# Age Induced Impairment of Nutrient Signaling Results in Bone Loss

> **NIH NIH P01** · AUGUSTA UNIVERSITY · 2020 · $154,000

## Abstract

ABSTRACT:
 Alzheimer's disease (AD) is a progressive degenerative disease of the brain characterized by
loss of memory and cognitive function. There is no cure for AD. The worldwide prevalence of AD was
46.8 million in 2015 and is expected to increase to 131.5 million by 2050. Therapeutic strategies to date
have had very limited success in slowing the progression of the disease. The potential beneficial impact
of exercise on AD disease is well known. Interestingly however in experiments in a mouse model of AD,
decreased exercise activity measured by voluntary wheel running precedes the onset of plaque
development.
 In our currently funded NIA PPG we have shown that kynurenine a tryptophan oxidation product
that accumulates with age results in loss of both bone and muscle mass. We have highlighted some of
these links in a recently co-edited (Hamrick and Isales) special issue in Experimental Gerontology: The
Kynurenine Pathway in Aging. Further, kynurenine has also been implicated in AD progression and
depression. A majority of kynurenine (60%) in the brain comes from peripheral sources and lowering
circulating kynurenine levels through exercise or activation of muscle PGC 1 alpha (in essence an
exercise mimetic) lowers circulating kynurenine levels by conversion to kynurenic acid (KNA which
does not cross the blood brain barrier) and protects against depression. We submitted an AD
supplemental request last year, which was not funded. In the current supplemental application, we
submit a less ambitious experimental plan whose purpose is to generate the preliminary data to then
submit a full RO1 application. Same approach to not only slow AD progression but also prevent bone
and muscle loss in the AD model. In this proposal we will use a PCG 1 alpha inducer, ZLN005 and
compare its effects to those of exercise (voluntary wheel running). Thus, the specific aims for this one-
year supplement are:
Specific Aim #1: Test the hypothesis that placing the AD mice on ZN005, compared to daily exercise,
will be beneficial in slowing AD progression.
Specific Aim #2: Test the hypothesis that, ZN005 will protect against muscle loss seen with AD onset
by lowering circulating kynurenic acid levels.

## Key facts

- **NIH application ID:** 10123627
- **Project number:** 3P01AG036675-09S1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** CARLOS M. ISALES
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $154,000
- **Award type:** 3
- **Project period:** 2011-05-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123627

## Citation

> US National Institutes of Health, RePORTER application 10123627, Age Induced Impairment of Nutrient Signaling Results in Bone Loss (3P01AG036675-09S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10123627. Licensed CC0.

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