The Aging Gut Microbiome Interferes with Innate Immunity in the Brain

The aging of the gut microbiome is a topic of growing interest in the research community. It is possible that changes to the gut microbiome have an effect on the progression of aging that is in the same ballpark as that of exercise. With advancing age, harmful inflammatory microbial species grow in number, while those that produce beneficial metabolites decline in number. This has consequences, both the rise of chronic inflammation and loss of tissue function. As today's open access review paper notes, this reaches even to the brain, separated as it is from much of the biochemistry of the rest of the body by the blood-brain barrier.

The immune cells of the brain, such as microglia, follow the rest of the immune system in becoming more inflammatory and dysfunctional with age. Evidence strongly suggests that this neuroinflammation is an important component driving the progression of age-related neurodegenerative conditions. How much of this is connected to the altered gut microbiome present in old individuals? Arguably a meaningful enough fraction to work towards treatments that can restore a youthful microbial population to older individuals. There are approaches close to realization, that would not take an excessive effort to bring to the clinic, such as repurposing fecal microbiota transplantation for use with young donors and old recipients. When conducted in short-lived animal models, that treatment improves heath and extends life.

Getting on in Old Age: How the Gut Microbiota Interferes With Brain Innate Immunity

The interaction between the gut microbiota and the innate and adaptive immune systems through direct engagements at mucosal surfaces or microbiota derived metabolites is unambiguous. The peripheral immune system is quite sensitive to slight alterations in the circulating metabolites and plasma cytokine composition, which can result due to microbiota dysbiosis. Intriguingly, parabiosis or plasma transfer experiments that expose a young animal to old blood decreases hippocampal neurogenesis, promotes microgliosis and, ultimately, impairs learning and memory function. On the other hand, exposing aged animals to young blood improves the cerebral vasculature, enhances neurogenesis in the subventricular zone and ameliorates the decline in olfaction.

The brain has long been thought to be immune-privileged. However, the test of time has proved this terminology not absolute. Under homeostatic conditions, the degree of immune-privilege varies depending on age and neurological health. Additionally to the aforementioned age-associated alteration of the microbiota in aging, the neurovascular unit of the blood-brain barrier undergoes a transition which could potentially allow atypical primary or secondary microbiota-derived molecules uptake into the central nervous system (CNS). Indeed, beyond peripheral immunity, microbiota-derived signaling molecules have been implicated in CNS immunity, neuropsychiatric, and neurodegenerative disorders

Compared to other understudied CNS innate immune cells, the microbiota-microglia axis has been well investigated during development and adulthood. There is an evident gap in understanding the direct and indirect links between the microbiota and CNS innate immune cells other than microglia. This gap is even wider when it comes to investigating these interactions in the context of aging. It is difficult to comprehend the biological and molecular basis of senescence, as well as the interplay between microglial senescence and the gut microbiota regulating various functions in the healthy and diseased brain. This, however, represents a therapeutic opportunity that could lead to the discovery of new pharmacological targets for maintaining or restoring physiological tasks in long-lived individuals.


Altered chromatin states drive cryptic transcription in aging mammalian stem cells

A repressive chromatin state featuring trimethylated lysine 36 on histone H3 (H3K36me3) and DNA methylation suppresses cryptic transcription in embryonic stem cells. Cryptic transcription is elevated with age in yeast and nematodes and reducing it extends yeast lifespan, though whether this occurs in mammals is unknown. We show that cryptic transcription is elevated in aged mammalian stem cells, including murine hematopoietic and neural stem cells and human mesenchymal stem cells. Precise mapping allowed quantification of age-associated cryptic transcription in human mesenchymal stem cells aged in vitro. Regions with significant age-associated cryptic transcription have a unique chromatin signature: decreased H3K36me3 and increased H3K4me1, H3K4me3 and H3K27ac with age. Genomic regions undergoing such changes resemble known promoter sequences and are bound by TATA-binding protein, even in young cells. Hence, the more permissive chromatin state at intragenic cryptic promoters likely underlies increased cryptic transcription in aged mammalian stem cells.

Posted by: Robert Read at August 3rd, 2021 2:38 AM
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