Progerin modulates the IGF-1R/Akt signaling involved in aging

Progerin, a product of LMNA mutation, leads to multiple nuclear abnormalities in patients with Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disorder. Progerin also accumulates during physiological aging. Here, we demonstrate that impaired insulin-like growth factor 1 receptor (IGF-1R)/Akt signaling pathway results in severe growth retardation and premature aging in Zmpste24(-/-) mice, a mouse model of progeria. Mechanistically, progerin mislocalizes outside of the nucleus, interacts with the IGF-1R, and down-regulates its expression, leading to inhibited mitochondrial respiration, retarded cell growth, and accelerated cellular senescence. Pharmacological treatment with the PTEN (phosphatase and tensin homolog deleted on chromosome 10) inhibitor bpV (HOpic) increases Akt activity and improves multiple abnormalities in Zmpste24-deficient mice. These findings provide previously unidentified insights into the role of progerin in regulating the IGF-1R/Akt signaling in HGPS and might be useful for treating LMNA-associated progeroid disorders.

Automated summary

Progerin, a result of LMNA mutation, causes nuclear abnormalities and premature aging. Impaired IGF-1R/Akt signaling pathway leads to growth retardation and aging. Progerin mislocalizes outside of nucleus, interacts with IGF-1R, and down-regulates its expression, resulting in inhibited mitochondrial respiration, retarded cell growth, and accelerated senescence. PTEN inhibitor bpV (HOpic) increases Akt activity and improves abnormalities in progeria. These findings provide important insights into the role of Progerin in regulating IGF-1R/Akt signaling and have potential implications in treating LMNA-associated progeroid disorders.