# Role of miRNA Argonautes in organismal aging

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $375,773

## Abstract

PROJECT SUMMARY
The discovery that regulatory RNAs control almost every biological pathway has revolutionized our
understanding of gene expression over the past decade. At the forefront, microRNAs (miRNAs) have
proven to be an abundant and essential class of RNA molecules in plants and animals. The
importance of miRNAs in human biology is highlighted by the increasing recognition that
misregulation of specific miRNA pathways contributes to complex diseases, including cancer, heart
ailments and neuronal pathologies. MiRNAs depend on Argonaute (AGO) proteins to bind and
regulate the expression of target genes at the post-transcriptional level. In C. elegans, the AGO Like
Genes 1 and 2 (ALG-1, ALG-2) proteins are over 85% identical at the amino acid level and function
redundantly during development. However, at adulthood these AGOs take on opposing roles, as alg-
1 or alg-2 mutants exhibit shortened or extended lifespans, respectively. Additionally, healthspan, as
measured by maximum velocity, is reduced in alg-1 and increased in alg-2 mutants compared to
wildtype adults. One longevity pathway that is differentially impacted by the loss of either AGO is
Insulin/ IGF-1 Signaling (IIS). These preliminary studies lead to the hypothesis that differences in the
expression or activity of alg-1 and alg-2 allow them to regulate distinct sets of genes in the IIS
pathway to control lifespan in adult animals. In Aims 1 and 2, the genetic basis and potential tissue
specific activities responsible for the opposing longevity functions of alg-1 and alg-2 will be
determined. Cutting edge methods for detecting the specific miRNAs and targets bound by ALG-1
and ALG-2 will be utilized in Aim 3. This will result in the first map of miRNA specific target sites in an
adult animal and provide unprecedented insights into the direct roles of alg-1 and alg-2 in the IIS, and
perhaps other, longevity pathways. Furthermore, by revealing the miRNA targeting landscape in adult
C. elegans a new foundation will be set for investigating longevity roles for conserved miRNAs and
targets in other species. Another broad impact of this study is that it will reveal how two proteins
considered redundant take on opposing roles in aging, which will provide a paradigm for considering
the importance of context for the function of related genes in any pathway. Additionally, the methods
used here to identify miRNA specific target sites are generally applicable across systems and, thus,
will help eliminate a longstanding barrier to matching miRNAs with their endogenous target sites.
Finally, a long-term goal of this work is to contribute to the rational design of strategies to modify gene
expression with the intention of preventing or counteracting age-related maladies.

## Key facts

- **NIH application ID:** 9920648
- **Project number:** 5R01AG056562-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** AMY E. PASQUINELLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $375,773
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920648

## Citation

> US National Institutes of Health, RePORTER application 9920648, Role of miRNA Argonautes in organismal aging (5R01AG056562-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920648. Licensed CC0.

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