Nat Med. 2014 Jun;20(6):659-63. doi: 10.1038/nm.3569. Epub 2014 May 4.

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

Villeda SA¹, Plambeck KE², Middeldorp J³, Castellano JM³, Mosher KI⁴, Luo J⁵, Smith LK⁶, Bieri G⁷, Lin K⁸, Berdnik D⁵, Wabl R⁵, Udeochu J⁹, Wheatley EG¹⁰, Zou B¹¹, Simmons DA⁵, Xie XS¹¹, Longo FM⁵, Wyss-Coray T¹².

Author information

¹1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, USA. [4] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA. [5] Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, USA. [6] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
²1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3].
³1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2].
⁴1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA. [3].
⁵Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
⁶1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA.
⁷1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [4] Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA.
⁸1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Neuroscience Graduate Program, University of California San Francisco, San Francisco, California, USA.
⁹1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, USA.
¹⁰1] Department of Anatomy, University of California San Francisco, San Francisco, California, USA. [2] The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, California, USA. [3] Developmental and Stem Cell Biology Graduate Program, University of California San Francisco, San Francisco, California, USA.
¹¹AfaSci Research Laboratory, Redwood City, California, USA.
¹²1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California, USA. [3] Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, California, USA.

Abstract

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.

Comment in

Young blood rejuvenates old brains. [Nat Med. 2014]
Brain ageing: Blood-derived rejuvenation. [Nat Rev Neurosci. 2014]
Ageing: Could young blood combat age-related cognitive decline? [Nat Rev Neurol. 2014]

PMID:: 24793238
PMCID:: PMC4224436
DOI:: 10.1038/nm.3569

[PubMed - indexed for MEDLINE]

Free PMC Article

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Figure 1

Heterochronic parabiosis enhances dendritic spine number and synaptic plasticity in the aged hippocampus and elicits a plasticity-related expression profile. (a) Schematic depicting the parabiotic pairings. (b,c) Microarray analysis performed on the hippocampi of aged (18 months) isochronic and heterochronic parabionts 5 weeks after surgery. n = 4 mice per group. For all analyses, downregulated genes are shown in shades of blue, and upregulated genes are shown in shades of yellow. (b) Biological pathways involved in synaptic plasticity identified as part of the top signaling network (P < 0.05) using IPA software based on differentially expressed genes in isochronic and heterochronic parabionts. Inferred molecular interactions identified by IPA are shown in gray. (c) Heat map generated by unsupervised hierarchical clustering with a data set of genes differentially expressed between hippocampi of aged isochronic (Iso) and heterochronic (Hetero) parabionts using a cutoff at P < 0.01 and d score > 2 on the basis of Significance Analysis of Microarray (SAM). Color bars reflect the z scores. (d–j) Histological and electrophysiological analysis performed on aged (18 months) isochronic (n = 6) and heterochronic (n = 5) parabionts analyzed 5 weeks after surgery. (d) Immunohistochemical detection of Egr1, c-Fos and phosphorylated Creb (pCreb) protein in the DG of the hippocampi of aged isochronic and heterochronic parabionts. Arrowheads indicate individual cells. Scale bars, 100 μm (low magnification); 50 μm (high magnification). (e–g) Quantification of the immunostaining for Egr1 (e), c-Fos (f) and pCreb (g). Five sections per mouse were analyzed. (h,i) Representative Golgi stain image (h; scale bar, 5 μm) and quantification of dendritic spine density on tertiary branches (i). Five neurons per mouse were analyzed. (j) Population spike amplitude (PSA) recorded from the DG of aged parabionts. Representative LTP levels are shown for isochronic and heterochronic parabionts. All data are shown as the mean ± s.e.m. *P < 0.05, **P < 0.01, t test (e–g,i).

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice

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