Sirtuins, a family of NAD+-dependent deacylase enzymes, play diverse roles in epigenetic regulation, DNA repair, and metabolic homeostasis. Initial research centered on yeast's Sir2 and its role in replicative lifespan. This led to interest in mammalian SIRT1, with subsequent studies revealing its potential in disease models. SIRT1 impacts aspects of late-life health but doesn't extend lifespan in mice, unlike SIRT6, which does. The role of other sirtuins, like SIRT2, in ageing remained less clear​​.

SIRT2 and Its Implications

A recent study aimed to understand the impact of SIRT2 on health and lifespan in mice. Previous findings indicated that SIRT2 could stabilise the kinetochore attachment protein BubR1, implicated in accurate chromosome segregation during mitosis. Over-expression of BubR1 extends lifespan, while its under-expression accelerates age-related pathologies. SIRT2 overexpression in a BubR1 hypomorph mouse model partially rescued lifespan in males. However, the relevance of SIRT2 to biological ageing under normal conditions was uncertain​​.

The researchers used a cohort of mice globally over-expressing SIRT2 under the CAGGS promoter. Both male and female mice were studied, and the impact of high-fat diet (HFD)-induced obesity in male mice was also assessed. The study was designed to detect a 10% difference in median lifespan, with animals maintained from 8 weeks of age until humane endpoints required euthanasia​​.

Key Findings

Lifespan Impact: SIRT2 overexpression showed no significant effect on lifespan in both male and female mice, regardless of diet. Interestingly, females had shorter lifespans than males, contrary to the typical trend of females living longer​​.

Healthspan Metrics: The team evaluated healthspan through serial measures at various ages, including body weight, composition, glucose homeostasis, mitochondrial function, brain metabolomics, motor coordination, bone health, and sperm quality. SIRT2 overexpression slightly affected body composition but not lifespan​​.

Glucose Homeostasis and Metabolism: No significant impact of SIRT2 overexpression on glucose homeostasis or metabolism was observed. This contradicted some previous studies suggesting a role for SIRT2 in these areas​​.

Discussion and Implications

• SIRT2's Role in Biological Ageing: The study found that under standard laboratory conditions, SIRT2 levels are not limiting factors for lifespan or late-life health in wild-type mice. This contrasts with previous findings in progeria models, suggesting that SIRT2's role in ageing might be context-dependent. Specifically, while SIRT2 overexpression could rescue lifespan in a progeria mouse model, this effect does not translate to normal ageing scenarios. This highlights the complexity of molecular pathways involved in ageing and suggests that interventions that are effective in disease models might not have the same impact on normal ageing processes​​.
• Implications for Age-Related Diseases: Despite previous studies suggesting roles for SIRT2 in neurodegenerative diseases, the current study observed no significant impact of SIRT2 overexpression on motor coordination or spontaneous tumour incidence. This finding challenges the hypothesis that manipulating SIRT2 levels could be a straightforward therapeutic strategy for age-related diseases like Alzheimer’s and Parkinson’s, as well as for cancer prevention. It underscores the need for more nuanced approaches in developing treatments based on sirtuin biology​​.
• Metabolic Aspects and Glucose Homeostasis: Contrary to some earlier studies, the overexpression of SIRT2 did not significantly affect glucose homeostasis and metabolism in the mice. This lack of effect, despite SIRT2's known roles in hepatic glucose output and insulin secretion, suggests a complex interplay of SIRT2 function across different tissues and conditions. It indicates that the influence of SIRT2 on metabolic processes might be more subtle and context-specific than previously understood​​.
• Brain Metabolites and Neuronal Health: One intriguing finding was the alteration in brain metabolites due to SIRT2 overexpression, particularly an increase in NAA, a marker of neuronal content. However, these changes did not translate into noticeable functional outcomes in the study. This observation opens up new avenues for investigating SIRT2's role in brain health and neuronal composition, potentially contributing to our understanding of neurodegenerative diseases and cognitive ageing​​.
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Limitations and Future Directions

The study acknowledges certain limitations, such as the humane endpoint for euthanasia potentially shortening lifespan measurements slightly. Additionally, the findings on brain cell composition based on metabolite levels call for further research, possibly involving more direct measurements or different experimental designs. Future studies might explore SIRT2's role in specific brain regions or under different dietary conditions to fully understand its impact on ageing and disease processes​​.

This study contributes to the growing body of literature that seeks to unravel the molecular mechanisms of ageing. The findings emphasise the importance of considering the context and complexity of biological pathways in ageing research. It also highlights the potential gap between disease models and natural ageing processes, urging caution in extrapolating findings from one to the other.

Conclusion

This research conducted at the School of Biomedical Sciences, UNSW Sydney, New South Wales, Australia, published in Aging Cell, provides valuable insights into the role of SIRT2 in ageing and healthspan. It demonstrates that SIRT2 overexpression does not significantly impact lifespan or healthspan under standard conditions, suggesting a more nuanced role of this protein in the ageing process.