Brain aging and rejuvenation at single-cell resolution

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Brain aging and rejuvenation at single-cell resolution

Eric D. Sun^1,2,3,8 ∙ Rahul Nagvekar^1,4,8 ∙ Angela N. Pogson^1,5,8 ∙ Anne Brunet^1,6,7 abrunet1@stanford.edu

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Summary

Brain aging leads to a decline in cognitive function and a concomitant increase in the susceptibility to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. A key question is how changes within individual cells of the brain give rise to age-related dysfunction. Developments in single-cell “omics” technologies, such as single-cell transcriptomics, have facilitated high-dimensional profiling of individual cells. These technologies have led to new and comprehensive characterizations of brain aging at single-cell resolution. Here, we review insights gleaned from single-cell omics studies of brain aging, starting with a cell-type-centric overview of age-associated changes and followed by a discussion of cell-cell interactions during aging. We highlight how single-cell omics studies provide an unbiased view of different rejuvenation interventions and comment on the promise of combinatorial rejuvenation approaches for the brain. Finally, we propose new directions, including models of brain aging and neural stem cells as a focal point for rejuvenation.

Keywords

1. brain
2. aging
3. single-cell transcriptomics
4. spatial transcriptomics
5. multi-omics
6. rejuvenation
7. cell-cell interactions
8. regeneration

Introduction

Aging is associated with a decline in brain function and a striking increase in the prevalence of neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. Indeed, the main risk factor for these neurodegenerative diseases is old age.¹ Even in the absence of disease, aging is associated with cognitive decline.² In humans, aging is often characterized by decline across multiple cognitive domains such as fluid intelligence, processing speed, attention, memory, and learning.² Hence, a systematic understanding of the changes that occur in the aging brain is critical to designing new strategies for countering age-related cognitive decline and neurodegenerative diseases.

In the past, most studies on brain aging have focused on select aspects, including performance on cognitive and behavioral tasks,^2,3,4,5 loss of synaptic plasticity and neural circuits,⁶ changes in gene expression from bulk profiling of brain tissues,^7,8,9 DNA damage and repair,¹⁰ compromised brain metabolism,¹¹ and comparisons between normal aging and neurodegenerative disease.¹² This has provided invaluable information on how the global state of the brain changes during aging. However, the ensemble of cellular changes in the brain during aging, and how they differ in diverse brain cells, is still not fully understood. The brain is arguably the most complex of all organs, consisting of many different cell types and subtypes, with specialized functions, and with intricate interactions between cell types. For example, neurons encompass many specialized subtypes with different functions across brain regions.^13,14 Non-neuronal cell types—oligodendrocytes, astrocytes, neural stem cells (NSCs), cells of the brain vasculature and meninges, and immune cells of the brain—have emerged as key players in brain aging.^{15,16,17,18,19} Thus, important questions arise: are all brain cells aging at the same pace and in the same manner? Are there shared hallmarks of aging across brain cell types or regions? How are interactions between these diverse cell types changing with age? Can specific aspects of cellular brain aging be rejuvenated by specific interventions?

The advent of single-cell omics technologies has resulted in an unprecedented wealth of data on gene expression, chromatin state, and other types of biomarkers in individual cell types. Unlike earlier single-cell-based techniques (immunohistochemistry, cell sorting, lineage tracing, etc.), single-cell omics technologies are high-dimensional and largely unbiased, capturing information across hundreds to thousands of molecular entities. High-dimensional data are powerful for machine learning modeling, notably to build “aging clocks” and for generating novel hypotheses about brain aging. Accordingly, single-cell omics technologies have been instrumental in establishing new systematic understandings of age-related changes at the cell-type level across multiple tissues and organ systems, including the brain.^20,21,22,23 Given the rapid development of single-cell technologies to study the diverse cell types and regions of the brain, there is a need to synthesize and understand the multitude of aging- and rejuvenation-induced changes in the brain.

Of particular interest are the interactions that occur between different cell types of the brain and how these interactions are impacted by aging. The high-dimensional nature of single-cell omics provides an opportunity to identify putative cell-cell interactions, which can be experimentally validated. The recent development of spatial technologies to profile tissues in situ at single-cell resolution provides an additional level of spatial insight that can be leveraged to identify cell-cell interactions in the context of brain aging. Spatially resolved datasets are also critical to compare aging of similar cell types but across different regions of the brain, which is particularly interesting given the highly specialized function of distinct brain regions.

An important goal for the study of brain aging is to identify avenues for rejuvenating the brain, which can slow or reverse different aspects of brain aging and cognitive decline. Several promising interventions, including physical exercise, dietary restriction, and the introduction of young circulating blood factors, have been shown to at least partially rejuvenate certain functions of the aged brain.^24,25,26 With single-cell omics, the response of different cell types to diverse rejuvenation interventions and their relative contributions to functional brain rejuvenation can be investigated in a systematic manner. Importantly, such analysis should lead to a better understanding of the shared and unique pathways by which different rejuvenation interventions achieve their effects—paving the way toward identification of synergistic combinations of multiple rejuvenation interventions.

In this review, we will focus on vertebrate brain aging and rejuvenation, mostly discussing work in mice and humans. While invertebrate nervous system aging has provided key insights into brain aging and its effect on organismal lifespan,^27,28,29,30 the vertebrate brain contains cell types not present in invertebrates, such as endothelial cells and specialized immune cells. We will also focus on “physiological” aging rather than specific age-related pathologies, though we will highlight interesting connections between brain aging and susceptibility to injury and neurodegenerative disease.

Here, we present an overview of recent insights into brain aging and rejuvenation that have been provided by single-cell omics technologies, and we highlight promising future directions that could lead to new discoveries and interventions. We review the key aging-related changes occurring in multiple different cell types of the adult brain and describe how cell-cell interactions change during the course of aging. We discuss the emergence of single-cell omics in systematically profiling rejuvenation interventions in the brain and in comparing their effects across cell types and regions. We also consider the potential role of single-cell omics in profiling cell-type-specific and pathway-specific rejuvenation responses to develop combinatorial rejuvenation interventions. We outline shared cell-type-specific signatures between aging and disease. Finally, we discuss promising in vitro models for studying human brain aging and highlight insights from non-mammalian vertebrate species.

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