The aging stress response

Abstract

Aging is the outcome of a balance between damage and repair. The rate of aging and the appearance of age-related pathology are modulated by stress response and repair pathways that gradually decline, including the proteostasis and DNA damage repair networks and mitochondrial respiratory metabolism. Highly conserved insulin/IGF-1, TOR, and sirtuin signaling pathways in turn control these critical cellular responses. The coordinated action of these signaling pathways maintains cellular and organismal homeostasis in the face of external perturbations, such as changes in nutrient availability, temperature, and oxygen level, as well as internal perturbations, such as protein misfolding and DNA damage. Studies in model organisms suggest that changes in signaling can augment these critical stress response systems, increasing life span and reducing age-related pathology. The systems biology of stress response signaling thus provides a new approach to the understanding and potential treatment of age-related diseases.

Figure 1

Age-related stress and disease. Aging is associated with mitochondrial dysfunction leading to reduced respiratory metabolism and increased generation of reactive oxygen species (ROS). Persistent DNA damage may arise from both increased oxidative damage and reduced efficiency of energy-intensive DNA repair, predisposing to apoptosis, senescence and inflammation. Aging is also associated with increased protein misfolding and aggregation in the cytoplasm, nucleus and endoplasmic reticulum. The various sites of age-related cellular damage and the physiological decline that ensues contribute to the pathogenesis of age-related diseases, including metabolic syndrome, inflammatory disorders, cancer, and neurodegenerative diseases.

Figure 2

Nutritional regulation of conserved signaling and stress response pathways. Dietary restriction extends lifespan and augments stress resistance in many species by altering cellular metabolism and mobilizing protective stress responses. Gene and protein networks that maintain mitochondrial function, genomic stability and proteostasis are coordinately regulated by insulin/IGF and TOR signaling, and modulated by sirtuins.