Sirtuin-Mediated Pathways in Neurodegenerative Disease Mechanisms

Sirtuins are a family of NAD⁺-dependent deacetylases and ADP-ribosyltransferases that regulate cellular metabolism, stress responses and genomic stability. In the central nervous system, these enzymes modulate key processes implicated in neurodegeneration, including protein homeostasis, mitochondrial function, neuroinflammation and synaptic plasticity. SIRT1, predominantly nuclear, activates transcriptional programmes that enhance antioxidant defences and suppress pro-inflammatory signalling. SIRT2, mainly cytosolic, influences microtubule dynamics and may exacerbate pathogenic protein aggregation when overactive. Mitochondrial sirtuins such as SIRT3 govern oxidative phosphorylation and reactive oxygen species clearance, thereby preserving neuronal bioenergetics. Dysregulation of sirtuin expression or activity has been linked to Alzheimer’s, Parkinson’s and Huntington’s pathologies through mechanisms such as aberrant amyloid precursor protein processing, α-synuclein accumulation and impaired autophagy. Restoration of NAD⁺ levels, small-molecule sirtuin activators and lifestyle interventions—calorie restriction and physical exercise—offer avenues to rebalance sirtuin-mediated networks. Ongoing work seeks to refine our understanding of isoform-specific roles, elucidate cross-talk between sirtuins and other longevity pathways, and translate these insights into targeted therapeutics that slow or reverse neurodegenerative decline.

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Sirtuin-Mediated Pathways in Neurodegenerative Disease Mechanisms publication trend

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Technical terms

Sirtuin: NAD⁺-dependent enzyme that removes acetyl groups from proteins, regulating metabolism and stress responses.

NAD⁺ (nicotinamide adenine dinucleotide): Coenzyme central to redox reactions and sirtuin catalytic activity.

Deacetylation: Enzymatic removal of an acetyl group from lysine residues, modulating protein function and interactions.

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha): Transcriptional coactivator that drives mitochondrial biogenesis and antioxidant pathways.

Amyloid precursor protein (APP): Transmembrane protein cleaved to form amyloid-β peptides implicated in Alzheimer’s disease pathology.

Mitochondrial dysfunction: Impairment of mitochondrial energy production and redox homeostasis contributing to neuronal vulnerability.

References

1. Cooperative effects of SIRT1 and SIRT2 on APP acetylation. Aging Cell (2023).
2. Astaxanthin attenuates cognitive deficits in Alzheimer’s disease models by reducing oxidative stress via the SIRT1/PGC-1α signaling pathway. Cell & Bioscience (2023).
3. SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease. Aging Cell (2017).