# Mechanisms of youth-associated blood-borne factors regulating CNS rejuvenation

> **NIH NIH RF1** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $1,518,274

## Abstract

Project Summary/Abstract: Novel approaches are needed to combat age-associated diseases of the brain,
including Alzheimer’s disease (AD). Aging is the strongest risk factor for AD, yet we lack a detailed mechanistic
understanding connecting normal aging to AD. Emerging data raise the possibility that neural plasticity can be
revitalized in aged organisms. These studies demonstrate that factors present in young blood are restorative
for aged tissues throughout the body, while suggesting links between the systemic environment and aging- and
AD-related changes in the brain. Aged mice sharing young blood via parabiosis or those treated via plasma
injections exhibit improved plasticity and improved cognitive performance. We provided evidence for specific
youth-associated proteins, tissue inhibitor of metalloproteinases 2 (TIMP2) and colony-stimulating factor 2
(CSF2), that revitalize hippocampal function in aged mice when provided systemically. Conversely, several
studies demonstrate that aged blood factors drive key aging phenotypes, including microgliosis and loss of
neurogenesis, as well as hippocampus-dependent cognitive deficits, working in part through CCL11 and B2M.
These studies leave fundamental questions open regarding the role of the systemic environment in aging and
its link to AD through modulation of pathology. Recent work supports a role of blood-borne factors in
modulating the state and function of the brain’s innate immune cells, microglia. Given this connection and data
linking many AD risk genes to innate immune function, there is clear rationale to explore the link between aging
and AD-related pathology through microglia. In preliminary studies, we find that exposure to young blood
reduces microgliosis in the brains of aged mice, suggesting that young blood factors regulate microglia state in
aging. In this proposal, we will rigorously address the role of youth-associated proteins in altering microglial
gene expression and morphological profiles with the goal of clarifying the link between aging and AD
pathomechanisms. We hypothesize that youth-associated factors rejuvenate microglia profiles in the aged
brain and in the context of AD pathology. We will address this hypothesis in three major aims: (1) To determine
the impact of systemic TIMP2 on microglia gene expression and morphology in aged mice; (2) to characterize
the extent to which blood-borne brain rejuvenation is regulated by microglia function; and (3) to evaluate the
impact of a combined systemic treatment of TIMP2 and CSF2 on age-associated vs. AD-associated changes
in microglia profile and state. Our aims will interrogate the role of youth-associated blood-borne factors in
regulating microglia using sophisticated approaches to rigorously define cellular and pathological regulation by
the systemic environment, potentially opening novel avenues for AD therapy development.

## Key facts

- **NIH application ID:** 10208164
- **Project number:** 1RF1AG072300-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Joseph Michael Castellano
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,518,274
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208164

## Citation

> US National Institutes of Health, RePORTER application 10208164, Mechanisms of youth-associated blood-borne factors regulating CNS rejuvenation (1RF1AG072300-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10208164. Licensed CC0.

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