RESUMEN
Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, http://mengwanglab.org/atlas ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling of alternative polyadenylation (APA) events in different tissues, we discovered cell-type-specific APA changes during aging and revealed how these changes are differentially affected by the pro-longevity strategies. Together, this study offers fundamental molecular insights into both somatic and reproductive aging and provides a valuable resource for in-depth understanding of the diversity of pro-longevity mechanisms.
Asunto(s)
Envejecimiento , Caenorhabditis elegans , Longevidad , Transcriptoma , Longevidad/genética , Animales , Envejecimiento/genética , Envejecimiento/fisiología , Caenorhabditis elegans/genética , Poliadenilación/genética , Especificidad de Órganos , Perfilación de la Expresión Génica , Células Germinativas/metabolismo , Células Germinativas/citologíaRESUMEN
Organism aging occurs at the multicellular level; however, how pro-longevity mechanisms slow down aging in different cell types remains unclear. We generated single-cell transcriptomic atlases across the lifespan of Caenorhabditis elegans under different pro-longevity conditions (http://mengwanglab.org/atlas). We found cell-specific, age-related changes across somatic and germ cell types and developed transcriptomic aging clocks for different tissues. These clocks enabled us to determine tissue-specific aging-slowing effects of different pro-longevity mechanisms, and identify major cell types sensitive to these regulations. Additionally, we provided a systemic view of alternative polyadenylation events in different cell types, as well as their cell-type-specific changes during aging and under different pro-longevity conditions. Together, this study provides molecular insights into how aging occurs in different cell types and how they respond to pro-longevity strategies.
RESUMEN
Proteomic analysis revealed the preservation of many proteins in the Heslington brain (which is at least 2600-year-old brain tissue uncovered within the skull excavated in 2008 from a pit in Heslington, Yorkshire, England). Five of these proteins-"main proteins": heavy, medium, and light neurofilament proteins (NFH, NFM, and NFL), glial fibrillary acidic protein (GFAP), and myelin basic (MBP) protein-are engaged in the formation of non-amyloid protein aggregates, such as intermediate filaments and myelin sheath. We used a wide spectrum of bioinformatics tools to evaluate the prevalence of functional disorder in several related sets of proteins, such as the main proteins and their 44 interactors, all other proteins identified in the Heslington brain, as well as the entire human proteome (20,317 manually curated proteins), and 10,611 brain proteins. These analyses revealed that all five main proteins, half of their interactors and almost one third of the Heslington brain proteins are expected to be mostly disordered. Furthermore, most of the remaining Heslington brain proteins are expected to contain sizable levels of disorder. This is contrary to the expected substantial (if not complete) elimination of the disordered proteins from the Heslington brain. Therefore, it seems that the intrinsic disorder of NFH, NFM, NFL, GFAP, and MBP, their interactors, and many other proteins might play a crucial role in preserving the Heslington brain by forming tightly folded brain protein aggregates, in which different parts are glued together via the disorder-to-order transitions.