# Distinct roles for calories, fasting, and mTOR in a calorie restricted diet

> **NIH NIH F31** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $32,702

## Abstract

PROJECT SUMMARY
 As the global population ages, developing interventions that can prevent or delay age-associated
diseases is of increasing importance to promote healthy aging. As a result, there is intense interest in
understanding the mechanisms by which calorie restriction (CR), an intervention which improves both lifespan
and healthspan in wide range of model organisms, functions. Despite a century of study, the mechanism by
which CR promotes health and longevity is still unknown. One prevailing model is that CR reduces the activity
of mTOR Complex 1 (mTORC1), a protein kinase that is a key regulator of metabolism. Genetic and
pharmaceutical inhibition of the mTORC1 signaling pathway extends lifespan, and studies in model organisms
suggest an epistatic interaction, suggesting a key role for mTORC1 in the response to CR. However, studies
from other labs have found that CR and mTORC1 inhibition have distinct effects on the transcriptome and
metabolome other tissues, and the interaction of CR and reduced mTORC1 signaling on metabolism, health,
and longevity have not been formally investigated in mammals. In fact, due to their very different feeding patterns,
it is not even clear that CR-fed animals have a reduction in mTORC1 signaling relative to ad libitum (AL) controls.
 During our preliminary studies, we determined that mTORC1 signaling is similar in AL and CR fed fasted
animals, and that CR-fed animals have elevated mTORC1 signaling as compared to AL-fed controls following
feeding. We also determined that constitutively activating hepatic mTORC1 signaling does not block the
metabolic effects of a CR diet. We also established that CR-fed animals are subject to both reduced calorie
intake and prolonged daily fasting, as they consume their entire allotment of food within a period of ~2 hours,
and fast for the remainder of the day, in sharp contrast to the normal food consumption pattern of a mouse. In
preliminary experiments using different feeding regiments to separate out the effects of fasting and calorie intake,
we have found that while many metabolic benefits of CR are mediated by calories, others may require fasting.
 The overall objective of the proposed project is to determine the role of mTORC1 in the mammalian
response to CR and if the benefits of CR are mediated by a reduction in calories and/or prolonged daily fast. We
will accomplish the objective with the following: 1) we will determine if CR-fed animals have reduced mTORC1
signaling over the course of a 24-hour cycle, and if reduced hepatic mTORC1 signaling is required in the
metabolic response to CR using genetically modified mice; and 2) We will utilize a novel experimental paradigm
to dissect fasting from calorie restriction in a calorie restriction paradigm, and longitudinally assess the effect of
reduced caloric intake with and without the imposition of daily fasting on the metabolic health, frailty, and
longevity of mice. Together, the proposed experiments will address long...

## Key facts

- **NIH application ID:** 10057212
- **Project number:** 5F31AG066311-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Heidi Hayang Pak
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,702
- **Award type:** 5
- **Project period:** 2019-09-09 → 2022-09-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057212

## Citation

> US National Institutes of Health, RePORTER application 10057212, Distinct roles for calories, fasting, and mTOR in a calorie restricted diet (5F31AG066311-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10057212. Licensed CC0.

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