SIRT1 in the brain—connections with aging-associated disorders and lifespan

Ng, Fanny; Wijaya, Laura; Tang, Bor Luen

doi:10.3389/fncel.2015.00064

Cited by 156 publications

(120 citation statements)

References 169 publications

(208 reference statements)

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…7). SIRT1 is an energy-sensing molecule that regulates PGC-1α, a transcriptional co-activator playing critical roles in regulating cellular energy metabolism (Ng et al 2015) and myelin formation (Rafalski et al 2013). SIRT1 protein was elevated by 1.2-fold by the combined effects of high fat consumption and exercise (P = 0.006), but not by either intervention alone.…”

Section: Resultsmentioning

confidence: 99%

“…SIRTs have emerged as key metabolic sensors that directly link environmental signals to metabolic homeostasis and stress responses. SIRT1 is a histone/protein deacetylase that regulates the activity of a variety of transcription factors and co-regulators, including PGC-1α to increase mitochondrial function, energy metabolism and gluconeogenesis (Ng et al 2015). Increases in spinal cord PLP and MBP protein under the influence of high dietary fat in combination with exercise occurred in conjunction with increases in SIRT1, suggesting a possible link between the events that warrants further study.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system

Yoon

Kleven

Paulsen

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Here we show that the interplay between exercise training and dietary fat regulates myelinogenesis in the adult central nervous system. Mice consuming high fat with coordinate voluntary running wheel exercise for 7 weeks showed increases in the abundance of the major myelin membrane proteins, proteolipid (PLP) and myelin basic protein (MBP), in the lumbosacral spinal cord. Expression of MBP and PLP RNA, as well that for Myrf1, a transcription factor driving oligodendrocyte differentiation were also differentially increased under each condition. Furthermore, expression of IGF-1 and its receptor IGF-1R, known to promote myelinogenesis, were also increased in the spinal cord in response to high dietary fat or exercise training. Parallel increases in AKT signaling, a pro-myelination signaling intermediate activated by IGF-1, were also observed in the spinal cord of mice consuming high fat alone or in combination with exercise. Despite the pro-myelinogenic effects of high dietary fat in the context of exercise, high fat consumption in the setting of a sedentary lifestyle reduced OPCs and mature oligodendroglia. Whereas 7 weeks of exercise training alone did not alter OPC or oligodendrocyte numbers, it did reverse reductions seen with high fat. Evidence is presented suggesting that the interplay between exercise and high dietary fat increase SIRT1, PGC-1α and antioxidant enzymes which may permit oligodendroglia to take advantage of diet and exercise-related increases in mitochondrial activity to yield increases in myelination despite higher levels of reactive oxygen species.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system

Yoon

Kleven

Paulsen

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

show abstract

“…Together, our findings illustrate a neuroprotective mechanism whereby RPC via neuronal Sirt1 promotes glycolytic efficiency to combat energetic stress. These results have far-reaching implications, as dysregulation of glycolysis plays a role in the pathogenesis and/or manifestation of Huntingtin’s disease, Alzheimer’s disease and Parkinson’s disease, in all of which Sirt1 has a neuroprotective role 40, 41 .…”

Section: Discussionmentioning

confidence: 99%

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance

Koronowski

Khoury

Saul

et al. 2017

Stroke

View full text Add to dashboard Cite

BACKGROUND AND PURPOSE Resveratrol, at least in part via Sirt1 activation, protects against cerebral ischemia when administered 2 days prior to injury. However, it remains unclear if Sirt1 activation must occur, and in which brain cell types, for the induction of neuroprotection. We hypothesized that neuronal Sirt1 is essential for resveratrol-induced ischemic tolerance and sought to characterize the metabolic pathways regulated by neuronal Sirt1 at the cellular level in the brain. METHODS We assessed infarct size and functional outcome following transient 60 minute middle cerebral artery occlusion in control and inducible, neuronal-specific Sirt1 knockout mice. Non-targeted primary metabolomics analysis identified putative Sirt1-regulated pathways in brain. Glycolytic function was evaluated in acute brain slices from adult mice and primary neuronal-enriched cultures under ischemic penumbra-like conditions. RESULTS Resveratrol-induced neuroprotection from stroke was lost in neuronal Sirt1 knockout mice. Metabolomics analysis revealed alterations in glucose metabolism upon deletion of neuronal Sirt1, accompanied by transcriptional changes in glucose metabolism machinery. Furthermore, glycolytic ATP production was impaired in acute brain slices from neuronal Sirt1 knockout mice. Conversely, resveratrol increased glycolytic rate in a Sirt1-dependent manner and under ischemic penumbra-like conditions in vitro. CONCLUSIONS Our data demonstrate that resveratrol requires neuronal Sirt1 to elicit ischemic tolerance and identify a novel role for Sirt1 in the regulation of glycolytic function in brain. Identification of robust neuroprotective mechanisms that underlie ischemia tolerance and the metabolic adaptations mediated by Sirt1 in brain are crucial for the translation of therapies in cerebral ischemia and other neurological disorders.

show abstract

“…In contrast, it is generally accepted that a higher activity of sirtuins is associated with protection against the majority of age-related diseases such as type 2 diabetes, cardiovascular disease, and Alzheimer's disease. [15][16][17][18] Notably, a calorie restriction diet (CR), the only intervention known so far to extend healthspan and lifespan, leads to SIRT1 and SIRT3 overexpression. 19,20 It has been also shown that SIRT1 transgenic mice present features similar to those of animals fed a CR: they are lean, resistant to cancer, as well as to the diet-induced metabolic syndrome.…”

Section: Introductionmentioning

confidence: 99%

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

Owczarz

Budzinska

Domaszewska-Szostek

et al. 2017

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Impact statementHigh expression of sirtuins, particularly SIRT1, lowers the risk of age-related diseases and probably slows down the rate of aging; therefore, their sustained expression should be one of the features of longevity. However, in this work we show that in peripheral blood mononuclear cells (PBMC) of long-lived individuals, expression of majority of the SIRT genes is significantly lower than in cells of young study subjects. In long-lived individuals, downregulation of SIRT1 coexists with upregulation of SIRT1 mRNA-interacting miR-34a and miR-9, indicating the role of epigenetic drift in age-dependent deregulation of SIRT1 expression. Such constellation of SIRT1, miR-34a, and miR-9 expression in PBMC of successfully aging long-lived individuals indicates that, at least in these individuals, it is not a risk factor for morbidity and mortality. It might however affect the function of the immune system and, therefore, aging individuals can profit from interventions increasing the level of SIRT1. AbstractIncreased expression of sirtuins lowers the risk of age-related diseases, while their role in the regulation of longevity is not firmly established. Since aging is associated with immunosenescence, we tested whether sirtuin expression was modified in peripheral blood mononuclear cells (PBMC) in an age-related manner and whether this might result from altered expression of the selected miRNAs. The expression of seven SIRT genes and of SIRT1 mRNA-interacting miR-9, miR-34a, miR-132, and miR-199a-5p was evaluated by real-time PCR in PBMC originating from young (Y, n ¼ 57, mean age 27 AE 4.3 years), elderly (E, n ¼ 52, 65 AE 3.4 years), and long-lived (L, n ¼ 56, 94 AE 3.5 years) individuals. Older age was associated with a decreased expression of the majority of the SIRT genes. Most severely affected were median expressions of SIRT1 (P ¼ 0.000001 for the whole studied group, Y vs. E: P < 0.000001, Y vs. L: P < 0.000001), and of SIRT3 (P ¼ 0.000001, Y vs. E: P ¼ 0.000004, Y vs. L: P ¼ 0.000028). Older age was also associated with the increased median expression of miR-34a (P ¼ 0.000001, Y vs. E: P ¼ 0.001, Y vs. L: P ¼ 0.000004) and of miR-9 (P ¼ 0.05, Y vs. L: P ¼ 0.054). In functional studies, miR-9 interacted with the 3 0 UTR of SIRT1 mRNA. The SIRT1 mRNA level negatively correlated with the expression of miR34a (r ¼ À0.234, P ¼ 0.003). In conclusion, age-related decrease of SIRT1 expression in PBMC might in part result from overexpression of miR-34a and miR-9. In addition, the sustained expression of the SIRT genes in PBMC is not a prerequisite to longevity in humans but might be one of the reasons for the immune system dysfunction in the elderly.

show abstract

SIRT1 in the brain—connections with aging-associated disorders and lifespan

Cited by 156 publications

References 169 publications

Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system

Interplay between exercise and dietary fat modulates myelinogenesis in the central nervous system

Neuronal SIRT1 (Silent Information Regulator 2 Homologue 1) Regulates Glycolysis and Mediates Resveratrol-Induced Ischemic Tolerance

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

Contact Info

Product

Resources

About