Sirtuins are certainly important in aging.
Sirtuins are proteins that regulate important cellular processes such as cellular metabolism, apoptosis, inflammation, stress resistance, genomic stability, and aging. There are five different groups of sirtuins all of which harbor varying enzymatic functions. Both Class I (SIRT1, 2, 3) and Class IV (SIRT6 and 7) sirtuins are protein deacetylases (enzymes that remove acetyl groups from lysine amino acids on proteins) and require the compound nicotinamide adenine dinucleotide (NAD+) to function. Sirtuin function is linked to caloric restriction and aging in yeast and other model organisms. Specifically, scientists found that caloric restriction increases sirtuin deacetylase activity mediated by NAD+ and results in increased lifespan in yeast. Sirtuins are also important for mitochondrial biogenesis and regulation of energy metabolism, which are two processes that are affected during aging.
Below are two studies published last week in Cell Metabolism that further investigate the role of sirtuins in rescuing premature aging and in maintaining appropriate mitochondrial function in cells.
High fat diet activates sirtuins and rescues premature aging in Cockayne Syndrome.
Cockayne syndrome (CS) is a genetic disorder characterized by growth retardation, eye abnormalities, impaired brain development, and premature aging. The cause of CS is damage to the DNA repair machinery in cells. Currently there is no cure or treatment for CS, a fact that has prompted scientists to explore ways to combat deficient DNA repair in cells.
A recent study by Scheibye-Knudsen et al. at the NIH discovered that feeding mice that have damaged DNA repair processes a high fat diet rescues CS phenotypes, including metabolic, transcriptomic and behavioral phenotypes. Their study elegantly showed that mice deficient in the Cockayne Syndrome B (CSB) DNA repair proteins had aberrant poly-ADP-ribose polymerase (PARP) activation. PARP is a DNA repair protein that localizes to sites of DNA damage and uses NAD+ to generate chemical signals that recruit other DNA damage repair proteins. In CSB mice, elevated PARP results in a reduction in NAD+ levels and consequently a reduction in SIRT1 levels and accelerated aging.
The authors tested a few scenarios to rescue CS phenotypes in mice including PARP inhibitors, NAD+ precursor supplementation, and feeding CSB mice a high fat diet. They found that each strategy was effective in elevating Sirt1 levels and reducing CS phenotypes. Interestingly, when CSB mice were on the high fat diet, the authors saw an improvement in mitochondrial function. SIRT1 activates PGC1α, a protein that regulates mitochondrial biogenesis. The authors found that a high fat diet induces production of high levels of ketones, such as β-hydroxybuterate, that increase SIRT1 levels and improve mitochondrial health.
This study identifies new strategies to treat CS and other diseases caused by defects in DNA damage repair mechanisms and mitochondrial dysfunction. It also raises the possibility of using NAD+ supplements or SIRT1 agonists will be effective as anti-aging therapies in our aging human population.
Sirtuin 7 is Important for Mitochondrial Homeostasis
Sirtuins are well known for their role in maintaining mitochondrial function and health. Recently, a study by Ryu et al. discovered that SIRT7 is important in maintaining mitochondrial homeostasis. The authors conducted a number of bioinformatics, molecular, and in vivo studies in mice and human cell lines to elucidate the mechanism by which Sirt7 facilitates proper mitochondrial function.
The authors studied Sirt7 knockout mice, which experience multisystemic mitochondrial dysfunction that results in liver and heart dysfunction, hearing loss, elevated lactate levels in the blood, and a reduced tolerance for exercise. By studying Sirt7 knockout mice, they discovered that SIRT7 mediates complex formation between two nuclear transcription factors, GABPα and GABPβ1. SIRT7 specifically deacetylates GABPβ1 and promotes formation of the transcriptionally active GABPα/GABPβ1 heterotetramer. This complex activates nuclear-encoded mitochondrial genes required for mitochondrial function (See Figure 2). The authors further confirmed the importance of Sirt7 in mitochondrial homeostasis by feeding Sirt7 knockout mice a calorie restricted diet. Under food restriction, these mice experienced elevated SIRT7 levels, reduced GABPβ1 acetylation, and increased mitochondrial protein expression.
In conclusion, Ryu et al. discovered that SIRT7 is as a critical regulator of mitochondrial function through modulation of SIRT7/GABPβ1 signaling. Their work provides a potential new approach for the treatment of mitochondrial dysfunction and patients with mitochondrial disease.
For an interesting review on Sirtuins in neurodegenerative diseases of aging, check out this review in Nature Cell Research.