Exercise-Induced Mitochondrial Stress and cGAS-STING Signaling in Healthy Aging

Abstract

Purpose: This review aims to examine the potential relationship between exercise-induced mitochondrial adaptation, mitochondrial DNA (mtDNA) homeostasis, and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling during brain aging. Particular emphasis is placed on the role of mitochondrial quality control and the proposed mitochondrial stress-resolution threshold as a potential mechanism linking exercise with healthy brain aging and longevity.

Method: A focused narrative review was conducted by evaluating human, animal, and in vitro/cellular studies, together with relevant review articles, addressing exercise-induced mitochondrial adaptation, mitochondrial quality control, mtDNA homeostasis, cGAS-STING signaling, neuroinflammation, and brain aging. Evidence from different biological levels was narratively synthesized to examine the potential mechanistic relationship between exercise-induced mitochondrial stress and age-related innate immune activation.

Results: Exercise-induced mitochondrial stress can promote mitochondrial biogenesis, turnover, antioxidant defense, and mitochondrial resilience. Aging may impair these adaptive processes and increase mitochondrial dysfunction and mtDNA dysregulation. Cytosolic mtDNA can activate cGAS-STING signaling, while emerging evidence links this pathway to microglial activation and neuroinflammation during brain aging. However, direct evidence connecting exercise with modulation of the brain mtDNA-cGAS-STING axis remains limited.

Conclusion: Exercise may influence age-related neuroinflammation primarily by improving mitochondrial quality control and maintaining mtDNA homeostasis rather than through direct suppression of cGAS-STING signaling. The proposed mitochondrial stress-resolution threshold provides a testable framework linking exercise dose, mitochondrial adaptation, mtDNA regulation, innate immune signaling, and healthy brain aging.

Keywords

• Exercise
• Aging
• Mitochondrial Dysfunction
• Mitochondrial DNA
• cGAS-STING
• Neuroinflammation

Sağlıklı Yaşlanmada Egzersize Bağlı Mitokondriyal Stres ve cGAS-STING Sinyalizasyonu

Abstract

Amaç: Bu derlemenin amacı, egzersize bağlı mitokondriyal adaptasyon, mitokondriyal DNA (mtDNA) homeostazı ve beyin yaşlanması sırasında siklik GMP-AMP sentaz–interferon genlerinin (cGAS-STING) uyarıcısı sinyal yolakları arasındaki potansiyel ilişkiyi incelemektir. Özellikle, mitokondriyal kalite kontrolünün ve önerilen mitokondriyal stres-çözülme eşiğinin egzersiz ile sağlıklı beyin yaşlanması ve uzun yaşam arasındaki potansiyel mekanizmadaki rolü ele alınmıştır.

Yöntem: Egzersize bağlı mitokondriyal adaptasyon, mitokondriyal kalite kontrolü, mtDNA homeostazı, cGAS-STING sinyalizasyonu, nöroinflamasyon ve beyin yaşlanmasını ele alan insan, hayvan ve in vitro/hücresel çalışmalar ile ilgili derleme makaleleri değerlendirilerek odaklanmış bir derleme gerçekleştirilmiştir. Farklı biyolojik düzeylerden elde edilen kanıtlar, egzersize bağlı mitokondriyal stres ile yaşa bağlı doğuştan bağışıklık aktivasyonu arasındaki potansiyel mekanistik ilişkiyi incelemek amacıyla sentezlenmiştir.

Bulgular: Egzersize bağlı mitokondriyal stres; mitokondriyal biyogenez, mitokondriyal dönüşüm, antioksidan savunma ve mitokondriyal dayanıklılığı destekleyebilir. Yaşlanma bu adaptif süreçleri bozarak mitokondriyal disfonksiyon ve mtDNA düzensizliğini artırabilir. Sitozolik mtDNA, cGAS-STING sinyal yolunu aktive edebilirken, gelişmekte olan kanıtlar bu yolun beyin yaşlanması sırasında mikroglial aktivasyon ve nöroinflamasyon ile ilişkili olduğunu göstermektedir. Bununla birlikte, egzersizin beyindeki mtDNA-cGAS-STING eksenini modüle ettiğini doğrudan gösteren kanıtlar halen sınırlıdır.

Sonuç: Egzersiz, cGAS-STING sinyalizasyonunu doğrudan baskılamaktan ziyade mitokondriyal kalite kontrolünü iyileştirerek ve mtDNA homeostazını koruyarak yaşlanmaya bağlı nöroinflamasyonu etkileyebilir. Önerilen mitokondriyal stres-çözülme eşiği modeli; egzersiz dozu, mitokondriyal adaptasyon, mtDNA düzenlenmesi, doğuştan bağışıklık sinyalizasyonu ve sağlıklı beyin yaşlanması arasındaki ilişkiyi açıklamak için test edilebilir bir çerçeve sunmaktadır.

Keywords

• Egzersiz
• Yaşlanma
• Mitokondriyal Disfonksiyon
• Mitokondriyal DNA
• cGAS-STING
• Nöroinflamasyon

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