# FSH - an Aging Hormone?

> **NIH NIH U19** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $4,204,185

## Abstract

PROGRAM SUMMARY
 Osteoporosis, obesity and Alzheimer's disease (AD) are public health hazards that affect millions of older
adults. Despite crippling consequences, their therapeutic armamentarium pales when compared with diseases
of similar magnitudes, such as diabetes and cancer. Our current U19 AG060917 and the ADRD supplement
have allowed us to create a highly collaborative transdisciplinary translational research program that
spans bone biology, metabolism and the neurosciences. The program builds on rigorous and transparent
research, born from a longstanding collaboration between Drs. Mone Zaidi and Clifford Rosen, wherein data
continues to be contemporaneously replicated in both labs. We have together identified the fertility hormone
FSH as a unique target to prevent osteoporosis, obesity and AD. We have developed antibodies that block the
action of FSH and, in doing so, prevent bone loss, obesity, and cognitive decline in mouse models1-4. We have
now created a therapeutic antibody—MS-Hu6—which has undergone early stage testing, including safety
studies in monkeys5,6—and, is therefore poised for efficacy testing in aging models of human disease. This is
particularly relevant as elderly women in the AGES–Reykjavik cohort show a correlation between a high serum
FSH, low bone mineral density (BMD) and fracture risk7. We have also unmasked a novel action of the second
gonadotropin LH in reducing body fat—raising the question whether the leanness induced by a small molecule
LH receptor agonist, ORG43553, can synergize with FSH blockade by MS-Hu6. Four projects will thus focus
on both mechanism and translation. In Project 1, we will examine if FSH blockade by MS-Hu6 or genetic Fshr
ablation in aged mice can reverse established osteoporosis, obesity and/or AD. Project 2 will use Cre lines to
delete the Fshr in specific bone cells—osteoblasts, osteocytes and osteoclasts—as well as in adipocytes and
examine the evolution of the respective phenotypes. This will be complemented by siRNA–mediated Fshr
knockdown in hypothalamic neurons that might contribute to obesity. Project 3 will likewise probe the
mechanism of action of LHCGR agonism on body fat, and specifically determine interactions between
downstream signals by using chemical inhibitors and in vivo genetic epistasis. Project 4 remains as the
program's epidemiological arm, which will utilize validated datasets from AGES–Reykjavik to probe
relationships between brain health and bone health, and examine, using a case–cohort design, whether high
serum FSH levels are associated with dementia or mild cognitive impairment. The Projects will be supported by
three overarching Cores, namely a Skeletal, Metabolic and Neurobehavioral Core (Core A), an Antibody
Production and Testing Core (Core B), and an Administrative, Biostatistics and Good Laboratory Practice
(GLP) Management Core (Core C). In sum, our U19 renewal should allow us to break new ground in
understanding the role of pituitary gonadotropins i...

## Key facts

- **NIH application ID:** 10764100
- **Project number:** 2U19AG060917-06
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** CLIFFORD JAMES ROSEN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $4,204,185
- **Award type:** 2
- **Project period:** 2019-02-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764100

## Citation

> US National Institutes of Health, RePORTER application 10764100, FSH - an Aging Hormone? (2U19AG060917-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10764100. Licensed CC0.

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