Saul Villeda, PhD

Assistant Professor
Department of Anatomy
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research
+1 415 502-1929

The ability to reverse aging in the brain may enable us to sidestep the effects of aging that promote vulnerability to neurodegenerative diseases, providing a unique and unexplored therapeutic approach. We have recently shown that systemic manipulations such as heterochronic parabiosis or young blood administration can partially reverse age-related impairments in regenerative, synaptic and cognitive functions in the aged brain. Interestingly, heterochronic parabiosis studies revealed an age-dependent bi-directionality in the influence of the systemic environment indicating pro-youthful factors in young blood elicit rejuvenation while pro-aging factors in old blood drive pre-mature aging. Therefore, targeting pro-aging factors in old blood may provide an alternative approach to rejuvenate aging phenotypes. Our lab is interested in understanding what drives regenerative and cognitive impairments in the aging brain, and how the effects of aging can be reversed in the old brain. Ultimately, our goal is to elucidate cellular and molecular mechanisms that promote brain rejuvenation as a means by which to combat age-related neurodegeneration and cognitive dysfunction.

Research Summary: 
Mechanisms of Brain Aging and Rejuvenation

Websites

Publications: 

Endogenous neuronal DNA double-strand breaks are not sufficient to drive brain aging and neurodegeneration.

bioRxiv : the preprint server for biology

Cohen S, Cheradame L, Pratt KJB, Collins S, Barillas A, Carlson A, Ramani V, Legube G, Villeda SA, Mullins RD, Schwer B

A maternal brain hormone that builds bone.

Nature

Babey ME, Krause WC, Chen K, Herber CB, Torok Z, Nikkanen J, Rodriguez R, Zhang X, Castro-Navarro F, Wang Y, Wheeler EE, Villeda S, Leach JK, Lane NE, Scheller EL, Chan CKF, Ambrosi TH, Ingraham HA

Spatial Coding Dysfunction and Network Instability in the Aging Medial Entorhinal Cortex.

bioRxiv : the preprint server for biology

Herber CS, Pratt KJB, Shea JM, Villeda SA, Giocomo LM

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

Clarke MT, Remesal L, Lentz L, Tan DJ, Young D, Thapa S, Namduri S, Borges B, Kirn G, Valencia J, Lopez ME, Lu 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

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

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

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

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

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

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

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

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, Kniewallner KM

Neurobiology of Aging: New Insights From Across the Research Spectrum.

The journals of gerontology. Series A, Biological sciences and medical sciences

Villeda S, Brown-Borg H, Anderson R

Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function.

Cell reports

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

Bieri G, Schroer AB, Villeda SA

Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function.

Cell reports

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

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, Villeda S, Watt MJ, Xia A, Zierath JR, Goodpaster BH, Snyder M

Corrigendum: Long-Term Cognitive Impairments and Pathological Alterations in a Mouse Model of Repetitive Mild Traumatic Brain Injury.

Frontiers in neurology

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

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

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, Villeda S, Watt MJ, Xia A, Zierath JR, Goodpaster BH, Snyder MP

SYSTEMIC MECHANISMS OF BRAIN REJUVENATION.

Innovation in Aging

Saul Villeda

MHC class I H2-Kb negatively regulates neural progenitor cell proliferation by inhibiting FGFR signaling.

PLoS biology

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

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

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

Coleen Murphy, Saul Villeda

Regeneration and Cognition in Aging.

Innovation in Aging

Saul Villeda

Dampening the Power of the Brain-When Aging Meets Cognition.

The journals of gerontology. Series A, Biological sciences and medical sciences

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

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

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.)

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

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, Siegrist M, Moullan N, Hofstetter W, Leib SL, Villiger PM, Auwerx J, Villeda SA, Wyss-Coray T, Noti M, Eggel A

Tolerance induction and microglial engraftment after fetal therapy without conditioning in mice with Mucopolysaccharidosis type VII.

Science translational medicine

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

White CW, Pratt K, Villeda SA

Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain.

Current biology : CB

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

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

Austad SN, Wood MA, Villeda SA, Voss JL, Sahay A, Albert M

Platelets Give a Running Start to Adult Hippocampal Neurogenesis.

Stem cell reports

Schroer AB, Horowitz AM, Villeda SA

MANF regulates metabolic and immune homeostasis in ageing and protects against liver damage.

Nature metabolism

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

Bieri G, Lucin KM, O'Brien CE, Zhang H, Villeda SA, Wyss-Coray T

Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain.

Cell reports

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

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

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, Citri A, Amit I, Schwartz M

Mechanisms of Hippocampal Aging and the Potential for Rejuvenation.

Annual review of neuroscience

Fan X, Wheatley EG, Villeda SA

Preclinical Assessment of Young Blood Plasma for Alzheimer Disease.

JAMA neurology

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

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

Udeochu JC, Shea JM, Villeda SA

Translational strategies in aging and age-related disease.

Nature medicine

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

Gontier G, Lin K, Villeda SA

ß2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.

Nature medicine

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

Bouchard J, Villeda SA

ALK5-dependent TGF-ß signaling is a major determinant of late-stage adult neurogenesis.

Nature neuroscience

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

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

Luo J, Nguyen A, Villeda S, Zhang H, Ding Z, Lindsey D, Bieri G, Castellano JM, Beaupre GS, Wyss-Coray T

Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival.

The Journal of experimental medicine

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 ageing systemic milieu negatively regulates neurogenesis and cognitive function.

Nature

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 DR, Xie XS, Rando TA, Wyss-Coray T

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

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

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

Villeda S, Wyss-Coray T

Absence of Reelin results in altered nociception and aberrant neuronal positioning in the dorsal spinal cord.

Neuroscience

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

Kubasak MD, Brooks R, Chen S, Villeda SA, Phelps PE