How To Reverse Aging in the Brain

The aging global population is the greatest challenge faced by 21st-century healthcare systems. Even COVID-19 is, in a sense, a disease of aging. The risk of death from the virus roughly doubles for every nine years of life, a pattern that is almost identical to a host of other illnesses. But why are old people vulnerable to so many different things?

It turns out that a major hallmark of the aging process in many mammals is inflammation. By that, I don’t mean intense local response we typically associate with an infected wound, but a low grade, grinding, inflammatory background noise that grows louder the longer we live. This “inflammaging” has been shown to contribute to the development of atherosclerosis (the buildup of fat in arteries), diabetes, high blood pressure , frailty, cancer and cognitive decline.

Now a new study published in Nature reveals that microglia — a type of white blood cells found in the brain — are extremely vulnerable to changes in the levels of a major inflammatory molecule called prostaglandin E2 (PGE2). The team found that exposure to this molecule badly affected the ability of microglia and related cells to generate energy and carry out normal cellular processes.

Fortunately, the researchers found that these effects occurred only because of PGE2’s interaction with one specific receptor on the microglia. By disrupting it, they were able to normalize cellular energy production and reduce brain inflammation. The result was improved cognition in aged mice. This offers hope that the cognitive impairment associated with growing older is a transient state we can potentially fix, rather than the inevitable consequence of aging of the brain. Levels of PGE2 increase as mammals age for a variety of reasons — one of which is probably the increasing number of cells in different tissues entering a state termed cellular senescence. This means they become dysfunctional and can cause damage to tissue by releasing PGE2 and other inflammatory molecules.

But the researchers also found that macrophages — another type of white blood cells related to microglia — from people over the age of 65 made significantly more PGE2 than those from young people. Intriguingly, exposing these white blood cells to PGE2 suppressed the ability of their mitochondria — the nearest thing a cell has to batteries — to function. This meant that the entire pattern of energy generation and cellular behavior was disrupted.

Although PGE2 exerts its effects on cells through a range of receptors, the team were able to narrow down the effect to interaction with just one type (the “EP2 receptor” on the macrophages). They showed this by treating white blood cells, grown in the lab, with drugs that either turned this receptor on or off. When the receptor was turned on, cells acted as if they had been exposed to PGE2. But when they were treated with the drugs that turned it off, they recovered. That’s all fine, but it was done in a petri dish. What would happen in an intact body?

The researchers took genetically modified animals in which the EP2 receptor had been removed and allowed them to grow old. They then tested their learning and memory by looking at their ability to navigate mazes (something of a cliche for researchers) and their behavior in an “object location test.” This test is a bit like someone secretly entering your house, swapping your ornaments around on the mantelpiece and then sneaking out again. The better the memory, the longer the subject will spend looking suspiciously at the new arrangement, wondering why it has changed.

It turned out that the old genetically modified mice learned and remembered just as well as their young counterparts. These effects could be duplicated in normal old mice by giving them one of the drugs that could turn the EP2 receptor off for one month. So it seems possible that inhibiting the interaction of PGE2 with this particular receptor may represent a new approach to treating late-life cognitive disorders.

Source: https://www.theconversation.com/

Priming The Immune System To Attack Cancer

Immunotherapies, such as checkpoint inhibitor drugs, have made worlds of difference for the treatment of cancer. Most clinicians and scientists understand these drugs to act on what’s known as the adaptive immune system, the T cells and B cells that respond to specific threats to the body.

New research from an international team co-led by George Hajishengallis of the University of Pennsylvania School of Dental Medicine suggests that the innate immune system, which responds more generally to bodily invaders, may be an important yet overlooked component of immunotherapy’s success.

Their work, published in the journal Cell, found that “training” the innate immune system with β-glucan, a compound derived from fungus, inspired the production of innate immune cells, specifically neutrophils, that were primed to prevent or attack tumors in an animal model.

The focus in immunotherapy is placed on adaptive immunity, like checkpoint inhibitors inhibit the interaction between cancer cells and T cells,” says Hajishengallis, a co-senior author on the work. “The innate immune cells, or myeloid cells, have not been considered so important. Yet our work suggests the myeloid cells can play a critical role in regulating tumor behavior.”

The current study builds on earlier work published in Cell by Hajishengallis and a multi-institutional team of collaborators, which showed that trained immunity, elicited through exposure to exposure to the fungus-derived compound β-glucan, could improve immune recovery after chemotherapy in a mouse model.

In that previous study, the researchers also showed that the “memory” of the innate immune system was held within the bone marrow, in hematopoetic stem cells that serve as precursors of myeloid cells, such as neutrophils, monocytes, and macrophages.

Source: https://penntoday.upenn.edu/

Antibodies + Immunotherapy Result In Complete Elimination Of Tumors

Immunotherapy has revolutionized cancer treatment by stimulating the patient’s own immune system to attack cancer cells, yielding remarkably quick and complete remission in some cases. But such drugs work for less than a quarter of patients because tumors are notoriously adept at evading immune assault.

A new study in mice by researchers at Washington University School of Medicine in St. Louis has shown that the effects of a standard immunotherapy drug can be enhanced by blocking the protein TREM2, resulting in complete elimination of tumors. The findings, which are published in the journal Cell, point to a potential new way to unlock the power of immunotherapy for more cancer patients.

Immune cells infiltrate a human tumor in the four colorized images above. In a mouse study, researchers at Washington University School of Medicine in St. Louis have found that an antibody that targets the protein TREM2 empowers tumor-destroying immune cells and improves the effectiveness of cancer immunotherapy.

Essentially, we have found a new tool to enhance tumor immunotherapy,” said senior author Marco Colonna, MD, the Robert Rock Belliveau, MD, Professor of Pathology. “An antibody against TREM2 alone reduces the growth of certain tumors, and when we combine it with an immunotherapy drug, we see total rejection of the tumor. The nice thing is that some anti-TREM2 antibodies are already in clinical trials for another disease. We have to do more work in animal models to verify these results, but if those work, we’d be able to move into clinical trials fairly easily because there are already a number of antibodies available.”

T cells, a kind of immune cell, have the ability to detect and destroy tumor cells. To survive, tumors create a suppressive immune environment in and around themselves that keeps T cells subdued. A type of immunotherapy known as checkpoint inhibition wakes T cells from their quiescence so they can begin attacking the tumor. But if the tumor environment is still immunosuppressive, checkpoint inhibition alone may not be enough to eliminate the tumor.

An expert on the immune system, Colonna has long studied a protein called TREM2 in the context of Alzheimer’s disease, where it is associated with underperforming immune cells in the brain. Colonna and first author Martina Molgora, PhD, a postdoctoral researcher, realized that the same kind of immune cells, known as macrophages, also were found in tumors, where they produce TREM2 and promote an environment that suppresses the activity of T cells.

When we looked at where TREM2 is found in the body, we found that it is expressed at high levels inside the tumor and not outside of the tumor,” Colonna said. “So it’s actually an ideal target, because if you engage TREM2, you’ll have little effect on peripheral tissue.”

Colonna and Molgora — along with colleagues Robert D. Schreiber, PhD, the Andrew M. and Jane M. Bursky Distinguished Professor; and William Vermi, MD, an immunologist at the University of Brescia — set out to determine whether inhibiting TREM2 could reduce immunosuppression and boost the tumor-killing powers of T cells. As part of this study, the researchers injected cancerous cells into mice to induce the development of a sarcoma.

The mice were divided into four groups. In one group, the mice received an antibody that blocked TREM2; in another group, a checkpoint inhibitor; in the third group, both; and the fourth group, placebo. In the mice that received only placebo, the sarcomas grew steadily. In the mice that received the TREM2 antibody or the checkpoint inhibitor alone, the tumors grew more slowly and plateaued or, in a few cases, disappeared. But all of the mice that received both antibodies rejected the tumors completely. The researchers repeated the experiment using a colorectal cancer cell line with similarly impressive results.

Source: https://medicine.wustl.edu/

How To Intercept Coronavirus Infection

Nanoparticles cloaked in human lung cell membranes and human immune cell membranes can attract and neutralize the SARS-CoV-2 virus in cell culture, causing the virus to lose its ability to hijack host cells and reproduce. The first data describing this new direction for fighting COVID-19 were published on June 17, 2020 in the journal Nano Letters. The “nanosponges” were developed by engineers at the University of California San Diego (UC San Diego) and tested by researchers at Boston University. The UC San Diego researchers call their nano-scale particlesnanosponges” because they soak up harmful pathogens and toxins.

In lab experiments, both the lung cell and immune cell types of nanosponges caused the SARS-CoV-2 virus to lose nearly 90% of its “viral infectivity” in a dose-dependent manner. Viral infectivity is a measure of the ability of the virus to enter the host cell and exploit its resources to replicate and produce additional infectious viral particles.

Instead of targeting the virus itself, these nanosponges are designed to protect the healthy cells the virus invades.

Nanosponges attacking and neutralizing the SARS-COV-2 virus

Traditionally, drug developers for infectious diseases dive deep on the details of the pathogen in order to find druggable targets. Our approach is different. We only need to know what the target cells are. And then we aim to protect the targets by creating biomimetic decoys,” said Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering.

His lab first created this biomimetic nanosponge platform more than a decade ago and has been developing it for a wide range of applications ever since. When the novel coronavirus appeared, the idea of using the nanosponge platform to fight it came to Zhang “almost immediately,” he said.

In addition to the encouraging data on neutralizing the virus in cell culture, the researchers note that nanosponges cloaked with fragments of the outer membranes of macrophages could have an added benefit: soaking up inflammatory cytokine proteins, which are implicated in some of the most dangerous aspects of COVID-19 and are driven by immune response to the infection.

Source: https://ucsdnews.ucsd.edu/

CRISPR-Cas9 gene editing could ‘turn off’ HIV virus

HIV treatment has come a long way over the years, due in large part to antiretroviral drugs that stop the HIV virus from replicating in the body. This gives the immune system a chance to repair itself and stop further damage. Thanks to these amazing advances, HIV is no longer the death sentence that it was in previous decades. However, antiretrovirals only keep HIV at bay for as long as they’re taken. Defaulting on the drugs means that the HIV virus comes back. Even worse, it can cause patients to build up resistance to the antiretrovirals so that they do not work so effectively in the future. In other words, there’s still room for improvement when it comes to treatment. Fortunately, researchers from thUniversity of California — San Diego School of Medicine are poised to provide help, courtesy of a new genetic-sequencing approach that could possibly provide a “kill switch” to clear out dormant HIV reservoirs inside cells.

The most exciting part of this discovery has not been seen before,” Tariq Rana, professor of pediatrics and genetics at UC San Diego School of Medicine, said in a statement. “By genetically modifying a long non-coding RNA, we prevent HIV recurrence in T cells and microglia upon cessation of antiretroviral treatment, suggesting that we have a potential therapeutic target to eradicate HIV and AIDS.”

The work is based on the discovery of a recently emerged gene that appears to regulate HIV replication in immune cells, including macrophages, microglia, and T cells. The team refers to this as HIV-1 Enchanced LncRNA (HEAL), and it is elevated in people with HIV. By using CRISPR-Cas9 gene editing, their work suggests that it could stop HIV from recurring in the event that antiretroviral treatment is stopped.

This has the potential for [being a] cure but, [we’ll] have to wait for animal studies,” Rana told Digital Trends. As for the next steps, Rana said that future studies “will determine if turning this regulator HEAL off can remove viral reservoirs, which are the key source for viral rebound when therapies are discontinued.” A paper describing the work was recently published in the journal mBio.

Source: https://mbio.asm.org/
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