Lifespan modulation in mice and the confounding effects of genetic background

We are currently in the midst of a revolution in ageing research, with several dietary, genetic and pharmacological interventions now known to modulate ageing in model organisms. Excitingly, these interventions also appear to have beneficial effects on late-life health. For example, dietary restriction (DR) has been shown to slow the incidence of age-associated cardiovascular disease, metabolic disease, cancer and brain ageing in non-human primates and has been shown to improve a range of health indices in humans. While the idea that DR's ability to extend lifespan is often thought of as being universal, studies in a range of organisms, including yeast, mice and monkeys, suggest that this may not actually be the case. The precise reasons underlying these differential effects of DR on lifespan are currently unclear, but genetic background may be an important factor in how an individual responds to DR. Similarly, recent findings also suggest that the responsiveness of mice to specific genetic or pharmacological interventions that modulate ageing may again be influenced by genetic background. Consequently, while there is a clear driver to develop interventions to improve late-life health and vitality, understanding precisely how these act in response to particular genotypes is critical if we are to translate these findings to humans. We will consider of the role of genetic background in the efficacy of various lifespan interventions and discuss potential routes of utilising genetic heterogeneity to further understand how particular interventions modulate lifespan and healthspan

The causes of individual and seasonal variation in the metabolic rate of knot calidris canutus

Basal metabolic rate (BMR), an individual bird's minimum rate of energy expenditure, was followed in adult and juvenile captive Knot throughout their annual cycle, in conjunction with measurements of total body mass (BM) and body composition (lean mass and fat mass, as predicted using Total Body Electrical Conductivity). Adult captive Knot increased significantly in BM during spring, primarily due to fat deposition. Most juvenile Knot did not display fat deposition in their first spring in captivity. A seasonal peak in BMR, often double the seasonal minimum, occurred during spring but typically took place, on average, 5,11 and 4 days (respectively) after the seasonal peaks in BM, lean mass and fat mass. Little of the variation in BMR seen within or amongst captive Knot, irrespective of physiological state, was explained by variation in a single parameter (BM, lean mass or fat mass). As variation in BMR was not simply a consequence of variation in total lean mass, the average metabolic output per gram of the lean tissues must also have altered seasonally. During fat deposition in spring, Knot exhibited a significant increase in liver mass and a significant elevation (approximately 50% higher) in the activity of succinate dehydrogenase (SDH, an indicator of metabolic activity) in the small intestine. Such adaptations may have assisted an increase in fat deposition rate. SDH activity decreased by approximately 60% in the pectoral muscle of Knot during this period. Such a reduction in SDH may also aid fat deposition as it lowered an individual’s overall BMR. As Knot BM decreased after the spring peak, then BMR decreased in parallel with a decrease in SDH activity in their pectoral muscles. The spring peak in overall BMR may indicate an increase in the maximal sustainable metabolic rate (MMR) of an individual during migratory flight. If a relationship exists between BMR and MMR, then variation in metabolic activity rather than variation in the mass of various lean tissues (e.g. pectoral muscle) will increase metabolic scope without increasing the energetic costs of flight

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

Extracellular vesicles, ageing, and therapeutic interventions

A more comprehensive understanding of the human ageing process is required to help mitigate the increasing burden of age-related morbidities in a rapidly growing global demographic of elderly individuals. One exciting novel strategy that has emerged to intervene involves the use of extracellular vesicles to engender tissue regeneration. Specifically, this employs their molecular payloads to confer changes in the epigenetic landscape of ageing cells and ameliorate the loss of functional capacity. Understanding the biology of extracellular vesicles and the specific roles they play during normative ageing will allow for the development of novel cell-free therapeutic interventions. Hence, the purpose of this review is to summarise the current understanding of the mechanisms that drive ageing, critically explore how extracellular vesicles affect ageing processes and discuss their therapeutic potential to mitigate the effects of age-associated morbidities and improve the human health span

Microvesicles as vehicles for tissue regeneration: Changing of the guards

Purpose of Review: Microvesicles (MVs) have been recognised as mediators of stem cell function, enabling and guiding their regenerative effects. Recent Findings: MVs constitute one unique size class of extracellular vesicles (EVs) directly shed from the cell plasma membrane. They facilitate cell-to-cell communication via intercellular transfer of proteins, mRNA and microRNA (miRNA). MVs derived from stem cells, or stem cell regulatory cell types, have proven roles in tissue regeneration and repair processes. Their role in the maintenance of healthy tissue function throughout the life course and thus in age related health span remains to be elucidated. Summary: Understanding the biogenesis and mechanisms of action of MVs may enable the development of cell-free therapeutics capable of assisting in tissue maintenance and repair for a variety of age-related degenerative diseases. This review critically evaluates recent work published in this area and highlights important new findings demonstrating the use of MVs in tissue regeneration

Chronic helminth infection burden differentially affects haematopoietic cell development while ageing selectively impairs adaptive responses to infection

Throughout the lifespan of an individual, the immune system undergoes complex changes while facing novel and chronic infections. Helminths, which infect over one billion people and impose heavy livestock productivity losses, typically cause chronic infections by avoiding and suppressing host immunity. Yet, how age affects immune responses to lifelong parasitic infection is poorly understood. To disentangle the processes involved, we employed supervised statistical learning techniques to identify which factors among haematopoietic stem and progenitor cells (HSPC), and both innate and adaptive responses regulate parasite burdens and how they are affected by host age. Older mice harboured greater numbers of the parasites’ offspring than younger mice. Protective immune responses that did not vary with age were dominated by HSPC, while ageing specifically eroded adaptive immunity, with reduced numbers of naïve T cells, poor T cell responsiveness to parasites, and impaired antibody production. We identified immune factors consistent with previously-reported immune responses to helminths, and also revealed novel interactions between helminths and HSPC maturation. Our approach thus allowed disentangling the concurrent effects of ageing and infection across the full maturation cycle of the immune response and highlights the potential of such approaches to improve understanding of the immune system within the whole organism

Putting a strain on diversity.

Human life expectancy is increasing on a global scale, but healthspan—the period of life free from age‐associated ill health—is not improving at a comparable rate. This disconnect means that a greater proportion of the general population will spend a longer period of their life suffering from one or more debilitating age‐associated diseases, such as cardiovascular disease, Alzheimer's disease, osteoporosis, sarcopenia and various cancers. Understanding the processes underlying ageing and age‐related diseases is therefore a major and pressing research challenge in biomedical research

Inadequate food intake at high temperatures is related to depressed mitochondrial respiratory capacity

Animals, especially ectotherms, are highly sensitive to the temperature of their surrounding environment. Extremely high temperature, for example, induces a decline of average performance of conspecifics within a population, but individual heterogeneity in the ability to cope with elevating temperatures has rarely been studied. In this study, we examined inter-individual variation in feeding ability and consequent growth rate of juvenile brown trout Salmo trutta acclimated to a high temperature (19°C), and investigated the relationship between these metrics of whole-animal performances and among-individual variation in mitochondrial respiration capacity. Food was provided ad libitum yet intake varied ten-fold amongst individuals, resulting in some fish losing weight whilst others continued to grow. Almost half of the variation in food intake was related to variability in mitochondrial capacity: low intake (and hence growth failure) was associated with high leak respiration rates within liver and muscle mitochondria, and a lower coupling of muscle mitochondria. These observations, combined with the inability of fish with low food consumption to increase their intake despite ad libitum food levels, suggest a possible insufficient capacity of the mitochondria for maintaining ATP homeostasis. Individual variation in thermal performance is likely to confer variation in the upper limit of an organism's thermal niche and in turn affect the structure of wild populations in warming environments

Unstructured Human Activity Detection from RGBD Images

Being able to detect and recognize human activities is essential for several applications, including personal assistive robotics. In this paper, we perform detection and recognition of unstructured human activity in unstructured environments. We use a RGBD sensor (Microsoft Kinect) as the input sensor, and compute a set of features based on human pose and motion, as well as based on image and pointcloud information. Our algorithm is based on a hierarchical maximum entropy Markov model (MEMM), which considers a person's activity as composed of a set of sub-activities. We infer the two-layered graph structure using a dynamic programming approach. We test our algorithm on detecting and recognizing twelve different activities performed by four people in different environments, such as a kitchen, a living room, an office, etc., and achieve good performance even when the person was not seen before in the training set.Comment: 2012 IEEE International Conference on Robotics and Automation (A preliminary version of this work was presented at AAAI workshop on Pattern, Activity and Intent Recognition, 2011

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