Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model

Abstract

Age-associated neurodegenerative diseases are known to have “impaired protein clearance” as one of the key features causing their onset and progression. Hence, homeostasis is the key to maintaining balance throughout the cellular system as an organism ages. Any imbalance in the protein clearance machinery is responsible for accumulation of unwanted proteins, leading to pathological consequences—manifesting in neurodegeneration and associated debilitating outcomes. Multiple processes are involved in regulating this phenomenon; however, failure to regulate the autophagic machinery is a critical process that hampers the protein clearing pathway, leading to neurodegeneration. Another important and widely known component that plays a role in modulating neurodegeneration is a class of proteins called sirtuins. These are class III histone deacetylases (HDACs) that are known to regulate various vital processes such as longevity, genomic stability, transcription and DNA repair. These enzymes are also known to modulate neurodegeneration in an autophagy-dependent manner. Considering its genetic relevance and ease of studying disease-related endpoints in neurodegeneration, the model system Caenorhabditis elegans has been successfully employed in deciphering various functional outcomes related to critical protein molecules, cell death pathways and their association with ageing. This review summarizes the vital role of sirtuins and autophagy in ageing and neurodegeneration, in particular highlighting the knowledge obtained using the C. elegans model system.

Nicotine-mediated therapy for Parkinson’s disease in transgenic Caenorhabditis elegans model

“…Further, small-scale NGM media culturing of C. elegans models significantly reduced the number of drugs needed for examinations. Assays based on C. elegans could be influential for rapid assessment, low cost, and screening many novel neuroprotective drugs ( Naseer et al, 2021 ). We assessed nicotine’s optical and toxic concentrations in our C. elegans PD models using a food clearance test.…”

Ageing in the brain: mechanisms and rejuvenating strategies

“…Sirtuins ameliorate autophagy dysfunction [ 82 ], neuroinflammation [ 83 ], and mitochondrial dysfunction in the ageing brain [ 84 ]. Sirtuin levels diminish with ageing [ 85 ] and, together with mTOR, are promising targets to increase life span [ 86 ].…”

Apoptosis and Autophagy, Different Modes of Cell Death: How to Utilize Them to Fight Diseases?

“…Sirtuins are evolutionarily conserved deacetylases regulating metabolic and aging processes, and have been shown to regulate autophagy as well [13]. The vital role of sirtuins and the mechanisms through which they modulate autophagy are described in Naseer et al, focusing on the knowledge obtained using the C. elegans model [14].…”

“…(C) Genetic regulation of autophagy was discovered in yeast [9]. (D) Some diseases related to abnormally regulated autophagy are discussed in this Special Issue: enhancing autophagic activity is an efficient tool to treat neurodegenerative disorders [14]. To prevent or treat sarcopenia, increasing mitophagy is a promising target [15].…”