Zhuowei Yu,1– 3 Madia Lozupone,4 Jie Chen,2,3 Zhijun Bao,1– 3 Qingwei Ruan,1,2 Francesco Panza5 

1Laboratory of Aging, Anti-Aging & Cognitive Performance, Shanghai Institute of Geriatrics and Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Clinical Geriatrics, Shanghai Institute of Geriatrics and Gerontology, Huadong hospital affiliated to Shanghai Medical college, Fudan University, Shanghai, People’s Republic of China; 3Department of Geriatrics, Huadong Hospital affiliated to Fudan University, Shanghai, People’s Republic of China; 4Department of Translational Biomedicine and Neuroscience “DiBraiN”, University of Bari Aldo Moro, Bari, Italy; 5Department of Interdisciplinary Medicine, Medical Clinic, and Geriatrics “Cesare Frugoni”, University of Bari Aldo Moro, Bari, Italy

Correspondence: Qingwei Ruan, Laboratory of Aging, Anti-aging & Cognitive Performance, Shanghai Institute of Geriatrics and Gerontology, Huadong Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Clinical Geriatrics, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China, Email 13661717346@163.com Francesco Panza, Department of Translational Biomedicine and Neuroscience “DiBraiN”, University of Bari g section. Aldo Moro, Bari, Italy, Unit of Research Methodology and Data Sciences for Population Health, National Institute of Gastroenterology “Saverio de Bellis” Research Hospital, Castellana Grotte, Bari, Italy, Email f_panza@hotmail.com

Abstract: The assessment and management of two function-centered clinical care models, frailty and intrinsic capacity decline have been proposed to achieve healthy aging. To implement these two care models, several different guidelines have been advocated by different health organizations, which has resulted in confusion and cost-ineffective results in healthcare practice. Although there are various operational definitions and screening tools of frailty, the most accepted operational definitions are based on the recognition of frailty phenotypes or deficit accumulation-based frailty indexes. Intrinsic capacity, referred to as the total physical and mental capacities for individual to undertake daily tasks in everyday life, is another care model, including five domains. Similar or identical instruments have been used to assess frailty and intrinsic capacity. In the present narrative review, we outlined the biological rationale for integrating intrinsic capacity into frailty models and highlighted the hierarchical and energy-dependent order of the intrinsic capacity domains. The vitality domain or energy metabolism-related capacity, is the highest order dimension and the basis of other intrinsic capacity domains. Vitality vulnerability manifests as a pre-frailty status in function-centered healthy aging. We provided a conceptual framework of frailty phenotypes and frailty indexes based on the hierarchical and energy-dependent order of the intrinsic capacity domains, particularly vitality capacity. To facilitate the clinical translation of the framework, some potential energy metabolism-related biomarkers have also been proposed as critical components for assessing and screening vitality capacity in older age. The integrating framework not only provides testable theoretical hypotheses, particularly about vitality as a foundational element in aging, but could serve as a starting point for further research to unravel the mechanisms of frailty. It also improves cost-effectiveness for optimizing aging interventions in clinical healthcare and public health policies of healthy aging.

Keywords: frailty, vitality, intrinsic capacity, frailty phenotype, frailty index, biomarkers