# The Role of Hypothalamic Dysfunction in Accelerating Aging in Humans

> **NIH NIH K76** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2024 · $211,567

## Abstract

The Role of Hypothalamic Dysfunction in Accelerating Human Aging
Sandra Aleksic, MD, M.S.
 Mentor: Sofiya Milman, MD, M.S.
Co-mentors: Michael Lipton, MD, PhD; Joe Verghese, MBBS, MS
Abstract:
Mechanisms underpinning biological aging in humans remain incompletely understood. The hypothalamus
integrates key metabolic and neuroendocrine longevity pathways; therefore, hypothalamic dysfunction could
accelerate aging in humans. Recent studies in rodents identified aging-related hypothalamic microinflam-
mation, referred to as gliosis, which was characterized by accumulation and activation of microglia and
astrocytes. Gliosis caused hypothalamic dysfunction and accelerated aging, but prevention of hypothalamic
gliosis delayed aging. Despite growing evidence that the hypothalamus may regulate the aging process, its
role in human aging has not been investigated.
My hypothesis is that hypothalamic dysfunction accelerates aging in humans. To test this hypothesis,
we have devised a unique approach tailored to human aging cohorts. We will test two different measures of
hypothalamic dysfunction as predictors of cognitive decline, frailty, and reduced lifespan, which are features
of accelerated aging: 1) Neuroendocrine hypothalamic dysfunction is a functional measure, represented by
hypothalamic dysregulation of gonadal axis. 2) Hypothalamic gliosis is a structural measure, established by
neuroimaging MRI-DTI parameters. This proposal leverages an established prospective cohort of adults age
≥65 (n=1,200), LonGenity, with detailed biochemical and phenotypic assessments, including high-quality
brain MRIs (n=240), which will be analyzed with a novel automated MRI processing pipeline developed by
our group to efficiently and objectively study hypothalamic gliosis. My hypothesis will be addressed through
the following Specific Aims: Aim 1: To establish the role of neuroendocrine hypothalamic dysfunction,
represented by hypothalamic dysregulation of gonadal axis at study baseline, in accelerating aging, deter-
mined by longitudinal assessments of neurocognitive scores, frailty index and all-cause mortality. Aim 2: To
establish cross-sectional relationships between hypothalamic gliosis and accelerated aging (2a) and neuro-
endocrine hypothalamic dysfunction (2b); and Aim 3: To identify circulating protein signatures of neuroen-
docrine hypothalamic dysfunction (3a) and hypothalamic gliosis (3b). This proposal will establish the role of
hypothalamic dysfunction in human aging and identify potential biological mechanisms that accelerate aging.
My career goal is to establish the role of the neuroendocrine system in the regulation of aging in
humans, and I have identified four main areas for further development over the 5-years of this K76 Award.
These include advanced training in 1) neuroimaging, 2) geriatrics, 3) data analysis, and 4) leadership. I have
devised, with input from my multidisciplinary team of mentors and collaborators, a comprehensive training
plan to at...

## Key facts

- **NIH application ID:** 10904021
- **Project number:** 5K76AG083274-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Sandra Aleksic
- **Activity code:** K76 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $211,567
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904021

## Citation

> US National Institutes of Health, RePORTER application 10904021, The Role of Hypothalamic Dysfunction in Accelerating Aging in Humans (5K76AG083274-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10904021. Licensed CC0.

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