# Role of immunosenescence in Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $360,473

## Abstract

ABSTRACT
The world’s population is rapidly aging. Seventy percent of persons over 65 years of age have two or more
chronic diseases1. This includes Alzheimer’s disease (AD) and related dementias, cardiovascular disease,
osteoarthritis and diabetes, all of which negatively impact quality of life and resilience. Identifying fundamental
cell autonomous and non-autonomous mechanisms driving aging and age-related diseases such as AD and
devising strategies to therapeutically target them is imperative to alleviate tremendous disease burden and
healthcare costs. It is generally accepted that damaged or stressed cells activate a variety of signaling cascades
that regulate cell fate decisions, including senescence and apoptosis. These cell autonomous events can lead
to impaired tissue homeostasis via loss of functional, terminally-differentiated cells or via loss of regenerative
capacity. For example, senescence increases in different cell types in the brains of mouse models of AD and
reduction in this senescent cell burden either genetically or pharmacologically improves pathology. There is also
strong evidence for cell non-autonomous mechanisms of aging, including data from experiments implementing
heterochronic parabiosis2-7, plasma transfer7 and measurement of the senescence-associated secretory
phenotype (SASP) produced by senescent cells8-11. To ask if “aging” of one organ or cell type is sufficient to
drive aging in other tissues, we created a series of mice with tissue-specific “aging”. Ercc1, a gene that encodes
one subunit of the DNA repair endonuclease ERCC1-XPF, was deleted in 7 organs or cell types using Cre-lox
technology. Loss of Ercc1 expression destabilizes the holoenzyme ERCC1-XPF in vivo12. As a consequence,
spontaneous, endogenous DNA damage accumulates more rapidly in tissues of mutant mice compared to wild-
type (WT) mice able to repair the damage13. For example, deletion of Ercc1 in pancreatic ß cells results in a type
II diabetes-like condition with evidence of senescence and SASP in fat and liver whereas deletion in podocytes
develop chronic kidney disease. Interestingly, deletion of Ercc1 in the hematopoietic compartment using the
Vav (HS21/45) promoter to drive Cre expression14 potently drove senescence and loss of tissue homeostasis in
the immune compartment, but also in multiple solid organs including the brain. Vav-Cre+/-;Ercc1-/fl mice have
premature senescence of immune cells and many characteristics of immunosenescence typical of aged mice
and humans15, including impaired immune function. This was accompanied by increased expression of
senescence markers p16Ink4a, p21Cip1 and senescence-associated secretory phenotype (SASP) factors in
multiple tissues including brain, liver, kidney, lung, GI and aorta. The “aged” immune system was sufficient to
damage and impair function of solid organs as evidenced by increased liver enzymes in the serum, proteinuria,
loss of repair of damaged muscle and loss of intervertebral disc proteo...

## Key facts

- **NIH application ID:** 10286343
- **Project number:** 3R01AG063543-03S1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** LAURA Jane NIEDERNHOFER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $360,473
- **Award type:** 3
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10286343

## Citation

> US National Institutes of Health, RePORTER application 10286343, Role of immunosenescence in Alzheimer's disease (3R01AG063543-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10286343. Licensed CC0.

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