Figure 4. The current clinically Based conceptualization of frailty (160, 450, 597).

Integrating the clinical manifestations of frailty with the hallmarks/pillars of aging results in the current conceptualization. Mitochondrial dysfunction, epigenetic alterations, and oxidative stress represent cellular/molecular factors that contribute to three central physiological systems that promote the Frailty Phenotype. The mitochondrial dysfunction accounts for a reduction in the efficiency of oxidative phosphorylation and a reduction in the energy production generating long-term exhaustion/fatigue. Epigenetic alterations such as DNA methylation and histone modifications are triggered by chronological aging and environmental factors, influencing pathways of health and longevity. Lastly, oxidative stress refers to excessive production of reactive oxygen species (ROS) that leads to cell and tissue damage. The metabolic system represents pathways that are centrally mediated by nutrient-sensing mechanisms, in which the glucose metabolism, insulin signaling cascade as well as AMP-activated protein kinase (AMPK) and nicotinamide adenine dinucleotide (NAD⁺) are pivotal players. The stress-response system is mainly influenced by the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system, and by the immune system. The cognitive and muscular declines, here illustrated by the neuromuscular category, are driven by tissue waste and dysfunction, leading to weight loss, weakness, fatigue, low activity, and slow gait at the organismal level. Illustrations were obtained on https://smart.servier.com, Published by LES LABORATORIES SERVIER, SAS.