SIRT1 Activation by Small Molecules: KINETIC AND BIOPHYSICAL EVIDENCE FOR DIRECT INTERACTION OF ENZYME AND ACTIVATOR?

SIRT1 is a protein deacetylase that has emerged as a therapeutic target for the development of activators to treat diseases of aging. SIRT1-activating compounds (STACs) have been developed that produce biological effects consistent with direct SIRT1 activation. At the molecular level, the mechanism by which STACs activate SIRT1 remains elusive. In the studies reported herein, the mechanism of SIRT1 activation is examined using representative compounds chosen from a collection of STACs. These studies reveal that activation of SIRT1 by STACs is strongly dependent on structural features of the peptide substrate. Significantly, and in contrast to studies reporting that peptides must bear a fluorophore for their deacetylation to be accelerated, we find that some STACs can accelerate the SIRT1-catalyzed deacetylation of specific unlabeled peptides composed only of natural amino acids. These results, together with others of this study, are at odds with a recent claim that complex formation between STACs and fluorophore-labeled peptides plays a role in the activation of SIRT1 (Pacholec, M., Chrunyk, B., Cunningham, D., Flynn, D., Griffith, D., Griffor, M., Loulakis, P., Pabst, B., Qiu, X., Stockman, B., Thanabal, V., Varghese, A., Ward, J., Withka, J., and Ahn, K. (2010) J. Biol. Chem. 285, 8340–8351). Rather, the data suggest that STACs interact directly with SIRT1 and activate SIRT1-catalyzed deacetylation through an allosteric mechanism.     

A novel tubular bioassay for measuring the production of antagonistic chemicals produced at the fungal/pathogen interface

A novel tubular bioassay system has been developed that allows both concentration profiles and the local production and concentration of antagonistic chemicals at the fungal/pathogen interface to be measured analytically.     

Low-Fat Diets May Prevent Weight Gain in Sedentary Women: Prospective Observations From the Population Study of Women in Gothenburg,Sweden

The Population Study of Women in Gothenburg, Sweden is an ongoing prospective study of female residents who were recruited from the local registry in 1968–1969 when they were 38–60 years old. The data presented here were collected from 361 healthy women who underwent a baseline physical examination including a supplementary dietary history interview and returned for a second general health examination 6 years later. This report identifies a subgroup of 57 women who were sedentary during their leisure time and appear to have been particularly susceptible to gaining weight as a function of the fat content of their diets. Specifically, longitudinal analysis of body weights in the whole sample revealed a statistical interaction between leisure-time physical activity and habitual dietary fat intake (energy-%), as reported at the baseline examination, in the prediction of subsequent weight change. Further stratified analysis suggested that weight changes were significantly dependent on dietary fat intake among the sedentary women only. High energy intake also predicted weight gain in the sedentary group, although the predictive value for a high-fat diet was of marginal significance after adjusting for total energy consumption. These results suggest that sedentary recreational activity plus a low-fat diet may have a combined contribution to weight change that is not equivalent to the sum of the separate effects. Such a synergy between two modifiable lifestyle factors seems highly relevant for prevention of obesity.