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Baricitinib and lonafarnib synergistically target Progerin and inflammation, improving lifespan and health in progeria mice.
Int. J. Mol. Sci. 26, 4849 - 4849 (2025)
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, fatal, and
premature aging disorder caused by progerin, a truncated form of lamin A
that disrupts nuclear architecture, induces systemic inflammation, and
accelerates senescence. While the farnesyltransferase inhibitor
lonafarnib extends the lifespan by limiting progerin farnesylation, it
does not address the chronic inflammation or the senescence-associated
secretory phenotype (SASP), which worsens disease progression. In this
study, we investigated the combined effects of baricitinib (BAR), a
JAK1/2 inhibitor, and lonafarnib (FTI) in a LmnaG609G/G609G
mouse model of HGPS. BAR + FTI therapy synergistically extended the
lifespan by 25%, surpassing the effects of either monotherapy. Treated
mice showed improved health, as evidenced by reduced kyphosis, better
fur quality, decreased incidence of cataracts, and less severe
dysgnathia. Histological analyses indicated reduced fibrosis in the
dermal, hepatic, and muscular tissues, restored cellularity and
thickness in the aortic media, and improved muscle fiber integrity.
Mechanistically, BAR decreased the SASP and inflammatory markers (e.g.,
IL-6 and PAI-1), complementing the progerin-targeting effects of FTI.
This preclinical study demonstrates the synergistic potential of BAR +
FTI therapy in addressing HGPS systemic and tissue-specific pathologies,
offering a promising strategy for enhancing both lifespan and health.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Progeria ; Premature Aging; baricitinib; Hutchinson–Gilford progeria syndrome; lamin A; progerin; JAK-STAT; lifespan; inflammation
ISSN (print) / ISBN
1422-0067
e-ISSN
1661-6596
Zeitschrift
International Journal of Molecular Sciences
Quellenangaben
Band: 26,
Heft: 10,
Seiten: 4849 - 4849
Verlag
MDPI
Verlagsort
Basel
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Experimental Genetics (IEG)
Förderungen
Progeria Research Foundation