Saul Villeda, PhD
Associate Professor
Anatomy
School of Medicine

As a consequence, we can now consider reactivating latent plasticity dormant in the aged brain as a means to rejuvenate regenerative, synaptic and cognitive functions late in life. Interestingly, work from my lab has revealed bi-directionality in the influence of the systemic environment indicating pro-youthful factors in young blood or following exercise elicit rejuvenation while pro-aging factors in old blood drive pre-mature aging. Our work has further indicated that mitigating the effect of pro-aging factors in old blood may also provide an effective approach to rejuvenate aging phenotypes. The goal of my research program is to elucidate cellular and molecular mechanisms that can be targeted to halt the aging process or promote rejuvenation in the old brain, as a means to counteract dementia-related neurodegenerative disease in the elderly, providing a unique therapeutic approach.

• Spatial Coding Dysfunction and Network Instability in the Aging Medial Entorhinal Cortex.
  bioRxiv : the preprint server for biology 2024 Herber CS, Pratt KJB, Shea JM, Villeda SA, Giocomo LM
• MICROGLIA AGING IN THE HIPPOCAMPUS ADVANCES THROUGH INTERMEDIATE STATES THAT DRIVE INFLAMMATORY ACTIVATION AND COGNITIVE DECLINE.
  bioRxiv : the preprint server for biology 2024 Shea JM, Villeda SA
• Prenatal delivery of a therapeutic antisense oligonucleotide achieves broad biodistribution in the brain and ameliorates Angelman syndrome phenotype in mice.
  Molecular therapy : the journal of the American Society of Gene Therapy 2024 Clarke MT, Remesal L, Lentz L, Tan DJ, Young D, Thapa S, Namuduri SR, Borges B, Kirn G, Valencia J, Lopez ME, Lui JH, Shiow LR, Dindot S, Villeda S, Sanders SJ, MacKenzie TC
• Plasma rejuvenation factor GDF11 associates with amyloid-related cognitive decline in older adults across the Alzheimer’s Disease spectrum.
  Alzheimer's & Dementia 2023 Shannon Y. Lee, Emily W. Paolillo, Rowan Saloner, Anna M VandeBunte, Gil D. Rabinovici, Renaud La Joie, Joel H. Kramer, Saul Villeda, Kaitlin B. Casaletto
• Brain-Derived CCN3 Is An Osteoanabolic Hormone That Sustains Bone in Lactating Females.
  bioRxiv : the preprint server for biology 2023 Babey ME, Krause WC, Herber CB, Chen K, Nikkanen J, Rodriquez R, Zhang X, Castro-Navarro F, Wang Y, Villeda S, Lane NE, Scheller EL, Chan CKF, Ambrosi TH, Ingraham HA
• Neuronal activation of Gαq EGL-30/GNAQ late in life rejuvenates cognition across species.
  Cell reports 2023 Stevenson ME, Bieri G, Kaletsky R, St Ange J, Remesal L, Pratt KJB, Zhou S, Weng Y, Murphy CT, Villeda SA
• Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice.
  Nature aging 2023 Park C, Hahn O, Gupta S, Moreno AJ, Marino F, Kedir B, Wang D, Villeda SA, Wyss-Coray T, Dubal DB
• Platelet factors attenuate inflammation and rescue cognition in ageing.
  Nature 2023 Schroer AB, Ventura PB, Sucharov J, Misra R, Chui MKK, Bieri G, Horowitz AM, Smith LK, Encabo K, Tenggara I, Couthouis J, Gross JD, Chan JM, Luke A, Villeda SA
• Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice.
  Nature communications 2023 Leiter O, Brici D, Fletcher SJ, Yong XLH, Widagdo J, Matigian N, Schroer AB, Bieri G, Blackmore DG, Bartlett PF, Anggono V, Villeda SA, Walker TL
• Pain and Itch Processing in Aged Mice.
  The journal of pain 2023 Braz JM, Hamel K, Craik V, Rodriguez-Rosado S, Bhardwaj K, Jewell M, Bieri G, Villeda SA, Basbaum AI
• The platelet transcriptome and proteome in Alzheimer's disease and aging: an exploratory cross-sectional study.
  Frontiers in molecular biosciences 2023 de Sousa DMB, Poupardin R, Villeda SA, Schroer AB, Fröhlich T, Frey V, Staffen W, Mrowetz H, Altendorfer B, Unger MS, Iglseder B, Paulweber B, Trinka E, Cadamuro J, Drerup M, Schallmoser K, Aigner L, …
• Neurobiology of Aging: New Insights From Across the Research Spectrum.
  The journals of gerontology. Series A, Biological sciences and medical sciences 2023 Villeda S, Brown-Borg H, Anderson R
• Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function.
  Cell reports 2023 Pratt KJB, Shea JM, Remesal-Gomez L, Bieri G, Smith LK, Couthouis J, Chen CP, Roy IJ, Gontier G, Villeda SA
• Blood-to-brain communication in aging and rejuvenation.
  Nature neuroscience 2023 Bieri G, Schroer AB, Villeda SA
• Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function.
  Cell reports 2022 Pratt KJB, Shea JM, Remesal-Gomez L, Bieri G, Smith LK, Couthouis J, Chen CP, Roy IJ, Gontier G, Villeda SA
• Reply to 'Lactate as a major myokine and exerkine'.
  Nature reviews. Endocrinology 2022 Chow LS, Gerszten RE, Taylor JM, Pedersen BK, van Praag H, Trappe S, Febbraio MA, Galis ZS, Gao Y, Haus JM, Lanza IR, Lavie CJ, Lee CH, Lucia A, Moro C, Pandey A, Robbins JM, Stanford KI, Thackray AE,…
• Corrigendum: Long-Term Cognitive Impairments and Pathological Alterations in a Mouse Model of Repetitive Mild Traumatic Brain Injury.
  Frontiers in neurology 2022 Luo J, Nguyen A, Villeda S, Zhang H, Ding Z, Lindsey D, Bieri G, Castellano JM, Beaupre GS, Wyss-Coray T
• Microglial GPR56 is the molecular target of maternal immune activation-induced parvalbumin-positive interneuron deficits.
  Science advances 2022 Yu D, Li T, Delpech JC, Zhu B, Kishore P, Koshi T, Luo R, Pratt KJB, Popova G, Nowakowski TJ, Villeda SA, Piao X
• Exerkines in health, resilience and disease.
  Nature reviews. Endocrinology 2022 Chow LS, Gerszten RE, Taylor JM, Pedersen BK, van Praag H, Trappe S, Febbraio MA, Galis ZS, Gao Y, Haus JM, Lanza IR, Lavie CJ, Lee CH, Lucia A, Moro C, Pandey A, Robbins JM, Stanford KI, Thackray AE,…
• SYSTEMIC MECHANISMS OF BRAIN REJUVENATION.
  Innovation in Aging 2021 Saul Villeda
• MHC class I H2-Kb negatively regulates neural progenitor cell proliferation by inhibiting FGFR signaling.
  PLoS biology 2021 Lin K, Bieri G, Gontier G, Müller S, Smith LK, Snethlage CE, White CW, Maybury-Lewis SY, Villeda SA
• Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions.
  The Journal of experimental medicine 2021 Ho TT, Dellorusso PV, Verovskaya EV, Bakker ST, Flach J, Smith LK, Ventura PB, Lansinger OM, Hérault A, Zhang SY, Kang YA, Mitchell CA, Villeda SA, Passegué E
• O27: MICROGLIAL CORRECTION AFTER FETAL THERAPY WITHOUT CONDITIONING IN MICE WITH MUCOPOLYSACCHARIDOSIS TYPE VII.
  British Journal of Surgery 2021 Quoc-Hung Nguyen, Russell G Witt, Wang Bowen, Carlo Eikani, Jeremy Shea, Lucas K Smith, Gabrielle Boyle, Jaclyn Cadaoas, Renan Sper, John D MacKenzie, Saul Villeda, Tippi C MacKenzie
• Cognitive Aging: New Insights Into How Our Brains Age.
  Innovation in Aging 2020 Coleen Murphy, Saul Villeda
• Regeneration and Cognition in Aging.
  Innovation in Aging 2020 Saul Villeda
• Dampening the Power of the Brain-When Aging Meets Cognition.
  The journals of gerontology. Series A, Biological sciences and medical sciences 2020 Shea JM, Villeda SA
• Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation.
  Proceedings of the National Academy of Sciences of the United States of America 2020 White CW, Fan X, Maynard JC, Wheatley EG, Bieri G, Couthouis J, Burlingame AL, Villeda SA
• The aged hematopoietic system promotes hippocampal-dependent cognitive decline.
  Aging cell 2020 Smith LK, Verovskaya E, Bieri G, Horowitz AM, von Ungern-Sternberg SNI, Lin K, Seizer P, Passegué E, Villeda SA
• Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain.
  Science (New York, N.Y.) 2020 Horowitz AM, Fan X, Bieri G, Smith LK, Sanchez-Diaz CI, Schroer AB, Gontier G, Casaletto KB, Kramer JH, Williams KE, Villeda SA
• Eosinophils regulate adipose tissue inflammation and sustain physical and immunological fitness in old age.
  Nature metabolism 2020 Brigger D, Riether C, van Brummelen R, Mosher KI, Shiu A, Ding Z, Zbären N, Gasser P, Guntern P, Yousef H, Castellano JM, Storni F, Graff-Radford N, Britschgi M, Grandgirard D, Hinterbrandner M, …
• Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII.
  Science translational medicine 2020 Nguyen QH, Witt RG, Wang B, Eikani C, Shea J, Smith LK, Boyle G, Cadaoas J, Sper R, MacKenzie JD, Villeda S, MacKenzie TC
• OPCs on a Diet: A Youthful Serving of Remyelination.
  Cell metabolism 2019 White CW, Pratt K, Villeda SA
• MECHANISMS OF BRAIN REJUVENATION.
  Innovation in Aging 2019 Saul Villeda
• Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain.
  Current biology : CB 2019 Wheatley EG, Albarran E, White CW, Bieri G, Sanchez-Diaz C, Pratt K, Snethlage CE, Ding JB, Villeda SA
• Tissue-Resident Group 2 Innate Lymphoid Cells Differentiate by Layered Ontogeny and In Situ Perinatal Priming.
  Immunity 2019 Schneider C, Lee J, Koga S, Ricardo-Gonzalez RR, Nussbaum JC, Smith LK, Villeda SA, Liang HE, Locksley RM
• Innovative approaches in cognitive aging.
  Neurobiology of aging 2019 Austad SN, Wood MA, Villeda SA, Voss JL, Sahay A, Albert M
• Platelets Give a Running Start to Adult Hippocampal Neurogenesis.
  Stem cell reports 2019 Schroer AB, Horowitz AM, Villeda SA
• Fetal enzyme replacement and stem cell transplantation in murine Sly syndrome targeting microglia.
  Molecular Genetics and Metabolism 2019 Quoc-Hung Nguyen, Russell Witt, Lucas Smith, Jeremy Shea, Bowen Wang, Carlo Eikani, Saul Villeda, Tippi MacKenzie
• MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage.
  Nature metabolism 2019 Sousa-Victor P, Neves J, Cedron-Craft W, Ventura PB, Liao CY, Riley RR, Soifer I, van Bruggen N, Kolumam GA, Villeda SA, Lamba DA, Jasper H
• Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration.
  Molecular neurodegeneration 2018 Bieri G, Lucin KM, O'Brien CE, Zhang H, Villeda SA, Wyss-Coray T
• Hematopoietic Stem Cell Transplantation Using a Non-Toxic Regimen to Ablate the Fetal Bone Marrow Niche Enables Engraftment of Brain Microglial Cells.
  Journal of the American College of Surgeons 2018 Quoc-Hung L. Nguyen, Russell G. Witt, Bowen Wang, Jeremy Shea, Saul Villeda, Tippi C. Mackenzie
• 1021 Origin of type 2 innate lymphoid cells in the skin.
  Journal of Investigative Dermatology 2018 J. Lee, C. Schneider, H. Liang, R. Ricardo-Gonzalez, J. Nussbaum, L. Smith, S. Villeda, R. Locksley
• Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.
  Cell reports 2018 Gontier G, Iyer M, Shea JM, Bieri G, Wheatley EG, Ramalho-Santos M, Villeda SA
• The systemic environment: at the interface of aging and adult neurogenesis.
  Cell and tissue research 2017 Smith LK, White CW, Villeda SA
• Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner.
  Nature communications 2017 Deczkowska A, Matcovitch-Natan O, Tsitsou-Kampeli A, Ben-Hamo S, Dvir-Szternfeld R, Spinrad A, Singer O, David E, Winter DR, Smith LK, Kertser A, Baruch K, Rosenzweig N, Terem A, Prinz M, Villeda S, …
• Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease.
  F1000Research 2017 Horowitz AM, Villeda SA
• Mechanisms of Hippocampal Aging and the Potential for Rejuvenation.
  Annual review of neuroscience 2017 Fan X, Wheatley EG, Villeda SA
• Preclinical Assessment of Young Blood Plasma for Alzheimer Disease.
  JAMA neurology 2016 Middeldorp J, Lehallier B, Villeda SA, Miedema SS, Evans E, Czirr E, Zhang H, Luo J, Stan T, Mosher KI, Masliah E, Wyss-Coray T
• Migratory and adhesive cues controlling innate-like lymphocyte surveillance of the pathogen-exposed surface of the lymph node.
  eLife 2016 Zhang Y, Roth TL, Gray EE, Chen H, Rodda LB, Liang Y, Ventura P, Villeda S, Crocker PR, Cyster JG
• Microglia communication: Parallels between aging and Alzheimer's disease.
  Clinical & experimental neuroimmunology 2016 Udeochu JC, Shea JM, Villeda SA
• Translational strategies in aging and age-related disease.
  Nature medicine 2015 Armanios M, de Cabo R, Mannick J, Partridge L, van Deursen J, Villeda S
• Fat Chance for Neural Stem Cells in Alzheimer's Disease.
  Cell stem cell 2015 Gontier G, Lin K, Villeda SA
• β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.
  Nature medicine 2015 Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, Gontier G, Wabl R, Plambeck KE, Udeochu J, Wheatley EG, Bouchard J, Eggel A, Narasimha R, Grant JL, Luo J, Wyss-Coray T, Villeda SA
• Aging and brain rejuvenation as systemic events.
  Journal of neurochemistry 2014 Bouchard J, Villeda SA
• ALK5-dependent TGF-β signaling is a major determinant of late-stage adult neurogenesis.
  Nature neuroscience 2014 He Y, Zhang H, Yung A, Villeda SA, Jaeger PA, Olayiwola O, Fainberg N, Wyss-Coray T
• Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.
  Nature medicine 2014 Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T
• Long-term cognitive impairments and pathological alterations in a mouse model of repetitive mild traumatic brain injury.
  Frontiers in neurology 2014 Luo J, Nguyen A, Villeda S, Zhang H, Ding Z, Lindsey D, Bieri G, Castellano JM, Beaupre GS, Wyss-Coray T
• Focused Plasma Proteomics for the Study of Brain Aging and Neurodegeneration.
  The OMICs 2013 Philipp A. Jaeger, Saul A. Villeda, Daniela Berdnik, Markus Britschgi, Tony-Coray Wyss
• Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.
  The Journal of experimental medicine 2013 Luo J, Elwood F, Britschgi M, Villeda S, Zhang H, Ding Z, Zhu L, Alabsi H, Getachew R, Narasimhan R, Wabl R, Fainberg N, James ML, Wong G, Relton J, Gambhir SS, Pollard JW, Wyss-Coray T
• The circulatory systemic environment as a modulator of neurogenesis and brain aging.
  Autoimmunity reviews 2012 Villeda SA, Wyss-Coray T
• The ageing systemic milieu negatively regulates neurogenesis and cognitive function.
  Nature 2011 Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko…
• Complement receptor 2 is expressed in neural progenitor cells and regulates adult hippocampal neurogenesis.
  The Journal of neuroscience : the official journal of the Society for Neuroscience 2011 Moriyama M, Fukuhara T, Britschgi M, He Y, Narasimhan R, Villeda S, Molina H, Huber BT, Holers M, Wyss-Coray T
• FoxO3 regulates neural stem cell homeostasis.
  Cell stem cell 2009 Renault VM, Rafalski VA, Morgan AA, Salih DA, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC, Palmer TD, Butte AJ, Brunet A
• Microglia--a wrench in the running wheel?
  Neuron 2008 Villeda S, Wyss-Coray T
• Absence of Reelin results in altered nociception and aberrant neuronal positioning in the dorsal spinal cord.
  Neuroscience 2006 Villeda SA, Akopians AL, Babayan AH, Basbaum AI, Phelps PE
• Developmental distribution of reelin-positive cells and their secreted product in the rodent spinal cord.
  The Journal of comparative neurology 2004 Kubasak MD, Brooks R, Chen S, Villeda SA, Phelps PE