Cellular Senescence in Brain Aging

 You'll have to ask your doctor how you get senolytics in your brain to eliminate senescent cells.

Cellular Senescence in Brain Aging

Ewa Sikora^1*, Anna Bielak-Zmijewska¹, Magdalena Dudkowska¹, Adam Krzystyniak¹, Grazyna Mosieniak¹, Malgorzata Wesierska² and Jakub Wlodarczyk³

• ¹Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland
• ²Laboratory of Neuropsychology, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland
• ³Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

Introduction

As with other organs and systems, the functional capabilities of the brain decline progressively during aging. As we age, cognitive performance generally declines which manifests as decrements in learning and memory, attention, decision-making speed, sensory perception (vision, hearing, touch, smell, and taste), and motor coordination (reviewed in Mattson and Arumugam, 2018). Aging is the leading risk factor of age-related diseases (ARDs), including neurodegenerative disorders. The aging process and ARDs are considered as a sort of a continuum with two extremes. One is represented by centenarians, who largely avoided or postponed most ARDs and are characterized by decelerated aging. Individuals 60+, 70+, 80+ who suffered from one or more severe ARDs, represent another extremum and show signs of accelerated aging. In between, there are relatively healthy aged people (Franceschi et al., 2018). Thus, precise boundaries between “normal” and “pathological” aging do not exist, especially when molecular and cellular mechanisms at the roots of aging are considered. Particularly, little is known about healthy brain aging outside of the realm of neurogenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Nonetheless, we must remember that the current consensus in geroscience (Kennedy et al., 2014) considers AD as a more severe form of pathologies associated with normal aging. With age physical fitness and cognitive functions often decline in human and animals (Leal and Yassa, 2015). However, we must not forget that in nature exist animal species, such as naked mole rats, ocean quahog, rockfish and Greenland shark, and many others that exhibit negligible senescence and superior resistance to age-related diseases (Finch, 2009).

In humans, cognitive abilities can be divided into such domains as: processing speed, attention, memory, language, visuospatial abilities, and executive functioning (Harada et al., 2013). Similarly, animal behavior is based on attention and different kinds of memory. Age-associated deterioration of cognitive functions correlates with impaired motor coordination of both animals and humans, who lose their independence and experience a decrease in the quality of life. The age-related cognitive impairment is associated with changes in the central nervous system, mainly in the prefrontal cortex and hippocampus. These changes may lead to development of not only neurodegenerative diseases, but also psychiatric diseases, for example, depression and schizophrenias (Baker and Petersen, 2018). However, in agreement with the idea of a continuum of the aging process (Franceschi et al., 2018), healthy aging, free of mental disabilities, is not a rare exception.

Transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after the age of 40. Genes that play a role in synaptic function and neuronal plasticity that underlies learning and memory, were among those most significantly affected in the aging human cortex. Significantly reduced expression of several neurotransmitter receptors that play a key role in synaptic plasticity, including the GluR1 AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit, the NMDA (Nmethyl- D-aspartate) R2A receptor subunit, and subunits of the GABA receptor, was shown in people over 40. Moreover, the expression of genes that mediate synaptic vesicle release and recycling, involved in protein transport, involved in protein turnover, also showed reduced expression in the aged cortex. Interestingly, most of the age-downregulated genes showed significantly greater oxidative DNA damage in the aged cortex. In line with this, the aging of the human frontal cortex was associated with increased expression of genes that mediate stress responses and repair. Those included genes involved in protein folding, DNA damage repair, antioxidant defense, metal ion homeostasis, and neuroinflammation (Lu et al., 2004). Generally, the study of Lu et al. may suggest that the main culprit of aging could be cellular senescence of brain cells.

Actually, the hallmarks of aging that are common to neurons and other cells have been described recently (Mattson and Arumugam, 2018). They include: mitochondrial dysfunction, intracellular accumulation of oxidatively damaged proteins, nucleic acids, and lipids, dysregulated energy metabolism, impaired cellular “waste disposal” mechanisms (autophagy-lysosome and proteasome functionality), impaired adaptive stress response signaling, compromised DNA repair, dysregulated neuronal Ca²⁺ homeostasis, stem cell exhaustion, and inflammation. Since the brain function relies on the neuronal network connectivity, the effects of aging are manifested at the level of synaptic plasticity, as shown by the age-associated decline in the number of synapses and in aberrant synaptic transmission in several brain regions. Moreover, a landmark of the aged brain is an increased level of neuroinflammation generated by glial cells, which can contribute to alterations in neuronal/synaptic function (Lupo et al., 2019).

Very recently an outstanding progress in elucidating molecular changes associated with cognitive decline through genome-wide profiling of aging brain cells at different molecular levels, namely genomic, epigenomic, transcriptomic, and proteomic, has been made (Ximerakis et al., 2019). Although the research of the role of cellular senescence in the aging brain is still in its infancy the concept has been laid (Tan et al., 2014; Baker and Petersen, 2018; Kritsilis et al., 2018; Wengerodt et al., 2019) (Figure 1). Therefore, in these review, we will focus on cellular senescence of the brain and discuss recent studies, which have shown that elimination of senescent cells can lead to alleviation of brain associated age-related diseases in many genetically modified mouse models (reviewed by Sikora et al., 2019). Accordingly, we ask the question of whether elimination of senescent brain cells may lead to brain rejuvenation.