Disentangling the body bass index, metabolic health and aging connection: weighty matters

As global populations age and the prevalence of obesity and metabolic disorders rises, understanding the complex relationships between body mass index (BMI), metabolic health, and aging becomes increasingly critical. This thesis sought to unravel these connections, focusing on how BMI and metabolic health are associated with biological aging and all-cause mortality while considering the nonlinear effects of BMI and age differences. By employing measures of biological aging - encompassing functional (functional aging Index, FAI), physiological (frailty index - FI), and cellular (epigenetic age acceleration - EAA) levels - we aimed to provide a comprehensive examination of the BMI, metabolic health, and biological aging connections.

Study I examined the independent and joint associations of midlife and late-life BMI and metabolic health status (MHS) assessments with risk of all-cause mortality. Data from 6,252 Swedish twins in midlife (65 years and below) and 6,215 in late life (over 65 years) were analyzed using Cox proportional hazards models. In the joint models, being metabolically unhealthy (MU) was consistently associated with increased mortality risk robust to BMI adjustments, while the mortality risk associated with BMI categories attenuated. In the interaction models, MU with obesity in midlife and across all BMI categories in late life was associated with higher mortality risk than metabolically healthy normal weight (MHN). Conversely, metabolically healthy with overweight (MHOw) or obesity in midlife and late life was not associated with higher mortality risks. In fact, late-life MHOw was associated with a lower mortality risk compared to MHN. These findings suggest that MHS plays a more significant role than BMI in predicting mortality risk.

Study II investigated how BMI and MHS jointly associate with biological aging, measured by FAI and FI, and whether these associations varied by chronological age. A cross-sectional analysis of 1,825 Swedish twins using mixed-effects linear models revealed a U-shaped association between BMI and FAI, where low and high BMI were associated with higher biological aging. MU was also associated with higher FAI. Significant three-way interactions between BMI, MHS, and chronological age on FI prompted the stratification of the analysis by age: below 65, 65 to 85, and over 85 years. In these groups, low BMI, high BMI and MU were consistently associated with greater FI, with significant modifications by MU and chronological age in the 65 to 85 and over 85 groups, respectively. This study highlights a complex interplay between BMI, MHS, and chronological age. Low BMI, high BMI, and MU were associated with higher biological aging, indicating their potential contribution to age acceleration.

Study III explored if biological aging, measured by EAA, mediates the BMI- mortality relationship. Using data from 3,840 participants in the U.S. Health and Retirement Study, a nonlinear association was found: both low and high BMI were associated with increased EAA and shorter life expectancy. Mediation analysis showed that high BMI's association with shorter life expectancy was strongly mediated by EAA, supporting the hypothesis that obesity accelerates biological aging. In contrast, the association of low BMI with shorter life expectancy was mainly driven by direct effects rather than mediation through biological aging.

Study IV analyzed the bidirectional relationship between change in BMI and biological aging, measured by FAI and FI, in 1,902-1,976 Swedish twins aged 60 to 91.9, using dual change score models. The age trajectory of BMI followed an almost linear, declining pattern, whereas FAI and FI exhibited exponentially increasing trends. The study found a unidirectional relationship where higher FAI predicted a steeper BMI decline. In contrast, the BMI-FI relationship was bidirectional - higher BMI predicted increased FI and higher FI contributed to a steeper BMI decline.

These findings underscore the complex nature of the relationships between BMI, metabolic health, and aging, revealing the distinct influences of high BMI, low BMI, and metabolic health on biological aging and life expectancy. Together, these results emphasized the importance of integrating BMI, metabolic health, and biological aging into the assessment of late-life health, offering new insights into how these factors may converge to potentially shape the aging process and survival.

Keywords: aging, all-cause mortality, biological aging, body mass index, frailty, epigenetic age, metabolic health, obesity, mediation analysis, dual change score models

List of scientific papers

I. Ler P, Li X, Hassing LB, Reynolds CA, Finkel D, Karlsson IK, Dahl Aslan AK. Independent and joint effects of body mass index and metabolic health in mid- and late-life on all-cause mortality: a cohort study from the Swedish Twin Registry with a mean follow-up of 13 years. BMC Public Health. 2022;22(1):718. https://doi.org/10.1186/s12889-022-13082-3

II. Ler P, Ploner A, Finkel D, Reynolds CA, Zhan Y, Jylhävä J, Dahl Aslan AK, Karlsson IK. Interplay of body mass index and metabolic syndrome: association with physiological age from midlife to late- life. Geroscience. 2024;46(2):2605 - 2617. https://doi.org/10.1007/s11357-023-01032-9

III. Ler P, Jylhava J, Finkel D, Aslan Dahl AK, Ploner A, Karlsson IK. Does biological aging mediate the association between body mass index and survival among older adults? [Manuscript]

IV. Ler P, Mak JKL, Reynolds CA, Ploner A, Pedersen NL, Jylhävä J, Aslan Dahl AK, Finkel D, Karlsson IK. Longitudinal study of body mass index and biological aging: investigating the temporal dynamics. [Submitted]

Paper I @ Ler et al., 2022. Published by Springer Nature. This is an open-access article under the terms of CC BY-NC-CD or CC BY 4.0.

Paper II @ Ler et al., 2022. Published by Springer Nature. This is an open-access article under the terms of CC BY 4.0.