Gilad Lehmann

Human Ageing Genomic Resources: Integrated databases and tools for the biology and genetics of ageing

The Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info) is a freely available online collection of research databases and tools for the biology and genetics of ageing. HAGR features now several databases with high-quality manually curated data: (i) GenAge, a database of genes associated with ageing in humans and model organisms; (ii) AnAge, an extensive collection of longevity records and complementary traits for >4000 vertebrate species; and (iii) GenDR, a newly incorporated database, containing both gene mutations that interfere with dietary restriction-mediated lifespan extension and consistent gene expression changes induced by dietary restriction. Since its creation about 10 years ago, major efforts have been undertaken to maintain the quality of data in HAGR, while further continuing to develop, improve and extend it. This article briefly describes the content of HAGR and details the major updates since its previous publications, in terms of both structure and content. The completely redesigned interface, more intuitive and more integrative of HAGR resources, is also presented. Altogether, we hope that through its improvements, the current version of HAGR will continue to provide users with the most comprehensive and accessible resources available today in the field of biogerontology.

The Human Ageing Genomic Resources: online databases and tools for biogerontologists

Aging is a complex, challenging phenomenon that requires multiple, interdisciplinary approaches to unravel its puzzles. To assist basic research on aging, we developed the Human Ageing Genomic Resources (HAGR). This work provides an overview of the databases and tools in HAGR and describes how the gerontology research community can employ them. Several recent changes and improvements to HAGR are also presented. The two centrepieces in HAGR are GenAge and AnAge. GenAge is a gene database featuring genes associated with aging and longevity in model organisms, a curated database of genes potentially associated with human aging, and a list of genes tested for their association with human longevity. A myriad of biological data and information is included for hundreds of genes, making GenAge a reference for research that reflects our current understanding of the genetic basis of aging. GenAge can also serve as a platform for the systems biology of aging, and tools for the visualization of protein–protein interactions are also included. AnAge is a database of aging in animals, featuring over 4000 species, primarily assembled as a resource for comparative and evolutionary studies of aging. Longevity records, developmental and reproductive traits, taxonomic information, basic metabolic characteristics, and key observations related to aging are included in AnAge. Software is also available to aid researchers in the form of Perl modules to automate numerous tasks and as an SPSS script to analyse demographic mortality data. The HAGR are available online at http://genomics.senescence.info.

On the linkage between the ubiquitin-proteasome system and the mitochondria

Several metabolic pathways critical for cellular homeostasis occur in the mitochondria. Because of the evolution of mitochondria and their physical separation, these pathways have traditionally been thought to be free from regulation by the ubiquitin-proteasome system. This perception has recently been challenged by evidence for the presence of ubiquitin system components in the mitochondria. Furthermore, it has been shown that certain mitochondrial proteins are conjugated by ubiquitin, and some of them are degraded by the proteasome. Of particular interest is the finding that some of these proteins are localized to the inner membrane and matrix, which rules out that their targeting is mediated by the cytosolic ubiquitin system. However, the extent of the involvement of the ubiquitin system in mitochondrial regulation is not known. The present study addresses this surprising finding, employing several independent approaches. First, we identified reported ubiquitin conjugates in human and yeast mitochondria and found that a large fraction of the mitochondrial proteome (62% in human) is ubiquitinated, with most proteins localized to the inner membrane and matrix. Next, we searched the literature and found that numerous ubiquitin system components localize to the mitochondria and/or contain mitochondrial targeting sequences. Finally, we identified reported protein-protein interactions between ubiquitin system components and mitochondrial proteins. These unexpected findings suggest that mitochondrial regulation by the ubiquitin system is fundamental and may have broad biomedical implications.

Human Ageing Genomic Resources: new and updated databases

Abstract In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR’s main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts and regularly updated to ensure a high quality data. Cross-links across our databases and to external resources help researchers locate and integrate relevant information. HAGR is freely available online (http://genomics.senescence.info/).

Telomere length and body temperature-independent determinants of mammalian longevity?

WHY DO SPECIES DIFFER IN LIFESPAN AND WHAT ARE THE DETERMINANTS OF THEIR LONGEVITY? Understanding the main factors that determine variation in species longevity may provide a clue into the leading mechanisms of aging and—what is even more important—outline the key targets for longevity-promoting interventions. Comparative studies on longevity in mammals revealed numerous variables that correlate with maximum lifespan (MLS). However, because of the intangibly intertwined biological relationships, only a limited number of the variables could be considered independent determinants of longevity. Most other correlations reflect intermediated (formal) co-variations rather than the “cause-andeffect” links. It is obvious that manipulations of the formal correlates have little chances to effect the longevity-ensuring systems, and thus be helpful for developing experimental strategies of lifespan extension. Therefore, in comparative longevity studies, it is important to discriminate the independent determinants from the formal correlates. One of the simple criteria to distinguish determinants of longevity is consistently high correlation of a given variable with MLS observed in various model systems. The other approach is based on more ambiguous statistical methods, multivariate analyses included (see, for example, Lehmann et al., 2008a). In particular, we have previously shown that body mass (BM) or resting metabolic rate alone explain around 40–50% of the variation in mammalian longevity, whereas their combination with mitochondrial DNA (mtDNA) GC content could explain over 70% of the MLS variation (Lehmann et al., 2008a,b). Consequently, we hypothesized that other putative players in MLS determination should have relatively small contribution or their effects should be mediated by the above factors. Recent finding by Gomes et al. (2011) demonstrating a strong negative correlation (p = 0.0032) between telomere length and MLS in 59 mammalian species calls for re-evaluation of this hypothesis. Indeed, the coefficient of MLS determination (R2) calculated using the data in their paper indicates that the telomere length could alone explain more than 1/3 of the variation in the lifespan of mammals. Here, we explore whether the telomere length has an independent impact on mammalian longevity or its effect is attributed to co-variation with other determinants of MLS, such as BM and mtDNA GC content. Our analysis was based on the set of mammalian species with the telomere length records presented in Gomes et al. (2011) (n = 55; four species from the orders Monotremata and Diprotodontia, with unusually short telomeres of 1 kb, were not included in the analysis). The MLS, BM, and body temperature (Tb) records were retrieved from the AnAge database (Tacutu et al., 2013; http://genomics. senescence.info/species/). Calculation of the mtDNA GC content was described elsewhere (Lehmann et al., 2008a). To ensure linear relationships, MLS and BM values were ln-transformed, i.e., MLS was presented as a natural logarithm of MLS (lnMLS) and BM was presented as a natural logarithm of BM (lnBM). Re-evaluation of combined effect of lnBM and mtDNA GC on lnMLS in the set of species analyzed by Gomes et al. (2011) gave an extremely significant coefficient of MLS determination (R2 = 0.713, P = 6.2E-10, n = 37), which is very close to that obtained on much bigger dataset of mammals (R2 = 0.703, P 0.5) or GC content (P > 0.4).

MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity

Mitochondria are the only organelles in the animal cells that have their own genome. Due to a key role in energy production, generation of damaging factors (ROS, heat), and apoptosis, mitochondria and mtDNA in particular have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases. The rapidly increasing number of species with fully sequenced mtDNA, together with accumulated data on longevity records, provides a new fascinating basis for comparative analysis of the links between mtDNA features and animal longevity. To facilitate such analyses and to support the scientific community in carrying these out, we developed the MitoAge database containing calculated mtDNA compositional features of the entire mitochondrial genome, mtDNA coding (tRNA, rRNA, protein-coding genes) and non-coding (D-loop) regions, and codon usage/amino acids frequency for each protein-coding gene. MitoAge includes 922 species with fully sequenced mtDNA and maximum lifespan records. The database is available through the MitoAge website (www.mitoage.org or www.mitoage.info), which provides the necessary tools for searching, browsing, comparing and downloading the data sets of interest for selected taxonomic groups across the Kingdom Animalia. The MitoAge website assists in statistical analysis of different features of the mtDNA and their correlative links to longevity.

Identification of UBact, a ubiquitin-like protein, along with other homologous components of a conjugation system and the proteasome in different gram-negative bacteria.

Systems analogous to the eukaryotic ubiquitin-proteasome system have been previously identified in Archaea, and Actinobacteria (gram-positive), but not in gram-negative bacteria. Here, we report the bioinformatic identification of a novel prokaryotic ubiquitin-like protein, which we name UBact. The phyletic distribution of UBact covers at least five gram-negative bacterial phyla, including Nitrospirae, Armatimonadetes, Verrucomicroba, Nitrospinae, and Planctomycetes. Additionally, it was identified in seven candidate (uncultured) phyla and one Archaeon. UBact might have been overlooked because only few species in the phyla where it is found have been sequenced. In most of the species where we identified UBact, its neighbors in the genome code for proteins homologous to those involved in conjugation and/or degradation of Pup and Pup-tagged substrates. Among them are PafA-, Dop-, Mpa- and proteasome-homologous proteins. This gene association as well as UBacts size and conserved C-terminal G[E/Q] motif, strongly suggest that UBact is used as a conjugatable tag for degradation. With regard to its C-terminus, UBact differs from ubiquitin and most ubiquitin-like proteins (including the mycobacterial Pup) in that it lacks the characteristic C-terminal di-glycine motif, and it usually ends with the sequence R[T/S]G[E/Q]. The phyla that contain UBact are thought to have diverged over 3000 million years ago, indicating that either this ubiquitin-like conjugation system evolved early in evolution or that its occurrence in distant gram-negative phyla is due to multiple instances of horizontal gene transfer.

NUMT (“New Mighty”) Hypothesis of Longevity

Maximum life span (MLS) and abundance of mitochondrial DNA (mtDNA) insertions in the nuclear DNA (NUMTs) were analyzed in 17 animal species with completely sequenced mitochondrial and nuclear genomes. Highly significant positive correlations were found between MLS and NUMT number, total size, or density (both in mammals and all animal species). In mammals, NUMT abundance correlated positively with the mtDNA guanine content and negatively with adenine and thymine contents, but did not correlate with such longevity-associated variables as the body mass and resting metabolic rate.

Human Ageing Genomic Resources: 2018 Update

In spite of a growing body of research and data, human ageing remains a poorly understood process. To facilitate studies of ageing, over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), which are now the leading online resource for biogerontologists. In this update, we present HAGR’s main functionalities, including new additions and improvements to HAGR. HAGR consists of five databases: 1) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; 2) the AnAge database of animal ageing and longevity, featuring >4000 species; 3) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; 4) the LongevityMap database of human genetic association studies of longevity with >500 entries; 5) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; 6) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts to ensure a high quality data and presented in an intuitive and clear interface that includes cross-links across our databases and to external resources. HAGR is freely available online (http://genomics.senescence.info/).