Molecular alterations contributing to brain aging
Aging is a process that is defined by the decline in intrinsic physiological functions that affect all organisms over time (Flatt, 2012). Although not considered a disease, aging involves an accumulation of deleterious events, including DNA damage, increased oxidative stress, and an accumulation of misfolded proteins (López-Otín, Blasco, Partridge, Serrano, & Kroemer, 2013). The accumulation of these deficits leads to the loss of functionality in cells and tissue and eventually results in an organism's mortality. Aging is also considered a catalyst in the onset of a growing number of pathologies such as cancer and neurodegenerative diseases (Niccoli & Partridge, 2012). Considering that everyone ages, the study of aging mechanisms and processes is an important challenge for our society. This In Focus Issue highlights how different events that take place at the molecular level affect brain performance as the brain ages. Although different elements drive aging, our focus in this collection is on how some of the most elementary functions of cells in the brain, including gene expression, control of nucleus–cytoplasmic transport and compartmentalization, and protein turnover are altered and how these changes influence major cellular functions, including synaptic plasticity and memory, in the case of neurons, or phagocytosis in the case of microglia, and finally on how all these alterations can lead to loss of cell viability.
Epigenetic mechanisms that control gene expression, including DNA methylation, and histone modification, are altered during normal and disease-related aging processes and could contribute to observable cognitive decline (Klein et al., 2019; Kosik et al., 2012; Palomer et al., 2016). In their review, Harman and Martin (2019), critically evaluate how these epigenetic mechanisms, in addition to other gene expression modulators such as transposons and miRNA, are altered and the consequences of these changes, including a diminished ability to establish and maintain connections with other neurons. Critical to this review is the perspective by Harmon and Martin about the contributions to these epigenetic modifications, including the role of age-related events such as oxidative stress, Ca2+ impairment, or different metabolic changes.
The trafficking of proteins and large molecules between the cytoplasm and nucleus is also known to deteriorate throughout aging (Benvegnù, Mateo, Palomer, Jurado-Arjona, & Dotti, 2017; D'Angelo, Raices, Panowski, & Hetzer, 2009). In the review Nucleus–cytoplasm cross-talk in the aging brain, Benvegnù describes how the aging process affects nucleocytoplasmic transport. Trafficking is mainly governed by the nuclear pore complexes, large protein complexes that span the nuclear envelope. However, with aging, proteins travelling from the cytoplasm to nucleus (and vice versa) oftentimes aggregate in a compartment where they are not expected and interfere with normal cellular functions or could directly alter nucleus–cytoplasm communication. These outcomes may be due to age-dependent decreases in the mechanisms responsible for the elimination of damaged or unfolded proteins. In addition to describing age-related changes in nucleocytoplasmic transport, Benvegnu compares the differences in nucleocytoplasmic cross-talk between normal aging processes with what occurs during different neurodegenerative diseases, including Huntington's disease, Alzheimer's disease (AD), and amyotrophic lateral sclerosis.
Alterations in protein homeostasis and in protein degradation pathways, which lead to protein aggregation, are a typical hallmark of neuronal aging and neurodegeneration (Kaushik & Cuervo, 2015). One mechanism by which neurons try to counteract the dysfunction in degradative pathways is via extracellular vesicles secretion (Baixauli, López-Otín, & Mittelbrunn, 2014). In a new review, Guix discusses how the secretion of unwanted material through extracellular vesicles may offer an alternative way for neurons to remove cellular waste. Yet, despite its beneficial effects, enhanced secretion of extracellular vesicles may trigger inter-cellular spreading of toxic and aggregation-prone proteins such as Beta-amyloid and Tau proteins, in AD, thereby contributing to the pathology of some neurodegenerative diseases.
While neurons are primarily discussed in the above articles, it cannot go unstated that glia and, in particular, microglia, play a critical role in aging. In their review, Microglial phagocytosis in ageing and Alzheimer´s disease, Gabandé-Rodriguez and colleagues discuss how microglia phagocytic capacity is altered during the course of aging and in neurodegenerative diseases. Microglia are responsible for clearing pathogens in the brain, but are also required for eliminating debris, dead cells, and influence synaptic pruning (Hammond, Robinton, & Stevens, 2018; Hong, Dissing-Olesen, & Stevens, 2016). A decline in the phagocytic ability of microglia is well documented in aging and leads to an accumulation of pathogens and abnormal proteins as well as dead cells (Koellhoffer, McCullough, & Ritzel, 2017), which could lead to inflammation and an overall decline in brain function. However, pathological phagocytosis by microglia may lead to the loss of live neurons, which might amplify the neurodegenerative phenotype. Particularly important is the correct function of microglial phagocytosis in neurodegenerative diseases like multiple sclerosis (MS) or AD. In the case of MS, a correct microglial performance favors the re-myelination process through myelin debris clearance and switching from a pro-inflammatory phenotype (M1) to a pro-reparative one (M2). In the case of AD or other neurodegenerative diseases like Parkinson's or Huntington's disease, microglia are responsible for the internalization and removal of accumulated proteins like Amyloid beta. For this purpose, microglia present specific lipid sensors and protein receptors that allow the recognition of myelin debris and deleterious proteins, triggering their phagocytosis. Those sensors appear altered in MS and AD, revealing the importance of these degradation pathways. Gabandé-Rodriguez and collaborators examine, in their review, the double-edged physiology of these particular cells whose main function, that is, the phagocytic process, requires a perfect balance in order to avoid disease.
In each of the discussed articles, many cellular process and pathways become dysregulated as aging progresses, but what triggers the changes from healthy aging to neurodegeneration? In their review, “Brain aging: A Ianus-faced player between health and neurodegeneration,” Vanni et al. address this question by exploring a proposed mechanism capable of “switching” healthy aging into pathological deterioration. For example, Vanni et al. describe a recent study in which there is an 11-fold upregulation of a serine protease inhibitor (SERPINA3) in the brain of healthy individuals over 65 compared with young adults, but when comparing expression levels to those of patients with AD, Vanni found between 40- to 300-fold increase in expression (Vanni et al., 2018). Similarly, the gene coding for repressor element-1 silencing transcription factor (REST), which is necessary to recruit histone deacetylases to induce gene silencing and is neuroprotective in normal aging by suppressing genes involved in neuronal cell death and oxidative stress was also discussed. While aged neurons show high levels of REST, there is a significant reduction of REST in patients with mild cognitive impairment and Alzheimer's Disorder, conferring increased neuronal susceptibility to toxic stress (Lu et al., 2014). REST levels can therefore be a crucial switch regulator between neuroprotection and neurodegeneration in the aging brain. In addition to these mechanisms, Vanni et al. also discuss the role of neuroinflammation in the aging brain, including how inflammatory processes can be either beneficial or detrimental.
Across the different reviews that are part of this In Focus issue, the different authors have shown how the hallmarks of aging, including epigenetic alterations, oxidative stress, proteostasis decline, or altered intercellular communication (López-Otín, Blasco, Partridge, Serrano, & Kroemer, 2013), take place in the brain. These alterations affect elemental process like gene expression or protein turnover leading to impairments in the general performance and function of the cells. The intention of this issue is to enlighten how this age-associated events take place and how they affect cellular mechanisms. A deeper knowledge of these particular processes is the challenge that scientists face nowadays and will allow the development of better interventions directed to improve our life style.
