【Nature sub-journal】Targeting senescent cells is expected to fight inflammation and cognitive decline!

This article is the original of the translational medicine network, please indicate the source when reprinting

Author: Mia

Cell senescence may be a mediating factor
in inflammation-related tissue dysfunction.
In the brains of older people, the properties of senescent cells and the mechanisms by which they adversely affect are unclear
.
Recently, a research team has used high-dimensional molecular spectroscopy analysis methods, combined with mechanical experiments, to study the properties of senescent cells in the brains of
aging mice.

On September 27, researchers at the Mayo Clinic Robert and Arlene Kogod Geriatric Center in Rochester, Minnesota, published an article in Nature Communications titled "Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell.
" clearance" research paper.

The study reveals the dynamic reconstruction of the brain's immune cell landscape during aging and suggests targeting senescent cells as a countermeasure to inflammatory changes and cognitive decline
.

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Research background

 01 

Inflammation is a common feature of aging, and different innate and adaptive immune cell types play a guiding role
in tissue dysfunction.
In the brain, microglia are multifunctional, resident immune cells
.
Throughout life, monocytes, macrophages, dendritic cells, neutrophils, B cells, and T cells are distributed in parenchymal tissues and marginal regions
.
Their function is to maintain homeostasis by reacting to injury and stress; However, changes in immune cell status and number may be the basis for
age-dependent changes in brain health and function.

In aging and neurodegenerative brains, disease-associated microglia (DAM) and white matter-associated microglia (WAMs) exhibit features of failure and activation, including downregulation of homeostatic genes (Cx3cr1, P2ry12, P2ry13, Tmem119), Itgax/Cd11c, major histocompatibility complex (MHC) components, neurodegenerative risk factors (Apoe, B2m, Fth1, Lpl, Tyrobp), Chemokines and cytokines (Ccl2, Ccl3, Ccl4, Spp1) and lysosomal stress factors are upregulated
.
Although it is speculated that DAM/WAM plays a role in mediating damage breakdown, it may chemisolate peripheral immune cells, which together lead to inflammatory activation and unadaptive disruption
of the microenvironment of the elderly brain.

Senescence is a fate of cells under stress and a conserved mechanism
of tissue aging.
It exhibits heterogeneously in many cell types and environments, characterized by macromolecular and organelle damage, cell cycle arrest mediated by cell cycle-dependent kinase inhibitors, activation of anti-apoptotic pathways and the generation of aging-related secretory phenotypes
.
Previously, experiments using transgenic p16-InkAttac mice (which eliminate p16-positive senescent cells systemically) and senolytic drugs (which kill senescent cells by targeting the anti-apoptosis pathway) have shown that the elimination of senescent cells is able to improve several age-related tissue declines, including central nervous system dysfunction
.
The researchers hypothesized that the mechanisms of aging associated with p16 could modulate age-related brain dysfunction
.

Research overview

 02 

Using NanoString's transcriptome analysis of the inflammatory and aging genomes, the researchers found that women and men showed different and shared age-dependent expression traits in brain regions with different hippocampal patterns
.
The total number of age-altered genes in women is higher, which may reflect a combination
of lower baseline expression and less expression variability in younger women relative to the amplified aging response in men.
The study also identified conserved features of DAM/WAM-related bone marrow cell activation that span aging brain regions and sexes
.
At the pathway and gene levels, it is possible to observe the activation of age-related aging-related genetic traits, especially in the hippocampus of
older women.
Aging and activation of DAM/WAM characteristics coincides with a decrease in glutamatergic receptor mRNA and protein abundance
.

Cognitive function is preserved by p16-positive senescent cell targeting and is associated with the abundance of activated resident microglia and infiltrated brain immune populations in older women

The findings suggest that senescent cell targeting may beneficially affect several conditions
of brain immune cell composition.
First, p16-positive brain marrow cells (resident microglia and infiltrated bone marrow cells) can drive peripheral immune cell recruitment, and their targeting prevents a shift to a
homeostatic imbalance.
Second, other senescent cell types (e.
g.
, p16-positive astrocytes, oligodendrocytes, and endothelial cells) that exert pro-inflammatory effects may also be cleared
.
Third, a systemic p16-InkAttac transgenic strategy may reduce the abundance of circulating aging immune cells, thereby depleting the pools
that can be used to recruit into the brain under steady-state inflammatory conditions.
Fourth, systemic senescent cell elimination may reduce the abundance
of senescent cells throughout the body.

Research summary

 03 

Overall, the study reveals important overlaps
in the emerging framework for understanding the brain's aging mechanisms at the cellular, molecular, and functional levels.
Importantly, p16-positive senescent bone marrow cells and their SASP may mediate peripheral immune cell recruitment, exacerbating brain inflammation during aging, while whole-body elimination of p16-positive senescent cells may restore brain immune cell composition to a more youthful state while improving cognitive function
.
Therefore, the findings suggest that senescent cell targeting is a processable strategy to combat age-related brain inflammation and maintain cognitive function
.

Resources:

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Note: This article is intended to introduce medical research advances and cannot be used as a reference for
treatment options.
For health guidance, please visit a regular hospital
.

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