Clearance of extracellular human amyloid-ß aggregates in C. elegans by nutraceutical and pharmaceutical interventions.

Numerous anti-amyloid therapies have seen recent clinical development and approval, such as the monoclonal antibodies aducanumab and lecanemab. However, in Alzheimer's disease patients, amyloid-ß (Aß) plaques are found embedded in the extracellular matrix and surrounded by collagens, which might hinder these antibodies from targeting the plaques. We reasoned that various different nutraceutical and pharmaceutical agents might induce collagen and extracellular matrix turnover and removal of these collagen-embedded amyloid-ß (Aß) plaques. To address this idea, here, we used a transgenic C. elegans strain, LSD2104 , expressing fluorescent human Aß 1-42 as an in-vivo model for secreted amyloid aggregation in the extracellular matrix. We performed a screen of various nutraceuticals and pharmaceuticals along with different combinations, and we found that quercetin 350 µM and rifampicin 75 µM successfully cleared the extracellular amyloid plaque burden compared to the 0.2% DMSO control group, with a combination of the two agents producing the maximum effect compared to either drug alone. These results may implicate the exploration of combination therapeutics of nutraceuticals and pharmaceuticals in the clearance of amyloid-ß (Aß) plaques in Alzheimer's disease.

The Human Extracellular Matrix Diseasome Reveals Genotype-Phenotype Associations with Clinical Implications for Age-Related Diseases.

The extracellular matrix (ECM) is earning an increasingly relevant role in many disease states and aging. The analysis of these disease states is possible with the GWAS and PheWAS methodologies, and through our analysis, we aimed to explore the relationships between polymorphisms in the compendium of ECM genes (i.e., matrisome genes) in various disease states. A significant contribution on the part of ECM polymorphisms is evident in various types of disease, particularly those in the core-matrisome genes. Our results confirm previous links to connective-tissue disorders but also unearth new and underexplored relationships with neurological, psychiatric, and age-related disease states. Through our analysis of the drug indications for gene-disease relationships, we identify numerous targets that may be repurposed for age-related pathologies. The identification of ECM polymorphisms and their contributions to disease will play an integral role in future therapeutic developments, drug repurposing, precision medicine, and personalized care.

Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan.

Disrupted biological function, manifesting through the hallmarks of aging, poses one of the largest threats to healthspan and risk of disease development, such as metabolic disorders, cardiovascular ailments, and neurodegeneration. In recent years, numerous geroprotectors, senolytics, and other nutraceuticals have emerged as potential disruptors of aging and may be viable interventions in the immediate state of human longevity science. In this review, we focus on the decrease in nicotinamide adenine dinucleotide (NAD+) with age and the supplementation of NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), in combination with other geroprotective compounds, to restore NAD+ levels present in youth. Furthermore, these geroprotectors may enhance the efficacy of NMN supplementation while concurrently providing their own numerous health benefits. By analyzing the prevention of NAD+ degradation through the inhibition of CD38 or supporting protective downstream agents of SIRT1, we provide a potential framework of the CD38/NAD+/SIRT1 axis through which geroprotectors may enhance the efficacy of NAD+ precursor supplementation and reduce the risk of age-related diseases, thereby potentiating healthspan in humans.

Perspectives of Circadian-Based Music Therapy for the Pathogenesis and Symptomatic Treatment of Neurodegenerative Disorders.

Music therapy (MT) and other rhythmic-based interventions for the treatment of neurodegeneration (ND) have been successful in improving the quality of life of affected individuals. Music therapy and rhythm-based stimuli affect patients with Alzheimer's disease (AD) and Parkinson's disease (PD) respectively not only through cognitive channels and subjective qualifications but also through altered brain structures and neural systems. Often implicated in the pathogenesis and resulting symptoms of these diseases is the role of aberrant circadian rhythmicity (CR), namely disrupted sleep. Recent literature suggests that proper maintenance of this timekeeping framework may be beneficial for patients with neurodegenerative disorders and serve a neuroprotective role. While music therapy can improve the quality of life for neurodegenerative patients, longitudinal studies analyzing sleep patterns of affected individuals and possible mechanisms of intervention remain sparse. Furthermore, the role of music therapy in the context of circadian rhythmicity has not been adequately explored. By analyzing the links between circadian rhythmicity, neurodegeneration, and music therapy, a more comprehensive picture emerges, suggesting that possible uses of non-pharmacological circadian-based music therapy to target mechanisms involved in the pathogenesis of Alzheimer's disease and Parkinson's disease may enhance clinical treatment and potentially indicate neuroprotection as a preventative measure.

Molecular Crosstalk Between Circadian Rhythmicity and the Development of Neurodegenerative Disorders.

Neurodegenerative disorders have been shown to exhibit substantial interconnectedness with circadian rhythmicity. Alzheimer's patients exhibit high degradation of the suprachiasmatic nucleus (SCN), the central endogenous circadian timekeeper, and Parkinson's patients have highly disrupted peripheral clock gene expression. Disrupted sleep patterns are highly evident in patients with neurodegenerative diseases; fragmented sleep has been shown to affect tau-protein accumulation in Alzheimer's patients, and rapid eye movement (REM) behavioral disorder is observed in a significant amount of Parkinson's patients. Although numerous studies exist analyzing the mechanisms of neurodegeneration and circadian rhythm function independently, molecular mechanisms establishing specific links between the two must be explored further. Thus, in this review, we explore the possible intersecting molecular mechanisms between circadian rhythm and neurodegeneration, with a particular focus on Parkinson's disease. We provide evidence for potential influences of E3 ligase and poly adenosine diphosphate (ADP-ribose) polymerase 1 (PARP1) activity on neurodegenerative pathology. The cellular stress and subsequent DNA damage signaling imposed by hyperactivity of these multiple molecular systems in addition to aberrant circadian rhythmicity lead to extensive protein aggregation such as α-synuclein pre-formed fibrils (α-Syn PFFs), suggesting a specific molecular pathway linking circadian rhythmicity, PARP1/E3 ligase activity, and Parkinson's disease.