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H2020Individual fellowship2021–2023

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

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2021-09-01 → 2023-08-31
EU contribution
€147,815
Participants
1
Scheme
MSCA-IF

Lines connect the coordinator with its partners.

Results in brief

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

Aging acts as a major risk factor for many human pathologies, including cancer, neurodegenerative disorders, diabetes, and cardiovascular diseases. Over the years, the global trend has been for people to live longer, with projections for 2030 indicating that individuals aged 60 and older will surpass the youth population and double the number of children under five. This has prompted a strong interest in aging research in the past decades. Nonetheless, additional information on the determinants of biological deterioration is still required if we aim at providing a better quality of life for aging individuals, together with creative and efficient ways to counteract them and prevent age-prone diseases. In the LipLAge project, the focus was to understand why human cell nuclei tend to lose structural integrity as age progresses, ultimately leading to functional impairment. We envisioned a new paradigm where the lipid composition of the nuclear envelope, and not only proteins and nucleic acids, would have an active role in regulating the overall integrity of the nucleus. More specifically, our strategy was to address the interplay between lamin proteins and the lipids of the nuclear envelope, and to understand how these interactions affect nuclear lamina architecture and nuclear structure during human aging. Overall, our results show that, as age progresses, there is a significant decrease in the content of ether lipids in the nucleus of human skin cells. Moreover, this difference in membrane composition results in altered membrane biophysical properties, ultimately leading to a differential binding of lamin proteins to the nuclear envelope.

Data: CORDIS, © European Union

Project objective

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.

Original text from CORDIS.

Participants

  • INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES · LisboaCoordinatorPortugal

Links

Data: CORDIS, © European Union