Exploring lamin-lipid interactions and the loss of nuclear structural integrity as the molecular determinants of human aging

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Aging is a major risk factor for many human pathologies. At a time when we are living longer than ever before, untangling the mechanisms of this biological deterioration is absolutely critical if we aim at providing a better quality of life for aging individuals. The loss of nuclear integrity, and the consequent defects in nuclear mechanics, is already among widely considered hallmarks of aging. In mammalian cells, the structural properties of the nucleus are maintained by the nuclear lamina (NL), especially lamin A (LA), and its interaction with the nuclear envelope (NE). In this innovative project, our working hypothesis is built upon the observation that progerin – truncated form of LA prevalent in premature aging – is abnormally associated with the inner nuclear membrane (INM) and the LA, due to its permanent farnesylation. Moreover, progerin levels were also shown to increase in healthy aged individuals, suggesting that LA and progerin differences in membrane association might be intimately involved in healthy human aging. Hence, the main goal of this project is to understand how the interplay between LA (at different proteolytic stages) and INM lipids affects NL architecture and nuclear structural integrity during physiological aging. To address this question, we will tackle lamin-lipid interactions (and lamin polymerization) in membrane models mimicking the NE during healthy and premature aging, and in intact nuclei, using a set of quantitative techniques, including fluorescence-based methods, atomic force microscopy and lipidomics. Overall, this is the first time a comprehensive lipid-driven molecular biophysics approach will be applied to the NE during healthy human aging. By achieving the proposed objectives, we will provide new knowledge on the role of INM lipids in proper nuclear function and aging.