Brain Aging and Rejuvenation

May 22-29, 2027

Director: Tony Wyss-Coray

Stanford University, Stanford, USA

Faculty:

Anne Brunet, Stanford University, Stanford, USA

Shane Liddelow, New York University Grossman School of Medicine, New York, USA

Henne Holstege, Amsterdam UMC, The Netherlands & VIB–KU Leuven, Belgium

Saul Villeda, University of California, San Francisco, USA

Rozalyn Anderson, University of Wisconsin-Madison, USA

Randy Buckner, Harvard University, Cambridge, USA

Tony Wyss-Coray, Stanford University, Stanford, USA

Aging brings a decline in cognitive and motor function and is the leading risk factor for neurodegeneration and dementia. Yet individuals differ markedly in when this decline begins and how it unfolds, shaped by their balance of susceptibility and resilience. Work in animal models has shown convincingly that brain aging can be slowed, and in some cases reversed, at the molecular, cellular, and functional levels, resulting in a genuine rejuvenation of the brain. This Advanced Course will explore these concepts alongside the latest advances in the field, covering the basic molecular pathways involved, the role of genetics, and the prospects for translation to humans.

Anne Brunet

Mechanisms of brain aging and rejuvenation

Aging is accompanied by a decline in cognitive and sensory functions. The mammalian brain contains regenerative neurogenic niches composed of neural stem cells (NSCs), neural progenitors, and other cells, including microglia and endothelial cells. Neurogenic niches become less functional with increasing age. This deterioration could underlie age-related cognitive and sensory decline, although the exact age at which it occurs remains debated in humans. Our lab has embarked on a global characterization of the neurogenic niche during aging, including transcriptomics, epigenomics, and lipidomic changes in aged NSCs. We have also characterized spatial changes in the aging brain at spatial resolution. Based on this spatial dataset, we have generated ‘spatial aging clocks’ to analyze the impact of rejuvenating interventions on different cell types and to understand the impact of cells on their neighboring cells in the aging brain. In parallel, we are developing genome-editing strategies to functionally test genes involved in brain aging and rejuvenation at scale. Intriguingly, our studies have uncovered infiltration of cytotoxic T cells in the aged brain, and we are currently identifying strategies to quench T cell-induced inflammation. Our work provides a systematic understanding of brain aging and rejuvenation and suggests possible causes of brain decline during aging. Results from these studies could open new avenues to counter age-related decline in the neurogenic niche and in brain aging.

Tony Wyss-Coray

Brain aging and rejuvenation: systemic and molecular mechanisms

The lectures will focus on how aging affects the molecular and functional states of cells, tissues, and organs, with particular emphasis on the brain. We will discuss how advances in high-throughput molecular technologies, especially large-scale proteomics, are transforming our ability to study human aging and age-related disease.
The lectures will cover how the blood and cerebrospinal fluid proteomes change across the human lifespan, and how these molecular signatures can be used to estimate the biological age of specific organs and cell types. We will explore the concept of biological age, its relationship to chronological age, and how proteomic biomarkers can identify individuals at increased risk of cognitive decline, neurodegeneration, and dementia.
We will then consider aging as a systemic process. Drawing on studies of young and old blood and plasma, we will examine evidence that circulating factors can influence brain aging and cognitive function. These experiments illustrate how signals originating outside the brain can either promote or counteract age-related changes in the nervous system.
Finally, we will discuss how these discoveries can be translated into biomarkers and potential therapeutic strategies. The lecture will highlight the emerging ability to measure aging at the level of individual organs and cell types and to identify circulating proteins that may serve not only as indicators, but also as regulators, of aging and age-related disease.

Henne Holstege

What cognitively healthy centenarians reveal about brain aging and resilience

Why do some people remain cognitively healthy beyond the age of 100, while others develop dementia decades earlier? The 100-plus Study examines brain aging through the lens of the most informative extreme: centenarians who have maintained cognitive health throughout exceptionally long lives. By following participants over time, assessing cognition, and studying donated blood and post-mortem brain tissue, we can link the brain’s molecular state to how a person functioned shortly before death.

These brains reveal more than one route to preserved cognition. Many of the highest-performing centenarians show little amyloid-β or tau pathology, suggesting resistance to processes associated with Alzheimer’s disease. A small but particularly revealing group remains cognitively intact despite substantial amyloid-β pathology, suggesting resilience to its effects. Understanding why tau accumulation and cognitive decline remain limited in these individuals may reveal protective processes that dementia studies alone cannot identify.

The genomes of cognitively healthy centenarians are enriched for variants associated with protection against Alzheimer’s disease and depleted of risk variants. In this lecture, I will examine how we move from these genetic associations to mechanisms, using findings on PLCG2, TMEM106B, and the HLA region to explore immune responses, protein handling, and other processes that may shape the aging brain. I will also discuss how longitudinal cognitive data and molecular profiling of centenarian brains can help test these ideas, while distinguishing mechanisms already supported by evidence from those we are still investigating.

Cognitively healthy centenarians do not show that human brain aging has been reversed. They pose a more tractable question: which naturally occurring forms of protection have allowed the human brain to function well for an exceptionally long time, and could understanding them help us prevent dementia?

Shane Liddelow

Astrocyte heterogeneity, reactivity, and network integrity in the aging brain

Astrocytes are principal architects of metabolic, synaptic, and vascular homeostasis in the mammalian brain. They are also profoundly remodeled by age. For decades, astrocyte aging was described in the coarse vocabulary of “reactivity” – a description that is increasingly inadequate. Our lab resolves reactive astrocytes at the level of individual cells within their anatomical context to determine what these cells actually do.

Reactivity does not yield a single homogeneous population: astrocytes undergo distinct transitions in response to the same stimulus, with multiple sub-states often present at the same anatomical location. This includes a rare interferon-responsive sub-state (IRRA) localized to vessels and around ventricles, and a white-matter “super-responder” population. IRRAs are present across models of Alzheimer’s disease, demyelination, and acute injury, as well as in human post-mortem tissue. We have defined them at the protein level, identifying conserved rodent-to-human markers. Several of these reactivity axes intersect with aging.

Normal ageing upregulates complement and interferon-stimulated genes – suggesting age-related reactivity. Aged astrocytes also downregulate cholesterol biosynthesis, accumulate lipid droplets, and lose proteostasis capacity. These are the same pathways that determine whether astrocytes support or kill neurons: these neurotoxic reactive astrocytes (NRAs) lose synaptogenic and phagocytic function and kill vulnerable neurons and oligodendrocytes via secreted saturated lipids that require the elongase ELOVL1 – a tractable target, since its deletion removes toxicity while preserving reactivity.

Finally, using gap-junction proximity labelling with whole-brain clearing and light-sheet imaging, we find that astrocyte networks are not a diffuse syncytium: they selectively interconnect specific regions, are reproducible across animals, are bilateral even after unilateral perturbation, and contract after sensory deprivation. Because these networks redistribute metabolic resources under neurodegenerative stress, we propose network integrity as a second, largely unexplored axis of brain aging – dissociable from transcriptional state and itself a potential substrate for rejuvenation.

Randy Buckner

Pushing the limits of precision to detect modifiers of brain aging in humans

Two individuals may look quite similar as they enter retirement, yet follow dramatically different paths thereafter. One person might maintain a high level of function into their ninth and tenth decades, while the other declines rapidly into dementia. How can we predict who will decline, and how can we measure progression? Moving forward, how can we measure brain change in ways that let us monitor whether an intervention is having the desired effect?

During the lectures, I will describe recent advances in biomarker development, including blood-based biomarkers, that provide strategies to predict individual aging trajectories and track disease progression. Biomarkers have been critical to recent therapeutic successes for Alzheimer’s disease. I will also describe emerging efforts to precisely measure neurodegeneration, brain maintenance, and rejuvenation via neuroimaging over short intervals. Structural brain change (atrophy) can now be measured in non-demented individuals over periods of six months to one year, revealing substantial between-person heterogeneity that is not explained by known biomarkers.

Finally, data modelling with generative AI is providing novel approaches for the study of aging. I will illustrate how generative models can simulate brain and cognitive aging trajectories in hundreds of thousands of individuals, including how biomarkers and cognition change over the course of each simulated lifespan, and how measurement error and study design affect the ability to detect change. This modelling framework provides insights into measurement precision limits and how best to design experiments to detect modifiers of brain and cognitive aging.

Rozalyn Anderson

Metabolic aspects of the neurobiology of aging

The underlying cause of vulnerability to age-related disease remains an unresolved question of relevance across biomedical research. Although aging itself is inevitable, studies in the biology of aging have made it abundantly clear that how we age is malleable. Across species, caloric restriction, a reduction in calorie intake without malnutrition, is the gold standard for enhancing longevity. In each case, it is associated with a delayed onset of age-related diseases and conditions. We have previously shown that caloric restriction is effective in nonhuman primates, including delaying indices of brain aging. In mice and in monkeys, we have identified changes in metabolism as a shared feature of brain aging and metabolic reprogramming as a signature event in the brain response to caloric restriction. Viewed through this lens it seems that age-associated changes in metabolic capacity are not just a biomarker of aging but may also be causally involved in creating disease vulnerability.

Longitudinally captured molecular profiling data from our +30-year caloric restriction intervention study show that aging follows a non-linear trajectory in non-human primates, with an inflection point in mid-life. Studies of brain tissue from the same animals underscore the importance of peripheral metabolic homeostasis for healthy brain aging. Innate metabolic status is strikingly distinct among neurons, astrocytes, microglia, etc., and we have identified major cell-type specificity in how aging manifests. Single-nucleus RNAseq and ATACseq confirm that the response to caloric restriction is also cell-type specific. Even when a shared adaptive mechanism, such as induction of Jun/Fos, is observed, the outcome is unique to cell type. This raises the question of how cells that differ so greatly can coordinate in response to age and/or caloric restriction. To address this, we have embarked on 2D and 3D studies in cultured primary cells to investigate how cells communicate and how metabolic coordination is achieved among cell types.

Saul Villeda

Body-brain communication in cognitive rejuvenation

Aging drives cellular and cognitive impairments in the adult brain, making it critical to gain mechanistic insight into the drivers of brain aging phenotypes to maintain, and even restore, functional integrity in later life. Indeed, recent evidence indicates that brain aging is surprisingly plastic and amenable to rejuvenating strategies. Systemic and lifestyle interventions that promote healthspan – such as heterochronic parabiosis, exercise and caloric restriction – can promote cognitive rejuvenation in the aging brain. Notably, the benefits of such interventions on the hippocampus, a memory-related brain region highly vulnerable to age-related dysfunction, can be transferred through plasma administration, indicating that blood carries signals from the periphery capable of rejuvenating the aged brain.

While the burgeoning field of cognitive rejuvenation research is rapidly expanding, fundamental questions remain unanswered, including which peripheral tissues brain-rejuvenating blood factors induce to restore cognition and which cellular targets mediate the cognitive benefits of these factors. During the lectures, we will delve into recent advances in body-brain communication, with a focus on the distinct tissues and soluble factors that restore cognition in the aging brain.

From a heterochronic parabiosis perspective, we will examine targeting the aged peripheral immune system as a strategy to attenuate neuroinflammation and promote synaptic plasticity in old age. We will discuss the emergence of a liver-brain axis as a mediator of the cognitive benefits of exercise in aging, and survey the growing number of exercise-induced blood factors (exerkines) that mediate these benefits through the brain border regions. We will also explore approaches to identify peripheral tissues and potential rejuvenating factors underlying the cognitive benefits of additional lifestyle interventions, such as caloric restriction. Looking ahead, we will discuss the translational potential of identifying molecular pathways that could be targeted for novel blood-based biologic therapies to restore age-related cognitive dysfunction and potentially treat dementia-related neurodegenerative diseases such as Alzheimer’s disease.