Our neurobiology of aging research is focused on both the positive and negative changes to the brain with aging and understanding how these contribute to or prevent age-related cognitive decline and susceptibility to neurodegenerative diseases.
Our scientific premise is that changes in genomic patterns of DNA modifications – methylation (mC) and hydroxymethylation hmC – are central regulators of altered genome function and gene expression with aging. Our studies are determining changes in mC and hmC patterns with aging in specific hippocampal cell populations (neurons, microglia, and astrocytes) across the lifespan in both female and male mice, testing whether a ‘youthful’ modification pattern can be retained through caloric restriction, and identifying how altered DNA modification patterns regulate gene expression. The long-term goal of this research is to prevent or reverse age-related changes in DNA modification patterns to maintain healthy brain function and prevent neurodegenerative diseases such as Alzheimer’s.
Age-related differentially methylated CGs (aDMCGs) in male and female hippocampus. aDMCGs are presented by chromosomal location in males (top) and females (bottom) and the difference in mean methylation (Old-Young) on the inner axis. Each point represents one aDMCG meeting false discovery rate (FDR) cut off of q < 0.05. Sites ≥ 5 % absolute change in methylation with age (hypermethylated) are in green, while in red are sites ≤ -5% change with age (hypomethylated). These sites were used in a principle component analysis of the samples. Samples clustered by group and separated by age in the 1st component and by sex in the 2nd component.
From: Sexually divergent DNA methylation patterns with hippocampal aging. Masser DR, Hadad N, Porter HL, Mangold CA, Unnikrishnan A, Ford MM, Giles CB, Georgescu C, Dozmorov MG, Wren JD, Richardson A, Stanford DR, Freeman WM. Aging Cell. 2017 Dec;16(6):1342-1352.
Contrary to common assumptions, the brain does not lose a significant number of neurons with aging. Our research is investigating activation of microglial and astrocyte cell populations in the brain with aging as a mechanism of synapse loss. Intriguingly, neuroinflammatory processes demonstrate some of the largest sex divergences with aging and could underlie differences between males and females in Alzheimer’s disease.
Sex divergent, age-related hippocampal C1q protein expression. e-related differentially methylated CGs (aDMCGs) in male and female hippocampus. In sagital brain sections qualitatively increased immunoreactivity in both female and male mice (c-f). Detail regions of 24-month-old female (g) and male (h) mice show patches of C1qa-positive signals through the brain neuropil. Boxed areas show further magnified details of C1qa-positive patches. Scale bars 1mm.
From: Sexually divergent induction of microglial-associated neuroinflammation with hippocampal aging. Mangold CA, Wronowski B, Du M, Masser DR, Hadad N, Bixler GV, Brucklacher RM, Ford MM, Sonntag WE, Freeman WM.
J Neuroinflammation. 2017 Jul 21;14(1):141.