Aging and Estrogenic Control of the Bioenergetic System in Brain

Our earlier mechanistic analyses of estrogen action in brain led to the discovery that estrogen is a master
regulator of the bioenergetic system in brain that promotes glucose transport, glucose metabolism,
mitochondrial respiration and ATP generation. Collectively, the data provided compelling evidence for estrogen
as a systems biology metabolic regulator in brain and illuminated compensatory mechanisms consistent with
an aging female brain that is starving. For estrogen to function as master regulator of the bioenergetic system
in the female brain, estrogen must be integrating nuclear and mitochondrial genomic responses. Further from a
systems level perspective, it would be necessary for estrogen to also regulate cytoplasmic signaling
mechanisms for real time feedback on the functional outcomes of nuclear and mitochondrial gene transcription.
The fundamental issues to be investigated are the mechanisms whereby estrogen integrates bioenergetic
responses across two genomic compartments while simultaneously monitoring energetic demand and
performance in real time. The proposed program of research is designed to test two hypotheses. First,
estrogenic control of the bioenergetic system in the female brain requires: 1) both nuclear and mitochondrial
genomes; 2) integration of gene expression across both genomic compartments and 3) activation of rapid
signaling cascades to provide real time feedback on bioenergetic performance. Second, we hypothesize that
loss of estrogen in the aging female brain leads to a systematic dis-integration of estrogenic control of nuclear
and mitochondrial genomes followed by decline in bioenergetic sensing mechanisms. Estrogenic control of the
bioenergetic system of the brain and the dismantling thereof has basic, translational and clinical significance.
From a discovery perspective the proposed program of research is unique in exploring the mechanisms
underlying estrogenic integration of nuclear and mitochondrial gene expression and the real time feedback
mechanisms that control the bioenergetic system of the brain. Further, the process by which this control
system is dismantled in the aging female brain is uncharted territory of high significance for understanding
bioenergetic aging in brain. Translationally, determining the mechanisms underlying the systematic dismantling
of estrogenic integration of bioenergetic compartments in brain has the potential to detect therapeutic targets to
sustain bioenergetic function in the aging female brain. Clinically, the aging transition of menopause, unique to
the female, is a process that dismantles both reproductive ability and potentially bioenergetic capacity in brain.
This is particularly relevant to age-related neurological conditions associated with deficits in glucose
hypometabolism such as Alzheimer's, depression and multiple sclerosis which have greater prevalence in
postmenopausal women. Research proposed herein aligns with NIA Strategic Research Goals A and C and
the “need to better distinguish patterns of brain aging” https://www.nia.nih.gov/about/living-long-well-21st-
century-strategic-directions-research-aging and to objectives of Office of Research on Women's Health.

Grant Number: 5R37AG053589-09
NIH Institute/Center: NIH
Principal Investigator: ROBERTA BRINTON