Exploring molecular mechanisms and genetic dysregulation in aging and age-associated diseases

Aging causes a progressive decline in function, which leads to age-associated diseases like neurodegenerative, inflammatory, and cardiovascular diseases. These diseases impact an individual’s quality of life and has significant economic and social effects.

Existing drugs have limited efficacy and do not target the underlying biological pathways, thus warranting further research.

Study: Underlying Mechanisms of Brain Aging and Neurodegenerative Diseases as Potential Targets for Preventive or Therapeutic Strategies Using Phytochemicals. Image Credit: pikselstock / Shutterstock.com

About the study

In a recent study published in Nutrients, researchers review existing data on the molecular basis of senescence and neurodegeneration in age-related brain diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD), and phytochemicals that regulate age-related molecular dysfunctions.

The Web of Science and PubMed databases were searched for original research studies conducted on animals and literature reviews, including their references. After evaluating 2,500 records, a list of the most important variables and the impacted genes was created for each ailment. This list was then periodically updated until April 2023.

Factors involved in aging and neurodegeneration

As age increases, cognitive decline and neurodegeneration occur, thereby leading to impaired cardiovascular and immune system function. This increases an individual’s vulnerability to cancer, infectious diseases, and inflammation. Aging also weakens the musculoskeletal system, thus increasing the risk of dementia, including AD.

In AD, misfolded β-amyloid proteins and tau-induced neuropathological changes contribute to reactive neurological inflammation and degeneration. In PD, aggregates of misfolded a-synuclein proteins cause neuroinflammation in dopaminergic cells which spreads across neurons, causing cognitive deterioration.

Interacting internal and external factors influence the function of key genes, which can be targeted by nutrients or phytochemicals.

Some of the different factors that regulate microglial activation and neuroinflammation include complement components, such as triggering receptor expressed on myeloid cells 2 (TREM2), complement C3A receptor (C3RA) receptor, and complement component 1Q (C1Q). These factors are mediated by receptors like transforming growth factor β2 (TGF-β2), silent mating type information regulation 2 homologs (SIRT-1), and yes-associated protein (YAP).

Telomere shortening is induced by psychological stress, chronic infections, reactive oxygen species (ROS), inflammation, and mitochondrial dysfunction. Certain factors like sex-determining region Y-box 2 (SOX2), Kruppel-like factor 4 (KLF4), and octamer-binding transcription factor 4 (OCT4) regulate neuronal stem cell inactivity. Metabolic disease and caloric intake are mediated by factors like SIRT-1, AMP-activated protein kinase (AMPK), and forkhead box O (FOXO).

Vascular system malfunctions are mediated by TGF-β1, complement component 3 (C3), and CRa1. Neuroinflammation and neurodegeneration are common in AD, with genes like complement C3 and C3aR1 affecting synapse pruning.

Inactivating C3aR can reduce tau pathology and neuroinflammation in AD mouse models. Nutritional components like vitamin B12, choline, and folic acid may also balance affected genes in AD.

Increased TGF-β2 in the brain activates a neuronal cell death pathway, with TGF-β2-induced cell death greater in AD-related mutations in the amyloid precursor protein (APP). High Mobility Group Box 1 (HMGB1), a marker of neuroinflammation, may also disrupt blood-brain-barrier functions in AD.

Role of phytochemicals in modulating neuroinflammation and aging

Phytochemicals have been shown to attenuate neuroinflammation and improve cognitive performance in mouse models of AD.

Bilberry anthocyanins, cyclanidin3-O-glucoside (C3G), fucoidan, phytic acid, black chokeberry, curcumin, rutin, α-tocopherol, ascorbic acid, galangin, sulforaphane, gallic acid, astin-C, apigenin, resveratrol, epigallocatechin gallate, acacetin, fisetin, alyssum homolocarpum seed oil, daucosterol, kuwanon V, silibinin, and telomere expression have been shown to increase neuroinflammation and neurogenesis.

These phytochemicals can also reduce the expression of TREM2 and other inflammatory cytokines, such as HMGB1/toll-like receptor 4 (TLR4), HMGB1/toll-like receptor 4 (TLR4), amyloid precursor protein (APP), and nuclear factor kappa B (NF-κB).

Phytochemicals like rutin, α-tocopherol, and ascorbic acid can reduce TGF-β expression in affected cells. Galangin inhibits astrocyte activation and neuroinflammation, thereby improving cognitive behavioral functions by suppressing the HMGB1/toll-like receptor 4 (TLR4) bond and inflammatory cytokine expression. Astin-C reduces innate immune responses triggered by cytosolic deoxyribonucleic acid (DNA) by inhibiting cyclic GMP-AMP synthase (cGAS)-STING activity.

Phytochemicals like apigenin, resveratrol, epigallocatechin gallate, acacetin, fisetin, alyssum homolocarpum seed oil, daucosterol, kuwanon V, silibinin, and telomere expression exhibit anti-inflammatory properties and protect dopamine neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in PD.

Conclusions

Neurodegeneration is exacerbated by microglial gene deregulation, neurological inflammation, telomere shortening, neural stem cell dysfunction, vascular malfunction, ROS, and gut microflora dysbiosis.

EGCG, curcumin, galangin, fucoidan, apigenin, astin C, phytic acid, resveratrol, daucosterol, acacetin, sulforaphane, silibinin, betulinic acid, and withaferin A are phytochemicals that alter the activity of important genes among aged brain cells.

Many phytochemicals have the potential to delay the advancement of age-associated brain disorders. Further research is needed to determine the efficacy of these chemicals to support the development of innovative dietary strategies for treating neurodegenerative disorders in individuals.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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