# In vivo and in vitro systems to validate geronic proteins and their mechanisms of action

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $519,161

## Abstract

Late onset chronic diseases associated with aging, including cardiovascular disorders, Alzheimer's and
Parkinson's disease, diabetes and tissue malignancies, are the leading causes of morbidity and mortality
creating the greatest emotional and financial burden on the individual and society. As the aging population
continues to expand, late onset chronic diseases will further dominate the attention of biomedicine. We
have been pursuing the role of the brain circuits and humoral factors in health and aging. We have identified
the hypothalamus as an intersection point between CNS and peripheral tissue communications, defined serum
proteins differentially expressed in young and old animals, and recognized cardiovascular health as a principal
determinant of lifespan. We and others have established that hypothalamic neurons sense the changing
peripheral milieu and also send out signals to control complex behaviors and organ system and peripheral
tissue functions. Our preliminary data and the work of others identified the same hypothalamic circuits to
control the aging process. For example, we found that neurons of the hypothalamus that control hunger have
significant impact on survival and lifespan. We also identified that these neurons mediate the action of
peripheral hormones implicated in the lifespan extending impact of calorie restriction. We hypothesize, that
action of circulating geronic substances on age related central and peripheral processes are mediated, at least
in part, by the hypothalamus. We will interrogate this question using mouse models in Specific Aim 1. We
will analyze complex behaviors, cardiac, muscle, bone and immune functions in control and experimental
animals, including animals with different age and genotype in a state of parabiosis. From a translational
perspective, it is crucial that the presence and relevance of geronic peptides are confirmed in higher species
such as primates, including humans. In an effort to address this issue, we have analyzed plasma from young
and aged nonhuman primates. Proteomics analysis identified candidate molecules in primates that have not
been identified in mice. In Specific Aim 2, we propose to utilize our newly established, high throughput in vitro
system to assess the cellular effects of putative geronic targets identified in our screen using nonhuman
primate fibroblasts. We will focus on intracellular events that are associated with aging cells. In Specific Aim
3, we will test primates to evaluate anti- and pro-geronic interventions on CNS and cardiovascular systems.
We will analyze the effects of young and aged plasma treatment of animals, known anti- and pro-geronic
peptides and those newly defined by in vivo analyses on cognitive brain functions of young, middle aged and
old nonhuman primates. Overall, execution of our aims will deliver new insights regarding the mechanisms of
action of geronic substances, new circulating geronic molecules and exploit robust test systems that will len...

## Key facts

- **NIH application ID:** 9928374
- **Project number:** 5R01AG052986-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** TAMAS L HORVATH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $519,161
- **Award type:** 5
- **Project period:** 2017-09-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928374

## Citation

> US National Institutes of Health, RePORTER application 9928374, In vivo and in vitro systems to validate geronic proteins and their mechanisms of action (5R01AG052986-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928374. Licensed CC0.

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