The Significance of Senescent Astrocytes in the Aging Brain

The best way to establish significance of a given form of damage or dysfunction in aging is to repair it and then observe the results of that repair. This form of investigation is now well underway for the accumulation of senescent cells in aging, as the research community has established numerous means of selectively destroying senescent cells in animals. These range from genetically engineered INK-ATTAC mice to senolytic small molecule drugs to programmable suicide gene therapies, and more are being added with each passing year. Recent demonstrations in mice (using navitoclax, dasatinib and quercetin, and piperlongumine as senolytic agents) have made it quite clear that senescent cells in the brain contribute to the progression of neurodegenerative conditions such as Alzheimer's disease, as removing those cells greatly improves matters.

Today's open access review paper looks at senescence in just one of the many populations of cells in the brain, the astrocytes. Previous work has examined glial cells in general in the context of cellular senescence and its detrimental effects on the brain, a category that includes astrocytes but also a range of other cell types. Astrocytes are support cells, and undertake a wide range of tasks to help ensure that neurons thrive and function correctly. It is not a loss of cells capable of carrying out these tasks that causes harm as a result of a small fraction of astrocytes becoming senescent. Rather it is that senescent cells produce a potent mix of inflammatory and other signals, and even a comparatively small number of them can produce significant disruption of tissue function as a result. It is well known that chronic inflammation in the brain is an important contributing factor to the progression and pathology of neurodegenerative conditions.

Astrocyte senescence: Evidence and significance

Aging is characterized as a time-dependent deterioration in the physiological integrity of living organisms. This functional decline has become incredibly relevant in the modern era, where advances in medicine have allowed humans to live longer than ever before. In light of the economic and social impact of aging and age-associated diseases, there has been extensive research into the underlying cellular mechanisms of aging. In fact, substandard results from clinical trials aimed at ameliorating age-associated neurodegenerative diseases suggest that aging is not only a risk factor for disease, but may rather be an underlying cause. In fact, the central nervous system (CNS) undergoes numerous detrimental changes as one ages including mitochondrial dysfunction, oxidative stress, and chronic inflammation. Therefore, targeting the mechanisms of CNS aging may be therapeutically prudent.

In order to examine possible mechanisms, definition of criteria to determine hallmarks of aging is critical. A landmark report has classified nine hallmarks of aging based on three criteria: (a) the hallmark should manifest during normal aging; (b) its experimental augmentation should accelerate aging; and (c) its experimental attenuation should hamper normal aging, thus increasing healthy lifespan. These hallmarks are genomic instability, telomere attrition, epigenetic alterations, stem cell exhaustion, altered intercellular communication, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence. There is an intimate relationship between these hallmarks with fluctuations to one instigating changes in another. The most notable instance of this interconnectedness is with cellular senescence, a state of irreversible growth arrest coupled with stereotyped changes in phenotype and gene expression that represent all of the other hallmarks. In fitting with the above criteria, cellular senescence increases with age, and its augmentation and reduction, respectively, accelerate or diminish aging.

As studies concerning the role of cellular senescence in age-related disorders become increasingly common, senescence in the CNS is emerging as a new research topic. Taking into consideration that many neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and other types of dementia have age as a primary risk factor; the possibility that cellular senescence of CNS cell types may be a contributing factor can no longer be overlooked. Of the CNS cells, astrocytes are potential candidates for involvement in neurological disorders given their myriad roles in the maintenance of brain homeostasis. The loss of astrocyte function or the gain of neuroinflammatory function as a result of cellular senescence could have profound implications for the aging brain and neurodegenerative disorders, and we propose the term "astrosenescence" to describe this phenotype.

Astrocytes have been shown to undergo replicative cellular senescence in vitro and can senesce prematurely in response to various stressors. In vivo, senescent astrocytes have been shown to accumulate with age and in the context of neurological disorders. The detrimental impact these cells could contribute to the tissue microenvironment suggests that astrosenescence may contribute to the pathology of age-associated neurological diseases. Within a senescent cell, there can be various disruptions to normal cellular physiology including increases in reactive oxygen species (ROS), mitochondrial dysfunction, and inflammation. Notably, these are features also associated with neurodegenerative disorders.

An alternative line of therapy for the treatment of these disorders may be the clearance of senescent cells. This concept has been demonstrated with great success in transgenic mice that express constructs capable of inducible senescent cell clearance in order to extend healthy lifespan and reduce the effects of several age-associated disorders. Most recently, this concept has successfully been tested in a mouse model of tau-dependent neurodegeneration. Mice in this study accumulate senescent astrocytes and microglia, clearance of which prevents tau deposition and degeneration of cortical and hippocampal neurons, the very first study to demonstrate a causal link between glial senescence and neurodegeneration. In humans a similar effect might be conceivable using a new class of drugs known as senolytics. The previous study of tau-dependent neurodegeneration also demonstrated therapeutic potential with senolytic treatment, suggesting that senolytics to clear senescent astrocytes could be beneficial to age-associated neurogenerative diseases.

Comments

This seems to establish a plausible cause-and-effect relationship of the etiology of Alzheimer's disease. After almost twenty years of taking dietary supplements, learning their mechanism of action and tweaking the regimen I take, this helps me understand how to hopefully tackle the prevention of Alzheimer's disease head on. One must pay constant attention to the supplements they take in navigating the obstacle course of aging.

Posted by: Stephen Snitzer at March 13th, 2019 6:10 AM

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