Nuclear lipid droplets: a novel regulator of nuclear homeostasis and ageing.

Abstract

Aging is a fundamental driver of numerous life-threatening diseases, significantly compromising cellular structures and functions, including the integrity of the nucleus. 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. Notably, aging is accompanied by a marked increase in nLD accumulation at the nuclear envelope. 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 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.