Recent discoveries of glymphatics and meningeal lymphatics have redefined our understanding of CNS immunosurveillance. Kim and Kipnis illustrate how the clearance of brain-derived antigens creates an “immune code” that, when presented by meningeal antigen-presenting cells, instructs T cells to safeguard neural homeostasis. They review how inflammation, aging, and neurodegeneration disrupt this finely tuned process and highlight emerging therapeutic opportunities.
From birth to the last moments of life, the human brain is known to change and evolve significantly, both in terms of its physical organization (i.e., structural connectivity) and the coordination between different brain regions (i.e., functional connectivity). Mapping and understanding the brain’s evolution over time is of crucial importance, as it could also shed light on differences in the brains of individuals who develop various mental health disorders or experience an aging-related cognitive decline.
Researchers at Beijing Normal University and other institutes in China recently carried out a large-scale study to gather new insights into how the brain’s functional connectivity of humans worldwide changes over the course of their lifespan. Their paper, published in Nature Neuroscience, unveils patterns in the evolution of the brain that could inform future research focusing on a wide range of neuropsychiatric and cognitive disorders.
“Functional connectivity of the human brain changes through life,” wrote Lianglong Sun, Tengda Zhao and their colleagues in their paper. “We assemble task-free functional and structural magnetic resonance imaging data from 33,250 individuals at 32 weeks of postmenstrual age to 80 years from 132 global sites.”
The strong links between changes in astrocyte structure and function in the context of neurodevelopment and disease have been supported by studies examining astrocyte cytoskeletal markers such as glial fibrillary acidic protein (GFAP) in disease models and postmortem human brain tissue, where increases or decreases in its expression in various brain nuclei are often linked with neurocognitive and psychiatric disorders. Hence, changes in GFAP expression are often the first-line test for astrocyte involvement in disease and support a role for astrocyte dysfunction in major depression, schizophrenia, alcohol and substance use disorders, anorexia nervosa, and bipolar disorder (7–19), where changes in astrocyte structure, density, complexity, and/or blood vessel association are linked with disrupted astrocyte function. Although reactive astrogliosis remains the single most studied astrocytic response involving morphological adaptations and changes in GFAP expression (20, 21), in recent years, astrocyte morphological plasticity has been shown to be more nuanced. GFAP expression is dynamic across the circadian cycle (22–24) and increases with physical exercise and environmental enrichment (25, 26). Moreover, in aging, astrocytes increase or decrease their GFAP expression in different brain regions (27, 28), suggesting heterogeneity in astrocyte form and function.
We previously found a notable relationship between astrocyte structure and vulnerability to substance use disorders, with astrocytes in the nucleus accumbens (NAc) altering their association with different neural subcircuits to drive or suppress drug-seeking behavior depending on heroin availability (29–31). The NAc is critical for regulating behavioral outputs in response to rewards, including substances of abuse and natural reinforcers, such as food or sucrose. The NAc is composed of core and shell subregions that are themselves heterogeneous structures with regard to synaptic input and output connectivity and function (32–36). Heterogeneity has been observed in astrocyte morphology within the NAc core (3, 30, 37), but studies have not yet examined how astrocyte structure and function differ across NAc subregions at baseline or in response to operant conditioning with natural or pathological reinforcers.
To address this gap, we developed an automated pipeline for single-cell morphological analysis of astrocytes that integrates state-of-the-art deep learning models for astrocyte detection and segmentation, together with highly sensitive geometrical tools for precise quantitation of single-cell morphological characteristics. We introduce the rigorous notion of morphological distance (MD) to measure alterations in astrocyte morphology and compare astrocyte subpopulations according to their structural characteristics. By applying this pipeline in combination with supervised machine learning, we found that single-astrocyte morphological characteristics were predictive not only of anatomical location within the NAc at baseline but also of the availability of heroin or sucrose at the moment of image capture. This geometrically sensitive approach yields substantially more detailed information about astrocyte structure than previously applied manual or semiautomated approaches and serves as a rigorous quantitative assay for identifying brain nuclei where astrocytes undergo plasticity in the context of disease. We found that astrocyte structural plasticity across the NAc was disrupted in animals that had been exposed to heroin but not sucrose, consistent with a largely protective role for NAc astrocytes in maintaining synaptic homeostasis and behavioral flexibility. We also found that astrocyte structural plasticity in the dorsomedial portion of the NAc shell was uniquely engaged during the initiation of opioid but not sucrose seeking, suggesting the involvement of this structure in drug relapse.
The researchers discovered that AP2A1 seemed to be responsible for switching cells between their “young” and “old” states—senescent cells were rejuvenated by the suppression of the protein, and younger cells aged by its overexpression.
The scientists also found that the AP2A1 was frequently in close proximity to another protein: integrin β1, which aids cells in binding to the collagen scaffold that envelops them. Both proteins, the researchers described, travel along stress fibers within cells.
Senolytics can prevent and treat age-related diseases in mice, but data in humans are lacking — for now.
The number of people suffering from osteoarthritis is expected to top 1 billion by 2050. The biggest risk factor for the prevalent, often painful, chronic joint disease is aging. And like aging, there is currently no way to stop it.
A discovery by scientists at Henry Ford Health + Michigan State University Health Sciences could pave the way for new breakthroughs in detecting and treating the disease. Their findings were recently published in Nature Communications.
“Our hope is that this discovery will one day allow doctors to catch the disease earlier and intervene before significant joint damage occurs,” said Shabana Amanda Ali, Ph.D., a Henry Ford Health assistant scientist and senior author of the paper. “Osteoarthritis is so complex and so heterogeneous that even with decades of research there hasn’t been a single therapeutic.”
Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.
#Aging #Longevity aging and longevity.
NAD depletion in skeletal muscle does not impair tissue integrity and function or accelerate aging, as shown in a mouse model with an 85% decrease in muscle NAD+ levels. Muscle structure, metabolism, and mitochondrial function remain unaffected, suggesting that NAD depletion does not drive age-related muscle decline.
Ambrosi and colleagues profile human skeletal stem cells (hSSCs) across ten fetal skeletal sites and from patients throughout adulthood, identifying, mapping, and functionally testing four distinct hSSC subtypes. Skeletal aging and disease are characterized by a dominant fibrogenic hSSC variant, but targeting defined gene regulatory networks reinstates functional hSSC diversity.
The dream of living forever has long been the stuff of science fiction. But for some scientists, it’s a real-world challenge worth pursuing. According to molecular… Continue Reading →
In our Founder Interview series, we highlight the brightest minds in preventive health, wellness, and longevity. In Episode 6, we’re honored to feature Dr. Emil Kenziorra, founder and CEO at Tomorrow Biostasis —one of the world-leading human cryopreservation experts.
Tell us a little about yourself and your current venture
Doctor and researcher by training, entrepreneur by trade. Longevity has always been my motivation, with a focus on maximal life span extension. I’m running Tomorrow.bio and the non-profit European Biostasis Foundation to push human cryopreservation forward.