The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.

The Saccharomyces cerevisiae chromatin silencing factor Sir2 suppresses genomic instability and extends replicative life span. In contrast, we find that mouse embryonic fibroblasts (MEFs) deficient for SIRT1, a mammalian Sir2 homolog, have dramatically increased resistance to replicative senescence. Extended replicative life span of SIRT1-deficient MEFs correlates with enhanced proliferative capacity under conditions of chronic, sublethal oxidative stress. In this context, SIRT1-deficient cells fail to normally upregulate either the p19(ARF) senescence regulator or its downstream target p53. However, upon acute DNA damage or oncogene expression, SIRT1-deficient cells show normal p19(ARF) induction and cell cycle arrest. Together, our findings demonstrate an unexpected SIRT1 function in promoting replicative senescence in response to chronic cellular stress and implicate p19(ARF) as a downstream effector in this pathway.

The purpose of this study was to investigate the previously unknown flow velocity in single lymphatic capillaries of humans in the supine position. Fifteen healthy subjects (10 women and 5 men; mean age 35.8 +/- 13.1 yr) were studied. Ten microliters of fluorescein isothiocyanate-dextran (150,000 mol wt) were injected into the subepidermal layer of the foot dorsum. The filling of the microlymphatics from the resulting depot was visualized by fluorescence video microscopy and stored on videotape. Flow velocity in the microlymphatics was determined on the video screen by direct measurement of the advancement of dyed lymph during a given time. The following median velocities were obtained: 0.51 mm/s (0.27 and 0.61 mm/s for lower and upper quartiles, respectively) for velocity during initial network filling and 9.7 microns/s (6.9 and 14.2 microns/s for lower and upper quartiles, respectively) for resting velocity at the end of the filling period. Mean lymphatic capillary diameter was 54.8 +/- 8.2 microns, and mean network extension was 8.3 +/- 3.2 mm. The high filling velocities are probably due to increased interstitial pressure and volume caused by dye microinjection, whereas the values measured during the end of network filling seem to approach resting flow velocities.