Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruit flies1–5. However, whether inhibition of mTOR signalling can extend life in a mammalian species was unknown. We report here that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. Based on age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. These are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.

Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging.

Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose threefold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet-restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet-restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects.

SummaryThe National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice. Each compound is tested in parallel at three sites, and all results are published. We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously. 17‐α‐estradiol at a threefold higher dose robustly extended both median and maximal lifespan, but still only in males. The male‐specific extension of median lifespan by NDGA was replicated at the original dose, and using doses threefold lower and higher. The effects of NDGA were dose dependent and male specific but without an effect on maximal lifespan. Protandim, a mixture of botanical extracts that activate Nrf2, extended median lifespan in males only. Metformin alone, at a dose of 0.1% in the diet, did not significantly extend lifespan. Metformin (0.1%) combined with rapamycin (14 ppm) robustly extended lifespan, suggestive of an added benefit, based on historical comparison with earlier studies of rapamycin given alone. The α‐glucosidase inhibitor, acarbose, at a concentration previously tested (1000 ppm), significantly increased median longevity in males and 90th percentile lifespan in both sexes, even when treatment was started at 16 months. Neither fish oil nor UDCA extended lifespan. These results underscore the reproducibility of ITP longevity studies and illustrate the importance of identifying optimal doses in lifespan studies.

Parkinson's disease (PD) is characterized by the progressive loss of nigrostriatal dopamine (DA) neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non-selective cannabinoid receptor agonist WIN55,212-2 (WIN) protects mouse nigrostriatal neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, i.p.), initiated 24 hr after MPTP administration, protected against MPTP-induced loss of tyrosine hydroxylase positive (TH + ) neurons in the substantia nigra pars compacta (SNc) independently of CB 1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the SNc and dorsal striatum of MPTP-treated mice. Three days post-MPTP, we found significant microglial activation and up-regulation of CB 2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB 2 receptor agonist JWH015 (4 mg/kg, i.p.) reduced MPTP-induced microglial activation, whereas genetic ablation of CB 2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTPassociated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB 2 cannabinoid receptors protects against MPTP-induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB 2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.

Aims. This study aims to characterize linear polarization structures in LOFAR observations of the interstellar medium (ISM) in the 3C 196 field, one of the primary fields of the LOFAR-Epoch of Reionization key science project. Methods. We have used the high band antennas (HBA) of LOFAR to image this region and rotation measure (RM) synthesis to unravel the distribution of polarized structures in Faraday depth. Results. The brightness temperature of the detected Galactic emission is 5−15 K in polarized intensity and covers the range from -3 to +8 rad m −2 in Faraday depth. The most interesting morphological feature is a strikingly straight filament at a Faraday depth of +0.5 rad m −2 running from north to south, right through the centre of the field and parallel to the Galactic plane. There is also an interesting system of linear depolarization canals conspicuous in an image showing the peaks of Faraday spectra. We used the Westerbork Synthesis Radio Telescope (WSRT) at 350 MHz to image the same region. For the first time, we see some common morphology in the RM cubes made at 150 and 350 MHz. There is no indication of diffuse emission in total intensity in the interferometric data, in line with results at higher frequencies and previous LOFAR observations. Based on our results, we determined physical parameters of the ISM and proposed a simple model that may explain the observed distribution of the intervening magneto-ionic medium. Conclusions. The mean line-of-sight magnetic field component, B , is determined to be 0.3 ± 0.1 µG and its spatial variation across the 3C 196 field is 0.1 µG. The filamentary structure is probably an ionized filament in the ISM, located somewhere within the Local Bubble. This filamentary structure shows an excess in thermal electron density (n e B > 6.2 cm −3 µG) compared to its surroundings.

Previous studies have reported elevated levels of biogenic aldehydes in the brains of patients with Parkinson's disease (PD). In the brain, aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). Reduced ALDH1 expression in surviving midbrain dopamine neurons has been reported in brains of patients who died with PD. In addition, impaired complex I activity, which is well documented in PD, reduces the availability of the NAD+ co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes. We hypothesized that chronically decreased function of multiple aldehyde dehydrogenases consequent to exposure to environmental toxins and/or reduced ALDH expression, plays an important role in the pathophysiology of PD. To address this hypothesis, we generated mice null for Aldh1a1 and Aldh2, the two isoforms known to be expressed in substantia nigra dopamine neurons. Aldh1a1−/−×Aldh2−/− mice exhibited age-dependent deficits in motor performance assessed by gait analysis and by performance on an accelerating rotarod. Intraperitoneal administration of L-DOPA plus benserazide alleviated the deficits in motor performance. We observed a significant loss of neurons immunoreactive for tyrosine hydroxylase (TH) in the substantia nigra and a reduction of dopamine and metabolites in the striatum of Aldh1a1−/−×Aldh2−/− mice. We also observed significant increases in biogenic aldehydes reported to be neurotoxic, including 4-hydroxynonenal (4-HNE) and the aldehyde intermediate of dopamine metabolism, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These results support the hypothesis that impaired detoxification of biogenic aldehydes may be important in the pathophysiology of PD and suggest that Aldh1a1−/−×Aldh2−/− mice may be a useful animal model of PD.

The redshifted ultraviolet light from early stars at z $ 10 contributes to the cosmic near-infrared background. We present detailed calculations of its spectrum with various assumptions about metallicity and the mass spectrum of early stars. We show that if the near-infrared background has a stellar origin, metal-free stars are not the only explanation of the excess near-infrared background; stars with metals (e.g., Z ¼ 1/50 Z ) can produce the same amount of background intensity as the metal-free stars. We quantitatively show that the predicted average intensity at 1-2 m is essentially determined by the efficiency of nuclear burning in stars, which is not very sensitive to metallicity. We predict I / à ' 4 8 nW m À2 sr À1 , where à is the mean star formation rate at z ¼ 7 15 (in units of M yr À1 Mpc À3 ) for stars more massive than 5 M . On the other hand, since we have very little knowledge about the form of the mass spectrum of early stars, the uncertainty in the average intensity due to the mass spectrum could be large. An accurate determination of the near-infrared background allows us to probe the formation history of early stars, which is difficult to constrain by other means. While the star formation rate at z ¼ 7 15 inferred from the current data is significantly higher than the local rate at z < 5, it does not rule out the stellar origin of the cosmic near-infrared background. In addition, we show that a reasonable initial mass function, coupled with this star formation rate, does not overproduce metals in the universe in most cases and may produce as little as less than 1% of the metals observed in the universe today.