Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice
Open accessAbstract
As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Blood from young mice may rejuvenate organs, with old mice showing improvements in synaptic plasticity and cognitive behavior in a parabiosis model.
“A study using a parabiosis mouse model comprising young and old mice indicates that blood from young mice may rejuvenate organs, where old mice showed improvements in synaptic plasticity and cognitive behavior [520].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [520]
Possible mechanisms of young blood rejuvenation include activation of CREB in the hippocampus and canonical neuroprotective mechanisms.
“The possible mechanisms include the activation of cAMP response element binding protein (CREB) in the hippocampus and canonical neuroprotective mechanisms.449,450”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [450]
Heterochronic parabiosis with young blood in old mice increased neurogenesis and dendritic spine density and improved age-related cognitive impairment.
“Recent heterochronic parabiosis experiments demonstrated that introduction of young blood in old mice led to increased neurogenesis and dendritic spine density, and improved age-related cognitive impairment, (Katsimpardi et al., 2014; Villeda et al., 2014).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Villeda et al., 2014
Genes that regulate lifespan in animal models and human studies, and multiple experimental paradigms, have demonstrated that it is possible to manipulate ageing biology to rejuvenate physiological functioning in complex model organisms.
“Genes that regulate lifespan in animal models6–9 and human studies10–14 as well as multiple experimental paradigms, such as caloric restriction, heterochronic parabiosis and partial epigenetic reprogramming, have demonstrated that it is possible to manipulate ageing biology to ‘rejuvenate’ physiological functioning in complex model organisms15–28.”
From Measuring biological age using omics data (2022) · cites this paper as [15]
Studies on heterochronic parabiosis and plasma exchange in animals have demonstrated that circulating proteins can have a causal influence on ageing phenotypes across the body, including in skeletal muscle, heart and brain.
“Studies on heterochronic parabiosis and plasma exchange in animals have demonstrated that circulating proteins can have a causal influence on ageing phenotypes across the body, including in skeletal muscle107,108, heart109 and brain15,110–112.”
From Measuring biological age using omics data (2022) · cites this paper as [15]
The ability of interventions not only to slow the rate of aging but actually to rejuvenate cells and tissues seemingly by reversing aging processes expands the spectrum of healthspan-promoting treatments.
“Furthermore, the ability of interventions not only to slow the rate of aging but actually to rejuvenate cells and tissues seemingly by reversing aging processes expands the spectrum of healthspan-promoting treatments.79,80,81,82,83”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [80]
Parabiosis models of heterochronically paired animals show increased neurogenesis and improved cognitive functions in aged mice following exposure to young blood.
“Recent studies from parabiosis models of heterochronically paired animals (aged and young animals that share the circulatory system via vascular anastomosis) showed increased neurogenesis and improved cognitive functions in the aged mice following exposure to young blood (Villeda et al, 2014).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A synaptic model of memory: long-term potentiation in the hippocampus
Bliss, T. V. P., & Collingridge, G. L. (1993) · Nature · doi:10.1038/361031a0 · Cited by 11,566 · see citing works
Rejuvenation of aged progenitor cells by exposure to a young systemic environment
Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005) · Nature · doi:10.1038/nature03260 · Cited by 2,287 · see citing works
Insights into the ageing mind: a view from cognitive neuroscience
Hedden, T., & Gabrieli, J. D. E. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1323 · Cited by 2,223 · see citing works
Alzheimer Disease in the US Population: Prevalence Estimates Using the 2000 Census
Hebert, L. E., Scherr, P. A., Bienias, J. L., Bennett, D. A., & Evans, D. A. (2003) · Archives of Neurology · doi:10.1001/archneur.60.8.1119 · Cited by 2,168 · see citing works
The ageing systemic milieu negatively regulates neurogenesis and cognitive function
Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., et al. (2011) · Nature · doi:10.1038/nature10357 · Cited by 1,763 · see citing works
Self-citationSynaptic tagging and long-term potentiation
Frey, U., & Morris, R. G. M. (1997) · Nature · doi:10.1038/385533a0 · Cited by 1,736 · see citing works
Disruption of Large-Scale Brain Systems in Advanced Aging
Andrews-Hanna, J. R., Snyder, A. Z., Vincent, J. L., Lustig, C., Head, D., Raichle, M. E., & Buckner, R. L. (2007) · Neuron · doi:10.1016/j.neuron.2007.10.038 · Cited by 1,592 · see citing works
Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis
Brack, A. S., Conboy, M. J., Roy, S., Lee, M., Kuo, C. J., Keller, C., & Rando, T. A. (2007) · Science · doi:10.1126/science.1144090 · Cited by 1,564 · see citing works
Neural mechanisms of ageing and cognitive decline
Bishop, N. A., Lu, T., & Yankner, B. A. (2010) · Nature · doi:10.1038/nature08983 · Cited by 1,323 · see citing works
Ageing and neuronal vulnerability
Mattson, M. P., & Magnus, T. (2006) · Nature reviews. Neuroscience · doi:10.1038/nrn1886 · Cited by 1,075 · see citing works
Transcription Factors in Long-Term Memory and Synaptic Plasticity
Alberini, C. M. (2009) · Physiological Reviews · doi:10.1152/physrev.00017.2008 · Cited by 991 · see citing works
The ageing cortical synapse: hallmarks and implications for cognitive decline
Morrison, J. H., & Baxter, M. G. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3200 · Cited by 965 · see citing works
Loffredo, F. S., Steinhauser, M. L., Jay, S. M., Gannon, J., Pancoast, J. R., Yalamanchi, P., Sinha, M., Dall’Osso, C., Khong, D., Shadrach, J. L., et al. (2013) · Cell · doi:10.1016/j.cell.2013.04.015 · Cited by 948 · see citing works
A pathophysiological framework of hippocampal dysfunction in ageing and disease
Small, S. A., Schobel, S., Buxton, R. B., Witter, M. P., & Barnes, C. A. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3085 · Cited by 920 · see citing works
Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment
Scheff, S. W., Price, D. A., Schmitt, F. A., DeKosky, S. T., & Mufson, E. J. (2007) · Neurology · doi:10.1212/01.wnl.0000260698.46517.8f · Cited by 824 · see citing works
Impact of aging on hippocampal function: plasticity, network dynamics, and cognition
Rosenzweig, E. S., & Barnes, C. A. (2003) · Progress in Neurobiology · doi:10.1016/s0301-0082(02)00126-0 · Cited by 730 · see citing works
Grimm, D., Lee, J. S., Wang, L., Desai, T., Akache, B., Storm, T. A., & Kay, M. A. (2008) · Journal of Virology · doi:10.1128/jvi.00254-08 · Cited by 696 · see citing works
Drapeau, E., Mayo, W., Aurousseau, C., Moal, M. L., Piazza, P., & Abrous, D. N. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2334169100 · Cited by 657 · see citing works
Rejuvenation of Regeneration in the Aging Central Nervous System
Ruckh, J. M., Zhao, J.-W., Shadrach, J. L., van Wijngaarden, P., Rao, T. N., Wagers, A. J., & Franklin, R. J. M. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2011.11.019 · Cited by 649 · see citing works
Neuroanatomical correlates of cognitive aging: Evidence from structural magnetic resonance imaging.
Raz, N., Gunning-Dixon, F. M., Head, D., Dupuis, J. H., & Acker, J. D. (1998) · Neuropsychology · doi:10.1037/0894-4105.12.1.95 · Cited by 454 · see citing works
Smith, T. D., Adams, M., Gallagher, M., Morrison, J., & Rapp, P. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-17-06587.2000 · Cited by 404 · see citing works
Cui, L., Supinski, A., Savas, J. N., Yates, J. R., Bordone, L., Guarente, L., Cohen, D. E., Mazzulli, J. R., Krainc, D., & Jeong, H. (2011) · PubMed Central · doi:10.1038/nm.2559 · Cited by 367 · see citing works
Alamed, J., Wilcock, D. M., Diamond, D. M., Gordon, M. N., & Morgan, D. (2006) · Nature Protocols · doi:10.1038/nprot.2006.275 · Cited by 256 · see citing works
Geinisman, Y., de Toledo‐Morrell, L., & Morrell, F. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.9.3027 · Cited by 234 · see citing works
Nicholson, D. A., Yoshida, R., Berry, R. W., Gallagher, M., & Geinisman, Y. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1725-04.2004 · Cited by 204 · see citing works
Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline
Bizon, J. L., & Gallagher, M. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02733.x · Cited by 200 · see citing works
Xu, W., Morishita, W., Buckmaster, P. S., Pang, Z. P., Malenka, R. C., & Südhof, T. C. (2012) · Neuron · doi:10.1016/j.neuron.2011.12.036 · Cited by 188 · see citing works
Hippocampal cell genesis does not correlate with spatial learning ability in aged rats
Merrill, D. A., Karim, R., Darraq, M., Chiba, A. A., & Tuszynski, M. H. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10616 · Cited by 150 · see citing works
Analysis of Grooming Behavior and Its Utility in Studying Animal Stress, Anxiety, and Depression
Smolinsky, A. N., Bergner, C., LaPorte, J. L., & Kalueff, A. V. (2009) · Neuromethods · doi:10.1007/978-1-60761-303-9_2 · Cited by 141 · see citing works
Luo, J., Ho, P. P.-K., Buckwalter, M. S., Hsu, T., Lee, L. Y., Zhang, H., Kim, D., Kim, S., Gambhir, S. S., Steinman, L., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31763 · Cited by 115 · see citing works
Self-citationMolecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48
Pavlopoulos, E., Jones, S., Kosmidis, S., Close, M., Kim, C., Kovalerchik, O., Small, S. A., & Kandel, E. R. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006373 · Cited by 109 · see citing works
Modulation of long-term potentiation in rat hippocampal pyramidal neurons by zinc
Xie, X., & Smart, T. (1994) · Pflügers Archiv · doi:10.1007/bf00374264 · Cited by 75 · see citing works
Self-citationMemory systems in normal and pathological aging
Rapp, P. R., & Heindel, W. C. (1994) · Current Opinion in Neurology · doi:10.1097/00019052-199408000-00003 · Cited by 66 · see citing works
Raber, J., Villasana, L., Rosenberg, J. S., Zou, Y., Huang, T., & Fike, J. R. (2009) · Hippocampus · doi:10.1002/hipo.20724 · Cited by 59 · see citing works
Flagged first, then by citations
2 of the 36 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- [29]Gould TD Mood and Anxiety Related Phenotypes in Mice: Characterization Using Behavioral Tests Humana Press New York 2009
Cited by
Sorted by citations
Daneman, R., & Prat, A. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020412 · Cited by 3,437 · see citing works
Ageing as a risk factor for neurodegenerative disease
Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0244-7 · Cited by 3,310 · see citing works
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Immune attack: the role of inflammation in Alzheimer disease
Heppner, F. L., Ransohoff, R. M., & Becher, B. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3880 · Cited by 2,134 · see citing works
Role of ROS and RNS Sources in Physiological and Pathological Conditions
Meo, S. D., Reed, T. T., Venditti, P., & Víctor, V. M. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1245049 · Cited by 1,638 · see citing works
Ageing, neurodegeneration and brain rejuvenation
Wyss-Coray, T. (2016) · Nature · doi:10.1038/nature20411 · Cited by 1,147 · see citing works
Self-citationFranceschi, C., Garagnani, P., Vitale, G., Capri, M., & Salvioli, S. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.09.005 · Cited by 997 · see citing works
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Undulating changes in human plasma proteome profiles across the lifespan
Lehallier, B., Gate, D., Schaum, N., Nanasi, T., Lee, S. E., Yousef, H., Moran Losada, P., Berdnik, D., Keller, A., Verghese, J., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0673-2 · Cited by 981 · see citing works
Self-citationA systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain
Wang, J., Gu, B. J., Masters, C. L., & Wang, Y.-J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.111 · Cited by 808 · see citing works
Single-cell transcriptomic profiling of the aging mouse brain
Ximerakis, M., Lipnick, S. L., Innes, B. T., Simmons, S. K., Adiconis, X., Dionne, D., Mayweather, B. A., Nguyen, L., Niziolek, Z., Ozek, C., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0491-3 · Cited by 736 · see citing works
The role of adult hippocampal neurogenesis in brain health and disease
Toda, T., Parylak, S. L., Linker, S. B., & Gage, F. H. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0036-2 · Cited by 719 · see citing works
Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke
Xiong, X., Liu, L., & Yang, Q. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.05.001 · Cited by 703 · see citing works
Ageing hallmarks exhibit organ-specific temporal signatures
Schaum, N., Lehallier, B., Hahn, O., Pálovics, R., Hosseinzadeh, S., Lee, S. E., Sit, R., Lee, D. P., Losada, P. M., Zardeneta, M. E., et al. (2020) · Nature · doi:10.1038/s41586-020-2499-y · Cited by 671 · see citing works
Self-citationThe effects of aging in the hippocampus and cognitive decline
Bettio, L. E. B., Rajendran, L., & Gil‐Mohapel, J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.04.030 · Cited by 654 · see citing works
Aging-induced type I interferon response at the choroid plexus negatively affects brain function
Baruch, K., Deczkowska, A., David, E., Castellano, J. M., Miller, O., Kertser, A., Berkutzki, T., Barnett-Itzhaki, Z., Bezalel, D., Wyss-Coray, T., et al. (2014) · Science · doi:10.1126/science.1252945 · Cited by 615 · see citing works
Self-citationMicroglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity
Nguyen, P. T., Dorman, L. C., Pan, S., Vainchtein, I. D., Han, R. T., Nakao-Inoue, H., Taloma, S. E., Barron, J. J., Molofsky, A. B., Kheirbek, M. A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.050 · Cited by 615 · see citing works
Human Umbilical Cord Mesenchymal Stem Cells: A New Era for Stem Cell Therapy
Ding, D., Chang, Y., Shyu, W., & Lin, S. (2015) · Cell Transplantation · doi:10.3727/096368915x686841 · Cited by 610 · see citing works
Hu, Y., Rao, S.-S., Wang, Z.-X., Cao, J., Tan, Y.-J., Luo, J., Li, H.-M., Zhang, W.-S., Chen, C.-Y., & Xie, H. (2018) · Theranostics · doi:10.7150/thno.21234 · Cited by 574 · see citing works
Self-citationMeasuring biological age using omics data
Rutledge, J., Oh, H., & Wyss-Coray, T. (2022) · Nature Reviews Genetics · doi:10.1038/s41576-022-00511-7 · Cited by 570 · see citing works
Self-citationTay, T. L., Savage, J. C., Hui, C. W., Bisht, K., & Tremblay, M. (2017) · The Journal of Physiology · doi:10.1113/jp272134 · Cited by 562 · see citing works
Restoring metabolism of myeloid cells reverses cognitive decline in ageing
Minhas, P. S., Latif-Hernandez, A., McReynolds, M. R., Durairaj, A. S., Wang, Q., Rubin, A., Joshi, A. U., He, J. Q., Gauba, E., Liu, L., et al. (2021) · Nature · doi:10.1038/s41586-020-03160-0 · Cited by 526 · see citing works
Self-citationβ2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis
Smith, L. K., He, Y., Park, J.-S., Bieri, G., Snethlage, C. E., Lin, K., Gontier, G., Wabl, R., Plambeck, K. E., Udeochu, J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3898 · Cited by 500 · see citing works
Self-citationHorowitz, A. M., Fan, X., Bieri, G., Smith, L. K., Sanchez-Diaz, C. I., Schroer, A. B., Gontier, G., Casaletto, K. B., Kramer, J. H., Williams, K. E., et al. (2020) · Science · doi:10.1126/science.aaw2622 · Cited by 496 · see citing works
Self-citationBoxer, A. L., Yu, J.-T., Golbe, L. I., Litvan, I., Lang, A. E., & Höglinger, G. U. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30157-6 · Cited by 485 · see citing works
Physiological blood–brain transport is impaired with age by a shift in transcytosis
Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stähli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., et al. (2020) · Nature · doi:10.1038/s41586-020-2453-z · Cited by 477 · see citing works
Self-citationThe quest to slow ageing through drug discovery
Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0067-7 · Cited by 468 · see citing works
Neuroinflammation and Perioperative Neurocognitive Disorders
Subramaniyan, S., & Terrando, N. (2019) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000004053 · Cited by 453 · see citing works
The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease
Minter, M. R., Taylor, J. M., & Crack, P. J. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13411 · Cited by 451 · see citing works
Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., et al. (2017) · Nature · doi:10.1038/nature22067 · Cited by 445 · see citing works
Self-citationYousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0440-4 · Cited by 442 · see citing works
Self-citationContributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging
Thomas, R., Wang, W., & Su, D.-M. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-0173-8 · Cited by 442 · see citing works
Aging of hematopoietic stem cells
de Haan, G., & Lazare, S. S. (2018) · Blood · doi:10.1182/blood-2017-06-746412 · Cited by 432 · see citing works
Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
Microglia Priming with Aging and Stress
Niraula, A., Sheridan, J. F., & Godbout, J. P. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.185 · Cited by 398 · see citing works
Rodent models for Alzheimer disease
Götz, J., Bodea, L., & Goedert, M. (2018) · Nature reviews. Neuroscience · doi:10.1038/s41583-018-0054-8 · Cited by 395 · see citing works
Cognitive frailty, a novel target for the prevention of elderly dependency
Ruan, Q., Yu, Z., Ma, C., Bao, Z., Li, J., & He, W. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.12.004 · Cited by 381 · see citing works
Oligodendrocyte Progenitor Cells Become Regionally Diverse and Heterogeneous with Age
Spitzer, S. O., Sitnikov, S., Kamen, Y., Evans, K. A., Kronenberg-Versteeg, D., Dietmann, S., de Faria, O., Agathou, S., & Káradóttir, R. T. (2019) · Neuron · doi:10.1016/j.neuron.2018.12.020 · Cited by 364 · see citing works
Calabrese, V., Santoro, A., Monti, D., Crupi, R., Di Paola, R., Latteri, S., Cuzzocrea, S., Zappia, M., Giordano, J., Calabrese, E. J., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.379 · Cited by 356 · see citing works
Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome
Tejera, D., Mercan, D., Sanchez‐Caro, J. M., Hanan, M., Greenberg, D., Soreq, H., Latz, E., Golenbock, D., & Heneka, M. T. (2019) · The EMBO Journal · doi:10.15252/embj.2018101064 · Cited by 351 · see citing works
Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults
Brickman, A. M., Khan, U., Provenzano, F. A., Yeung, L., SUZUKI, W. A., Schroeter, H., Wall, M. M., Sloan, R. P., & Small, S. A. (2014) · Nature Neuroscience · doi:10.1038/nn.3850 · Cited by 349 · see citing works
Goodell, M. A., & Rando, T. A. (2015) · Science · doi:10.1126/science.aab3388 · Cited by 347 · see citing works
Immune Signaling in Neurodegeneration
Hammond, T. R., Marsh, S. E., & Stevens, B. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.016 · Cited by 336 · see citing works
When stem cells grow old: phenotypes and mechanisms of stem cell aging
Schultz, M. B., & Sinclair, D. A. (2016) · Development · doi:10.1242/dev.130633 · Cited by 331 · see citing works
Can physical exercise in old age improve memory and hippocampal function?
Duzel, E., van Praag, H., & Sendtner, M. (2016) · Brain · doi:10.1093/brain/awv407 · Cited by 329 · see citing works
Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease
Babcock, K. R., Page, J. S., Fallon, J. R., & Webb, A. E. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.01.019 · Cited by 311 · see citing works
Gpr158 mediates osteocalcin’s regulation of cognition
Khrimian, L., Obri, A., Ramos-Brossier, M., Rousseaud, A., Moriceau, S., Nicot, A.-S., Mera, P., Kosmidis, S., Karnavas, T., Saudou, F., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20171320 · Cited by 308 · see citing works
A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood
Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016) · Nature Communications · doi:10.1038/ncomms13363 · Cited by 291 · see citing works
Anemia: progress in molecular mechanisms and therapies
Sankaran, V. G., & Weiss, M. J. (2015) · Nature Medicine · doi:10.1038/nm.3814 · Cited by 279 · see citing works
Xiang, Y., Bu, X.-L., Liu, Y.-H., Zhu, C., Shen, L.-L., Jiao, S.-S., Zhu, X.-Y., Giunta, B., Tan, J., Song, W.-H., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1477-1 · Cited by 277 · see citing works
Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 275 · see citing works
A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice
Bilkei‐Gorzó, A., Albayram, Ö., Draffehn, A. M., Michel, K., Piyanova, A., Oppenheimer, H., Dvir‐Ginzberg, M., Rácz, I., Ulas, T., Imbeault, S., et al. (2017) · Nature Medicine · doi:10.1038/nm.4311 · Cited by 271 · see citing works
Regulation of Stem Cell Aging by Metabolism and Epigenetics
Ren, R., Ocampo, A., Liu, G., & Belmonte, J. C. I. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.019 · Cited by 269 · see citing works
Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline
Glatigny, M., Moriceau, S., Rivagorda, M., Ramos-Brossier, M., Nascimbeni, A. C., Lante, F., Shanley, M. R., Boudarene, N., Rousseaud, A., Friedman, A. K., et al. (2019) · Current Biology · doi:10.1016/j.cub.2018.12.021 · Cited by 257 · see citing works
The Ageing Brain: Molecular and Cellular Basis of Neurodegeneration
Azam, S., Haque, M. E., Balakrishnan, R., Kim, I., & Choi, D. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.683459 · Cited by 257 · see citing works
Schneider, C., Lee, J., Koga, S., Ricardo-González, R. R., Nussbaum, J. C., Smith, L. K., Villeda, S., Liang, H.-E., & Locksley, R. M. (2019) · Immunity · doi:10.1016/j.immuni.2019.04.019 · Cited by 256 · see citing works
Self-citationPlatelet factors attenuate inflammation and rescue cognition in ageing
Schroer, A. B., Ventura, P. B., Sucharov, J., Misra, R., Chui, M. K. K., Bieri, G., Horowitz, A. M., Smith, L. K., Encabo, K., Tenggara, I., et al. (2023) · Nature · doi:10.1038/s41586-023-06436-3 · Cited by 252 · see citing works
Self-citationAging and Rejuvenation of Neural Stem Cells and Their Niches
Navarro Negredo, P., Yeo, R. W., & Brunet, A. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.07.002 · Cited by 246 · see citing works
Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis
Grabrucker, S., Marizzoni, M., Silajdžić, E., Lopizzo, N., Mombelli, E., Nicolas, S., Dohm-Hansen, S., Scassellati, C., Moretti, D. V., Rosa, M., et al. (2023) · Brain · doi:10.1093/brain/awad303 · Cited by 236 · see citing works
Brain Endothelial Cells Are Exquisite Sensors of Age-Related Circulatory Cues
Chen, M. B., Yang, A. C., Yousef, H., Lee, D., Chen, W., Schaum, N., Lehallier, B., Quake, S. R., & Wyss-Coray, T. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.012 · Cited by 233 · see citing works
“Immunofluorescence tissue staining—Brain tissue processing and immunofluorescence experiments were performed as described previously (Castellano et al., 2017; Villeda et al., 2014).”
Self-citationThe Neuroprotective Effects of Exercise: Maintaining a Healthy Brain Throughout Aging
Vecchio, L. M., Meng, Y., Xhima, K., Lipsman, N., Hamani, C., & Aubert, I. (2018) · Brain Plasticity · doi:10.3233/bpl-180069 · Cited by 230 · see citing works
Osteocalcin in the brain: from embryonic development to age-related decline in cognition
Obri, A., Khrimian, L., Karsenty, G., & Oury, F. (2018) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.181 · Cited by 223 · see citing works
Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease
Lewcock, J. W., Schlepckow, K., Di Paolo, G., Tahirovic, S., Monroe, K. M., & Haass, C. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.029 · Cited by 221 · see citing works
Atlas of the aging mouse brain reveals white matter as vulnerable foci
Hahn, O., Foltz, A. G., Atkins, M., Kedir, B., Moran-Losada, P., Guldner, I. H., Munson, C., Kern, F., Pálovics, R., Lu, N., et al. (2023) · Cell · doi:10.1016/j.cell.2023.07.027 · Cited by 213 · see citing works
Self-citationSierra, F. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025163 · Cited by 213 · see citing works
Senotherapeutics: emerging strategy for healthy aging and age-related disease
Kim, E.-C., & Kim, J. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.1.293 · Cited by 211 · see citing works
Biochemistry and Biology of GDF11 and Myostatin
Walker, R. G., Poggioli, T., Katsimpardi, L., Buchanan, S. M., Oh, J., Wattrus, S. J., Heidecker, B., Fong, Y. W., Rubin, L. L., Ganz, P., et al. (2016) · Circulation Research · doi:10.1161/circresaha.116.308391 · Cited by 210 · see citing works
Aging alters the immunological response to ischemic stroke
Ritzel, R. M., Lai, Y., Crapser, J. D., Patel, A. R., Schrecengost, A., Grenier, J. M., Mancini, N. S., Patrizz, A., Jellison, E. R., Morales‐Scheihing, D., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1859-2 · Cited by 209 · see citing works
Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage
Fafián-Labora, J. A., Rodríguez-Navarro, J. A., & O’Loghlen, A. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.004 · Cited by 203 · see citing works
Yang, J., Huang, T., Petralia, F., Long, Q., Zhang, B., Argmann, C., Zhao, Y. B., Mobbs, C. V., Schadt, E. E., Zhu, J., et al. (2015) · Scientific Reports · doi:10.1038/srep15145 · Cited by 198 · see citing works
Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17
Iram, T., Kern, F., Kaur, A., Myneni, S., Morningstar, A. R., Shin, H., García, M. Á., Yerra, L. P., Pálovics, R., Yang, A. C., et al. (2022) · Nature · doi:10.1038/s41586-022-04722-0 · Cited by 198 · see citing works
Self-citationStructural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug
Marschallinger, J., Schäffner, I., Klein, B., Gelfert, R., Rivera, F. J., Illes, S., Grassner, L., Janssen, M., Rotheneichner, P., Schmuckermair, C., et al. (2015) · Nature Communications · doi:10.1038/ncomms9466 · Cited by 193 · see citing works
Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration
Pluvinage, J. V., & Wyss-Coray, T. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0255-9 · Cited by 191 · see citing works
Self-citationBuckley, M. T., Sun, E., George, B. M., Liu, L. A., Schaum, N., Xu, L., Reyes, J. M., Goodell, M. A., Weissman, I. L., Wyss‐Coray, T., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00335-4 · Cited by 189 · see citing works
Self-citationThe Signaling of Cellular Senescence in Diabetic Nephropathy
Xiong, Y., & Zhou, L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7495629 · Cited by 185 · see citing works
Adult Hippocampal Neurogenesis: A Coming-of-Age Story
Kuhn, H. G., Toda, T., & Gage, F. H. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2144-18.2018 · Cited by 181 · see citing works
Translational strategies and challenges in regenerative medicine
Dimmeler, S., Ding, S., Rando, T. A., & Trounson, A. (2014) · Nature Medicine · doi:10.1038/nm.3627 · Cited by 179 · see citing works
Chen, X., Luo, Y., Zhu, Q., Zhang, J., Huang, H., Kan, Y., Li, D., Xu, M., Liu, S., Li, J., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00612-4 · Cited by 174 · see citing works
Young microglia restore amyloid plaque clearance of aged microglia
Daria, A., Colombo, A., Llovera, G., Hampel, H., Willem, M., Liesz, A., Haass, C., & Tahirovic, S. (2017) · The EMBO Journal · doi:10.15252/embj.201694591 · Cited by 174 · see citing works
Egawa, J., Pearn, M. L., Lemkuil, B. P., Patel, P. M., & Head, B. P. (2015) · The Journal of Physiology · doi:10.1113/jp270590 · Cited by 174 · see citing works
Lei, Q., Gao, F., Liu, T., Ren, W., Chen, L., Cao, Y., Chen, W., Guo, S., Zhang, Q., Chen, W., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz8697 · Cited by 170 · see citing works
Liu, Q., Sun, Y.-M., Huang, H., Chen, C., Wan, J., Ma, L., Sun, Y.-Y., Miao, H., & Wu, Y. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02089-z · Cited by 170 · see citing works
Leiter, O., Zhuo, Z., Rust, R., Wasielewska, J. M., Grönnert, L., Kowal, S., Overall, R. W., Adusumilli, V. S., Blackmore, D. G., Southon, A. G., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.01.005 · Cited by 170 · see citing works
Liu, C.-C., Zhao, J., Fu, Y., Inoue, Y., Ren, Y., Chen, Y., Doss, S. V., Shue, F., Jeevaratnam, S., Bastea, L., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01127-0 · Cited by 168 · see citing works
The Business of Anti-Aging Science
de Magalhães, J. P., Stevens, M., & Thornton, D. (2017) · Trends in biotechnology · doi:10.1016/j.tibtech.2017.07.004 · Cited by 167 · see citing works
Targeting synapse function and loss for treatment of neurodegenerative diseases
Dejanovic, B., Sheng, M., & Hanson, J. E. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00823-1 · Cited by 168 · see citing works
Dá Mesquita, S., Ferreira, A. C., Sousa, J. C., Correia-Neves, M., Sousa, N., & Marques, F. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.014 · Cited by 166 · see citing works
Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases
Ji, S., Xiong, M., Chen, H., Liu, Y., Zhou, L., Hong, Y., Wang, M., Wang, C., Fu, X., & Sun, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01343-5 · Cited by 166 · see citing works
Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
Jiang, Q., Liu, J., Huang, S., Wang, X.-Y., Chen, X., Liu, G.-H., Ye, K., Song, W., Masters, C. L., Wang, J., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02145-7 · Cited by 165 · see citing works
Blue Journal Conference. Aging and Susceptibility to Lung Disease
Thannickal, V. J., Murthy, M., Balch, W. E., Chandel, N. S., Meiners, S., Eickelberg, O., Selman, M., Pardo, A., White, E. S., Levy, B. D., et al. (2015) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201410-1876pp · Cited by 164 · see citing works
Clinical Research on Alzheimer’s Disease: Progress and Perspectives
Sun, B., Li, W., Zhu, C., Jin, W., Zeng, F., Liu, Y.-H., Bu, X., Zhu, J., Yao, X., & Wang, Y. (2018) · Neuroscience Bulletin · doi:10.1007/s12264-018-0249-z · Cited by 164 · see citing works
Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance
Salta, E., Lazarov, O., Fitzsimons, C. P., Tanzi, R. E., Lucassen, P. J., & Choi, S. H. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.01.002 · Cited by 164 · see citing works
Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions
Miquel, S., Champ, C., Day, J. E. L., Aarts, E., Bahr, B. A., Bakker, M. J., Bánáti, D., Calabrese, V., Cederholm, T., Cryan, J. F., et al. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.12.004 · Cited by 163 · see citing works
Turning back time with emerging rejuvenation strategies
Mahmoudi, S., Xu, L., & Brunet, A. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0206-0 · Cited by 163 · see citing works
Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., & Andreasson, K. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77487 · Cited by 161 · see citing works
Signaling networks determining life span
Riera, C. E., Merkwirth, C., De Magalhaes Filho, C. D., & Dillin, A. (2016) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014451 · Cited by 161 · see citing works
Small molecule cognitive enhancer reverses age-related memory decline in mice
Krukowski, K., Nolan, A., Frias, E. S., Boone, M., Ureta, G., Grue, K. A., Paladini, M. S., Elizarraras, E., Delgado, L. M., Bernales, S., et al. (2020) · eLife · doi:10.7554/elife.62048 · Cited by 161 · see citing works
Qiu, X.-Y., Liu, J., Zheng, C.-X., Su, Y., Bao, L.-L., Zhu, B., Liu, S.-Y., Wang, L.-L., Wang, X., Wang, Y., et al. (2020) · Cell Proliferation · doi:10.1111/cpr.12830 · Cited by 137 · see citing works
Immunosenescence: signaling pathways, diseases and therapeutic targets
Fu, Y., Wang, B., Alu, A., Hong, W., Hong, L., He, X., Shi, H., Cheng, P., & Yang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02371-z · Cited by 157 · see citing works
Blood-to-brain communication in aging and rejuvenation
Bieri, G., Schroer, A. B., & Villeda, S. A. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01238-8 · Cited by 156 · see citing works
Self-citation
- Authors
- Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., Wabl, R., Udeochu, J., Wheatley, E. G., Zou, B., Simmons, D. A., Xie, X. S., Longo, F. M., & Wyss-Coray, T.
- Affiliations
- University of California, San Francisco (US)
- Stanford Medicine (US)
- AfaSci (United States) (US)
- Corresponding author
- Villeda, Saul A
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-05-04
- Volume
- 20
- Issue
- 6
- Pages
- 659-663
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4224436
- OpenAlex
- W1978927200
- Cited by
- 1,081
- References
- 36
- Citations by year
- 2026: 55 · 2025: 84 · 2024: 101 · 2023: 93 · 2022: 99 · 2021: 90 · 2020: 118 · 2019: 85 · 2018: 81 · 2017: 91 · 2016: 69 · 2015: 77 · 2014: 36 · 2013: 1
- FWCI
- 31.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP5-OD1217, UL1TR001085, DP5OD012178, UL1TR000004)
- University of California, San Francisco
- National Institute on Aging (AG03144, AG045034, R01AG045034, F31AG034045)
- National Institute of Mental Health (T32MH020016)
- National Institute of General Medical Sciences (T32GM008568)
- National Center for Research Resources (UL1RR025744)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007470)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- young blood, brain aging, cognitive impairment, synaptic plasticity, dendritic spine density, hippocampus, learning and memory, contextual fear conditioning, spatial learning, CREB, gene expression changes, aging reversal
- MeSH terms
- Age Factors, Aging, Animals, Blood Transfusion, Cell Line, Cognition Disorders, Hippocampus, Immunohistochemistry, Mice, Inbred C57BL, Neuronal Plasticity, Parabiosis, Blotting, Western, Polymerase Chain Reaction, Cyclic AMP Response Element-Binding Protein, DNA Primers, Microarray Analysis, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
