Project Details
Description
Project Summary
Poor diet and chronic physical inactivity synergize with aging to induce physical decline and cognitive
dysfunction. As a result, there is a current push to test various diet and exercise modalities that can improve
metabolic health, preserve cognition, and expand health span. Both various forms of caloric restriction and
exercise have been shown to provide benefits for metabolism, cognition, and physical function. One popular
notion is that fuel oscillations alternating between carbohydrate and fat utilization are beneficial for long term
metabolic and cognitive health. A key corollary is that ketone metabolism, triggered by carbohydrate restriction
and fat catabolism, may mediate the observed benefits. Indeed, exploiting ketone body metabolism has garnered
recent attention as a tool to improve both peripheral metabolism and treat impaired cognition in aging individuals.
Rationale for ketone metabolism in brain health originates from the benefits of ketogenic diets or starvation for
seizure disorders. Due to the robust stimulation of adipose tissue lipolysis and increased fat oxidation in the liver,
exercise is another trigger for hepatic ketogenesis, raising the question of whether the beneficial relationship
between brain health and exercise could at least in part be transduced by ketone metabolism. Currently there
are large clinical trials testing if ketogenic diets can mitigate or treat cognitive decline and neurodegenerative
conditions associated with aging, however, studies investigating mechanisms of action are lacking. This proposal
will fill this void by leveraging novel genetic mouse models and cutting-edge approaches to test the central
hypothesis that nutritional and exercise-mediated oscillations of integrated ketone metabolism improve
neurometabolic health span. Studying mice with selective loss of either hepatic ketogenesis or neuronal ketone
oxidation will allow independent dissection of the mechanistic roles of integrated ketone metabolism in mediating
the well-described benefits of intermittent fasting (Aim 1) and exercise (Aim 2), which are both established
models that provoke ketosis and ketone utilization by the brain, while also improving metabolic and cognitive
phenotypes. The specific roles of ketone metabolism on caloric intake; body composition; whole-body energy
homeostasis, glucose metabolism, lipid metabolism, and ketone turnover; cognitive function, including memory
and executive function; mitochondrial function in brain; metabolic flux (quantified using stable isotope tracers) in
brain; as well as the metabolome and transcriptome of discrete anatomic brain regions will all be quantified. Both
male and female mice will be examined in mid-life (12 months of age) after chronic Western diet feeding when
differences in health span will emerge via cognition, physical function, and metabolic phenotypes. By defining
the independent roles of both hepatic ketogenesis and neuronal ketone body oxidation in health span-promoting
interventions, the results will optimize therapies to be tested in future clinical trials. Moreover, this work will
elucidate specific therapeutic targets linking metabolism, cognition, and physical function in aging.
Status | Active |
---|---|
Effective start/end date | 9/30/20 → 5/31/24 |
Funding
- National Institute on Aging: $385,500.00
- National Institute on Aging: $314,880.00
- National Institute on Aging: $385,204.00
- National Institute on Aging: $385,375.00
- National Institute on Aging: $385,500.00
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