Since the beginning of the century, the mammalian sirtuin protein family ( SIRT1–SIRT7) has received much attention for its regulatory role, mainly in metabolism and ageing. Sirtuins act in different cellular compartments: they deacetylate histones and several transcriptional regulators in the nucleus, but also specific proteins in other cellular compartments, such as in the cytoplasm and in mitochondria. As a consequence, sirtuins regulate fat and glucose metabolism in response to physiological changes in energy levels, thereby acting as crucial regulators of the network that controls energy homeostasis and as such determines healthspan.
Houtkooper et al. 2012 Nature Reviews . MolecularCell Biology vol 13 | 225
Sirtuins as regulators of metabolism and healthspan
Metabolic control involves a delicate balance among energy intake, utilization and storage. When food is ample, the excess energy is stored so that it can be used in times of scarcity. A carefully tuned regulatory and evolutionary conserved programme controls these switches in nutrient intake, use and storage, involving classical food excess signalling pathways, such as those revolving around insulin, insulin growth factor 1 (IGF1) and target of rapamycin (TOR; mTOR in mammals), and food restriction pathways involving AMP-activated protein kinase (AMPK) and sirtuins (for further reading on these pathways.
Sirtuins have received significant attention since the discovery that the yeast sirtuin silent information regulator 2 (Sir2), which was originally described as a regulator of transcriptional silencing of mating-type loci, telomeres and ribosomal DNA extends yeast lifespan. Sir2 is an NAD-dependent histone deacetylase (HDAC)8, and sirtuins serve both as energy sensors and as transcriptional effectors by controlling the acetylation state of histones. What is more, sirtuins do not just deacetylate histones, but also a wide range of trascriptional regulators, thereby controlling their activity.
In mammals the sirtuin family comprises seven proteins (SIRT1–SIRT7), which vary in tissue specificity, subcellular localization, enzymatic activity and targets. Sirtuins, notably SIRT1, have been studied for their role in caloric restriction (the only physiological intervention that extends lifespan), the prevention of ageing-related diseases and the maintenance of metabolic homeostasis. A polyphenol found in red grapes, berries and peanuts that is known as resveratrol has received a lot of attention. Activation of sirtuins is thought to be beneficial not only for diseases relating to metabolism, such as type 2 diabetes and obesity, but also for neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. This is in part because sirtuins stimulate the activity of mitochondria,, and of mitochondrial proteins.
Sirtuins and Longevity
NAD+-dependent deacetylases of the sirtuin family have long been implicated in lifespan regulation, and the significance and molecular mechanism (or mechanisms) of this effect have engendered spirited debate. Two articles now spotlight the catabolism of NAD+ itself as a mediator of lifespan regulation.
Nature Chemical Biology 9, 666–667 (2013)
Nematodes define a new role for sirtuins in lifespan extension, in which the sirtuin product nicotinamide is converted to a substrate for aldehyde oxidase; turnover of this enzyme generates hydrogen peroxide, causing upregulation of defense mechanisms that promote longevity.
Schmeisser K et al Nature Chemical Biology 2013 Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide pp693 – 700