image: Figure 1. Age-dependent nLDs accumulation affects nuclear homeostasis. Over time, lipid droplets (LDs) accumulate progressively in the cytoplasm and within the nuclear lamina, closely associated with age-related changes in the nuclear lamina protein LMN-1 (the nematode homolog of lamin A/C), which supports nuclear morphology. This nLD accumulation may disrupt Lamin-Associated Domains (LADs), chromatin regions anchored to the nuclear periphery, leading to chromatin remodelling, heterochromatin destabilization, and compromised nuclear integrity, which are well-established hallmarks of ageing. Longevity-promoting interventions activate the lipase ATGL-1, regulated by HLH-30/TFEB, linking lipid metabolism to pathways that promote cellular longevity. These changes in nLDs could impact key nuclear processes, including gene expression and DNA repair, thereby contributing to cellular ageing. Created in BioRender (Palikaras, K., 2024, https://BioRender.com/t49f941).
Credit: © 2024 Palikaras and Tavernarakis
“A consistent feature of aging across diverse species is the progressive accumulation of lipid droplets (nLDs) within the nuclear compartment, which disrupts nuclear architecture and functionality.”
BUFFALO, NY- January 7, 2025 – A new research perspective was published in Aging (listed by MEDLINE/PubMed as “Aging (Albany NY)” and “Aging-US” by Web of Science) Volume 16, Issue 22 on December 9, 2024, entitled “Nuclear lipid droplets: a novel regulator of nuclear homeostasis and ageing.”
In this article, Dr. Konstantinos Palikaras from the National and Kapodistrian University of Athens and Dr. Nektarios Tavernarakis from the University of Crete explore how tiny fat droplets, known as nuclear lipid droplets (nLDs), accumulate in the nucleus of cells as we age. Unlike regular lipid droplets, which store energy in the cytoplasm, these nuclear droplets may weaken the nucleus by disrupting critical cellular processes.
The authors suggest that excessive buildup of nLDs could lead to nuclear instability and may be linked to metabolic conditions such as fatty liver disease, obesity-related disorders, and premature aging. This highlights the potential role of nLDs in cellular aging and age-related diseases.
Previous research by the authors using Caenorhabditis elegans (C. elegans), a model organism commonly used to study aging, revealed the role of ATGL-1, an enzyme that regulates fat storage in the nucleus. When functioning properly, ATGL-1 helps maintain a healthy lipid balance. However, when it becomes inactive or overwhelmed, fat droplets build up around the nuclear lamina, making it more difficult for the cell to function properly.
“These findings establish excessive nuclear lipid deposition as a key hallmark of aging, with profound implications for nuclear processes such as chromatin organization, DNA repair, and gene regulation.”
The authors emphasize that lifestyle interventions, such as caloric restriction and better insulin regulation, can significantly reduce harmful nLD buildup, reinforcing the role of healthy metabolism in slowing cellular aging. They also call for further studies to understand how nLDs behave in human experimental models, particularly in patients with conditions like metabolic syndrome and progeria. A deeper understanding of these processes could lead to treatments designed to preserve cell health and delay age-related diseases.
In summary, by presenting nuclear lipid droplets as potential therapeutic targets, this research perspective presents a new path for exploring treatments aimed at combating age-related diseases driven by lipid dysregulation.
Read the full paper: DOI: https://doi.org/10.18632/aging.206175
Corresponding authors: Konstantinos Palikaras – palikarask@med.uoa.gr, and Nektarios Tavernarakis – tavernarakis@imbb.forth.gr
Keywords: aging, ATGL-1, HLH-30/TFEB, lipid droplet, non-linear optical phenomena, nucleus
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The journal Aging aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.)
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Journal
Aging-US
Method of Research
News article
Subject of Research
Not applicable
Article Title
Nuclear lipid droplets: a novel regulator of nuclear homeostasis and ageing
Article Publication Date
9-Dec-2024
COI Statement
The authors declare no conflicts of interest related to this study.