Exploring the Molecular Landscape of Lung Health and Aging Through a Multi-Omics Lens

/ABSTRACT Lung function (LF) decline, a key indicator of respiratory health, is closely linked to age-related diseases, driving up healthcare costs and reducing quality of life. Understanding and mitigating LF decline is therefore essential. Aging, influenced by cellular senescence, inflammation, and oxidative stress, plays a central role in chronic disease progression. However, the molecular mechanisms underlying lung aging and disease susceptibility remain poorly understood. Inflammation and oxidative stress accelerate LF decline, while miRNAs and metabolites serve as key regulators, shaping both aging and disease trajectories. Clustering longitudinal lung function (LLF) data helps to identify patient subgroups with distinct disease patterns, enabling risk prediction and deeper insights into disease mechanisms. The central hypothesis of this proposal is that LF trends over time can cluster individuals, showing differences in epigenetic aging and predicting health outcomes, with multi-omics data uncovering the association between poor LF and accelerated aging. The overall objective of this proposal is to 1) develop and validate LLF based SpiroClusters in two large cohorts with electronic medical records (EMR) data and investigate associations between SpiroClusters, epigenetic age acceleration (EAA), and lung health outcomes; 2) identify shared and unique molecular signatures between SpiroClusters, LF decline and epigenetic aging rate (EAA) to reveal the molecular mechanisms associating worse LF trajectories to accelerated aging; 3) Develop a Molecular Knowledge Graph (MKG) of lung aging as a comprehensive resource for scientific community with multiple utilities, including biomarker identification, therapeutic target prioritization, and decoding mechanism of lung aging. Dr. Rinku Sharma, a bioinformatician, aims to become an independent data scientist specializing in multi- omic approaches to aging and lung disease. Her career plan focuses on: (1) deepening her understanding of aging and related lung diseases; (2) expanding her statistical skills, including integrative omics and longitudinal lung function clustering; (3) refining her skills in handling, QC, and integrating diverse omics data, such as epigenetics and metabolomics; and (4) enhancing her skills in study design, mentorship, and research ethics/communication. Dr. Sharma's strong quantitative and methodological background, combined with the support from a diverse and world-class mentoring and advisory team from the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School, has well prepared her to complete the aims of this proposal, and establish a successful, independent research career. Project Number: 1K99HL183694-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Rinku Sharma | Institution: BRIGHAM AND WOMEN'S HOSPITAL, BOSTON, MA | Award Amount: $170,570 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 IVBH-A (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K99HL18369401