# Direct and Indirect Effects of GDF11 in the Aging Central Nervous System

> **NIH NIH R01** · HARVARD UNIVERSITY · 2024 · $625,920

## Abstract

Late onset neurodegenerative diseases together affect more than 7 million Americans with associated
healthcare costs currently reach hundreds of billions of dollars per year. Cognitive decline is a common feature
of many of these diseases, especially Alzheimer’s disease, Parkinson’s disease, and vascular dementia. In
spite of exciting progress being made in studying those disorders, currently, there are no available
therapeutics capable of improving cognition. Therefore, it came as a surprise when a set of observations from
a few labs, including ours, supported the notion that recovery of brain function after damage to the CNS might
be achievable. Much of the data was obtained from studies of heterochronic parabiotic mice – young and old
mice whose circulatory systems had been surgically joined. Our additional studies were equally exciting in that
they demonstrated that injection of a single factor, GDF11, a normal serum protein, into aged mice was also
able to improve important properties of the CNS. Specifically, GDF11 stimulated neurogenesis, increased
neural activity and improved vascular structure. Surprisingly, we found that GDF11 does not cross the blood-
brain barrier and instead may exert its effects by acting directly on aging brain vasculature. This proposal
focuses on understanding in much greater detail how GDF11 exerts these ameliorative effects on the CNS.
First, we will use a combination of histological, molecular and transcriptomic methods to investigate the effects
of GDF11 on the cells of the brain more broadly. We will employ several measures including markers of neural
activity, neurogenesis, angiogenesis, as well as changes in gene expression of the different cell types, and we
will determine the sequence of GDF11’s actions (testing the hypothesis that GDF11’s neural effects are
indirect and follow direct effects on brain vasculature). Next, we will compare GDF11’s effects on cells of the
CNS with effects of other TGFβ-family ligands such as GDF8, TGFβ2 and modified forms of GDF11.
Identifying the most effective ligand will help us understand the molecular changes these ligands produce, as
well as position us to develop effective therapeutics in the future. Finally, our unpublished findings show that
GDF11 and the components of its signaling pathway are expressed by multiple brain cell types well into
adulthood. We will compare and contrast the functions of systemically injected GDF11 with those of GDF11
acting from within the brain. We will use a combination of histology and genetic perturbation to quantify the
expression of GDF11 and its receptors across various regions the brain and how they are altered by aging. We
will then measure the consequences of reducing brain GDF11 on neurogenesis and neural function. This will
provide a better understanding of what might happen if systemic GDF11 gained direct access to neural cells in
diseases in which the blood-brain barrier becomes compromised. From this work, we hope to gain ...

## Key facts

- **NIH application ID:** 10847522
- **Project number:** 5R01AG072086-05
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Lee L Rubin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $625,920
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10847522

## Citation

> US National Institutes of Health, RePORTER application 10847522, Direct and Indirect Effects of GDF11 in the Aging Central Nervous System (5R01AG072086-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10847522. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*