Fight Aging!

Cardiovascular disease and cancer receive much of the public and scientific attention devotes to causes of human mortality, but it might surprise many people to know just how prominent respiratory conditions are in the list of causes of death. The various forms of damage and dysfunction accompanying aging predispose the lungs to all of the common fatal respiratory conditions, and incidence rates increase with age, even when the cause of disease is external, such as respiratory infections. Here, researchers take a tour of the present state of research into the aging of the respiratory system. Unlike past years, such a review now usually contains a discussion on the development of means to target mechanisms of aging and their potential relevance to the treatment of age-related conditions. It is a welcome change.

The respiratory system undergoes substantial ageing-related changes. The loss of function comes with a reduced adaptability to the ever-changing demands of the body, and more importantly, to an increase in disease states, such as sleep apnoea. The reduction in defences such as mucociliary clearance, coughing, and macrophage function causes increased respiratory infections. A reduction in autophagy, alongside replicative senescence and with chronic inflammation, contributes to age-related diseases such as COPD and pulmonary fibrosis. Sequential spatial analysis of biopsies or resection samples in individuals with airway disease will reveal altered structural and immune cell interactions associated with pathophysiological changes.

Much of what we know about lung ageing comes from the study of ageing in other systems or later-onset diseases, rather than a direct assessment from lung tissue sampled across all time periods of the life course from healthy individuals. The inference from other organ systems is particularly evident in the epigenetics and comes mainly from studies on blood cells or individuals with respiratory disease, rather than from studies on healthy lung tissue. In parallel, much of the genetic and molecular mechanisms are drawn from studies using tissue from individuals with COPD. Although COPD might represent a form of accelerated lung ageing, whether the mechanisms that underlie COPD are entirely replicative of normative ageing of the lung remains uncertain and cannot be elucidated without further study. Furthermore, a large proportion of our current understanding of lung ageing comes from animal models rather than human populations, and several areas of great importance remain almost completely unexplored. For example, research on the ageing of the mucociliary system in humans is restricted to only three studies, with one dating back to 1979.

Advances in genetic studies such as GWAS and whole-genome sequencing have been revolutionary in understanding the complexities of molecular alterations associated with diseases, and in uncovering new molecular targets. However, distinguishing which associations arise from direct effects of biological ageing on an organ system and which arise indirectly through other ageing-related pathologies is difficult. For example, GWAS on lung function found associations with genes that are related to confounding factors such as cancer and hypertension and genes related to environmental stressors, in addition to biological factors such as adult body size and BMI; whether these associations are genuine or arise due to overmatching remains to be elucidated.

Drugs that target the ageing process (senotherapies) could be of clinical value in treating respiratory diseases. Senotherapies include drugs that reduce the development of cellular senescence (senomorphics) and those that result in removal of senescent cells from lung tissue (senolytics). Several senotherapies have shown promising results in experimental models of age-related lung diseases, but only few clinical studies have been reported to date. Clinical studies of geroprotective therapies in lung diseases are challenging because the slow progression in these diseases is difficult to measure in clinical trials. However, changes in markers of senescence, such as p16INK4a and p21CIP1, and SASP mediators, are feasible. There is a need to know clinical biomarkers of lung ageing to identify the most suitable individuals for clinical trials and to monitor anti-ageing interventions.

Link: https://doi.org/10.1016/j.lanhl.2026.100842