# A genomic and functional genetic approach to elucidate the genetic basis of immunosenescence

> **NIH NIH R03** · UNIVERSITY OF MARYLAND BALTIMORE COUNTY · 2020 · $69,917

## Abstract

Age-related dysfunction of the immune system (immunosenescence) is a hallmark of aging and a significant
health risk for the elderly. Studies of humans and other vertebrates have identified many age-related changes
in the cellular components and physiology of the immune system that contribute to reduced immune function.
However, the underlying causes of these changes, including the genetic influences on immunosenescence,
are poorly understood. This is a major gap in our knowledge and limits our ability to design age appropriate
targeted therapy to address this important health risk. A promising and novel approach to this problem is to
apply age-specific genome wide association mapping to identify genes that influence immunosenescence.
The proposed project combines a genomic and functional genetics approach to identify genes that regulate the
age-specific ability to clear infection. The first aim uses the Drosophila Genetic Reference Panel, a set of 205
fully sequenced lines of Drosophila derived from a natural population, to identify genes that influence the age-
specific ability of Drosophila to clear bacterial infection by E. coli. The second aim will validate the effects of
candidate genes on a key component of innate immunity, age-specific phagocytosis. Drosophila are ideal for
this study for three primary reasons. First, the genes and signaling pathways regulating the innate immune
response are highly conserved between insects and mammals, so our results will provide gene targets for
follow-up studies in vertebrates. Second, genome-wide association studies in flies can be carried out on large
numbers of replicated genotypes under environmentally controlled conditions for the entire life span of
the organism, greatly enhancing our power to identify candidate genes. Third, extensive genetic resources for
Drosophila allow follow-up functional genetic tests to validate the effects of genes/pathways on age-
specific immunity. We expect to accomplish two goals: (1) use genome wide association tests to identify
candidate genes influencing the age-specific ability to clear infection; (2) to characterize the role of Arl2
(human orthologue ARL2), for its effect on phagocytosis in young and old flies. The expression of this gene,
and those involved in actin regulation and endosomal transport, were significantly associated with age-specific
bacterial clearance ability in our earlier transcriptomic study. Our strategy for verifying the effects of Arl2 on
immunity will be used on additional candidate genes identified in Aim 1 as time allows. The project is
innovative in its focus on genes influencing age-specific immune function, with focus on different aspects
of phagocytosis (engulfment and processing of ingested bacteria). The results will advance our
understanding of the genetic basis of age-specific immune function and provide genetic targets for
enhancement or restoration of immune function in the elderly.

## Key facts

- **NIH application ID:** 9849150
- **Project number:** 5R03AG061484-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE COUNTY
- **Principal Investigator:** Jeffery Leips
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,917
- **Award type:** 5
- **Project period:** 2019-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849150

## Citation

> US National Institutes of Health, RePORTER application 9849150, A genomic and functional genetic approach to elucidate the genetic basis of immunosenescence (5R03AG061484-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9849150. Licensed CC0.

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