Life span extending mutations in growth signaling pathways protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian subjects with mutations in the growth hormone receptor gene leading to severe growth hormone receptor (GHR) and IGF-I deficiencies and combined this information with surveys to identify the cause and age of death for subjects who died before this period. The individuals with GHR deficiency (GHRD) exhibited only one non-lethal malignancy and no cases of diabetes, in contrast to 17% cancer and 5% diabetes prevalence in the controls. A possible explanation for the very low incidence of cancer may be revealed by in vitro studies: serum from GHRD subjects reduced DNA breaks but increased apoptosis in human mammary epithelial cells (HMECs) treated with hydrogen peroxide. We also observed reduced insulin concentrations (1.4 μU/ml vs. 4.4μU/ml in unaffected relatives) and a very low homoeostasis model assessment of insulin resistance (HOMA-IR) index (0.34 vs. 0.96 in unaffected relatives) in GHRD individuals, indicating increased insulin sensitivity, which could explain the absence of diabetes in these subjects. Incubation of HMECs with GHRD serum also resulted in reduced expression of RAS, PKA and TOR, and up-regulation of SOD2, changes that promote cellular protection and life span extension in model organisms. These results provide evidence for a role of evolutionarily conserved pathways in promoting aging and diseases in humans and identify a candidate drug target for healthy life span extension.

A detailed study of the pre-Silurian geology of the Sierras de Córdoba, Eastern Sierras Pampeanas, is used to define the sequence of magmatic and metamorphic events during the Pampean orogeny. This primarily involved Early to Mid-Cambrian subduction and terrane collision at the western margin of Gondwana during the amalgamation of the super-continent. Evidence for this is based principally on new information concerning (a) regional mapping and field relations, (b) analysis of the structures, deformational history and meta-morphic evolution and (c) geochronology and geochemistry of the igneous and metamorphic rocks. The main events recognized are (1) Late Proterozoic break-up of Rodinia (Nd model ages of 1500 ± 200 Ma, inherited zircons 800–1400 Ma), (2) development of an Early Cam-brian passive margin sequence (Puncoviscana Formation and equivalents), (3) emplacement of metaluminous calc-alkaline granitoids (G1a, dated at 530 ± 3 Ma) as a result of NE-directed subduction, (4) crustal thickening, ophiolite obduction, compression and high-grade metamorphism (M2: 8.6±0.8 kbar, 810 ± 50°C, c. 525 Ma) related to collision, and culmina-ting in (5) isothermal uplift and widespread low- P anatexis (M3, 4.0±0.5 kbar, 715 ± 15°C, c. 520 Ma). The last event is responsible for the linked generation of highly peraluminous granites (G1b) and cordieritites. Subsequent emplacement into the accreted terrane of Ordovician trondhjemite-tonalites (500-470 Ma) and dextral wrench shear are interpreted as inner cordilleran counterparts of the Famatinian arc, which developed to the west along the newly-formed proto-Andean margin.

A new multi-disciplinary study of the central Sierras Pampeanas encompasses fieldwork, petrography, metamorphic and micro-structural analysis, geochemistry and geochronology. Remnants of a low-to-medium grade metasedimentary sequence, which also occurs in the Sierras de Córdoba to the east, are considered regionally equivalent to the Puncoviscana Formation; a ?mid-Cambrian Rb-Sr whole-rock isochron of 513 ± 31 Ma probably dates their main metamorphism. The predominant granitoids of the Los Llanos-Ulapes batholith constitute a calc-alkaline suite representative of the Famatinian subduction-related magmatic arc. The main granodiorite phase of the batholith is associated with an S2 fabric and shear zone formation, and was emplaced late during the deformational history of the metasediments. Conventional and SHRIMP U-Pb zircon dating yielded a combined age of 490 ± 5 Ma. Younger monzogranites gave Rb-Sr whole-rock ages of 470–450 Ma, typical of granites in the Sierra de Famatina, but geochemical continuity with the main granodiorite suite raises the possibility that these are partially reset ages. A minor cordierite granite phase is ascribed to local anatexis caused by heat from the granodiorites. All the calc-alkaline rocks of the Los Llanos-Ulapes batholith have high initial 87 Sr/ 86 Sr (0.7075–0.7105) and low ɛNd t (−4.6 to −6.3), inherited from lower crust. Sm-Nd model ages of 1600–1700 Ma indicate that the underlying crust is identical to that beneath the foreland to the east. This part of the Famatinian arc was thus a continental magmatic arc and was established significantly before the arrival of the allochthonous Precordillera terrane in mid-Ordovician times.

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The evolution of the Gondwana margin proposed here is based on new geochemical, isotopic, petrological, and sedimentological data from a 500 km traverse across the Eastern Sierras Pampeanas and Precordillera (Fig. 1). Pre-Silurian metamorphic and magmatic history is inferred from (1) dating by conventional U-Pb on abraded zircons, U-Pb SHRIMP analyses, and whole-rock Rb-Sr and K-Ar, (2) thermo-barometry based on microprobe mineral analyses, and (3) Nd and Sr isotopes, and major and trace element geochemistry of the magmatic suites. Detailed data and interpretation have been presented for the Sierras de Córdoba (Rapela et al., 1998) and Sierras de La Rioja (Pankhurst et al., 1998). THE GONDWANA MARGIN Geological and paleontological evidence indicating that the Argentine Precordillera is a Laurentian terrane has revolutionized ideas about the proto-Andean margin of South America (Dalziel, 1997, and references therein). The exotic origin of the Precordillera is now widely accepted, although the timing of accretion and the associated geotectonic models remain controversial (e.g.