# Investigating the pro-aging role  of B2M and MHC molecules on regenerative and cognitive function in the brain

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $324,925

## Abstract

PROJECT SUMMARY/ABSTRACT
Aging drives regenerative and cognitive impairments in the adult brain, increasing susceptibility to
neurodegenerative disorders in healthy individuals. One exciting possibility is to harness the regenerative
capacity of stem cells in the adult brain to reverse normal aging and ameliorate cognitive dysfunction by
enhancing neurogenesis. We, and others, have shown that systemic manipulations such as heterochronic
parabiosis (in which the circulatory system of a young and old animal are joined) or young plasma
administration can partially reverse age-related impairments in neural stem/progenitor cell (NPC) function and
loss of cognitive faculties in the aged brain. Interestingly, heterochronic parabiosis studies have revealed an
age-dependent bi-directionality in the influence of the systemic environment indicating anti-aging factors in
young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that
mitigating the effect of pro-aging factors may also provide an effective approach to rejuvenate aging
phenotypes, however functional investigation of individual pro-aging factors is lacking. Recently my lab
identified β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules,
as a systemic pro-aging factor that negatively regulates regenerative and cognitive functions in the adult
hippocampus. The purpose of the proposed study is to gain mechanistic insight into the pro-aging effects of
MHC I molecules on the aging brain, and ascertain the therapeutic potential of targeting these molecules at old
age. Specifically, our hypothesis is that B2M in concert with classical MHC I molecules act as pro-aging factors
driving age-related regenerative and cognitive impairments in the adult hippocampus. We will test this theory
with Three Specific Aims: 1: Characterize age-related molecular mechanisms downstream of B2M and MHC I
underlying regenerative and cognitive enhancements in the adult brain. 2: Determine effectiveness of reducing
cell surface MHC I expression to ameliorate age-related regenerative and cognitive impairments. 3: Investigate
classical MHC I molecules, H2-Kd and H2-Db, as pro-aging negative regulators of regenerative and cognitive
function in the brain. Successful completion of these studies will have significant translational potential,
identifying molecular pathways that could be targeted for novel therapies to ameliorate dementia-related
neurodegenerative disorders and their downstream consequences in terms of impaired regenerative and
cognitive functions.

## Key facts

- **NIH application ID:** 10112790
- **Project number:** 5R01AG055797-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** SAUL A VILLEDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $324,925
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112790

## Citation

> US National Institutes of Health, RePORTER application 10112790, Investigating the pro-aging role  of B2M and MHC molecules on regenerative and cognitive function in the brain (5R01AG055797-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10112790. Licensed CC0.

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