Cognitive decline continues to be one of greatest health threats affecting the elderly. In fact, aging remains the single most dominant risk factor for dementia-related neurodegenerative diseases, including Alzheimer's disease. When considering, the rate at which the human population is aging, it becomes imperative to identify means by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of aging. Presupposed dogma holds that the old brain is unable to combat the effects of aging due to a lack of inherent plasticity that facilitates permanent age-related functional impairments. We, and others, have begun to challenge such dogma by showing that systemic manipulations such as heterochronic parabiosis (in which the circulatory systems of young and old animals are connected) can enhance adult stem cell function in the aged brain. Moreover, my lab recently demonstrated that neuronal and cognitive rejuvenation is possible in the aged brain by systemic administration of young blood plasma, and identified the transcription factor Creb as a critical mediator of brain rejuvenation. While the burgeoning field of rejuvenation research is fast growing, the current focus thus far has been placed on identifying individual blood-borne factors in young blood. However, this approach has left fundamental questions unexplored: 1. How long lasting are the rejuvenating effects of young blood on the old brain? 2. What mechanistic changes does young blood elicit in the old brain to promote rejuvenation? 3. Do the beneficial effects of young blood on the aged brain extend to dementia-related neurodegenerative diseases such as Alzheimer's disease? The purpose of the proposed study is thus to investigate the rejuvenating and therapeutic effects of young blood on the aged brain. Specifically, our hypothesis is that systemic exposure to young blood elicits long lasting rejuvenation of synaptic and cognitive functions, while ameliorating neurodegenerative phenotypes. We will test this theory with three Specific Aims: 1. Characterize the kinetics of brain rejuvenation following systemic exposure to young blood. 2. Identify molecular mechanisms downstream of Creb underlying brain rejuvenation by young blood. 3. Distinguish rejuvenating versus therapeutic effects of young blood in a model of accelerated aging and Alzheimer's disease. Ultimately, these studies will challenge traditional views of brain aging by using the rejuvenating effects of young blood to obtain a mechanistic understanding of the cellular events required for unleashing the latent plasticity within the old brain. The results will also have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative diseases such as Alzheimer's disease.

Public Health Relevance

The research described in this proposal aims to challenge traditional views of brain aging by using the rejuvenating effects of young blood to obtain a mechanistic understanding of the cellular events required for unleashing the latent plasticity within the old brain. The results will have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate cognitive dysfunction associated with dementia-related neurodegenerative diseases such as Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG053382-01
Application #
9159810
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Wise, Bradley C
Project Start
2016-08-15
Project End
2021-04-30
Budget Start
2016-08-15
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
$396,250
Indirect Cost
$146,250
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Gontier, Geraldine; Iyer, Manasi; Shea, Jeremy M et al. (2018) Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain. Cell Rep 22:1974-1981
Smith, Lucas K; White 3rd, Charles W; Villeda, Saul A (2018) The systemic environment: at the interface of aging and adult neurogenesis. Cell Tissue Res 371:105-113
Fan, Xuelai; Wheatley, Elizabeth G; Villeda, Saul A (2017) Mechanisms of Hippocampal Aging and the Potential for Rejuvenation. Annu Rev Neurosci 40:251-272