Sirtuins such as SIRT1 are conserved protein NAD+-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins and more specifically SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.

Summary SIRT1 is a NAD+-dependent protein deacetylase that governs many physiological pathways, including circadian rhythm in peripheral tissues. Here we show that SIRT1 in the brain governs central circadian control by activating transcription of the two major circadian regulators, BMAL1 and CLOCK. This activation itself comprises an amplifying circadian loop involving SIRT1, PGC-1α and Nampt. In aged wild type mice, SIRT1 levels in the suprachiasmatic nucleus are decreased, as are levels of BMAL1 and PER2, giving rise to a longer intrinsic period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 pheno-copy these aging-dependent circadian changes, while mice that over-express SIRT1 in brain are protected from the effects of aging. Our findings indicate that SIRT1 activates the central pacemaker to maintain robust circadian control in young animals, and a decay in this activity may play an important role in aging.

Cellular chaperone networks prevent potentially toxic protein aggregation and ensure proteome integrity. Here, we used Escherichia coli as a model to understand the organization of these networks, focusing on the cooperation of the DnaK system with the upstream chaperone Trigger factor (TF) and the downstream GroEL. Quantitative proteomics revealed that DnaK interacts with at least ~700 mostly cytosolic proteins, including ~180 relatively aggregation-prone proteins that utilize DnaK extensively during and after initial folding. Upon deletion of TF, DnaK interacts increasingly with ribosomal and other small, basic proteins, while its association with large multidomain proteins is reduced. DnaK also functions prominently in stabilizing proteins for subsequent folding by GroEL. These proteins accumulate on DnaK upon GroEL depletion and are then degraded, thus defining DnaK as a central organizer of the chaperone network. Combined loss of DnaK and TF causes proteostasis collapse with disruption of GroEL function, defective ribosomal biogenesis, and extensive aggregation of large proteins.