# mTOR Regulation of Basal Antiviral Immunity in the Elderly

> **NIH NIH R01** · RESTORBIO, INC. · 2020 · $293,156

## Abstract

Immunosenescence, or the decline in immune function with age, results in a reduced ability of elderly patients
to effectively detect and fight infections. Respiratory tract infections (RTIs), the majority of which are caused by
viruses, are a leading cause of death in the elderly, and few therapies exist to treat them. Inhibition of the
mechanistic Target of Rapamycin (mTOR) pathway has been shown to extend lifespan and ameliorate multiple
aging-related pathologies including immunosenescence. mTOR functions as part of at least two multi-protein
complexes, TORC1 and TORC2. TORC1 inhibition has been shown to ameliorate immunosenesence in both
preclinical models and clinical studies, including two Phase 2a studies in almost 500 elderly subjects. At doses
that selectively inhibit TORC1, the small-molecule drugs BEZ235 and RAD001 enhanced vaccination response
and reduced infections, including RTIs, in elderly subjects. Importantly, these beneficial effects were
accompanied by an increase in blood antiviral interferon stimulated gene (ISG) expression. Based on these
findings, we hypothesize that basal innate antiviral gene expression is deficient in the elderly, and that TORC1
inhibitors upregulate antiviral gene expression in blood and respiratory tract epithelium in the elderly and thereby
reduce the incidence of RTIs. We will leverage our ongoing and planned clinical trials of these drugs to test the
hypothesis that TORC1 inhibition reduces the incidence of RTIs in elderly subjects by upregulating antiviral ISG
expression. Specifically, we will measure the extent and kinetics of blood and pharyngeal ISG upregulation
following TORC1 inhibitor administration and examine the relationship between ISG expression upregulation,
TORC1 inhibitor exposure, and RTI incidence. We further propose to determine the mechanism by which TORC1
inhibitors upregulate ISG expression using an in vitro influenza infection model. We will use this model to
investigate potential nodes within the interferon-signaling pathway that mediate the upregulation of ISG
expression and antiviral effects of TORC1 inhibitors. Finally, we will determine if populations known to be at risk
of RTI-related morbidity and mortality have deficient ISG expression by comparing baseline ISG expression in
blood and nasopharyngeal swabs between young and elderly subjects, and between subjects of both age groups
with and without COPD and asthma. We expect that the proposed work will provide important insights into the
mechanism by which TORC1 inhibitors improve immune function and decrease infection rates in the elderly.
Moreover, broadening our understanding of the mechanism underlying the immune enhancing effects of TORC1
inhibitors will help define new targets to exploit for treatment of immunosenescence.

## Key facts

- **NIH application ID:** 9928349
- **Project number:** 5R01AG064802-02
- **Recipient organization:** RESTORBIO, INC.
- **Principal Investigator:** JOAN B MANNICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $293,156
- **Award type:** 5
- **Project period:** 2019-05-15 → 2021-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928349

## Citation

> US National Institutes of Health, RePORTER application 9928349, mTOR Regulation of Basal Antiviral Immunity in the Elderly (5R01AG064802-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9928349. Licensed CC0.

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