# Role for prelamin A in premature and physiological aging

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $623,433

## Abstract

PROJECT SUMMARY
This project aims to define the role of farnesylated prelamin A in premature and physiological aging.
Genetic mutations leading to defective processing of prelamin A, the precursor for the nuclear scaffold protein
lamin A, result in persistence of its farnesyl modification and cause premature aging disorders. The best known
of these is Hutchinson-Gilford progeria syndrome (HGPS), in which a truncated farnesylated prelamin A variant
called “progerin” is expressed. Mandibuloacral dysplasia-type B (MAD-B) is a related disease, where
unprocessed farnesylated prelamin A itself accumulates in cells. Some evidence suggests that prelamin A also
accumulates during physiological aging. However, the mechanistic role of farnesylated prelamin A in
premature aging disorders remains unclear, and its association with physiological aging has not been
rigorously tested. We hypothesize that prelamin A is a driver of osteoporosis and cardiovascular
disease that occurs in premature and possibly physiological aging. To specifically examine the
consequences of prelamin A accumulation, we generated a novel mouse strain (LmnaL648R/L648R) with a
mutation that abolishes its processing by the zinc metalloprotease ZMPSTE24. These mice express solely
prelamin A (and no mature lamin A), exhibit profound bone loss, but have a significantly longer lifespan than
other progeria models and are thus ideal to study the effects of prelamin A during aging. In Aim 1, we will
determine how prelamin A affects the number, function, development, transcriptomes and signaling of bone
cells, and compare these to what occurs in physiological aging. We will also assess whether these mice
develop vascular disease as they age or develop accelerated atherosclerosis when combined with genetic
(Ldlr-/-) and high-fat diet interventions that sensitize mice to atherosclerosis. In Aim 2, we will determine how
prelamin A affects cultured cells and define the mechanism(s) by which it promotes cellular alterations related
to aging. We will carry out chronological transcriptomic analyses in cultured cells to define the earliest events
promoted by prelamin A to distinguish causal changes from chronic responses. We will also test the hypothesis
that prelamin A induces nuclear envelope rupture that could stimulate a cytosolic DNA sensor and lead to a
transcriptional program of inflammation. We will relate the mechanistic insights obtained from these in vitro
experiments to affected cells in the LmnaL648R/L648R mice. In Aim 3, we will determine if prelamin A actually
accumulates during physiological aging by examining bone and vascular tissue of young and old mice. We will
also probe human tissue arrays and a panel of fibroblasts from young and aged individuals for prelamin A.
Elucidating the cellular mechanisms and consequences of prelamin A accumulation could change clinical
paradigms for the treatment of prelamin A-based premature aging disorders. More broadly, the results of this
project coul...

## Key facts

- **NIH application ID:** 10520327
- **Project number:** 1R01AG075047-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Susan D. Michaelis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $623,433
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520327

## Citation

> US National Institutes of Health, RePORTER application 10520327, Role for prelamin A in premature and physiological aging (1R01AG075047-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10520327. Licensed CC0.

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