LAUSR

The term “resilience” has existed for many decades and defines the ability to bounce back after a stressful encounter or adversity in life (1). Resilience in older adults has gained increasing attention in recent years, and many countries are trying to build resilience at individual, community, and system levels, especially after the Covid-19 pandemic (2, 3). Resilience is dynamic and multidimensional, frequently distinguished into physical resilience and psychological (mental and/or cognitive) resilience (4, 5). Physical resilience is defined as “the ability to recover or optimize function in the face of age-related losses or disease” and is one of the top research priorities for the US National Institute on Aging (1, 6, 7). Declining resilience is considered a marker of accelerated aging and a risk factor for incident frailty. It is associated with adverse functional outcomes in later life. There are multiple risk and protective factors described with the mnemonic “PURPOSE OF LIFE” (Figure 1) (8). Due to its dynamic and multidimensional nature, resilience is a difficult construct to measure (6, 8, 9). There is no mechanism in place to predict dose-response and tipping point for adverse outcomes (10). The response to stress and recovery is unpredictable due to the co-occurrence of chronic diseases and age-related declines in multiple physiological systems. A stressor can act alone (e.g., bedrest causing muscle wasting and delirium) or in combination with other multiple factors (e.g., osteoarthritis, sedatives and antihypertensives causing falls and fractures) in the onset of adverse outcomes. In addition, aging and resilience trajectories are determined by multiple interacting factors (including environment, exposure to toxins across lifespan, comorbidities, polypharmacy, genetics, lifestyle), all of which contribute to immune-senescence and decline in physical and biological reserves (11, 12). A recent study described four distinct trajectories of recovery in nursing home residents admitted to the emergency department, where those with good baseline function had better post-discharge functional recovery (13). Static evaluations, such as disease burden, geriatric assessment, frailty, gait speed and/or handgrip strength, may predict adverse outcomes but not sufficiently the capacity to recover. Multiple longitudinal assessments across the health trajectory may better estimate such capacity (9, 10). While it may be easier to measure physical resilience, this is often inseparable in real life from psychological resilience. To date, there is no scoring system incorporating both measures (14). Adaptations to adversity are influenced by age, gender, ethnicity, generation differences, cultural variation, type and intensity of the stressor, and intended outcome (15-17). The New Mexico Aging Process Study focused on chronological age where the rate of decline in walking speed and cognition was much higher, and recovery was much lower in the oldold compared with the young-old (18). Age-related changes occur at the cellular, physiological system, and clinical level. A decline in resilience is possibly mediated through the dysregulated immune system, insulin resistance, mitochondrial dysfunction, impaired autophagy and endoplasmic reticulum stress, epigenetics, autonomic and vascular dysfunction (11, 19, 20). Similar dysfunction contributes to the development of frailty syndrome. One may argue that changes at the cellular level may be general changes with aging and not specific to physical resilience as a clinical phenotype (21). There are emerging studies exploring the contribution of biological mechanisms of aging to resilience trajectory in older adults. Higher Growth Differentiation Factor-15 and Tumor Necrosis Factor Receptor-1 levels are associated with frailty, decline in intrinsic capacity, mitochondrial dysfunction, and poor recovery after acute illness (20, 22, 23). In a group of patients with hip fracture, 27% of the differences in physical resilience or expected differential recovery could be explained by biomarkers (24). Various ongoing trials evaluate geroscience-based interventions, including pharmacotherapy and vaccinations on resilience trajectory (such as metformin, resveratrol, omega-3, senolytics e.g., Dasatinib and Quertin, and low-dose mammalian Target of Rapamycin [mTOR] inhibitors) (25-28). Frailty is a state of declining physiological reserves, and physical resilience can be described as the ability to mobilize reserves. While static measures, such as gait speed and handgrip strength can be used as a surrogate for underlying reserve, the intrinsic capacity framework proposed by the World Health Organization (WHO; including the assessment of cognition, vitality, mobility, psychological and sensory functions) has shown to predict functional recovery after exposure to adversity (29, 30). Intrinsic capacity can be considered an indirect measure of physical resilience through the physiologic reserve concept (31). The INSPIRE integrated Resilience and the Future