Fight Aging!

The processes of autophagy act to remove damaged molecular machinery and structures in the cell. Autophagy becomes dysfunctional with age, however. This is likely downstream of underlying causes of aging that cause changes in gene expression that degrade the function of autophagic processes in one way or another. For example mitophagy, the clearance of damaged mitochondria by autophagy, is indirectly negatively impacted by changes in mitochondrial dynamics resulting from altered gene expression. Equally, age-related changes in gene expression produce defects in the formation of autophagosomes, and this affects all aspects of autophagy.

Many of the known interventions that slow aging in animal models appear to improve the efficiency of autophagy, and functional autophagy is required for the extension of healthy life span via calorie restriction to take place. While improvement of autophagy has been a goal in the research community for quite some time, surprisingly little concrete progress has been made towards the development of therapies that specifically target dysfunction in autophagic processes.

Calorie restriction mimetics such as mTOR inhibitors improve autophagy, and mitochondrially targeted antioxidants and NAD+ upregulation may act to restore mitophagy. These were not designed with the enhancement of autophagy in mind; rather, it has been found to be one of their outcomes. The research and development communities have yet to see success in the development of narrowly targeted means of restoring a youthful function of autophagy in old tissues, though a few groups, such as the startup Selphagy Therapeutics that emerged from work on LAMP2A upregulation in the liver, are working in that area.

Selective Autophagy as a Potential Therapeutic Target in Age-Associated Pathologies

Cellular garbage disposal is critical for recycling defective cell constituents, such as proteins and organelles, towards the maintenance of cellular homeostasis. One of the main degradative molecule pathways is autophagy, which is a physiological catabolic process shared by all eukaryotes. Derived from the Greek words 'auto' meaning self, and 'phagy', meaning eating, autophagy, it was initially considered to be a bulk degradation process, while now its highly selective nature is increasingly appreciated. This self-digestive mechanism relieves the cell from proteotoxic, genotoxic, oxidative, and nutrient stress. It is accomplished in an intricate stepwise manner, which leads to clearance of damaged cell constituents, in the degradative organelle, the lysosome. Failure to complete this procedure has been implicated in many age-related diseases.

Homeostatic mechanisms that respond to mitochondrial damage are less efficient during aging. Mitophagy is a physiological eukaryotic pathway, which involves the degradation of superfluous or damaged mitochondria. When perturbed, normal mitochondrial function is hindered, resulting in the production of excessive reactive oxygen species (ROS). This ultimately leads to cellular dysfunction and tissue damage. Defective mitophagy is evident in a variety of age-related pathologies such as neurodegeneration, metabolic syndromes, and myopathies.

Aggrephagy degrades aggregation-prone proteins via targeted macroautophagy, in addition to chaperone-mediated autophagy and the proteasomal pathway. These proteins typically form aggresomes near the nucleus, which are surrounded by intermediate filament cytoskeleton, and are further processed to be degraded by autophagy. Protein aggregation usually occurs due to misfolding and can cause, among others, dysregulation of calcium homeostasis, inflammation, neurotoxicity.

Recycling of peroxisomes is also regulated by autophagy. These small dynamic single membrane organelles regulate fatty acid oxidation, production of bile acid and other lipids, while also producing ROS, which is neutralized by catalase. Moreover, peroxisomes interact with a multitude of other cellular constituents, such as lipids, the endoplasmic reticulum (ER), and mitochondria. Pexophagy and peroxisome biogenesis have recently been implicated with disease. During aging, peroxisomal targeting signal 1 (PTS1) protein import deteriorates and catalase function is diminished. Peroxisomes become more abundant and PEX5 accumulates on their membranes. This causes increased production of ROS, which further blocks peroxisomal protein import and contributes to aging.

With regard to therapeutic intervention, several pharmacological compounds have been shown to activate mitophagy and alleviate symptoms of age-related diseases, dependent on dysfunctional mitochondria. Rapamycin activates AMPK, while blocking mTOR, maintaining energetic demands and preventing neurological symptoms, such as neuroinflammation. Metformin and pifithrin induce Parkin by inhibiting p53 activity and alleviating diabetic phenotypes. Resveratrol, mainly found in grape skin, as well as, NAD+ precursors found in natural compounds activate mitophagy and mitochondrial biogenesis through the sirtuin 1 (SIRT1)-PGC-1α axis. Urolithin A, an intestinal microbiome-derived metabolite from dietary intake, induces both mitochondrial degradation and biogenesis, and increases health span of model organisms such as C. elegans and mice.

Selective autophagic induction by genetic intervention or chemical compound administration is currently being investigated in multiple diseases as potential therapeutic approach, although no drug has reached the clinic yet. Indeed, clinical studies concerning druggable autophagy targets remains limited. This highlights the complexity and intricacies of selective autophagic pathways, which in humans, cannot be easily targeted due to context-dependence and extensive crosstalk with other functional networks. Thus, initial optimism has subsided, with research now focusing on specific compounds that could target specific aspects of selective autophagy. An important objective of the collective efforts of the research community and pharmaceutical companies is to achieve targeting selective autophagy mediators, while not affecting other cellular processes.