Recent research from the University of Pittsburgh has linked the increasing levels of the biomarker growth differentiation factor 15 (GDF15) with aging, demonstrating how mitochondrial dysfunction contributes to this phenomenon. The study highlights the relationship between elevated circulating GDF15, insulin resistance, and metabolic changes typically observed as organisms age.
GDF15, part of the TGF-β superfamily, is known to influence metabolic processes and is increased under various stress conditions like mitochondrial dysfunction. This research centers on its specific behaviors within young (12 weeks old) and middle-aged (52 weeks old) C57BL/6 J mice. The 52-week-old mice exhibited significant increases in GDF15—approximately 2.5 times higher than their younger counterparts—alongside notable metabolic dysfunction.
To understand the origins of GDF15 elevation, the researchers conducted comprehensive metabolic phenotyping on the two mouse groups, focusing on skeletal muscle, liver, and other tissues. They discovered increased GDF15 levels primarily originated from skeletal muscle, contradicting previous assumptions about liver contributions.
"Gdf15 expression was increased in skeletal muscle but not liver, white or brown adipose tissue, kidney or heart of middle-aged mice," stated the authors of the article, emphasizing the importance of skeletal muscle's role. Insulin resistance was apparent, indicated by elevated basal insulin levels and reduced glucose uptake across multiple tissues.
Fifty-two-week-old mice displayed significantly lower energy expenditure compared to the younger cohort, with findings showing energy expenditure normalized to lean mass at approximately 0.47 ± 0.02 kcal/h versus 0.54 ± 0.02 kcal/h for the younger mice.
Results from the hyperinsulinemic euglycemic clamps revealed alarming levels of insulin resistance, characterized by greater glucose infusion rates necessary to maintain euglycemia. The physiological mechanisms demonstrated reduced ability to utilize glucose effectively, particularly affecting skeletal muscle and adipose tissue.
Research involving mitochondrial function underscored the link between reduced energy expenditure and enhanced GDF15 levels. The 52-week-old mice presented impaired mitochondrial respiratory capacity within their skeletal muscle, pointing to potential declines in muscle health contributing to GDF15 upregulation and broader health complications related to aging.
The evidence indicates metabolic dysfunction occurs earlier than previously identified, even as early as middle age. These findings not only lend insight to GDF15's role as biomarkers of age-related changes but also pose novel therapeutic avenues for addressing metabolic disorders associated with aging.
Understanding GDF15—the primary contributor to energy balance and metabolic stress—could inform approaches for mitigating insulin resistance and other metabolic diseases. The researchers believe their work provides valuable insights and encourages future studies exploring GDF15 pathways to ascertain practical applications for aging individuals.
Overall, this study significantly advances our comprehension of GDF15, muscular health, and associated metabolic functions during aging, reaffirming GDF15 as a potential therapeutic target.