Mammalian models of extended healthy lifespan

Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans

Focused Local Search for Random 3-Satisfiability

A local search algorithm solving an NP-complete optimisation problem can be viewed as a stochastic process moving in an 'energy landscape' towards eventually finding an optimal solution. For the random 3-satisfiability problem, the heuristic of focusing the local moves on the presently unsatisfiedclauses is known to be very effective: the time to solution has been observed to grow only linearly in the number of variables, for a given clauses-to-variables ratio $\alpha$ sufficiently far below the critical satisfiability threshold $\alpha_c \approx 4.27$. We present numerical results on the behaviour of three focused local search algorithms for this problem, considering in particular the characteristics of a focused variant of the simple Metropolis dynamics. We estimate the optimal value for the ``temperature'' parameter $\eta$ for this algorithm, such that its linear-time regime extends as close to $\alpha_c$ as possible. Similar parameter optimisation is performed also for the well-known WalkSAT algorithm and for the less studied, but very well performing Focused Record-to-Record Travel method. We observe that with an appropriate choice of parameters, the linear time regime for each of these algorithms seems to extend well into ratios $\alpha > 4.2$ -- much further than has so far been generally assumed. We discuss the statistics of solution times for the algorithms, relate their performance to the process of ``whitening'', and present some conjectures on the shape of their computational phase diagrams.Comment: 20 pages, lots of figure

Lifelongα-tocopherol supplementation increases the median life span of C57BL/6 mice in the cold but has only minor effects on oxidative damage

The effects of dietary antioxidant supplementation on oxidative stress and life span are confused. We maintained C57BL/6 mice at 7 ± 2°C and supplemented their diet with α-tocopherol from 4 months of age. Supplementation significantly increased (p = 0.042) median life span by 15% (785 days, n = 44) relative to unsupplemented controls (682 days, n = 43) and also increased maximum life span (oldest 10%, p = 0.028). No sex or sex by treatment interaction effects were observed on life span, with treatment having no effect on resting or daily metabolic rate. Lymphocyte and hepatocyte oxidative DNA damage and hepatic lipid peroxidation were unaffected by supplementation, but hepatic oxidative DNA damage increased with age. Using a cDNA macroarray, genes associated with xenobiotic metabolism were significantly upregulated in the livers of female mice at 6 months of age (2 months supplementation). At 22 months of age (18 months supplementation) this response had largely abated, but various genes linked to the p21 signaling pathway were upregulated at this time. We suggest that α-tocopherol may initially be metabolized as a xenobiotic, potentially explaining why previous studies observe a life span extension generally when lifelong supplementation is initiated early in life. The absence of any significant effect on oxidative damage suggests that the life span extension observed was not mediated via any antioxidant properties of α-tocopherol. We propose that the life span extension observed following α-tocopherol supplementation may be mediated via upregulation of cytochrome p450 genes after 2 months of supplementation and/or upregulation of p21 signaling genes after 18 months of supplementation. However, these signaling pathways now require further investigation to establish their exact role in life span extension following α-tocopherol supplementation

Corrigendum: RNA Polymerase III, Ageing and Longevity

[This corrects the article DOI: 10.3389/fgene.2021.705122.]

Dietary restriction in ILSXISS mice is associated with widespread changes in splicing regulatory factor expression levels.

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record Dietary restriction (DR) represents one of the most reproducible interventions to extend lifespan and improve health outcomes in a wide range of species, but substantial variability in DR response has been observed, both between and within species. The mechanisms underlying this variation in effect are still not well characterised. Splicing regulatory factors have been implicated in the pathways linked with DR-induced longevity in C. elegans and are associated with lifespan itself in mice and humans. We used qRT-PCR to measure the expression levels of a panel of 20 age- and lifespan-associated splicing regulatory factors in brain, heart and kidney derived from three recombinant inbred strains of mice with variable lifespan responses to short-term (2 months) or long-term (10 months) 40% DR to determine their relationship to DR-induced longevity. We identified 3 patterns of association; i) splicing factors associated with DR alone, ii) splicing factors associated with strain alone or iii) splicing factors associated with both DR and strain. Tissue specific variation was noted in response to short term or long-term DR, with the majority of effects noted in brain following long term DR in the positive responder strain TejJ89. Association in heart and kidney were less evident, and occurred following short term DR. Splicing factors associated with both DR and strain may be mechanistically involved in strain-specific differences in response to DR. We provide here evidence concordant with a role for some splicing factors in the lifespan modulatory effects of DR across different mouse strains and in different tissues

Confronting the Superbubble Model with X-ray Observations of 30 Dor C

We present an analysis of XMM-Newton observations of the superbubble 30 Dor C and compare the results with the predictions from the standard wind-blown bubble model. We find that the observed X-ray spectra cannot be fitted satisfactorily with the model alone and that there is evidence for nonthermal X-ray emission, which is particularly important at > 4 keV. The total unabsorbed 0.1-10 keV luminosities of the eastern and western parts of the bubble are ~3 10^36 erg/s and ~5 10^36 erg/s, respectively. The unabsorbed 0.1-10 keV luminosity of the bubble model is 4 10^36 erg/s and so the power-law component contributes between 1/3 and 1/2 to the total unabsorbed luminosity in this energy band. The nature of the hard nonthermal emission is not clear, although recent supernovae in the bubble may be responsible. We expect that about one or two core-collapse supernovae could have occured and are required to explain the enrichment of the hot gas, as evidenced by the overabundance of alpha-elements by a factor of 3, compared to the mean value of 0.5 solar for the interstellar medium in the Large Magellanic Cloud. As in previous studies of various superbubbles, the amount of energy currently present in 30 Dor C is significantly less than the expected energy input from the enclosed massive stars over their lifetime. We speculate that a substantial fraction of the input energy may be radiated in far-infrared by dust grains, which are mixed with the hot gas because of the thermal conduction and/or dynamic mixing.Comment: 25 pages, 4 figures. To appear in The Astrophysical Journal, August 20, 2004 issu

The role of insulin receptor substrate 2 in hypothalamic and β cell function

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in β cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and β cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced β cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in β cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis

The scale-free character of the cluster mass function and the universality of the stellar IMF

Our recent determination of a Salpeter slope for the IMF in the field of 30 Doradus (Selman and Melnick 2005) appears to be in conflict with simple probabilistic counting arguments advanced in the past to support observational claims of a steeper IMF in the LMC field. In this paper we re-examine these arguments and show by explicit construction that, contrary to these claims, the field IMF is expected to be exactly the same as the stellar IMF of the clusters out of which the field was presumably formed. We show that the current data on the mass distribution of clusters themselves is in excellent agreement with our model, and is consistent with a single spectrum {\it by number of stars} of the type $n^\beta$ with beta between -1.8 and -2.2 down to the smallest clusters without any preferred mass scale for cluster formation. We also use the random sampling model to estimate the statistics of the maximal mass star in clusters, and confirm the discrepancy with observations found by Weidner and Kroupa (2006). We argue that rather than signaling the violation of the random sampling model these observations reflect the gravitationally unstable nature of systems with one very large mass star. We stress the importance of the random sampling model as a \emph{null hypothesis} whose violation would signal the presence of interesting physics.Comment: 9 pages emulateap

On random graphs and the statistical mechanics of granular matter

The dynamics of spins on a random graph with ferromagnetic three-spin interactions is used to model the compaction of granular matter under a series of taps. Taps are modelled as the random flipping of a small fraction of the spins followed by a quench at zero temperature. We find that the density approached during a logarithmically slow compaction - the random-close-packing density - corresponds to a dynamical phase transition. We discuss the the role of cascades of successive spin-flips in this model and link them with density-noise power fluctuations observed in recent experiments.Comment: minor changes, to appear in EP