Species differences: The dark matter of longevity genetics
Creators: name: Bahry, David
Publisher: name: Zenodo
Year: 2022
Subjects: senescence; ageing; comparative biogerontology; cancer; protein misfolding; long-lived species; obscurin; hyccin

description: Mainstream genetics of ageing and longevity studies modest longevity interventions known from short-lived model organisms, such as caloric restriction or rapamycin in nematodes or mice; and the evolutionarily conserved, nutrient-sensing metabolic fine-tuning pathways involved, such as insulin-like signaling (ILS) and target of rapamycin (TOR). Yet these effects are dwarfed by what evolution can do: a calorically restricted mouse lives 4–5 years; but a naked mole-rat lives decades, while a bowhead whale or an ocean quahog live centuries. The study of species differences in ageing and longevity is an emerging field. It requires non-classical genetic methods, including comparative genomics to generate hypotheses and gene-editing or cell culture experiments to test them. So far it has yielded some answers, and more questions: for instance, we know ocean quahog proteins resist misfolding, but we don’t know how; and we know that elephants have extra pseudogene copies of the tumour-suppressor <em>TP53</em>, but whales don’t. It has suggested some roles for old friends, such as the ILS pathway in microbats; as well as for new friends, such as <em>FAM126B</em>, a barely-studied protein related to hyccin, in mammals; and <em>OBSCN</em>, a giant gene with many isoforms due to alternative RNA splicing, in Pacific rockfish. <strong>Poster references</strong> Austad, SN. (2022). <em>Methuselah's Zoo: What Nature Can Teach Us About Living Longer, Healthier Lives</em>. MIT Press. Bahry, D. (2022<em>a</em>). Book review: <em>Methuselah's Zoo</em> by Steven N. Austad. <em>BioEssays</em> [early view]: 2200144. https://doi.org/10.1002/bies.202200144 Bahry, D. (2022<em>b</em>). Two genes of interest from comparative longevity genomics: <em>FAM126B</em> and <em>OBSCN</em> [preprint]. Zenodo, Sep 14. https://doi.org/10.5281/zenodo.7080278 Finch, CE. (1990). <em>Longevity, Senescence, and the Genome</em>. The University of Chicago Press. Kolora, SRR. et al. (2021). Origins and evolution of extreme life span in Pacific Ocean rockfishes. <em>Science</em> <strong>374</strong>: 842–847. https://doi.org/10.1126/science.abg5332 Lees, JA. et al. (2017). Architecture of the human PI4KIIIα lipid kinase complex. <em>Proc. Natl. Acad. Sci. U. S. A.</em> <strong>114</strong>: 13720–13725. https://doi.org/10.1073/pnas.1718471115 Li, Y. &amp; de Magalhães, JP. (2013). Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity. <em>Age (Dordr.)</em> <strong>35</strong>: 301–314. https://doi.org/10.1007/s11357-011-9361-y Seluanov, A. et al. (2018). Mechanisms of cancer resistance in long-lived mammals. <em>Nat. Rev. Cancer</em> <strong>18</strong>: 433–441. https://doi.org/10.1038/s41568-018-0004-9 Steele, A. (2020). <em>Ageless: The New Science of Getting Older Without Getting Old</em>. Bloomsbury.
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