Sirtuins or Sir2 (silent information regulator 2)-related enzymes are a class of proteins that possess either mono-ADP-ribosyltransferase, or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. Sirtuins are remarkably conserved throughout evolution from archaebacteria to eukaryotes. Geneticist Dr. Amar Klar discovered the first sirtuin, called Sir2, in the 1970s, and their primary function was discovered in the 1990s. Since then, researchers have flocked to study them, identifying their importance while also raising questions about what else we can learn about them. From in vitro studies, sirtuins are implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation and stress resistance, as well as energy efficiency and alertness during low-calorie situations.
Sirtuins can only function in the presence of NAD+, nicotinamide adenine dinucleotide, a coenzyme found in all living cells. This dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or nicotinamide or a combination of these variables. Mammalian sirtuins are a family of seven proteins (SIRT 1-7) that play a role in cellular health. If sirtuins are a company’s CEO, then NAD+ is the money that pays the salary of the CEO and employees, all while keeping the lights on and the office space rent paid. A company, and the body, cannot function without it. But levels of NAD+ decline with age, limiting the function of sirtuins with age as well.
The controversy around sirtuins and their functions in aging has drawn in the past few years as much attention, if not more, from the scientific community and the public as they did when first proposed as the key conserved aging regulators in eukaryotes. With some of the basic observations on sirtuin longevity promoting functions being questioned in popular model systems, researchers are wondering if this family of conserved enzymes still holds strong potential as therapeutic targets. Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1, led some scientists to speculate that resveratrol may extend lifespan, there was no clinical evidence for such an effect. Although resveratrol has been shown to extend the lifespan of mice made obese with a high-fat diet, resveratrol has not been shown to extend the lifespan of normal mice fed resveratrol from four months of age. Whether or not sirtuin activators can extend lifespan, genetically modified mice with enhanced sirtuin gene expression have shown extended lifespan. In vitro studies shown that calorie restriction regulates the plasma membrane redox system, involved in mitochondrial homeostasis, and the reduction of inflammation through cross-talks between SIRT1 and AMP-activated protein kinase (AMPK), but the role of sirtuins in longevity is still unclear, as calorie restriction in yeast could extend lifespan in the absence of Sir2 or other sirtuins, while the in vivo activation of Sir2 by calorie restriction or resveratrol to extend lifespan has been challenged in multiple organisms.
Although some data put in question direct involvement of sirtuins in extending human lifespan, it was documented that proper lifestyle including physical activity and diet can influence healthspan via increasing the level of sirtuins. The search for an activator of sirtuins is one of the most extensive and robust topics of research. Some hopes are put on natural compounds, including curcumin. In addition, numerous questions remain unresolved, such as the role of other sirtuins in addition to SIRT1 and SIRT6 on aging, the redundancy of the sirtuin family members to regulate lifespan, whether other enzymatic activities (apart from deacetylation activity) participate in the process of aging, and whether sirtuin activators could be promoted as drugs to treat aging or age-related diseases in humans. These questions will be answered in the near future, and sirtuins may provide the effective approach to extend lifespan and improve our quality of life.