Cognitive function in humans declines in essentially all domains starting around age 50-60, and neurodegeneration and dementia seem to be inevitable in all but a few who survive to very old age. Mice with a fraction of the human lifespan show similar cognitive deterioration indicating that specific biological processes rather than time alone are responsible for brain aging. While age-related cognitive dysfunction and dementia in humans are clearly distinct entities and affect different brain regions, the aging brain shows the telltale molecular and cellular changes that characterize most neurodegenerative diseases including synaptic loss, dysfunctional autophagy, increased inflammation, and protein aggregation. Remarkably, the aging brain remains plastic and exercise or dietary changes can increase cognitive function in humans and animals, with animal brains showing a reversal of some of the aforementioned biological changes associated with aging. Using heterochronic parabiosis we showed recently that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing an old mouse to a young systemic environment or to plasma from young mice increased neurogenesis, synaptic plasticity, and improved contextual fear conditioning and spatial learning and memory. Preliminary proteomic studies show several proteins with stem cell activity increase in old "rejuvenated" mice supporting the notion that young blood may contain increased levels of beneficial factors with regenerative capacity. In this application we intend to test the hypothesis that blood-borne protein factors in young mice are sufficient to increase adult neurogenesis and regenerate the old brain, and that a focused proteomic screen will allow us to identify the most potent such factors. Our studies pursue the innovative concept that brain aging and cognitive dysfunction is at least in part under control of factors from the circulatory environment and that such factors are sufficient to rejuvenate the aging brain.

Public Health Relevance

The proposed research will follow up on studies from our lab showing that blood from young mice can increase the generation of new neurons and improve cognition in old mice. We will test putative factors that can mimic this effect and carry out discovery projects to identify additional protein factors with regenerative and rejuvenating activity on the old brain. Halting or reversing brain aging by only a small fraction could have a significant impact not only on quality of life in older persons but possibly delay neurodegenerative processes and dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG045034-02
Application #
8660260
Study Section
Special Emphasis Panel (ZAG1-ZIJ-1 (J3))
Program Officer
Wise, Bradley C
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$289,050
Indirect Cost
$84,050
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Wyss-Coray, Tony (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539:180-186
Castellano, Joseph M; Palner, Mikael; Li, Shi-Bin et al. (2016) In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model. Sci Rep 6:29015
Middeldorp, Jinte; Lehallier, Benoit; Villeda, Saul A et al. (2016) Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. JAMA Neurol 73:1325-1333
Jaeger, Philipp A; Lucin, Kurt M; Britschgi, Markus et al. (2016) Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain. Mol Neurodegener 11:31
Kirby, Elizabeth D; Kuwahara, Akela A; Messer, Reanna L et al. (2015) Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF. Proc Natl Acad Sci U S A 112:4128-33
Mosher, Kira Irving; Wyss-Coray, Tony (2015) Go with your gut: microbiota meet microglia. Nat Neurosci 18:930-1
Smith, Lucas K; He, Yingbo; Park, Jeong-Soo et al. (2015) β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med 21:932-7
Castellano, Joseph M; Kirby, Elizabeth D; Wyss-Coray, Tony (2015) Blood-Borne Revitalization of the Aged Brain. JAMA Neurol 72:1191-4
Mosher, Kira Irving; Wyss-Coray, Tony (2014) Microglial dysfunction in brain aging and Alzheimer's disease. Biochem Pharmacol 88:594-604
Baruch, Kuti; Deczkowska, Aleksandra; David, Eyal et al. (2014) Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346:89-93

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