AMSTERDAM — Aging is a significant public health issue that also profoundly affects the lungs. Research presented at the European Respiratory Society (ERS) International Congress 2025 suggests that injuries and exposures from before conception through early life can predict how our lungs will age.

“In life, there are windows of susceptibility to exposures or to other factors like obesity, that have an impact on people and their children,” Didier Cataldo, MD, PhD, a pulmonologist and professor at the University of Liège, Belgium, told Medscape Medical News. Understanding these windows is critical for protecting young people from pollutants, such as cigarette smoke and environmental pollution, to prevent health issues later in their own lives and even in the next generation, he explained.

Before Conception: A Father’s Influence 

A father’s lifestyle and health status, particularly during his puberty, can have a strong effect on his offspring’s respiratory health. The pre-conception environment appears to be as important as the in utero environment for shaping future lung health, with evidence pointing toward epigenetic inheritance through the male germline.

Cecilie Svanes, MD, PhD, professor and physician at the University of Bergen, Norway, presented findings from RHINE, a large-scale cohort study involving more than 27,000 offspring-parent pairs, and revealed that fathers who started smoking before the age of 15 had offspring with a significantly higher risk for asthma, comparable to that observed with maternal smoking during pregnancy. In contrast, if a mother smoked and quit before conception, no association to asthma was observed. These findings have been replicated in multiple independent studies. The European Community Respiratory Health Survey (ECRHS) study and the Tasmanian Longitudinal Health Study found the same trends.

In addition, the RHINESSA study, which investigated the children and parents of participants in the RHINE and ECRHS studies, found that a father smoking before the age of 15 and a father’s exposure to secondary smoking as a child were also associated with lower offspring lung function.

Paternal overweight status during this same pubertal window was also linked to an increased asthma risk in children, an effect not seen with maternal overweight status. These findings highlight a clear sex-specific effect, Svanes explained.

In a genome-wide analysis, researchers found that a father’s overweight status was associated with changes at over 2000 CpG sites — locations where DNA methylation occurs — in their children, and these sites were linked to asthma and lung function. Similarly, paternal smoking was associated with its own unique DNA methylation signals in offspring, distinct from those caused by personal or maternal smoking. 

Svanes also showed that a father smoking before age 15 was linked to accelerated epigenetic aging, or a faster biological clock, specifically in his daughters. “The father’s pre-conception environment and lifestyle, particularly during puberty, appear to be as important as the in utero environment,” Svanes said.

The biological explanation for these findings likely lies in “susceptible windows in sperm development,” Svanes proposed. Prior to puberty, when primordial germ cells mature into spermatogonia, there seems to be a phase where extensive epigenetic reprogramming occurs, making the cells especially susceptible to environmental factors, such as tobacco smoke or metabolic alterations brought on by obesity. These exposures have the potential to disrupt this delicate process, resulting in changed germline epigenetic patterns that are subsequently transferred to the fetus, affecting the child’s development and raising the risk for disease in later life.

Questions remain on whether these effects could be passed down through multiple generations. While human data is limited, animal studies suggest transgenerational epigenetic inheritance is possible, though the exact mechanisms — whether through DNA methylation, microRNAs, or other factors — remain unclear, Svanes explained.

Triggers of Premature Lung ‘Inflammaging’ 

Maternal obesity can trigger a premature aging process in the lungs of offspring, characterized by “inflammaging,” or chronic, low-grade inflammation. Miguel Angel Alejandre Alcázar, MD, PhD, a pediatrician and assistant professor for translational experimental pediatrics at the University Hospital Cologne, Germany, discussed how these early metabolic stressors can uncouple biological age from chronological age.

Using an animal model where female mice were fed a high-fat diet, his research demonstrated that maternal obesity leads to a metabolic syndrome-like condition in the offspring at 3 weeks of age, characterized by increased fat mass and impaired glucose tolerance. Even when these offspring were switched to a normal diet and recovered metabolically, the lung was still damaged when examined at 10 weeks of age, Alcázar said. The mice showed persistent increased bronchial muscularization and thickened microvessels, which led to airway obstruction and pulmonary hypertension in adulthood.

The researchers identified the inflammatory cytokine interleukin-6 (IL-6) as the key driver of this lung damage. First, they observed that the offspring of obese mothers had high levels of IL-6. This cytokine was found to trigger a chain reaction inside lung cells that shut down a protective protein called FOXO1, which normally prevents excessive cell growth. When FOXO1 is turned off, the smooth muscle cells in the airways and blood vessels began to multiply uncontrollably, causing thickening and obstruction in the lungs. To confirm that IL-6 was the culprit, the researchers treated a group of these offspring with an antibody that specifically blocked IL-6, which prevented the lung damage from occurring, demonstrating their hypothesis.

The harmful effects of maternal obesity were also observed in the lung’s gas-exchange region. Alcázar explained that development of the alveoli was halted in the offspring of obese mothers. This led to the lungs developing an emphysema-like structure in adulthood. Alcázar said that the high-fat environment caused DNA damage in the alveolar type 2 (AT2) progenitor cells, which are responsible for maintaining and repairing the alveoli. This damage triggered a stress response that stopped the cells from functioning properly. Just as with the airways, blocking IL-6 signaling protected these progenitor cells from damage and allowed the alveoli to develop normally.

Why Do We Age and Can We Slow It Down? 

Understanding the fundamental biology of aging can help developing interventions that can slow its progression. 

Mareike Lehmann, PhD, professor of translational inflammation research at the University of Marburg, Germany, explained that the lung’s ability to heal itself declines with age due to such processes as exhaustion of its stem cells and buildup of chronic inflammation. A major contributor to this decline is the accumulation of senescent cells. In a mouse model of lung fibrosis induced by bleomycin, she demonstrated that while young mice could resolve the injury, old mice were unable to resolve the fibrotic response, a failure that was directly associated with a persistent accumulation of these senescent cells. 

These cells, Lehmann explained, are “zombie cells”: They stop dividing but don’t die. Instead, they secrete a cocktail of inflammatory signals that disrupt the surrounding tissue; prevent stem cells from working properly; and promote fibrosis.

Targeting this accumulation is therefore a promising therapeutic strategy. Senolytics, a class of drugs that selectively trigger the death of these harmful senescent cells, have shown success in preclinical models. Treatment with a combination of dasatinib and quercetin effectively cleared senescent cells from mouse lungs, reducing the existing fibrosis and improving the lung’s overall health. 

Lehmann said several ongoing clinical trials are now testing senolytics and other drugs with antiaging properties, such as metformin, for idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, but the challenge of identifying patients with accelerated lung aging as early as possible remains.

Clinical Implications 

The seeds of adult lung disease are often sown decades earlier, even before birth. Such factors as a father’s health during puberty and a mother’s health during pregnancy can have lasting, intergenerational effects on lung structure, function, and the pace of aging.

Understanding these connections opens new possibilities for prevention and treatment. As Cataldo said, a “deep understanding of these basic biological mechanisms is crucial because it could lead to new treatments.”

Cataldo, Svanes, Alcázar, and Lehmann report no relevant financial relationships.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.