A new frontier in anti-aging: hepatic klotho and molecular targets

Öz

Aging is a complex biological process characterized by the progressive accumulation of molecular and cellular damage, leading to a decline in homeostatic capacity and increased susceptibility to disease. The liver plays a central role in systemic aging due to its key functions in metabolism, detoxification, and immune regulation. Liver aging is driven by interconnected mechanisms inclu-ding cellular senescence, chronic low-grade inflammation (inflammaging), and mitochondrial dys-function, all of which contribute to a decline in hepatic function. Senescent hepatocytes secrete pro-inflammatory factors that enter systemic circulation and promote multi-organ aging. In recent years, the klotho protein family has emerged as a critical regulator of aging. Circulating α-Klotho exerts anti-inflammatory, antioxidant, and anti-fibrotic effects, whereas β-Klotho plays a pivotal role in hepatic metabolic regulation through FGF19 and FGF21 signaling pathways. Klotho has been shown to modulate key signaling pathways associated with aging, including TGF-β, NF-κB, IGF-1, and Wnt/β-catenin, thereby attenuating age-related pathological processes. This review provides a comprehensive overview of the role of the liver in aging and the mechanistic effects of klotho pro-teins, highlighting their potential as therapeutic targets in liver aging and associated metabolic disorders.

Anahtar Kelimeler

• Liver
• Klotho Proteins
• Aging
• Inflammation

Yaşlanma karşıtı yeni bir ufuk: karaciğerde klotho ve moleküler hedefler

Öz

Yaşlanma, moleküler ve hücresel düzeyde biriken hasarın organizmanın homeostatik kapasitesini azaltmasıyla karakterize karmaşık bir süreçtir. Bu süreçte karaciğer, metabolizma, detoksifikasyon ve immün yanıtın düzenlenmesindeki merkezi rolü nedeniyle sistemik yaşlanmanın önemli bir belirleyicisi olarak öne çıkmaktadır. Karaciğer yaşlanması; hücresel yaşlanma kronik inflamasyon ve mitokondriyal disfonksiyon gibi birbiriyle ilişkili mekanizmalar aracılığıyla gelişmekte ve or-ganın fonksiyonel kapasitesinde azalmaya yol açmaktadır. Yaşlanmış hücrelerin salgıladığı pro-inflamatuvar faktörler sistemik dolaşıma katılarak çoklu organ yaşlanmasını hızlandırmaktadır. Son yıllarda klotho protein ailesi, yaşlanma biyolojisinde önemli bir düzenleyici olarak dikkat çekmek-tedir. α-Klotho’nun dolaşımdaki formu anti-inflamatuvar, antioksidan ve anti-fibrotik etkiler göste-rirken; β-Klotho karaciğerde FGF19 ve FGF21 aracılığıyla metabolik homeostazın düzenlenmesin-de kritik rol oynamaktadır. Klothonun TGF-β, NF-κB, IGF-1 ve Wnt/β-katenin gibi temel sinyal yolaklarını düzenleyerek yaşlanma ile ilişkili süreçleri baskıladığı gösterilmiştir. Bu derlemede, karaciğerin yaşlanma sürecindeki rolü ve klotho proteinlerinin bu süreçteki etkileri güncel literatür ışığında ele alınmış; klothonun karaciğer yaşlanması ve ilişkili metabolik hastalıklarda potansiyel bir terapötik hedef olabileceği vurgulanmıştır.

Anahtar Kelimeler

• Karaciğer
• Klotho Proteinleri
• Yaşlanma
• İnflamasyon

Kaynakça

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