Abnormal localized excesses of lipids in tissues, particularly cholesterol, is a feature of aging. It is disruptive to cell function, such as via accumulation of intracellular free cholesterol when the cell’s ability to safely store that cholesterol in the form of lipid droplets is overwhelmed. Cholesterol is essentially toxic in its unmodified form. Researchers here note another potential problem resulting from a local excess of lipids, which is the formation of lipid droplets in the cell nucleus rather than in the cytoplasm as is usually the case. Some work remains in order to determine exactly how this introduction of lipid droplets into the cell nucleus might cause harm, but we might hypothesize that it results in altered gene expression at the very least.
A prominent hallmark of ageing is the accumulation of dysfunctional cellular components, which disrupts tissue homeostasis, contributing to age-related pathologies. This feature includes the abnormal deposition of lipids in non-adipose tissues, known as ectopic fat, which is highly associated with metabolic syndrome and various age-related conditions, including cardiovascular disease, type 2 diabetes, and neurodegenerative disorders, among others.
Lipid droplets (LDs) are primarily recognized as cytoplasmic organelles and have a pivotal role in energy storage, lipid metabolism, and cellular homeostasis. Traditionally, LDs presence has been confined to the cytoplasm, where they serve as reservoirs of neutral lipids, supporting energy balance and membrane biosynthesis. For a long time, the association between LDs and the nucleus was under-investigated. However, recent studies have unveiled an unexpected aspect of lipid biology demonstrating that LDs can also exist within the nucleus, forming nuclear lipid droplets (nLDs).
Interventions known to extend lifespan, such as caloric restriction and reduced insulin signaling, significantly reduce both the rate of accumulation and the size of nLDs. The triglyceride lipase ATGL-1, which localizes to the nuclear envelope, plays a critical role in limiting nLD buildup and maintaining nuclear lipid balance, especially in long-lived mutant nematode worms. 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. In addition, ATGL-1 emerges as a promising therapeutic target for preserving nuclear health, extending organismal healthspan, and combating age-related disorders driven by lipid dysregulation.
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