Aging, Geroscience and Longevity: A Special Issue

Breakthroughs in aging-related research are revealing details of how cellular processes and tissue functions decline during aging and have pinpointed longevity factors conserved among eukaryotes. In parallel, investigations in model organisms are uncovering potential approaches to extend lifespan in humans.

To highlight recent advances in the mechanistic understanding of aging and interventions that extend longevity, eLife is pleased to present a Special Issue devoted to this exciting topic. This issue presents a collection of highly influential research selected for publication by a specially convened group of experts.

To support the launch of the issue, Senior Editors Jessica Tyler and Matt Kaeberlain explore a new era for research into aging in their Editorial.

Collection

1. 1. Epidemiology and Global Health

   Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up

   Xia Li, Alexander Ploner ... Sara Hägg

   Biological ages have the potential to provide aging-related information beyond chronological age and can be predictive of mortality independently of both chronological age and different types of biological ages.
2. 1. Computational and Systems Biology
   2. Genetics and Genomics

   Pan-mammalian analysis of molecular constraints underlying extended lifespan

   Amanda Kowalczyk, Raghavendran Partha ... Maria Chikina

   Cancer control, DNA repair, and immunity are key functionalities underlying the evolution of extended lifespan in mammals.
3. 1. Genetics and Genomics

   Germline burden of rare damaging variants negatively affects human healthspan and lifespan

   Anastasia V Shindyapina, Aleksandr A Zenin ... Vadim N Gladyshev

   Rare highly damaging mutations that are present in most human genomes decrease lifespan and are associated with an earlier onset of chronic diseases.
4. 1. Cell Biology
   2. Immunology and Inflammation

   Rapamycin rejuvenates oral health in aging mice

   Jonathan Y An, Kristopher A Kerns ... Matt Kaeberlein

   Short-term treatment with rapamycin reverses periodontal bone loss, attenuates inflammation, and remodels the oral microbiome toward a more youthful state.
5. 1. Epidemiology and Global Health

   Quantification of the pace of biological aging in humans through a blood test, the DunedinPoAm DNA methylation algorithm

   Daniel W Belsky, Avshalom Caspi ... Terrie E Moffitt

   Methylation pace of aging is a novel measure requiring only a blood sample that clinical-trial and observational studies can use to test if treatments modify how fast participants are aging.
6. 1. Genetics and Genomics

   mRNA decapping is an evolutionarily conserved modulator of neuroendocrine signaling that controls development and ageing

   Fivos Borbolis, John Rallis ... Popi Syntichaki

   mRNA decapping function in neuronal cells regulates neurosecretion and intertissue signaling, affecting developmental and ageing processes in two model organisms.
7. 1. Cell Biology
   2. Stem Cells and Regenerative Medicine

   Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish

   Mounir El Maï, Marta Marzullo ... Miguel Godinho Ferreira

   Telomere shortening with age promotes a switch from p53-dependent apoptosis to senescence prompted by tissue damage that triggers conflicting mTOR/AKT signalling, lower OxPhos defences and ROS, mitochondria dysfunction and senescence.
8. 1. Chromosomes and Gene Expression
   2. Genetics and Genomics

   Translational control of one-carbon metabolism underpins ribosomal protein phenotypes in cell division and longevity

   Nairita Maitra, Chong He ... Michael Polymenis

   Extensive molecular profiling shows how loss of highly similar, paralogous ribosomal proteins lead to distinct phenotypic outputs, through translational control of specific mRNAs.
9. 1. Medicine

   Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

   Ying Ann Chiao, Huiliang Zhang ... Peter Rabinovitch

   Mitochondrial-targeted SS-31 peptide ameliorates mitochondrial dysfunction and rescues pre-existing cardiac dysfunction in old mice, supporting the translational potential of mitochondrial protective interventions to treat age-related diseases.
10. 1. Genetics and Genomics

    Ovariectomy uncouples lifespan from metabolic health and reveals a sex-hormone-dependent role of hepatic mTORC2 in aging

    Sebastian I Arriola Apelo, Amy Lin ... Dudley W Lamming

    Metabolic health and longevity can be separated by ovariectomy, which also protects female mice lacking hepatic mTORC2 from midlife mortality.
11. 1. Biochemistry and Chemical Biology

    Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans

    Nicole L Jenkins, Simon A James ... Gawain McColl

    As worms age reduced glutathione together with increased ferrous iron increases frailty and leads to ferroptosis, which is amenable to therapeutic intervention.
12. 1. Cell Biology
    2. Medicine

    Senotherapeutic drugs for human intervertebral disc degeneration and low back pain

    Hosni Cherif, Daniel G Bisson ... Lisbet Haglund

    Targeting senescent cells in human intervertebral discs, using senotherapeutics, provides a potential therapeutic strategy to prevent or reduce disc degeneration and pain.
13. 1. Evolutionary Biology
    2. Genetics and Genomics

    Intra-species differences in population size shape life history and genome evolution

    David Willemsen, Rongfeng Cui ... Dario Riccardo Valenzano

    Population genetics in turquoise killifish wild populations reveals how small population size and genetic drift determine the accumulation of deleterious gene variants leading to short lifespan.
14. 1. Computational and Systems Biology
    2. Genetics and Genomics

    A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin

    Morgan Levine, Ross A McDevitt ... Luigi Ferrucci

    The first epigenetic clock for rats was developed and revealed to reflect phenotypic aging and captured the effects of longevity interventions.
15. 1. Cancer Biology
    2. Immunology and Inflammation

    The effects of age and systemic metabolism on anti-tumor T cell responses

    Jefte M Drijvers, Arlene H Sharpe, Marcia C Haigis

    A comprehensive literature review delineates the current knowledge of how systemic context, such as age and obesity, can impact CD8⁺ T cell function, anti-tumor immunity, and immunotherapy responsiveness.
16. 1. Cell Biology

    Polo-like kinase acts as a molecular timer that safeguards the asymmetric fate of spindle microtubule-organizing centers

    Laura Matellán, Javier Manzano-López, Fernando Monje-Casas

    Molecular and cell biology analyses reveal novel roles of Polo-like kinases in establishing non-random segregation patterns of spindle-associated microtubule-organizing centers during mitosis, a phenomenon linked with replicative cell aging.
17. 1. Cell Biology

    Casein kinase 1G2 suppresses necroptosis-promoted testis aging by inhibiting receptor-interacting kinase 3

    Dianrong Li, Youwei Ai ... Xiaodong Wang

    Casein kinase 1G2 interacts with and inhibits the activation of receptor-interacting kinase 3, RIP3, in response to TNF and toll-like receptor family members and attenuates its necroptosis signaling activity.
18. 1. Neuroscience

    Small molecule cognitive enhancer reverses age-related memory decline in mice

    Karen Krukowski, Amber Nolan ... Susanna Rosi

    Inhibition of the integrated stress response restores neuronal and immune dysfunction and alleviates memory deficits in aged mice.
19. 1. Immunology and Inflammation

    Autophagy in T cells from aged donors is maintained by spermidine and correlates with function and vaccine responses

    Ghada Alsaleh, Isabel Panse ... Anna Katharina Simon

    Declining TFEB and autophagy levels with age are key to poor vaccination efficacy in the elderly.
20. 1. Genetics and Genomics

    Downregulation of the tyrosine degradation pathway extends Drosophila lifespan

    Andrey A Parkhitko, Divya Ramesh ... Norbert Perrimon

    The tyrosine degradation pathway reprogramming connects mitochondrial dysfunction, aging, and production of tyrosine-derived neuromediators that can be targeted with an FDA-approved drug, Tigecycline.
21. 1. Cell Biology

    Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte

    Huiliang Zhang, Nathan N Alder ... Peter S Rabinovitch

    The primary respiratory defect seen in aged cardiomyocytes is an elevated proton leak mediated by ANT1, and this is prevented by treatment with SS-31 (elamipretide).
22. 1. Genetics and Genomics
    2. Neuroscience

    Cell non-autonomous regulation of health and longevity

    Hillary A Miller, Elizabeth S Dean ... Scott F Leiser

    Modulation of the aging process through cell signaling represents a recent and exciting area of study with the potential for development of therapeutics to extend human health.
23. 1. Developmental Biology

    Optogenetic control of gut bacterial metabolism to promote longevity

    Lucas A Hartsough, Mooncheol Park ... Jeffrey J Tabor

    Light controls can fine tune microbiome–host interaction to qualitatively regulate host longevity with temporal and spatial precision.
24. 1. Medicine

    Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

    Shivani N Mann, Niran Hadad ... Michael B Stout

    17α-Estradiol, a life-span extending compound, signals through estrogen receptor α (ERα) in the liver and hypothalamus to elicit health benefits in a sex-specific manner.
25. 1. Evolutionary Biology
    2. Medicine

    A dietary sterol trade-off determines lifespan responses to dietary restriction in Drosophila melanogaster females

    Brooke Zanco, Christen K Mirth ... Matthew DW Piper

    Micronutrients, not macronutrients, regulate lifespan.
26. 1. Genetics and Genomics

    Drosophila serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice

    Yang Lyu, Kristina J Weaver ... Scott D Pletcher

    Dietary choice per se is sufficient to modulate aging in Drosophila and through serotonergic control of peripheral metabolism.
27. 1. Cell Biology
    2. Medicine

    Research: A new era for research into aging

    Matt Kaeberlein, Jessica K Tyler

    eLife is publishing a special issue on aging, geroscience and longevity to mark the rapid progress made in this field over the past decade, both in terms of mechanistic understanding and translational approaches that are poised to have clinical impact on age-related diseases.
28. 1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics

    A physicochemical perspective of aging from single-cell analysis of pH, macromolecular and organellar crowding in yeast

    Sara N Mouton, David J Thaller ... Liesbeth M Veenhoff

    In mitotically aging yeast cells, the cytosol acidifies, the distances between the organellar membranes decrease dramatically, but crowding on the scale of the average size protein is relatively stable.
29. 1. Cell Biology
    2. Chromosomes and Gene Expression

    Cytoplasmic chromatin fragments—from mechanisms to therapeutic potential

    Karl N Miller, Nirmalya Dasgupta ... Maria Grazia Vizioli

    Cytoplasmic chromatin fragment formation pathways in senescent cells are a potential therapeutic target for modulation of inflammation in aging, which contributes to age-associated diseases.
30. 1. Cell Biology
    2. Developmental Biology

    A Non-stop identity complex (NIC) supervises enterocyte identity and protects from premature aging

    Neta Erez, Lena Israitel ... Amir Orian

    A nuclear Non-stop identity complex (NIC) supervises enterocyte (EC) identity, preserves tissue homeostasis, and prevents premature aging by maintaining EC-specific gene expression, silencing non-relevant programs, and safeguarding large-scale nuclear organization.
31. 1. Chromosomes and Gene Expression
    2. Medicine

    Cardiovascular disease risk factors induce mesenchymal features and senescence in mouse cardiac endothelial cells

    Karthik Amudhala Hemanthakumar, Shentong Fang ... Riikka Kivelä

    Endothelial dysfunction due to cardiovascular disease risk factors explained by cardiac endothelial cell transcriptome remodelling.
32. 1. Chromosomes and Gene Expression
    2. Computational and Systems Biology

    Increased longevity due to sexual activity in mole-rats is associated with transcriptional changes in the HPA stress axis

    Arne Sahm, Matthias Platzer ... Philip Dammann

    The fact that sexual activity/reproduction doubles the lifespan of certain rodent species is most likely linked to critical changes in the regulation of the hypothalamic–pituitary–adrenal stress axis.
33. 1. Genetics and Genomics

    Age-related changes in polycomb gene regulation disrupt lineage fidelity in intestinal stem cells

    Helen M Tauc, Imilce A Rodriguez-Fernandez ... Heinrich Jasper

    Global, multi-angled genetic analyses identified an age-associated loss of stem cell lineage fidelity that was linked to changes in polycomb regulation in the Drosophila intestinal epithelium.
34. 1. Computational and Systems Biology

    Proteomic and transcriptomic profiling reveal different aspects of aging in the kidney

    Yuka Takemon, Joel M Chick ... Ron Korstanje

    mRNA profiling alone provides an incomplete picture of molecular aging and examination of changes in proteins is essential to understand aging processes that are not transcriptionally regulated.
35. 1. Computational and Systems Biology

    Mouse aging cell atlas analysis reveals global and cell type-specific aging signatures

    Martin Jinye Zhang, Angela Oliveira Pisco ... James Zou

    Comprehensive single-cell transcriptome analysis reveals global and tissue-specific aging markers and characterizes the heterogeneous aging status of different cell types and tissues in mouse.
36. 1. Biochemistry and Chemical Biology
    2. Genetics and Genomics

    Selenium supplementation inhibits IGF-1 signaling and confers methionine restriction-like healthspan benefits to mice

    Jason D Plummer, Spike DL Postnikoff ... Jay E Johnson

    Dietary selenium supplementation confers to mice all of the short-term healthspan benefits of the longevity-promoting intervention methionine restriction, and thus may represent a method to promote healthy aging in mammals.
37. 1. Cell Biology

    A genetic screen identifies new steps in oocyte maturation that enhance proteostasis in the immortal germ lineage

    Madhuja Samaddar, Jérôme Goudeau ... Cynthia Kenyon

    A whole-genome genetic screen links new aspects of oocyte maturation to proteostasis renewal in the immortal Caenorhabditis elegans germ-cell lineage and reveals similarities to somatic cell maintenance during aging.
38. 1. Genetics and Genomics
    2. Neuroscience

    Integrated transcriptomic and neuroimaging brain model decodes biological mechanisms in aging and Alzheimer’s disease

    Quadri Adewale, Ahmed F Khan ... Alzheimer's Disease Neuroimaging Initiative

    Identification of causal genes and their effects on other biological determinants untangles the complexities of aging and Alzheimer's and can facilitate drug discovery for sustaining healthy aging and treating Alzheimer's.
39. 1. Genetics and Genomics

    Whole-genome sequencing analysis of semi-supercentenarians

    Paolo Garagnani, Julien Marquis ... Claudio Franceschi

    Genetic variants located in DNA repair genes and a reduced burden of somatic mutations protect the oldest living persons from age-related diseases, allowing an healthy aging phenotype.
40. 1. Computational and Systems Biology
    2. Stem Cells and Regenerative Medicine

    The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function

    Zachary Clemens, Sruthi Sivakumar ... Fabrisia Ambrosio

    Transcriptomic analysis using a novel information-based network entropy approach provides mechanistic insights into the ability of Klotho to successfully ameliorate age-related sarcopenia in old mice, but not oldest-old mice.
41. 1. Computational and Systems Biology

    A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice

    Michael A Petr, Irene Alfaras ... Rafael de Cabo

    A comprehensive cross-sectional assessment reveals functional decline in mice consistent with increased energetic cost of physical activity with age through metabolic rewiring in multiple organs.
42. 1. Epidemiology and Global Health

    Sex differences in biological aging with a focus on human studies

    Sara Hägg, Juulia Jylhävä

    Biological aging processes and age-related diseases demonstrate sexual dimorphism where complex interactions between underlying aging mechanisms and sex chromosomes and hormones are seen in humans and animals.
43. 1. Cell Biology
    2. Chromosomes and Gene Expression

    A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing

    Yu-Xuan Lu, Jennifer C Regan ... Linda Partridge

    Modulation of histone levels in gut enterocytes by rapamycin treatment alters chromatin organisation and induces intestinal autophagy through transcriptional regulation to prevent age-related decline in the intestine and extend lifespan.
44. 1. Immunology and Inflammation

    NHR-49/PPAR-α and HLH-30/TFEB cooperate for C. elegans host defense via a flavin-containing monooxygenase

    Khursheed A Wani, Debanjan Goswamy ... Javier E Irazoqui

    Genetic and molecular characterization showed that evolutionarily conserved flavin-containing monooxygenase (FMO-2) plays an important role in host defense in Caenorhabditis elegans, and its induction is dependent on conserved transcription factors, TFEB and PPAR-α.
45. 1. Genetics and Genomics

    NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants

    Gabriel A Guerrero, Maxime J Derisbourg ... Martin S Denzel

    Separate genetic pathways mediate longevity, pathogen resistance, and cell-nonautonomous regulation of xenobiotic detoxification in chemosensory defective Caenorhabditis elegans mutants.
46. 1. Cell Biology

    The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging

    Suzanne Angeli, Anna Foulger ... Gordon Lithgow

    Loss of the F-ATP synthase c-subunit inhibits a pathological mitochondrial permeability transition pore that is coupled to a maladaptive mitochondrial unfolded protein response while also extending lifespan.