Heterochronic parabiosis: the promise of pro- and anti-geronic - - PowerPoint PPT Presentation

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Heterochronic parabiosis: the promise of pro- and anti-geronic - - PowerPoint PPT Presentation

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Heterochronic parabiosis: the promise of pro- and anti-geronic factors Joseph M. Castellano, Ph.D. Stanford University School of Medicine, Wyss-Coray Laboratory 2016 OAIC Annual Meeting, April 19, 2016 Aging is a major risk factor for disease

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Heterochronic parabiosis: the promise of pro- and anti-geronic factors

Joseph M. Castellano, Ph.D.

Stanford University School of Medicine, Wyss-Coray Laboratory 2016 OAIC Annual Meeting, April 19, 2016

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Aging is a major risk factor for disease

Young (31 y) Old (88 y)

  • Normal brain aging alterations:

– Cognitive – Cellular – Molecular

  • Aging is major risk factor for many

neurological disorders

  • Aged population projected to double

by 2030

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Young Systemic environment Old Positive factors Positive factors

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Conboy et al., 2005 Sinha et al., 2014

?

Young blood regulates aging processes in diverse tissues

Castellano et al., JAMA Neurol, 2015 (for review)

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Conboy et al., 2005 Conboy et al., 2005 Sinha et al., 2014

?

Young blood regulates aging processes in diverse tissues

Castellano et al., JAMA Neurol, 2015 (for review)

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Salpeter et al., 2013 Conboy et al., 2005 Conboy et al., 2005 Sinha et al., 2014

?

Young blood regulates aging processes in diverse tissues

Castellano et al., JAMA Neurol, 2015 (for review)

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Loffredo et al., 2013 Salpeter et al., 2013 Conboy et al., 2005 Conboy et al., 2005 Sinha et al., 2014

?

Young blood regulates aging processes in diverse tissues

Castellano et al., JAMA Neurol, 2015 (for review)

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Loffredo et al., 2013 Salpeter et al., 2013 Conboy et al., 2005 Conboy et al., 2005 Sinha et al., 2014 Baht et al., 2015

?

Young blood regulates aging processes in diverse tissues

Castellano et al., JAMA Neurol, 2015 (for review)

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Loffredo et al., 2013 Salpeter et al., 2013 Conboy et al., 2005 Conboy et al., 2005 Sinha et al., 2014 Villeda et al., 2011 Villeda et al., 2014 Katsimpardi et al., 2014 Baht et al., 2015

?

Young blood regulates aging processes in diverse tissues

Castellano et al., JAMA Neurol, 2015 (for review)

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Loffredo et al., 2013 Salpeter et al., 2013 Conboy et al., 2005 Conboy et al., 2005 Sinha et al., 2014 Villeda et al., 2011 Villeda et al., 2014 Katsimpardi et al., 2014 Baht et al., 2015

?

Young blood regulates aging processes in diverse tissues

Castellano et al., JAMA Neurol, 2015 (for review)

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Adult neurogenesis occurs in lateral ventricles and the hippocampus (DG)

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Signals in the systemic environment regulate neurogenesis in dentate gyrus

Villeda et al., 2011

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Pro-aging factor CCL11 increases with age and impairs learning/memory

Villeda et al., 2011

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Pro-aging factor CCL11 increases with age and impairs learning/memory

Villeda et al., 2011

B2M also revealed to be anti-neurogenic, pro-aging factor

Smith et al., 2015, Nat Med

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Blood-borne factors that promote plasticity and/or cognition e.g., GDF11, many others

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Exposure to young blood revitalizes the aged brain

Plasticity gene networks Dendritic spines/LTP Microgliosis Rejuvenation Neurogenesis

Villeda et al., Nat Med, 2014 and unpublished

Learning/memory

Young blood plasma

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Strategy for the identification of rejuvenating factors

Cellular/molecular changes Cognitive assessment Mouse Aging Heterochronic Parabiosis Human Donors

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Strategy for the identification of rejuvenating factors

Mouse Aging Heterochronic Parabiosis Human Donors

Umbilical cord ~ 20 years ~ 65 years

Cognitive assessment Cellular/molecular changes

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Cytokines Chemokines Growth factors Neurotrophins Hormone-like proteins Acute-phase proteins Complement factors Secreted receptors Sample array w/ differential plasma protein signals

Plasma protein factors 150 µm spot

Protein microarray to assess relative plasma protein expression

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Protein microarray reveals many elevated factors in cord plasma

Low High Cord Young Old

Secreted Plasma Factors

Castellano et al., in revision

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Protein microarray reveals many elevated factors in cord plasma

Low High Cord Young Old

Secreted Plasma Factors

Castellano et al., in revision

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Administration of human plasma in “NSG” mice

Heterochronic Parabiosis Changes Mouse Human

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Administration of human plasma in “NSG” mice

NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ aka “NOD Scid Gamma” (NSG) Heterochronic Parabiosis Changes Mouse Human

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Age-dependent changes in immediate early gene marker c-Fos

Castellano et al., in revision

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NSG mice exhibit other age-dependent hippocampal pathology

Castellano et al., in revision

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NSG mice exhibit age-dependent learning and memory deficits

Castellano et al., in revision

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NSG mice exhibit age-dependent learning and memory deficits

Castellano et al., in revision

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Administration of human plasma in aged NSG mice

Aged NSG Days 14 Human plasma donors Behavior Microarray/qPCR/IHC

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Human plasma treatment results in distinct gene profiles in hippocampi

Castellano et al., in revision

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Human plasma treatment results in distinct gene profiles in hippocampi

Castellano et al., in revision Ontology-based activation prediction

  • Long-term memory
  • Long-term potentiation
  • neuritogenesis

Plasticity upregulation by qPCR

  • c-Fos, Egr1, junb, camk2a, etc.
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Aged NSG

Cord plasma increases c-Fos+ cell number in aged but not young dentate gyrus

Castellano et al., in revision

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Aged NSG Young NSG

Cord plasma increases c-Fos+ cell number in aged but not young dentate gyrus

Castellano et al., in revision

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Cord PLM activates DG granule neurons (excitatory)

Castellano et al., in revision

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RE SE

Treatment with cord plasma enhances LTP in dentate gyrus

Castellano et al., in revision

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LTP is unaffected following young or elderly human plasma treatment

Castellano et al., in revision

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Treatment with cord plasma improves learning and memory performance

Castellano et al., in revision

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Strategy for the identification of rejuvenating factors

Cellular/molecular changes Mouse Aging Heterochronic Parabiosis Human Aging

Umbilical cord plasma

Cognitive assessment

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Strategy for the identification of rejuvenating factors

Cellular/molecular changes Mouse Aging Heterochronic Parabiosis Human Aging Cognitive assessment

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In vivo “screen” of potential rejuvenating factors in aged WT mice

0 2 4 6 10 Putative Factors

  • r vehicle i.p.

Days

Castellano et al., in revision

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Plasma TIMP2 is reduced very early in life in blood and brain

Castellano et al., in revision

Human Mouse

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Systemic supplementation with TIMP2 enhances synaptic plasticity in aged mice

0 2 4 6 8 10 12 14 rTIMP2 or vehicle i.p.

Days

Castellano et al., in revision

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Systemic treatment with TIMP2 improves learning and memory in aged WT mice

Castellano et al., in revision

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Systemic TIMP2 is necessary for spatial memory

Training Novel Location Day 1 Day 2

Castellano et al., in revision

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Translational potential of blood-borne proteins

  • TIMP2

– 21-24 kDa; non-glycosylated – Limits tumor angiogenesis and plays role in tissue remodeling – Broad MMP inhibitor Marimastat proceeded to Phase III trials (discontinued)

  • Ongoing plasma trials related to CNS

– AMBAR (Alzheimer’s Management by Albumin Replacement - Grifols) – PLASMA (PLasma for Alzheimer’s SyMptom Amelioration)

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Conclusions

  • Blood factors can regulate aging process in diverse

tissues

– Developmental-stage human plasma (UC) improves neuronal and cognitive function – Young plasma proteins (TIMP2) restore or improve function of aged hippocampus – Use of NSG mouse model allows for identification of relevant blood-borne proteins with possible translational implications

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Acknowledgements

Wyss-Coray Lab Tony Wyss-Coray Kira I. Mosher Rachelle Abbey Daniela Berdnik Jadon Shen Xie Lab/AfaSci Simon Xie Bende Zou Stanford Tom Rando Martin Angst Funding Sources

  • NIH/NIA
  • Jane Coffin Childs Postdoctoral

Fellowship/Simons Foundation

  • Stanford Child Health Research Institute

Postdoctoral Fellowship

  • Donor’s Cure Foundation, CCAD
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Youthful systemic factors Stimulated vascular endothelium Disrupted BBB? Youth-associated leukocytes? Transport? Diffusion? Secondary signals? Synaptic plasticity Neurogenesis Cell-to-cell Signaling? Oligodendrocyte activity

Castellano et al., JAMA Neurol, 2015

Young blood alters brain via unknown mechanisms/factors

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Human plasma does not alter the number of neuroblasts in dentate gyrus of NSG mice

Castellano et al., in revision

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rTIMP2 treatment does not appear to alter DCX+ cell number in aged DG

Castellano et al., in revision

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TIMP2 expression in plasma and hippocampus declines gradually with age in mice

Castellano et al., in revision

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Blood-borne factor GDF11 mediates SVZ neurogenesis rejuvenation

Katsimpardi et al., 2014