# Sirtuins in Lung Aging and Fibrosis

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2022 · —

## Abstract

Human fibrotic disorders affect many organ systems including heart, blood vessels, kidney, liver and lung,
accounting for excessive disease burden in the U.S., including among our Veterans Administration (VA) patient
population. The most common fibrotic lung disease, idiopathic pulmonary fibrosis (IPF), is characterized by
excessive scar tissue formation and irreversible destruction of the lung parenchyma, resulting in gas-exchange
abnormalities and ultimately respiratory failure. Aging is strongest risk factor for IPF; however, the
cellular/molecular mechanisms that account for the age-associated predilection to fibrotic disease are only
beginning to be explored. Improved understanding of the role of aging in this disease will aid in the
development of novel therapies with greater clinical efficacy.
 In support of this VA Merit Award renewal application, we have made several recent contributions to our
understanding of aging mechanisms in lung injury and repair mechanisms. Human subjects with IPF express
low levels of the mitochondrial sirtuin, SIRT3, in myofibroblastic foci and in ex-vivo fibroblasts isolated from IPF
lungs. This down-regulation of SIRT3 is replicated in an aging model of non-resolving fibrosis in mice; while
fibrosis in young mice largely resolves over 2-4 months post-bleomycin, aged mice manifest persistent fibrosis.
Our data indicate that this capacity for fibrosis resolution in young mice is associated with recovery of SIRT3
levels in the late reparative phase of lung injury, while this is absent in aged mice. However, re-constitution of
SIRT3 (via lung-targeted non-viral cDNA plasmid delivery) restores the capacity for fibrosis resolution in aged
mice. This protective effect is associated with in-vivo activation of FoxO3a, evidenced by higher levels of
nuclear FoxO3a. Both cellular senescence and the pro-fibrotic cytokine, transforming growth factor-β1 (TGF-
β1) induce a down-regulation of SIRT3 and FoxO3a, events that lead to mitochondrial dysfunction,
senescence and apoptosis resistance of lung fibroblasts. Our studies also support the possibility that
modulation of SIRT3 in alveolar macrophages regulates fibroblast activation of FoxO3a by a paracrine
mechanism. Additionally, the histone acetyltransferases, p300 and cyclic AMP-response element binding
protein (CREB)-binding protein (CBP), are implicated in the epigenetic down-regulation of SIRT3 by TGF-β1
and cellular senescence. Impaired activation of the SIRT3-FoxO3a signaling axis promotes a senescent and
apoptosis-resistant fibroblast phenotype, which drives persistent/non-resolving fibrosis.
 The central hypothesis to be tested in this grant proposal is that persistent/non-resolving fibrosis
associated with aging is mediated by impaired activation of Foxo3a in fibroblasts, either by SIRT3 deficiency in
fibroblasts themselves or by macrophage-derived paracrine mechanisms, contributes to mitochondrial
dysfunction, senescence and apoptosis resistance of lung fibroblast...

## Key facts

- **NIH application ID:** 10610127
- **Project number:** 7I01BX003056-06
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** Victor J. Thannickal
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 7
- **Project period:** 2016-01-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610127

## Citation

> US National Institutes of Health, RePORTER application 10610127, Sirtuins in Lung Aging and Fibrosis (7I01BX003056-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10610127. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*