Risk factors for frailty in aging: from sex and gender and genetic determinants to the exposome

Frailty is a multidimensional geriatric syndrome of loss of physical and cognitive reserves and increased vulnerability that leads to an increased risk of adverse health outcomes. Although age is recognized as the strongest driver of frailty, dynamic nature of this syndrome enables bidirectional changes in the frailty continuum, implying that this syndrome might be prevented and even reverted when detected in early stages. The pathophysiological changes underlying frailty syndrome are initiated by prolonged exposure to a series of risk factors, in a downward spiral of events leading to manifestation of frailty-associated symptomatology. This review is focused on key factors influencing frailty onset. Accumulated evidence demonstrates that the pathway for frailty development starts in early life and might be influenced by (1) sex/gender-related factors, (2) behavioral and social differences, (3) genetic load, and (4) a series of modifiable risk factors including lifestyle and consumption habits, environmental pollution, occupational conditions, as well as other exposures experienced throughout life. In addition, psychosocial and economic factors such as depression, cognitive decline, and limited access to healthcare resources, which influence cognitive reserve, play a critical role in accelerating physiological vulnerability and functional decline, thereby facilitating transition from robustness to frailty. Advancing our knowledge on the risk factors associated with frailty is crucial to implementing effective preventive measures, particularly when the detrimental effects of these factors may be corrected or mitigated through targeted interventions.