Demographic analysis reveals gradual senescence in the flatworm Macrostomum lignano

Free-living flatworms ("Turbellaria") are appropriate model organisms to gain better insight into the role of stem cells in ageing and rejuvenation. Ageing research in flatworms is, however, still scarce. This is partly due to culture difficulties and the lack of a complete set of demographic data, including parameters such as median lifespan and age-specific mortality rate. In this paper, we report on the first flatworm survival analysis. We used the species Macrostomum lignano, which is an emerging model for studying the reciprocal influence between stem cells, ageing and rejuvenation. This species has a median lifespan of 205 ± 13 days (average ± standard deviation [SD]) and a 90th percentile lifespan of 373 ± 32 days. The maximum lifespan, however, is more than 745 days, and the average survival curve is characterised by a long tail because a small number of individuals lives twice as long as 90% of the population. Similar to earlier observations in a wide range of animals, in M. lignano the age-specific mortality rate increases exponentially, but levels off at the oldest ages. To compare the senescence of M. lignano with that of other ageing models, we determined the mortality rate doubling time, which is 0.20 ± 0.02 years. As a result, we can conclude that M. lignano shows gradual senescence at a rate similar to the vertebrate ageing models Rattus norvegicus and Mus musculus. We argue that M. lignano is a suitable model for ageing and rejuvenation research, and especially for the role of stem cells in these processes, due to its accessible stem cell system and regeneration capacity, and the possibility of combining stem cell studies with demographic analyses

ROS in Aging Caenorhabditis elegans: Damage or Signaling?

Many insights into the mechanisms and signaling pathways underlying aging have resulted from research on the nematode Caenorhabditis elegans. In this paper, we discuss the recent findings that emerged using this model organism concerning the role of reactive oxygen species (ROS) in the aging process. The accrual of oxidative stress and damage has been the predominant mechanistic explanation for the process of aging for many years, but reviewing the recent studies in C. elegans calls this theory into question. Thus, it becomes more and more evident that ROS are not merely toxic byproducts of the oxidative metabolism. Rather it seems more likely that tightly controlled concentrations of ROS and fluctuations in redox potential are important mediators of signaling processes. We therefore discuss some theories that explain how redox signaling may be involved in aging and provide some examples of ROS functions and signaling in C. elegans metabolism. To understand the role of ROS and the redox status in physiology, stress response, development, and aging, there is a rising need for accurate and reversible in vivo detection. Therefore, we comment on some methods of ROS and redox detection with emphasis on the implementation of genetically encoded biosensors in C. elegans

Modeling age-dependent decline of metabolic activity in Caenorhabditis elegans. UNIVERSITEIT

Metabolic patterns of wild type and daf-2(e1370) differ considerably. Wild type worms show an exponential decline of metabolic activity over the whole life trajectory, while the long-lived mutant daf-2(e1370) shows an initial exponential decline, which gradually slows down with age, and may finally become linear. The equation derived from the general model fits very well to both sets of experimental data. It is very remarkable that, in wild type worms, parameters b and b of the equation 2 3 seem to be insignificant. We found an exponential decrease of metabolic activity over the whole adult life span which can be accurately described by a two-parameter exponential decay. What does this mean in relation to the model? In wild type, we found that: b = 0 2 or implicating that which in turn shows that the impact of the ‘protection ’ factor is very low compared to the combined effects of repair mechanisms and damage resulting from metabolic activity. b = 0 3 or: since: implicating that indicating that also the repair mechanisms may not play prominent role, or are at least insufficient counteracting the damage inflicted by metabolic activity. For daf-2(e1370), b and b were <> 0 suggesting that, in this mutant, protection 2 3 and/or repair systems might play an important role extending their life span. This agrees well with the increased stress resistance (UV, heat, temperature) and higher SOD levels of daf-2 mutants as reported in other studies (Barsyte et al., 2001; Larsen

Disruption of insulin signalling preserves bioenergetic competence of mitochondria in ageing <it>Caenorhabditis elegans</it>

Abstract Background The gene daf-2 encodes the single insulin/insulin growth factor-1-like receptor of Caenorhabditis elegans. The reduction-of-function allele e1370 induces several metabolic alterations and doubles lifespan. Results We found that the e1370 mutation alters aerobic energy production substantially. In wild-type worms the abundance of key mitochondrial proteins declines with age, accompanied by a dramatic decrease in energy production, although the mitochondrial mass, inferred from the mitochondrial DNA copy number, remains unaltered. In contrast, the age-dependent decrease of both key mitochondrial proteins and bioenergetic competence is considerably attenuated in daf-2(e1370) adult animals. The increase in daf-2(e1370) mitochondrial competence is associated with a higher membrane potential and increased reactive oxygen species production, but with little damage to mitochondrial protein or DNA. Together these results point to a higher energetic efficiency of daf-2(e1370) animals. Conclusions We conclude that low daf-2 function alters the overall rate of ageing by a yet unidentified mechanism with an indirect protective effect on mitochondrial function.</p

CBP-1 Acts in GABAergic Neurons to Double Life Span in Axenically Cultured Caenorhabditis elegans

When cultured in axenic medium, Caenorhabditis elegans shows the largest life-span extension compared with other dietary restriction regimens. However, the underlying molecular mechanism still remains elusive. The gene cbp-1, encoding the worm ortholog of p300/CBP (CREB-binding protein), is one of the very few key genes known to be essential for life span doubling under axenic dietary restriction (ADR). By using tissue-specific RNAi, we found that cbp-1 expression in the germline is essential for fertility, whereas this gene functions specifically in the GABAergic neurons to support the full life span-doubling effect of ADR. Surprisingly, GABA itself is not required for ADR-induced longevity, suggesting a role of neuropeptide signaling. In addition, chemotaxis assays illustrate that neuronal inactivation of CBP-1 affects the animals' food sensing behavior. Together, our results show that the strong life-span extension in axenic medium is under strict control of GABAergic neurons and may be linked to food sensing.status: publishe

Prediction of biological age by morphological staging of sarcopenia in **Caenorhabditis elegans**

Sarcopenia encompasses a progressive decline in muscle quantity and quality. Given its close association with ageing, it may represent a valuable healthspan marker. The commonalities with human muscle structure and facile visualization possibilities make Caenorhabditis elegans an attractive model for studying the relationship between sarcopenia and healthspan. However, classical visual assessment of muscle architecture is subjective and has low throughput. To resolve this, we have developed an image analysis pipeline for the quantification of muscle integrity in confocal microscopy images from a cohort of ageing myosin::GFP reporter worms. We extracted a variety of morphological descriptors and found a subset to scale linearly with age. This allowed establishing a linear model that predicts biological age from a morphological muscle signature. To validate the model, we evaluated muscle architecture in long-lived worms that are known to experience delayed sarcopenia by targeted knockdown of the daf-2 gene. We conclude that quantitativ e microscopy allows for staging sarcopenia in C . elegans and may foster the development of image-based screens in this model organism to identif y modulators that mitigate age-related muscle frailty and thus improve healthspan