# Proteostasis and metabolism in brain aging

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $626,560

## Abstract

PROJECT SUMMARY
Age-related neurodegenerative diseases like Alzheimer’s Disease exhibit a breakdown in neuronal protein
homeostasis (proteostasis). The relationship between age-related metabolic dysfunctions and protein
aggregation in such diseases remains poorly understood. Elucidating the molecular basis for the age-related
loss of proteostasis is expected to inspire new therapeutic approaches, not only for diseases like Alzheimer’s,
but more broadly for a wide range of age-related diseases. Increasingly, this promise of “Geroscience” is being
recognized as critical for extending our healthspan.
Among the most productive experimental approaches in Geroscience is the use of genetically accessible model
systems for the study of longevity. These models have allowed the identification of single gene mutations and of
interventions that extend lifespan, highlighting the plasticity of the aging process and suggesting avenues to
significantly alter its course. The cellular events impacted by such interventions and causing the lifespan
extension, however, remain largely unclear. In many cases, the effect on longevity is associated with changes
in proteostasis and metabolism.
To understand the relationship between proteostasis and longevity in detail, however, requires an integrated
approach that investigates the effects of lifespan extending perturbations on global protein homeostasis and
metabolic flux in a well-defined genetic system. Here, the applicants propose such integration by combining the
expertise of groups using genetic approaches (Jasper), proteomic and bioinformatic approaches (Schilling and
Ghaemmaghami), and metabolomic approaches (Ramanathan) to develop models for protein and metabolic
homeostasis in long-lived mutants of Drosophila.
Recent technological advances in the field of mass spectrometry have enabled global analyses of protein
turnover rates and metabolic flux in complex organisms. Combining these technologies with detailed analysis of
lifespan-extending genetic perturbations is expected to provide transformative new insights into molecular
changes required for longevity. The aims proposed by the applicants are to (i) assess age-related changes in
global protein turnover and metabolic flux, (ii) determine if changes in energy metabolism downstream of the
Jun-N-terminal Kinase and Insulin signaling pathways influence protein turnover, and (iii) perform genetic studies
to explore the causes of aging and longevity.
It is anticipated that combining the strengths of the Drosophila system with state-of-the-art proteomic and
metabolomic approaches will significantly accelerate the discovery of fundamental mechanisms influencing
physiology and cell function with age, providing new therapeutic avenues for age-related diseases.

## Key facts

- **NIH application ID:** 9934079
- **Project number:** 5R01AG057353-04
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Ali Pejmun Haghighi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $626,560
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934079

## Citation

> US National Institutes of Health, RePORTER application 9934079, Proteostasis and metabolism in brain aging (5R01AG057353-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934079. Licensed CC0.

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