# The Role of Hypothalamic Dysfunction in Accelerating Aging in Humans

> **NIH AG K76** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2026 · $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 

## Key facts

- **NIH application ID:** 11322616
- **Project number:** 5K76AG083274-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Sandra  Aleksic
- **Activity code:** K76 (R01, R21, SBIR, etc.)
- **Funding institute:** AG
- **Fiscal year:** 2026
- **Award amount:** $211,567
- **Award type:** 5
- **Project period:** 2023-08-15T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11322616

## Citation

> US National Institutes of Health, RePORTER application 11322616, The Role of Hypothalamic Dysfunction in Accelerating Aging in Humans (5K76AG083274-04). Retrieved via AI Analytics 2026-07-03 from https://api.ai-analytics.org/grant/nih/11322616. Licensed CC0.

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