Longevity Briefs: Can SIRT2 Slow Cardiac Ageing?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Like all organs in the human body, the heart undergoes ageing leading to age-related cardiac diseases. Due to the central importance of the heart in supplying blood to the rest of the body, cardiac ageing has knock-on detrimental effects on many organs, particularly the brain. Finding ways to slow down or reverse cardiac ageing would therefore have a significant impact on human health. 

Sirtuins are a family of proteins that have been shown to regulate ageing through various mechanisms, such as enhancing DNA repair and reducing inflammation. Their activity decreases with age in part due to the age-related depletion of NAD+, a molecule that is required for sirtuins to function. Boosting the activity of sirtuins is one of many proposed strategies for slowing the ageing process. Mouse models suggest that reduced activity of sirtuins (particularly sirtuin 2 (SIRT2)) causes cardiac ageing. However, due to their short lifespans, mice do not naturally get heart disease and don’t tell us whether SIRT2 is important in normally ageing human hearts.

What did the researchers do: In this study, researchers used non-human primates (long-tailed macaques) as a model to study the molecular changes that occur in the heart during ageing. Unlike rodents, macaques do naturally get age-related heart problems, and their hearts are structurally similar to those of humans. Researchers compared the hearts of eight young (4-6 year-old) and eight aged (18-21 year-old) monkeys, with the latter being roughly equivalent to 65 year-old humans. They analysed proteins and gene expression to understand how the hearts of older monkeys were different from those of younger animals.

Researchers also used human embryonic stem cells to generate heart cells lacking the (SIRT2) protein, and studied how this affected their function.

Key takeaway(s) from this research:

• SIRT2 was found to be a protein of particular importance. SIRT2 levels were reduced in aged monkey hearts.
• Stem cell-derived human heart cells lacking SIRT2 showed signs of ageing.
• SIRT2 alters the activity of STAT3, a regulator of gene expression, thereby opposing age-related changes in the heart.
• Enhancing SIRT2 gene expression in the hearts of old mice improves cardiac function, suggesting possible therapeutic value.

When comparing the hearts of young and aged monkeys, the researchers identified differences in the levels of 169 proteins related to ageing. Researchers then cross-referenced these proteins with genes known to be involved in cardiovascular disease in order to identify proteins of particular importance. They found that of all downregulated genes, the gene coding for SIRT2 had been associated with the widest range of different cardiovascular diseases, and was also downregulated in aged monkey hearts.

When generating human heart cells lacking SIRT2, they found that the cultured cells showed signs of ageing relative to the controls – they became oversized (hypertrophy), their mitochondria became less efficient, and a larger proportion of them lost the ability to multiply (senescence). Further genetic analysis revealed the likely culprit of these changes to be a transcription factor (a protein that controls the expression of other genes) called STAT3. STAT3 regulates inflammation and activates genes that promote senescence. SIRT2 modifies STAT3 in a process called deacetylation, which alters its activity.

To test whether this pathway might be targeted for therapeutic effect, researchers used gene therapy to enhance the expression of SIRT2 in the hearts of old mice. They found that this resulted in functional improvements when compared to controls: the hearts of treated mice had larger ejection fractions (the percentage of blood in the heart ejected each beat) as well as less hypertrophy.

How can we apply this knowledge today: This study suggests that boosting SIRT2 activity in the heart with drugs or gene therapy could be a potential strategy to delay or reverse cardiac ageing and prevent age-related heart diseases. However, more research is needed to confirm the safety and efficacy of this approach in humans. Natural compounds capable of enhancing SIRT2 exist, such as resveratrol and quercetin. However, the effects of these and similar supplements on cardiac ageing in humans are also in need of further study.

Calorie restriction and physical exercise also appear to enhance SIRT2 activity (sirtuins play an important role in the body’s response to nutrient scarcity). These practices are both beneficial for cardiovascular health, though we don’t know exactly how important SIRT2 is for these benefits.