An Investigation of Declining Autophagy in Aging

Cellular quality control and maintenance processes such as autophagy are important to health and longevity. Unfortunately, like near all systems in our biology, they decline in effectiveness with advancing age, impacted by the accumulation of molecular damage that they cannot effectively deal with. This includes the hardy waste compounds making up lipofuscin, for example, which clutter up the recycling system of the lysosome in long-lived cells and degrade its operation. Researchers here survey some of the noteworthy quality control mechanisms and their failure over time in mice:

Sarcopenia and decreased cardiac function are common features of the decline in physical performance associated with aging. Sarcopenia refers to a loss of skeletal muscle mass that is accompanied by a decrease in muscle strength and increased fatigue. Aging in the heart is associated with pathological hypertrophy and thickening of the ventricle wall, leading to decreased cardiac output. Changes in both metabolism and macroautophagy, a lysosomal-dependent degradation process, have been associated with aging in both these tissues. These, in turn may contribute to the decline in function observed in these tissues during aging.

Macroautophagy, referred as autophagy in the remainder of this manuscript, is the most studied form of autophagic process. It involves the formation of double-membrane vesicles termed "autophagosomes", the sequestration of cytosolic substrate within autophagosomes, and the subsequent fusion of autophagosome and lysosome to form autophagolysosomes, where the engulfed macromolecules are degraded to provide substrates for cellular metabolism as well as damaged proteins and organelles to maintain cellular homeostasis. There is a tight connection between autophagy and life-span, as genetic manipulation to increase expression of specific autophagy genes in lower organisms promotes longevity. Autophagy-deficient mice also mimic several characteristics of age-related diseases, suggesting that autophagy is a key mechanism for protecting against cellular damage during aging. Furthermore, autophagy is a critical process for maintaining muscle and heart function, and tissue-specific impairment of autophagy in muscle and heart leads to sarcopenia and cardiomyopathy, respectively. Although there is evidence suggesting a potential role of autophagy in aging, the specific changes in basal levels of autophagy in skeletal and cardiac muscle during the natural aging process and the underlying mechanisms have not been well characterized.

Chaperone-mediated autophagy (CMA) is another type of autophagic process that specifically targets proteins that have a KFERQ amino acid recognition sequence for degradation. During CMA, target proteins are first recognized and bound by Hsc70. The resulting complex then is targeted to the lysosomes by binding to the lysosomal CMA receptor LAMP-2A, whereupon the target protein is unfolded and translocated into the lysosome for degradation. A decline of CMA during aging has been reported to occur in both the liver and central nervous system that is associated with decreased function; however, little is known about CMA in other tissues during aging.

Mitochondria are the key organelles for oxidative phosphorylation and ATP production. Mitochondria preferentially use fatty acid or glucose as energy sources depending on the availability of the type of fuel. The fuel selectivity by mitochondria also is subjected to hormonal regulation. During aging, cellular and metabolic stresses can increase generation of reactive oxygen species (ROS) that can damage mitochondria and lead to mitochondrial dysfunction, as well as perturb fuel utilization. Thus, mitochondrial quality control is critical for maintaining normal mitochondrial function and metabolism during aging. This quality control can be achieved by mitochondrial fusion, fission, and/or mitochondrial turnover through removal of damaged mitochondria by autophagy (mitophagy) and concomitant biosynthesis of new mitochondria. Currently, little is known about the changes in mitochondrial quality control and relevant metabolites that occur in aged muscle and heart.

In this study, we systematically examined and compared the markers for autophagy, CMA, and mitochondrial quality control in skeletal and cardiac muscle isolated from young and aged mice, as well as performed metabolomics profiling of acylcarnitines, amino acid and ceramides. Our studies confirm that autophagy declines in both the muscle and heart during aging, although the mechanism for the impairment in autophagy appears to be different between these tissues. Furthermore, there are decreased markers for CMA and mitochondrial quality control in the muscle whereas they are unchanged in the heart. The fuel preference and metabolism are differentially altered in these two tissues during aging, with skeletal muscle from aged mice showing a metabolomic signature suggestive of insulin resistance and fatty acid fuel inflexibility whereas the heart exhibited decreased fatty acid β-oxidation. These differential effects in muscle and heart metabolism during aging suggest that different types of metabolic derangements may occur in muscle vs. heart, and thus may require different therapeutic approaches to optimize the function of these two tissues during aging and aging-associated diseases.



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