Cellular Senescence in Brain Aging

Abstract

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.

Keywords: autophagy; brain aging; cellular senescence; cognitive impairment; neuroinflammation; neuronal plasticity.

Figure 1

Senescent cells impact on aging-related changes in the brain. Accumulation of senescent glia cells and neurons lead to structural and functional changes in the brain that result in cognitive impairment. All figures were prepared using BioRender.com.

Figure 2

Age-associated changes in synaptic plasticity at hippocampal and cortical neurons. Synaptic plasticity is altered in the aged brain in a region specific manner. Decreased size of postsynaptic density (PSD) of CA1 neurons together with increased baseline level of intracellular calcium ions [Ca⁺²] have been reported in the hippocampus of aged animals. In other hippocampal regions spine densities decrease with age, with selective pruning of less mature spines in CA3. In cortical neurons not only spine densities but also dendritic tree length and complexity decrease with age. ↑, increase; ↓, decrease.

Figure 3

Age-dependent lysosome impairment affects function of the brain cells. With age, lysosomes become large with altered membrane protein content, namely, increased LAMP1 level, at least in quiescent neural stem cells, and decreased level of LAMP2A. Reduced LAMP2A level in lysosomal membrane is believed to be the reason of declined CMA observed in old animals. Additionally, with age, lysosomal membrane permabilization (LMP) occurs resulting in leakage of protons and lysosomal hydrolases into cytosol. Uncontrolled protein hydrolysis, e.g., of microtubule-associated proteins (MAPs), affect their function and may lead to cell death. proton leakage impedes maintenance of low lysosomal pH, which is necessary for proper functioning of hydrolases. Hence, decline in lysosomal function results in autophagy impairment and, in consequence, accumulation of various aggregated proteins, lipofuscin, and damaged organelles.

Figure 4

Senescent cells contribute to aging-related neuroinflammation. Glia and neurons can undergo cellular senescence, the characteristics of which includes SASP (senescence-associated secretory phenotype). Secretion of bio-active factors like cytokines, chemokines, extracellular matrix modifying enzymes etc. boosts the pro-inflammatory state observed in the aging brain. Release of senescent cell-derived cellular components that are recognized by neighboring cells as danger-associated molecular patterns (DAMPs) triggers inflammatory gene expression in brain cells.

Figure 5

Mouse models applied in experimental senotherpy. Two experimental approaches for the eradication of senescent cells are used: (A) transgenic mouse in which transgene expression is under control of the promoter of a senescence-specific gene coding for p16^INK4A or p19^ARF protein. Activation of the transgene via an adequate compound leads to induction of cell death in p16^INK4A or p19^ARF-expressing cells. Additionally, transgene might carry GFP protein sequence enabling identification of GFP-positive senescent cells before and after treatment; (B) senolytic treatment of wild type mice leads to death of senescent cells; death-inducing activity of senolytics stems from the ability to inhibit prosurvival or antiapoptotic pathways that are upregulated in senescent cells.

Figure 6

The potential role of senotherapy in counteracting aging-related brain dysfunction. The cell-autonomous and non-autonomous features that accompany senescence of brain cells may lead to cognition impairment and memory decline. Treatment of aged organism with senolytic or senomorphic compounds entails the elimination of senescent cells or, alternatively, lower the deleterious influence of senescent cells on brain microenvironment (SASP reduction). In consequence, restoration of proper brain activity may be achieved.