Prediction of C. elegans Longevity Genes by Human and Worm Longevity Networks

Intricate and interconnected pathways modulate longevity, but screens to identify the components of these pathways have not been saturating. Because biological processes are often executed by protein complexes and fine-tuned by regulatory factors, the first-order protein-protein interactors of known longevity genes are likely to participate in the regulation of longevity. Data-rich maps of protein interactions have been established for many cardinal organisms such as yeast, worms, and humans. We propose that these interaction maps could be mined for the identification of new putative regulators of longevity. For this purpose, we have constructed longevity networks in both humans and worms. We reasoned that the essential first-order interactors of known longevity-associated genes in these networks are more likely to have longevity phenotypes than randomly chosen genes. We have used C. elegans to determine whether post-developmental inactivation of these essential genes modulates lifespan. Our results suggest that the worm and human longevity networks are functionally relevant and possess a high predictive power for identifying new longevity regulators

Just-DNA-Seq, open-source personal genomics platform: longevity science for everyone

Genomic data has become increasingly accessible to the general public with the advent of companies offering whole genome sequencing at a relatively low cost. However, their reports are not verifiable due to a lack of crucial details and transparency: polygenic risk scores do not always mention all the polymorphisms involved. Simultaneously, tackling the manual investigation and interpretation of data proves challenging for individuals lacking a background in genetics. Currently, there is no open-source or commercial solution that provides comprehensive longevity reports surpassing a limited number of polymorphisms. Additionally, there are no ready-made, out-of-the-box solutions available that require minimal expertise to generate reports independently. To address these issues, we have developed the Just-DNA-Seq open-source genomic platform. Just-DNA-Seq aims to provide a user-friendly solution to genome annotation by allowing users to upload their own VCF files and receive annotations of their genetic variants and polygenic risk scores related to longevity. We also created GeneticsGenie custom GPT that can answer genetics questions based on our modules. With the Just-DNA-Seq platform, we want to provide full information regarding the genetics of long life: disease-predisposing variants, that can reduce lifespan and manifest at different age (cardiovascular, oncological, neurodegenerative diseases, etc.), pro-longevity variants and longevity drug pharmacokinetics. In this research article, we will discuss the features and capabilities of Just-DNA-Seq, and how it can benefit individuals looking to understand and improve their health. It's crucial to note that the Just-DNA-Seq platform is exclusively intended for scientific and informational purposes and is not suitable for medical applications.Comment: 41 pages, 7 figure

Systematic analysis of the gerontome reveals links between aging and age-related diseases

In model organisms, over 2,000 genes have been shown to modulate aging, the collection of which we call the ‘gerontome’. Although some individual aging-related genes have been the subject of intense scrutiny, their analysis as a whole has been limited. In particular, the genetic interaction of aging and age-related pathologies remain a subject of debate. In this work, we perform a systematic analysis of the gerontome across species, including human aging-related genes. First, by classifying aging-related genes as pro- or anti-longevity, we define distinct pathways and genes that modulate aging in different ways. Our subsequent comparison of aging-related genes with age-related disease genes reveals species-specific effects with strong overlaps between aging and age-related diseases in mice, yet surprisingly few overlaps in lower model organisms. We discover that genetic links between aging and age-related diseases are due to a small fraction of aging-related genes which also tend to have a high network connectivity. Other insights from our systematic analysis include assessing how using datasets with genes more or less studied than average may result in biases, showing that age-related disease genes have faster molecular evolution rates and predicting new aging-related drugs based on drug-gene interaction data. Overall, this is the largest systems-level analysis of the genetics of aging to date and the first to discriminate anti- and pro-longevity genes, revealing new insights on aging-related genes as a whole and their interactions with age-related diseases

The Digital Ageing Atlas: integrating the diversity of age-related changes into a unified resource

Multiple studies characterizing the human ageing phenotype have been conducted for decades. However, there is no centralized resource in which data on multiple age-related changes are collated. Currently, researchers must consult several sources, including primary publications, in order to obtain age-related data at various levels. To address this and facilitate integrative, system-level studies of ageing we developed the Digital Ageing Atlas (DAA). The DAA is a one-stop collection of human age-related data covering different biological levels (molecular, cellular, physiological, psychological and pathological) that is freely available online (http://ageing-map.org/). Each of the >3000 age-related changes is associated with a specific tissue and has its own page displaying a variety of information, including at least one reference. Age-related changes can also be linked to each other in hierarchical trees to represent different types of relationships. In addition, we developed an intuitive and user-friendly interface that allows searching, browsing and retrieving information in an integrated and interactive fashion. Overall, the DAA offers a new approach to systemizing ageing resources, providing a manually-curated and readily accessible source of age-related changes

Targeting EDEM protects against ER stress and improves development and survival in C. elegans.

EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological conditions. In addition, chronic impairment of EDEM functioning attenuated both XBP-1 activation and up-regulation of the stress chaperone GRP78/BiP, in response to acute ER stress. We also show that pre-conditioning to EDEM loss in acute ER stress restores ER homeostasis and promotes survival by activating ER hormesis. We propose a novel role for EDEM in fine-tuning the ER stress responsiveness that affects ER homeostasis and survival

edem response to thapsigargin

S4 Fig. edem response to thapsigargin. (A) Quantitative RT-PCR measurements of edem mRNA levels in WT young animals under non stress (NS) and treatment with 5 μM thapsigargin (TG), (n = 3 independent experiments). (B) Percentage of eggs that developed into L4 larvae after 3 days on 10 μM thapsigargin. Each strain was scored in three independent experiments in triplicates. (C) Quantification of WT (EV) or RNAi-treated day one adults carrying Phsp-4::GFP transgene, treated or not with 5 μM thapsigargin. The worms were kept on RNAi plates for one generation before exposure to ER stress treatments. Values represent mean fluorescence/µm2 x 1000. The red bars indicate the average ±SEM. (D) Analysis of xbp-1 spliced/unspliced ratio from young adults of indicated strains. Total RNA was isolated, reverse transcribed and used for PCR analysis of xbp-1 splicing forms.Peer reviewe