1. Research Background:

Our research group studies the mechanisms underlying brain longevity and fitness. We aim to identify key molecular and cellular processes that support neuronal longevity and determine neuronal susceptibility to neurodegeneration. We strive to define the rules of physiological and pathological brain aging by investigating the intrinsic and extrinsic mechanisms of neuronal longevity. Like other cells in our body, neurons' life "ticks" along the epigenetic aging clock, which defines their true biological age. We aim to elucidate the mechanisms that govern this aging clock and its connection to neuronal metabolism and gene regulation. Our overarching hypothesis is that neuronal aging results from epigenetically determined deregulation of coordinated gene and protein expression, followed by excessive energy expenditure and aging. We also focus on the role of brain cells such as astrocytes and microglia, which support neuronal survival and function. We hypothesize that neuronal aging alters the adaptive capacity of microglia, leading to altered neuron-microglia interactions, microglia-mediated changes in neuronal function, and subsequent microglia-mediated “attacks” on neurons. Many of our research aims are supported by human and mouse genetic data and involve multidisciplinary approaches and cutting-edge technologies.

2. Research questions addressed by the group and possible project(s):

1. We are interested in identifying the mechanisms that control the progression of the epigenetic aging clock. Our ultimate goal is to define the factors that drive the clock and could be used to slow it down and mitigate aging. We are particularly interested in identifying neuronal and microglia type differences in “clocking” and its possible connection to the ability of neurons to enter a transient metabolic dormancy state that temporarily slows down the aging process.

2. Microglia, the innate immune cells of the brain, are a highly heterogeneous cell population with remarkable brain region specificity. We have shown that this brain region specificity plays a major role in the regulation of specialized neuronal function and longevity. Recently, we identified a microglia subpopulation with neuroprotective activity, which may play a key role in determining the speed of neurodegenerative diseases in both animals and humans. We aim to characterize these neuroprotective microglia with the purpose of possible pharmacological modulation of microglia-driven neuroprotective states. We have identified a unique set of surface receptors that can be used to identify and manipulate this population and will target these cells to protect the brain against neurodegenerative diseases.

3. Organismal aging is linked to soluble factors found in various bodily fluids such as blood, lymph, or interstitial fluid. These factors can either accelerate or suppress aging. We speculate that the concentration of anti- or pro-aging factors may be influenced by auto-reactive antibodies that become prevalent during aging. Our aim is to test whether age-associated autoimmunity contributes to the aging process via antibody-mediated neutralization of anti- and/or pro-aging factors. 

4. One of our key aims involves understanding the role of human viral diseases in brain aging. We aim to determine whether peripheral infections, early versus late in life,  can lead to stable changes in neuronal and/or microglial function and their impact on brain aging. We are also keen to understand the role of brain-resident human viruses in neuronal aging and neuron-microglia interactions. One goal of this program is to investigate whether peripheral impacts during early life can epigenetically alter microglia and neurons throughout the lifespan, setting the stage for age-associated neuronal changes.

Our studies are highly multidisciplinary and include approaches such as biochemistry, cellular biology, imaging, cutting-edge molecular techniques, large-scale genomic research and epigenetics, mouse genetics, immunology, and neurobiology. Our research is highly collaborative and involves research centers around the world. All of our immunology and virus-related studies are conducted in collaboration with Dr. Alexander Tarakhovsky, a Max Planck Fellow at the Institute and Professor at the Rockefeller University in New York. 

3. Applied Methods and model organisms:

Model Organisms: Transgenic mouse models, in vitro cell systems

Methods:

• Ribosome-bound RNA profiling (TRAP) and single cell/nuclei RNA sequencing
• Chromatin studies, Cut&Run, ATAC-seq, ChIP-sequencing analysis 
• Mouse genetics and behavioral analysis
• Neuron Glia culture and activity assays (Axiom, Incucyte, Imaris)
• Immunostaining, brain clearance, in-situ, imaging analysis, 
• Molecular systems neuroscience, optogenetics, Ca-imaging in vivo.
• High resolution microscopy

4. Desirable skills and qualifications:

Molecular biology, immunology, biochemistry, imaging, electrophysiology, neuroscience, behavior analysis and genetics

5. References and key publications:

Ayata P, Crowley JM, Challman MF, Sahasrabuddhe V, Gratuze M, Werneburg S, Ribeiro D, Hays EC, Durán-Laforet V, Faust TE, Hwang P, Mendes Lopes F, Nikopoulou C, Buchholz S, Murphy RE, Mei T, Pimenova AA, Romero-Molina C, Garretti F, Patel TA, De Sanctis C, Ramirez Jimenez AV, Crow M, Weiss FD, Ulrich JD, Marcora E, Murray JW, Meissner F, Beyer A, Hasson D, Crary JF, Schafer DP, Holtzman DM, Goate AM, Tarakhovsky A, Schaefer A. Lymphoid gene expression supports neuroprotective microglia function. Nature. 2025 Dec;648(8092):157-165. doi: 10.1038/s41586-025-09662-z. Epub 2025 Nov 5. PMID: 41193812; PMCID: PMC12675299.

Travis E. Faust, Yi-Han Lee, Ciara D. O’Connor, Margaret A. Boyle, Georgia Gunner, Ana Badimon, Pinar Ayata, Anne Schaefer, Dorothy P. Schafer. Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling. Cell. 2025 Sep 18;188(19):5212-5230.e21. doi: 10.1016/j.cell.2025.08.023. Epub 2025 Sep 10. PMID: 40934914; PMCID: PMC12489809.

Badimon A, Strasburger H,  Ayata P, Chen X,  Nair A, Ikegami A,  Hwang P, Chan A, Graves S, Uweru J, Ledderose C, Kutlu M, Wheeler M, Kahan A, Ishikawa M, Wang Y, Loh Y, Jiang J, Surmeier DJ, Robson S, Junger W, Sebra R, Calipari E, Kenny P, Eyo U, Colonna M, Quintana F, Wake H, Gradinaru V, Schaefer A. Negative feedback control of neuronal activity by microglia. Nature, 2020 Oct;586(7829):417-423. doi: 10.1038/s41586-020-2777-8. Epub 2020 Sep 30. PMID: 32999463

Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh YE, Ebert A, Pimenova AA, Ramirez BR, Chan AT, Sullivan JM, Purushothaman I, Scarpa JR, Goate AM, Busslinger M, Shen L, Losic B, Schaefer A. Epigenetic regulation of brain region-specific microglia clearance activity. Nature Neuroscience. 2018 Jul 23. doi: 10.1038/s41593-018-0192-3. PMID: 30038282

von Schimmelmann M, Feinberg PA, Sullivan JM, Ku SM, Badimon A, Duff MK, Wang Z, Lachmann A, Dewell S, Ma'ayan A, Han MH, Tarakhovsky A, Schaefer A. Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nature Neuroscience. 2016 Oct;19(10):1321-30. doi: 10.1038/nn.4360. Epub 2016 Aug. 15. PMID: 27526204