Willard Freeman, Ph.D.


  • Donald W. Reynolds Chair in Aging Research
  • Associate Professor of Physiology
  • Research Scientist, Oklahoma City Veterans Affairs Medical Center
  • Adjunct Associate Professor of Geriatric Medicine
  • B.A. Chemistry and English, Wake Forest University
  • Ph.D. Pharmacology, Wake Forest University School of Medicine
  • Fellowships, Vollum Institute and Yerkes National Primate Research Center

Research Interests:    

  • Neurobiology of Aging and Neurodegeneration
  • Epigenomic Regulation
  • Neurobiology of Sex Differences
  • Diabetic Retinopathy

Research Summary:

  • Our research is primarily focused on molecular neurobiology, specifically in the areas of brain aging, diabetic retinopathy, and substance abuse.  These areas of investigation share a common theme of understanding how stimuli, e.g., the myriad experiences across a lifetime, diet, hyperglycemia with diabetes, chronic exposure to a drug with substance abuse, cause pathological changes to the central nervous system that remain even after the stimulus subsides.  The overarching concept behind these questions is that the cells of the central nervous system are extremely long lived and could continue to express an altered phenotype long after any specific stimulus is withdrawn. Epigenomic mechanisms are of specific interest to us as DNA modifications (cyosine methylation and hydroxymethylation) can persist for the lifetime of a cell.To study these modifications, we have developed a number of new next generation sequencing approaches and transgenic mouse models to investigate the epigenome of specific cell types.
  • Our studies involve the full spectrum from in vivo animal models to large scale 'omic analyses, and bioinformatics.  By bringing all of these capabilities into a single team we hope to obtain more biological insight into these questions than would be possible from any of these domains alone.
  • An area of growing emphasis in our studies is the inclusion of both male and female animal models.  Despite the well known sex differences in many human diseases of the central nervous system most studies have only used one sex or the other in studies.  In several recent studies we have found that sex differences are commonly found in the brain and retina.
  • www.freeman-lab.org

Recent Publications:

  • Unnikrishnan A, Freeman WM, Jackson J, Wren JD, Porter H, Richardson A. The role of DNA methylation in epigenetics of aging. Pharmacol. Ther. 2018 Nov 9. pii: S0163-7258.
  • Hadad N, Unnikrishnan A, Jackson JA, Masser DR, Otalora L, Stanford DR, Richardson A, Freeman WM. Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation. Neurobiology of Aging 2018; 67:53-66.
  • Masser DR, Hadad N, Porter H, Stout MB, Unnikrishnan A, Stanford DR, Freeman WM. Analysis of DNA modifications in aging research. Geroscience. 2018 Feb;40(1):11-29.
  • Unnikrishnan A, Hadad N, Masser DR, Jackson J, Freeman WM, Richardson A. Revisiting the genomic hypomethylation hypothesis of Aging. Annals NY Acad. Sci. 2018; 1418:69-79.
  • Imperio CG, McFalls AJ, Hadad N, Blanco-Berdugo L, Masser DR, Colechio EM, Coffey AA, Bixler GV, Stanford DR, Vrana KE, Grigson PS, Freeman WM. Exposure to environmental enrichment attenuates addiction-like behavior and alters molecular effects of heroin self-administration in rats. Neuropharmacology 2018 139:26-40.
  • Masser DR, Niran Hadad N, Mangold CA, Unnikrishnan A, Ford MM, Giles CB, Georgescu C, Dozmorov MG, Wren JD, Richardson A, Stanford DR, Freeman WM. Sexually divergent DNA methylation patterns with brain aging. Aging Cell 2017 16(6):1342-1352.
  • Mangold CA, Wronowski B, Du M, Masser DR, Hadad N, Bixler GV, Brucklacher RM, Ford MM, Sonntag WE, Freeman WM. Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. Journal of Neuroinflammation 2017; 14:141.
  • Masser DR, Otalora L, Clark NW, Kinter MT, Elliott MH, Freeman WM. Functional neural retinal changes occur in the absence of mitochondrial dysfunction in a rodent model of diabetic retinopathy. J. Neurochemistry 2017 143(5):595-608.
  • Mangold CA, Masser DR, Stanford DR, Bixler GV, Pisupati A, Giles CB, Wren JD,Ford MM, Sonntag WE, Freeman WM. CNS-wide Sexually Dimorphic Induction of the Major Histocompatibility Complex 1 Pathway with Aging. Journal of Gerontological Sciences. 2017 72:16-29
  • Hadad N, Masser DR, Logan S, Wronowski B, Mangold C, Clark N, Otalora L, Unnikrishnan A, Ford M, Giles C, Wren JD, Richardson A, Sonntag WE, Stanford DR, Freeman WM. Absence of genomic hypomethylation or regulation of cytosine modifying enzymes with aging in male and female mice. Epigenetics & Chromatin 2016; 9:30.
  • Masser DR, Stanford DR, Giles C, Wren J, Sonntag WE, Richardson A, Freeman WM. Bisulfite oligonucleotide-capture sequencing for targeted base- and strand-specific absolute 5-methylcytosine quantitation. AGE, 2016 38:49.


  • Sex divergence and cell specificity of age-related hippocampal DNA modifications. 1R56AG059430-01 NIA/NIH Role: PI.
  • Dynamics of the brain epigenome with aging. I01BX003906 VA Role: PI.
  • A new pathogenic mechanism for diabetic retinopathy. R01EY019309 NEI/NIH Role: Co-I.
  • Neuroepigenomics of Neural Stem Cell Aging. OCASCR Role: PI.
  • Mentoring Diabetes Research in Oklahoma P30GM122744 NIGMS/NIH Role: Co-I.
  • Oklahoma Nathan Shock Center of Excellence in the Biology of Aging. P30AG050911 NIA/NIH Role PI of Core.
  • Effect of HPV16 and ART on the epigenome leading to AIDS-Associated oral cancer. 1R01DE024964 NIDCR/NIH Role: Co-I.