A new study links genetic regions that predate the divergence of modern humans and Neanderthals to language
Category: genetics – Page 6
A hidden DNA region helps drive frailty, exposing brain and immune links that reshape aging risk
Researchers at McMaster University have identified, for the first time, a novel region of DNA and two associated genes connected to frailty, offering neurological and immune-related insights that might help explain why some older adults are more likely to be frail than others.
The McMaster team’s findings, published in the journal npj Aging, fill an important gap by revealing genetic factors that contribute to the development of frailty. The discovery provides a biological connection to the condition and points toward new avenues for early detection and targeted intervention.
Stem cell gene editing to produce B cell protein factories
As a proof of concept, the team used CRISPR gene-editing tools to insert the genetic blueprint for producing rare, protective antibodies directly into hematopoietic stem and progenitor cells of mice. Once transplanted back into mice, the edited stem cells gave rise to B cells programmed to produce the engineered antibody. A conventional vaccination would then serve as the trigger.
It worked. Even when only a few dozen stem cells were edited, vaccination triggered rare cells to expand, mature into plasma cells, and produce large amounts of antibodies that persisted long-term and could be boosted if necessary. The engineered B cells behaved just like normal immune cells, and even provided protection from disease. Mice engineered to produce a broadly neutralizing influenza antibody were spared from an otherwise lethal influenza infection.
The team went on to demonstrate their novel platform’s versatility. Engineered B cells were able to secrete non-antibody proteins, pointing to potential applications in treating genetic diseases caused by missing enzymes or other essential proteins.
The researchers also showed that stem cells carrying different antibody instructions could be combined, enabling a single immune system to produce multiple antibodies at once—an approach that could limit viral escape and ultimately lead to functional cures for rapidly mutating pathogens such as HIV.
And the team showed that human stem cells edited using the same approach gave rise to functional immune cells, providing a key proof of feasibility that the platform could one day work in humans, as well. Science Mission sciencenewshighlights.
An innovative gene-editing strategy could establish a new way for the body to manufacture therapeutic proteins—including certain kinds of highly potent antibodies the are naturally difficult to produce—by reprogramming the immune system itself.
Mini brain-like structures grown in lab may help scientists treat, diagnose and stage Alzheimer’s disease
Scientists from Johns Hopkins Medicine report new evidence that clusters of brain tissue derived from the cells of patients with Alzheimer’s disease may be used to evaluate how certain patients with the neurodegenerative condition may respond to drugs commonly prescribed to treat psychiatric symptoms of the disorder. The findings, based on a study of lab-grown brain tissues known as organoids, contribute to a growing body of evidence that brain organoids may also one day be used to more precisely develop and prescribe treatments for subgroups of patients with Alzheimer’s disease, which is the most common form of dementia, and affects more than seven million Americans.
In addition, the researchers found that tiny particles, known as extracellular vesicles, which are secreted by organoids, may contain cellular information that could help scientists find new biomarkers to diagnose and stage Alzheimer’s disease. A report of the findings is published in Alzheimer’s & Dementia.
“Our study suggests that large-scale, patient-derived brain organoids and the vesicles they secrete can help us stage Alzheimer’s disease, investigate the mechanisms that drive it and assess how patient subgroups may respond to different treatments,” says study leader Vasiliki Machairaki, Ph.D., associate professor of genetic medicine at the Johns Hopkins University School of Medicine.
Ancient DNA reveals pervasive directional selection across West Eurasia
The researchers found that natural selection has played a much larger role in determining which traits survived or declined since the Ice Age, identifying 479 genetic variations that were greatly impacted — many more than the 20 previous instances of directional selection.
Analysis of 15,836 ancient West Eurasian genomes reveals hundreds of instances of directional selection, showing that sustained changes in allele frequency were widespread, rather than being rare over this period as previously assumed.
Negative social ties as emerging risk factors for accelerated aging, inflammation, and multimorbidity
Negative social ties, or “hasslers,” are pervasive yet understudied components of social networks that may accelerate biological aging and morbidity. Using ego-centric network data and DNA methylation-based biological aging clocks (i.e., DunedinPACE and age-accelerated GrimAge2) from saliva from a state representative probability sample in Indiana, we examine how negative social ties are associated with accelerated biological aging and a broad range of health outcomes, including inflammation and multimorbidity. Negative relationships are not rare within close relationships, as nearly 30% of individuals report having at least one hassler in their network. These hasslers tend to occupy peripheral network positions and are more likely to be connected through weak, uniplex ties. Importantly, exposure to negative social ties follows patterns of social and health vulnerability, with women, daily smokers, people in poorer health, and those with adverse childhood experiences more likely to report having hasslers in their networks. Having more hasslers is associated with accelerated biological aging in both rate and cumulative burden: Each additional hassler corresponds to approximately 1.5% faster pace of aging and roughly 9 mo older biological age. Moreover, not all hasslers exert the same influence; kin and nonkin hasslers show detrimental associations, whereas spouse hasslers do not. Finally, a greater number of hasslers is associated with multiple adverse health outcomes beyond epigenetic aging. These findings together highlight the critical role of negative social ties in biological aging as chronic stressors and the need for interventions that reduce harmful social exposures to promote healthier aging trajectories.
Nanobody repairs misfolded CFTR inside cells, boosting function in cystic fibrosis
A tiny antibody component could fundamentally transform the treatment of cystic fibrosis: For the first time, researchers have succeeded in developing a so-called nanobody that penetrates directly into human cells and can repair the chloride channel most commonly affected in cystic fibrosis. The innovative therapeutic approach was developed in collaboration between teams from Charité—Universitätsmedizin Berlin and the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP). The results have now been published in the journal Nature Chemical Biology.
The clinical picture of cystic fibrosis—also known as CF—is caused by genetic defects in the so-called CFTR channel. This channel regulates water and salt transport in the lung mucosa and ensures the production of sufficiently fluid mucus. In about 90% of cystic fibrosis patients, a mutation known as F508del is present in the CFTR channel, meaning that a single amino acid is missing at position 508 in its protein chain. This change causes CFTR to fold incorrectly and break down prematurely inside the cell, rather than functioning as a channel in the cell membrane of the airways.
As a result, patients have thick mucus in their lungs, and pathogens can no longer be effectively cleared. The consequence is chronic infection and inflammation of the airways, leading to a progressive loss of lung function—in the worst-case scenario, this necessitates a lung transplant.
The longevity effects of reduced IGF-1 signaling depend on the stability of the mitochondrial genome
This insight has major implications for the development of antiaging therapies. First, they suggest that mtDNA integrity is not simply one of the many hallmarks of aging, but rather the foundation upon which others are built. And when that platform is broken, downstream hallmarks such as proteostasis or DNA repair cannot be engaged by typical means. Second, it suggests that interventions that target nutrient-sensing pathways may fail, or even backfire, when applied to organisms or tissues with high levels of mitochondrial damage. Hence, the next generation of geroprotective treatments must be tested in diverse models of aging, including those that combine multiple hallmarks, to better understand the scope and boundaries of their efficacy. Last, the efficacy of those treatments could be amplified by measures that improve the stability of the mitochondrial genome. While a reduction in IGF-1 signaling did not alter the frequency of mutations in WT or PolgD257A mice, it did slow the pace with which they reached homoplasmy. Thus, although it may not be possible today to reduce mitochondrial mutagenesis in human cells, our data show that it may already be possible to curtail the impact of mtDNA mutations on mammalian health span by slowing their clonal expansion in nondividing cells, the cells that are most sensitive to metabolic dysfunction.
While the precise mechanism by which Pappa influences clonal expansion of mtDNA mutations remains uncertain, several plausible explanations can be proposed. In the absence of cell division (the major driver for homoplasmy in dividing cells), the progression of mtDNA mutations toward homoplasmy is primarily driven by random genetic drift, the rate of mtDNA replication, and mitochondrial quality control. Thus, it is likely that loss of Pappa influences one of these three processes. Loss of Pappa may either reduce the rate of random genetic drift (potentially by changing mitochondrial fusion and fission or the spatial segregation of semi-isolated pockets of mtDNA), reduce the rate of mtDNA replication (less replication lowers the chance that a mutant mtDNA molecule expands enough to reach homoplasmy), or improve mitochondrial quality control by degrading mitochondria with mutant mtDNA molecules. It will be important to distinguish between these possibilities in future work to clear the way for novel interventions aimed at curbing the impact of mtDNA mutations on human health.
Regardless of the mechanism, these findings provide a compelling example of how the interplay between distinct hallmarks of the aging process can fundamentally alter the outcome of otherwise beneficial interventions. They reveal that the efficacy of antiaging strategies such as IGF-1 suppression is not absolute but context dependent. They are contingent on the integrity of underlying systems, including proteostasis and DNA repair. Without an intact mitochondrial genome, these pathways cannot be engaged, indicating that mtDNA integrity is required for these critical antiaging pathways. More broadly, our results underscore the need for a more integrated model of aging, one that considers not only individual pathways but also their interactions, hierarchies, and points of failure. By mapping these interactions, we can better anticipate the limitations of existing interventions and design next-generation therapies that are robust to the complex biology of aged tissues. In this light, strategies that target the expansion of mtDNA mutations, rather than their origin, may offer a powerful new axis for preserving tissue function and extending health span, even when the underlying genomic damage cannot be undone.