Predicting Future Years of Life, Health, and Functional Ability: A Healthy Life Calculator for Older Adults

Introduction Planning for the future would be easier if we knew how long we will live and, more importantly, how many years we will be healthy and able to enjoy it. There are few well-documented aids for predicting our future health. We attempted to meet this need for persons 65 years of age and older. Methods Data came from the Cardiovascular Health Study, a large longitudinal study of older adults that began in 1990. Years of life (YOL) were defined by measuring time to death. Years of healthy life (YHL) were defined by an annual question about self-rated health, and years of able life (YABL) by questions about activities of daily living. Years of healthy and able life (YHABL) were the number of years the person was both Healthy and Able. We created prediction equations for YOL, YHL, YABL, and YHABL based on the demographic and health characteristics that best predicted outcomes. Internal and external validity were assessed. The resulting CHS Healthy Life Calculator (CHSHLC) was created and underwent three waves of beta testing. Findings A regression equation based on 11 variables accounted for about 40% of the variability for each outcome. Internal validity was excellent, and external validity was satisfactory. As an example, a very healthy 70-year-old woman might expect an additional 20 YOL, 16.8 YHL, 16.5 YABL, and 14.2 YHABL. The CHSHLC also provides the percent in the sample who differed by more than 5 years from the estimate, to remind the user of variability. Discussion The CHSHLC is currently the only available calculator for YHL, YABL, and YHABL. It may have limitations if today’s users have better prospects for health than persons in 1990. But the external validity results were encouraging. The remaining variability is substantial, but this is one of the few calculators that describes the possible accuracy of the estimates. Conclusion The CHSHLC, currently at http://diehr.com/paula/healthspan, meets the need for a straightforward and well-documented estimate of future years of healthy and able life that older adults can use in planning for the future

Polyamine pathway activity promotes cysteine essentiality in cancer cells

Cancer cells have high demands for non-essential amino acids (NEAAs), which are precursors for anabolic and antioxidant pathways that support cell survival and proliferation. It is well-established that cancer cells consume the NEAA cysteine, and that cysteine deprivation can induce cell death; however, the specific factors governing acute sensitivity to cysteine starvation are poorly characterized. Here, we show that that neither expression of enzymes for cysteine synthesis nor availability of the primary precursor methionine correlated with acute sensitivity to cysteine starvation. We observed a strong correlation between efflux of the methionine-derived metabolite methylthioadenosine (MTA) and sensitivity to cysteine starvation. MTA efflux results from genetic deletion of methylthioadenosine phosphorylase (MTAP), which is frequently deleted in cancers. We show that MTAP loss upregulates polyamine metabolism which, concurrently with cysteine withdrawal, promotes elevated reactive oxygen species and prevents cell survival. Our results reveal an unexplored metabolic weakness at the intersection of polyamine and cysteine metabolism

One-carbon metabolism in cancer

Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism

The redshift and mass dependence on the formation of the Hubble sequence at z > 1 from CANDELS/UDS

In this paper we present a detailed study of the structures and morphologies of a sample of 1188 massive galaxies with M-* >= 10(10) M-circle dot between redshifts z = 1 and 3 within the Ultra Deep Survey (UDS) region of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) field. Using this sample we determine how galaxy structure and morphology evolve with time, and investigate the nature of galaxy structure at high redshift. We visually classify our sample into discs, ellipticals and peculiar systems and correct for redshift effects on these classifications through simulations. We find significant evolution in the fractions of galaxies at a given visual classification as a function of redshift. The peculiar population is dominant at z > 2 with a substantial spheroid population, and a negligible disc population. We compute the transition redshift, z(trans), where the combined fraction of spheroidal and disc galaxies is equal to that of the peculiar population, as z(trans) = 1.86 +/- 0.62 for galaxies in our stellar mass range. We find that this transition changes as a function of stellar mass, with Hubble-type galaxies becoming dominant at higher redshifts for higher mass galaxies (z(trans) = 2.22 +/- 0.82), than for the lower mass galaxies (z(trans) = 1.73 +/- 0.57). Higher mass galaxies become morphologically settled before their lower mass counterparts, a form of morphological downsizing. We furthermore compare our visual classifications with the Sersic index, the concentration, asymmetry and clumpiness (CAS) parameters, star formation rate and rest-frame U - B colour. We find links between the colour of a galaxy, its star formation rate and how extended or peculiar it appears. Finally, we discuss the negligible z > 2 disc fraction based on visual morphologies and speculate that this is an effect of forming disc appearing peculiar through processes such as violent disc instabilities or mergers. We conclude that to properly define and measure high-redshift morphology and structure a new and more exact classification scheme is needed

The Redshift and Mass Dependence on the Formation of the Hubble Sequence at \u3cem\u3ez\u3c/em\u3e \u3e 1 from CANDELS/UDS

In this paper we present a detailed study of the structures and morphologies of a sample of 1188 massive galaxies with M* ≥ 1010 M⊙between redshifts z = 1 and 3 within the Ultra Deep Survey (UDS) region of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey (CANDELS) field. Using this sample we determine how galaxy structure and morphology evolve with time, and investigate the nature of galaxy structure at high redshift. We visually classify our sample into discs, ellipticals and peculiar systems and correct for redshift effects on these classifications through simulations. We find significant evolution in the fractions of galaxies at a given visual classification as a function of redshift. The peculiar population is dominant at z \u3e 2 with a substantial spheroid population, and a negligible disc population. We compute the transition redshift, ztrans, where the combined fraction of spheroidal and disc galaxies is equal to that of the peculiar population, as ztrans = 1.86 ± 0.62 for galaxies in our stellar mass range. We find that this transition changes as a function of stellar mass, with Hubble-type galaxies becoming dominant at higher redshifts for higher mass galaxies (ztrans = 2.22 ± 0.82), than for the lower mass galaxies (ztrans = 1.73 ± 0.57). Higher mass galaxies become morphologically settled before their lower mass counterparts, a form of morphological downsizing. We furthermore compare our visual classifications with the Sérsic index, the concentration, asymmetry and clumpiness (CAS) parameters, star formation rate and rest-frame U − B colour. We find links between the colour of a galaxy, its star formation rate and how extended or peculiar it appears. Finally, we discuss the negligible z \u3e 2 disc fraction based on visual morphologies and speculate that this is an effect of forming disc appearing peculiar through processes such as violent disc instabilities or mergers. We conclude that to properly define and measure high-redshift morphology and structure a new and more exact classification scheme is needed

Galaxy Zoo: CANDELS barred discs and bar fractions

The formation of bars in disc galaxies is a tracer of the dynamical maturity of the population. Previous studies have found that the incidence of bars in discs decreases from the local Universe to z ~ 1, and by z > 1 simulations predict that bar features in dynamically mature discs should be extremely rare. Here, we report the discovery of strong barred structures in massive disc galaxies at z ~ 1.5 in deep rest-frame optical images from the Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey. From within a sample of 876 disc galaxies identified by visual classification in Galaxy Zoo, we identify 123 barred galaxies. Selecting a subsample within the same region of the evolving galaxy luminosity function (brighter than L*), we find that the bar fraction across the redshift range 0.5 ≤ z ≤ 2 (fbar = 10.7+6.3 -3.5 per cent after correcting for incompleteness) does not significantly evolve.We discuss the implications of this discovery in the context of existing simulations and our current understanding of the way disc galaxies have evolved over the last 11 billion yearsPeer reviewedFinal Accepted Versio

Subclinical Vascular Disease Burden and Longer Survival

OBJECTIVES: Subclinical vascular disease (SVD) contributes to the aging process and may decrease life expectancy. We aimed to determine the contribution of gradations of SVD to the likelihood of achieving longer survival, and to determine what allows some individuals to achieve longer survival in the presence of high SVD. DESIGN: Cohort Study SETTING: Cardiovascular Health Study PARTICIPANTS: Adults who were born after June 30th, 1918 and before June 30th, 1921 (n=2,082); participants were age 70-75 years at baseline visit (1992-1993). MEASUREMENTS: A SVD index was scored as 0, 1, or 2 for no, mild, or severe abnormalities on ankle-arm index, electrocardiogram, and common carotid intima-media thickness measured at baseline. Survival groups were categorized as <80, 80-84, 85-89, and 90+ years. RESULTS: A one point lower SVD score was associated with a 1.22 (95% confidence interval: 1.14, 1.31) higher odds of achieving longer survival, independent of potential confounders. This association was unchanged after adjustment for intermediate incident cardiovascular events. There was suggestion of an interaction of kidney function, smoking, and CRP with SVD; the association of SVD and longer survival appeared modestly increased in persons with poor kidney function, inflammation, or a history of smoking. CONCLUSION: A lower burden of SVD is associated with longer survival, and this association was independent of intermediate cardiovascular events. Abstinence from smoking, better kidney function, and lower inflammation may attenuate the effects of higher SVD and further promote longer survival.This is an author's peer-reviewed final manuscript, as accepted by the publisher. The article is copyrighted by the authors; the Journal compilation is copyrighted by the American Geriatrics Society and published by John Wiley & Sons, Inc. It can be found at: http://onlinelibrary.wiley.com/journal/10.1111/%28ISSN%291532-5415Keywords: kidney function, inflammation, smoking, survival, cardiovascular disease, subclinical diseas

TBK1 Kinase Addiction in Lung Cancer Cells Is Mediated via Autophagy of Tax1bp1/Ndp52 and Non-Canonical NF-kappa B Signalling

K-Ras dependent non-small cell lung cancer (NSCLC) cells are 'addicted' to basal autophagy that reprograms cellular metabolism in a lysosomal-sensitive manner. Here we demonstrate that the xenophagy-associated kinase TBK1 drives basal autophagy, consistent with its known requirement in K-Ras-dependent NSCLC proliferation. Furthermore, basal autophagy in this context is characterised by sequestration of the xenophagy cargo receptor Ndp52 and its paralogue Tax1bp1, which we demonstrate here to be a bona fide cargo receptor. Autophagy of these cargo receptors promotes non-canonical NF-κB signalling. We propose that this TBK1-dependent mechanism for NF-κB signalling contributes to autophagy addiction in K-Ras driven NSCLC