Proteostasis and ageing: insights from long-lived mutant mice

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis- where proteostasis is defined here as the maintenance of the proteome- appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, all appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants

Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress

Reduced signalling through the insulin/insulin-like growth factor-1 signalling (IIS) pathway is a highly conserved lifespan determinant in model organisms. The precise mechanism underlying the effects of the IIS on lifespan and health is currently unclear, although cellular stress resistance may be important. We have previously demonstrated that mice globally lacking insulin receptor substrate 1 (Irs1−/−) are long-lived and enjoy a greater period of their life free from age-related pathology compared with wild-type (WT) controls. In this study, we show that primary dermal fibroblasts and primary myoblasts derived from Irs1−/− mice are no more resistant to a range of oxidant and nonoxidant chemical stressors than cells derived from WT mice

Animal Studies Journal 2015 4 (1): Cover Pages, Table of Contents, Notes on Contributors and Editorial

Cover pages, table of contents, contributor biographies and editorial for Animal Studies Journal Vol. 4 No.1, 2015. Guest editor - Colin Salter

Dietary restriction increases skeletal muscle mitochondrial respiration but not mitochondrial content in C57BL/6 mice

Dietary restriction (DR) is suggested to induce mitochondrial biogenesis, although recently this has been challenged. Here we determined the impact of 1, 9 and 18 months of 30% DR in male C57BL/6 mice on key mitochondrial factors and on mitochondrial function in skeletal muscle, relative to age-matched ad libitum (AL) controls. We examined proteins and mRNAs associated with mitochondrial biogenesis and measured mitochondrial respiration in permeabilised myofibres using high resolution respirometry. 30% DR, irrespective of duration, had no effect on citrate synthase activity. In contrast, total and nuclear protein levels of PGC-1?, mRNA levels of several mitochondrial associated proteins (Pgc-1?, Nrf1, Core 1, Cox IV, Atps) and cytochrome c oxidase content were increased in skeletal muscle of DR mice. Furthermore, a range of mitochondrial respiration rates were increased significantly by DR, with DR partially attenuating the age-related decline in respiration observed in AL controls. Therefore, DR did not increase mitochondrial content, as determined by citrate synthase, in mouse skeletal muscle. However, it did induce a PGC-1? adaptive response and increased mitochondrial respiration. Thus, we suggest that a functionally ‘efficient’ mitochondrial electron transport chain may be a critical mechanism underlying DR, rather than any net increase in mitochondrial content per se

Mezcala – a new segregate genus of mimosoid legume (Leguminosae, Caesalpinioideae, mimosoid clade) narrowly endemic to the Balsas Depression in Mexico

Recent results have demonstrated that the genus Desmanthus is non-monophyletic because the genus Kanaloa is nested within it, with a single species, Desmanthus balsensis placed as sister to the clade comprising Kanaloa plus the remaining species of Desmanthus. Here we transfer D. balsensis to a new segregate genus Mezcala, discuss the morphological features supporting this new genus, present a key to distinguish Mezcala from closely related genera in the Leucaena subclade, and provide a distribution map of M. balsensis

Leveraging a Community-Based Research Approach to Explore Research Perceptions Among Suburban Poor and Underserved Populations

This qualitative study explored perceptions of research among a rapidly growing underserved population within a suburban community, a setting that has yet to be sufficiently explored using a community-based research (CBR) approach. We recruited community members from community health care agencies in DuPage County, Illinois, and 79 participants were enrolled in the study. Community researchers conducted nine focus groups comprised of agency clients and eight stakeholder interviews to collect community perspectives regarding the meaning of research and its community impact, current and desired channels of research information, and research motives, discrimination, and funding. Findings revealed four major themes: community members 1) often associate research with medical research or community engagement; 2) rely most heavily on the internet for research information; 3) perceive financial barriers, rather than racial or ethnic barriers, as a significant obstacle to receiving the benefits of research; and 4) trust research conducted by academic institutions

Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice

Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice

An Experimental Investigation of Strain Rate, Temperature and Humidity Effects on the Mechanical Behavior of a Perfluorosulfonic Acid Membrane

The time-dependent hygro-thermal mechanical behavior of a perfluorosulfonic acid (PFSA) membrane (Nafion® 211 membrane) commonly used in Proton Exchange Membrane Fuel Cells (PEMFCs) is investigated at selected strain rates for a broad range of temperatures and humidities. Tensile tests and relaxation tests are conducted to determine Young’s modulus and proportional limit stress as functions of strain rate, temperature and humidity. The results show that Young’s modulus and proportional limit stress increase as the strain rate increases, and decrease as the temperature or humidity increases. The results also show that the mechanical response of Nafion® 211 membrane is more sensitive to typical changes in strain rate or temperature than to typical changes in humidity. In addition, two temperature/humidity cycles are conducted to determine the steady state swelling behavior of Nafion® 211 membrane as a function of temperature and humidity. The results show that the membrane swells with increasing temperature and humidity, and that there is little or no hygro-thermal history effect for the swelling strains