrested for felony offenses are now brought before a “Youth Part” in the criminal court as “Adolescent Offenders.”
This appearance before the special Youth Part is brief because the law presumes a prompt removal of the case to the Family Court for processing as a juvenile delinquent. Unless the prosecutor can demonstrate that the defendant caused (1) significant physical injury, (2) displayed a gun or deadly weapon (but not just possession), (3) committed an illegal sexual act, or provides the Court with “extraordinary circumstances,” the case — and the adolescent offender — are moved to the Family Court.
Gun possession cases must be removed to the Family Court absent any proof that the young offender displayed the firearm as part of a criminal act.Another incident, involves a 14-year-old boy, who had a .38 loaded gun at a Brooklyn high school.
But the new legislation provides no definitions for “extraordinary circumstances,” or “significant physical injury,” so prosecutors and judges have no way of knowing the standard for keeping a young felon in the criminal courts.
What is conspicuously absent from these conditions is any consideration for community safety.
In the fatal shooting of Dandre Johnson, the 17-year-old defendant was alleged to have had three prior gun possession charges within the past year.
Yet this fact was irrelevant to the drafters of the RTA law. Currently, gun possession cases must be removed to the Family Court absent any proof that the young offender displayed the firearm as part of a criminal act.
Removal to the Family Court, however, does not mean that the young offender will appear in a courtroom at all. Most of the youth do not get sent to court to be prosecuted, but rather they appear before the NYC Probation Service, in the Family Court, for “Adjustment Services.”
Adjustment diverts offenders away from the court system to community-based counseling and other social services.
In 2019-2021, approximately one-third of all probation intake cases were adjusted. Those cases were closed without any court action or record.
Whether the offender completes the adjustment program, or is sent back to the Family Court for prosecution, the youth’s records remain forever shrouded under a veil of confidentiality.
The Family Court Act specifically forbids any appearances or proceedings to be used at any time against the interests of the offender in any other court.
Teenagers under 18 such as Camrin Williams, 16, are responsible for between 15%-20% of NYC thefts.
So even if an adolescent offender appears on a new felony arrest, before the same Youth Court judge one month, one year — even one week — after the removal, information from the Family Court cannot be considered in determining whether the new arrest should remain in the criminal system.
In effect, the state Legislature has passed a law that ignores community safety in favor of keeping judges uninformed on the criminal histories of recidivist defendants.
The state Legislature’s commitment to hiding the histories of violent young offenders was made even more apparent when, as part of the RTA legislation, the victims of young offenders prosecuted by the Family Court are now forbidden from knowing the disposition of their own case.
Simply put, the state Legislature has decreed that you cannot know what happened to the person who mugged you.
How does this square with Gov. Cuomo’s promise that the RTA law made New York a “progressive beacon for the nation” assuring a “more just society for all?”
So, has the RTA lived up to any of its promises?
Yes and no. The law properly removes 16- and 17-year-old offenders from Riker’s Island and mandates that incarcerated offenders be housed in facilities designed for teens.
But these facilities will need expansion to accommodate the burgeoning crime wave in the wake of RTA’s passage.
According to NYPD data, teens under 18 years of age are responsible for between 15%-20% of NYC thefts despite the fact that 15– to 17-year-olds are only 5% of the city population.
But the real impact of the RTA is with guns. According to a seasoned Family Court prosecutor, “I have never seen so many guns.
And more troubling is the fast escalation of crime among those who are initially charged with firearms possession.
According to NYPD data, first reported by W. Dyer Halpern at the Manhattan Institute, in 2017, 4.4% of youths arrested for gun possession were involved in a shooting within one year of that first arrest.
In 2021, that rate more than tripled to 13.7%.
Offenders under 18 arrested for gun possession and involved in a shooting within the subsequent two years skyrocketed from 6.7% to 23.4% between 2017 and 2020.
Gun crime has increased 200%.
The police also disclosed that juveniles committed 48 shootings throughout the city in 2019. In 2020 that number jumped to 62 and last year, in 2022, that number reached 148.
NYPD also reports that in the year following the passage of RTA, 48% of 16-year-olds were rearrested.
That represented a 39% increase from the previous year.
Experts believe that gangs have younger members hold onto guns, knowing they can’t be prosecuted. By “Raising the Age,” legislators have lowered the age of the average hardened criminal.
The court results are also troubling.
The majority of 16- and 17-year-olds arrested for felonies have their cases transferred out of the criminal courts to the Family Court. In 2021 (the latest year for which data is available) 1,520 Adolescent Offenders appeared in Youth Parts; 1,331 of the 1,520 (88%) were removed to the Family Court for processing as juvenile delinquents.
Only 112 (7%) of the original 1,500+ felons were convicted of felony offenses before the criminal courts.
How many of these transferred cases were armed or violent felony offenses?
We will never know. Thanks to an overabundance of confidentiality and the RTA, the public and crime victims cannot be told.
Can changes be made to the RTA to get better results?
Of course.
The Legislature needs to loosen its ideological grip and make sure that judges and prosecutors can make informed decisions about who should remain in the criminal justice system and who is best suited for juvenile processing.
Community safety needs to be a consistent factor when considering any transfer to the juvenile system.
Further, information from the Family Court and from probation needs to be made available to the Youth Part so that informed decisions are made that meet the best needs of the public and the youth.
Democrats from Gov. Hochul to President Biden claim that guns are the biggest threat to safety, yet the fact that gun possession results in almost no punishment for someone under 18 in New York suggests that they don’t want to help solve the problem.
Last week, the violent crime wave in Chicago cost an incumbent mayor her job.
Her loss is a historic event. New York state legislators should remember that the voters are watching.
Attorney Peter Reinharz was the Chief Prosecutor in New York City’s Family Courts from 1987-2002. Andrew Stein, a Democrat, served as New York City Council president, 1986-94.
