Nigral dopaminergic sirtuin 3 inhibits aging-related locomotor decline

Aging reduces locomotor capacity. Although a decrease in the activity of the nigrostriatal dopamine (DA) system is one of key mechanisms linked to the drop-in locomotor activity in aging, the specific molecule responsible for controlling this decline remains elusive. Here we report that sirtuin 3 (SIRT3), a mitochondrial deacetylase associated with an anti-aging effect, is downregulated in nigral DA neurons of 20-month-old mice, showing the decline in locomotor activity, and that the declined locomotor activity by aging was deteriorated with more serious alteration in the levels of mitochondria-related proteins in mice with genetic deletion of SIRT3 compared to age-matched control mice. Moreover, SIRT3 upregulation through the administration of adeno-associated virus serotype 1 (AAV1) encoding the SIRT3 gene in the substantia nigra (SN) mitigated the age-dependent loss of locomotor activity by the preservation of the nigrostriatal DA system from aging in vivo. Therefore, we conclude that SIRT3 preservation in the nigrostriatal DA system has resistance to age-related locomotor decline, suggesting that SIRT3 upregulation in nigral DA neurons can be useful to preserve locomotor capacity in aging. Overall design: The substantia nigra was obtained from WT (Intact), GFP-overexpressed (AAV-GFP), and SIRT3-overexpressed (AAV-SIRT3) mice (six mice per group). They were sequenced using 2 x 100bp paired-end Illumina NovaSeq to understand transcriptional changes that occur in the SIRT3-overexpressed substantia nigra.