The same biological processes that drive aging — such as energy loss — may also contribute to lung diseases such as chronic obstructive pulmonary disease (COPD).
Cleveland Clinic researchers have developed a metabolic age clock that evaluates an individual’s metabolic function relative to the expected norm for their age group. Using this tool, they identified a link between COPD and accelerated metabolic aging.
Led by pulmonologist Russell P. Bowler, MD, PhD, the study, published in Metabolites, is the first to establish a connection between metabolic age and COPD. Bowler believes the findings deepen our understanding of biological age (ie, how well organs and systems function) compared with chronological age, and how both factors contribute to COPD.
A New Way to Measure Metabolic Aging
“We have long known that lung function decreases by about 50% from age 25 to age 75. We also know that COPD is strongly associated with age and is usually diagnosed in the latter half of life,” said Bowler, who is also chair of genomic medicine, Lerner Research Institute, Cleveland Clinic, Cleveland.
To further investigate this connection, Bowler and his team developed a metabolic clock that estimates an individual’s metabolic age by decade using blood test results. Previously, there was no standardized method to measure metabolic age beyond assessing calorie-burning efficiency.
The researchers analyzed lab results from nearly 6000 individuals aged 40-80 years, identifying metabolites that change with age. They found shifts in metabolites linked to inflammation, stress response, and nutrient absorption. Using this data, they established a normal range of metabolic values for each decade of life.
Metabolic Dysfunction and COPD Progression
Bowler’s findings suggest that early metabolic dysfunction may accelerate lung aging, linking metabolic decline to COPD. Several critical metabolic pathways appear to contribute to COPD progression:
1. Energy Production and Mitochondrial Dysfunction
- Impaired adenosine triphosphate (ATP) generation: COPD is associated with mitochondrial dysfunction, leading to reduced ATP production. This limits cellular energy availability, exacerbating lung tissue damage and reducing repair capacity.
- Increased reactive oxygen species: Mitochondrial inefficiency leads to oxidative stress, which promotes inflammation and lung cell apoptosis.
2. Amino Acid Deficiencies and Muscle Wasting
- Branched-chain amino acids (BCAAs): Patients with COPD often have reduced BCAA levels, which are critical for muscle protein synthesis. This contributes to skeletal muscle wasting and respiratory muscle weakness.
- Glutathione deficiency: Low glutathione levels in patients with COPD impair antioxidant defenses, increasing susceptibility to oxidative stress and further lung tissue damage.
3. Lipid Metabolism Dysregulation
- Altered fatty acid beta-oxidation: Patients with COPD often exhibit inefficient fatty acid metabolism, leading to lipid accumulation and cellular stress.
- Leptin and adipokine dysregulation: Elevated leptin and low adiponectin levels contribute to systemic inflammation and increased COPD severity.
4. Chronic Inflammation and Stress Responses
- Monophosphate-activated protein kinase (AMPK) and mechanistic/mammalian target of rapamycin (mTOR) dysregulation: Reduced AMPK activation impairs cellular energy homeostasis, while excessive mTOR signaling drives inflammation and fibrosis.
- Endoplasmic reticulum stress and unfolded protein response (UPR): Chronic lung stress activates UPR pathways, leading to lung epithelial cell dysfunction and fibrosis progression.
5. Glucose Metabolism and Insulin Resistance
- Hyperglycemia and glycolytic shift: Patients with COPD often exhibit increased reliance on glycolysis due to mitochondrial dysfunction, leading to excessive lactate production and metabolic acidosis.
- Insulin resistance: Metabolic inflexibility in COPD is associated with insulin resistance, which exacerbates systemic inflammation and impairs lung tissue repair.
Building Upon Research
Understanding these metabolic pathways could pave the way for targeted anti-aging therapies for COPD. For example, “energy production could be enhanced through diets or medications that reduce mitochondrial stress and improve energy metabolism,” Bowler explained. “Several drugs already approved for targeting inflammatory processes might be useful, and improving glucose control could also benefit certain patients.”
Beyond COPD, the metabolic age clock may help reveal underlying mechanisms of age-related diseases such as Alzheimer’s, cancer, and diabetes, Bowler said.
Clinical Implications
Prescott Woodruff, MD, MPH, pulmonologist and chief of the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, emphasized the importance of addressing aging-related comorbidities in COPD. Issues such as cardiovascular disease, diabetes and metabolic syndrome, osteoporosis, and sleep disorders can exacerbate COPD, he said.
“The main value of this research paper is that it points to molecular mechanisms that may underlie morbidities of aging, and which could be targets of therapy in the future. Thus, it is a first step in understanding the biology and will require follow-up research.”
In the meantime, he said, proven lifestyle interventions such as smoking cessation, regular exercise, a healthy diet, and good sleep hygiene, can mitigate the effects of these comorbidities. “Enrollment in a pulmonary rehabilitation program,” Woodruff added, “is a great way for people with COPD to learn more about them.”
Bowler and Woodruff reported no relevant financial relationships.
