Associations of a Plant-centered Diet and Lung Function Decline across Early to Mid-Adulthood: The CARDIA Lung Study

Background Lung function throughout adulthood predicts morbidity and mortality even among adults without chronic respiratory disease. Diet quality may represent a modifiable risk factor for lung function impairment later in life. We investigated associations between nutritionally-rich plant-centered diet and lung function decline across early and middle adulthood from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Methods Diet was assessed at baseline and years 7 and 20 of follow-up using the validated CARDIA diet history questionnaire. Plant-centered diet quality was scored using the validated A Priori Diet Quality Score (APDQS), which weights food groups to measure adherence to a nutritionally-rich plant-centered diet 1 to 5 points for 20 beneficially rated foods and 5 to 1 points for 13 adversely rated foods. Scores were cumulatively averaged over follow-up and categorized into quintiles. The primary outcome was lung function decline, including forced expiratory volume in 1 second (FEV1) and functional vital capacity (FVC), measured at years 0, 2, 5, 10, 20, and 30. We estimated the association of APDQS with annual pulmonary function changes in a repeated measures regression model, adjusting for clinically relevant covariates. Results The study included 3,787 Black and White men and women aged 18–30 in 1985–86 and followed for 30 years. In multivariable repeated measures regression models, individuals in the lowest APDQS quintile (poorest diet) had declines in FEV1 that were 1.6 ml/year greater than individuals in the highest quintile (35.0 vs. 33.4 ml/year, ß±SE per 1 SD change APDQS 0.94 ± 0.36, p = 0.009). Additionally, declines in FVC were 2.4 ml/year greater in the lowest APDQS quintile than those in the highest quintile (37.0 vs 34.6 ml/year, ß±SE per 1 SD change APDQS 1.71 ± 0.46, p < 0.001). The association was not different between never and ever smokers (pint = 0.07 for FVC and 0.32 for FEV1). In sensitivity analyses where current asthma diagnosis and cardiorespiratory fitness were further adjusted, results remained similar. Conclusions In this 30-year longitudinal cohort study, long-term adherence to a nutritionally-rich plant-centered diet was associated with slower decline in lung function, highlighting diet quality as a potential treatable trait supporting long-term lung health.


Abstract Background
Lung function throughout adulthood predicts morbidity and mortality even among adults without chronic respiratory disease. Diet quality may represent a modi able risk factor for lung function impairment later in life. We investigated associations between nutritionally-rich plant-centered diet and lung function decline across early and middle adulthood from the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Methods
Diet was assessed at baseline and years 7 and 20 of follow-up using the validated CARDIA diet history questionnaire. Plant-centered diet quality was scored using the validated A Priori Diet Quality Score (APDQS), which weights food groups to measure adherence to a nutritionally-rich plant-centered diet 1 to 5 points for 20 bene cially rated foods and 5 to 1 points for 13 adversely rated foods. Scores were cumulatively averaged over follow-up and categorized into quintiles. The primary outcome was lung function decline, including forced expiratory volume in 1 second (FEV 1 ) and functional vital capacity (FVC), measured at years 0, 2, 5, 10, 20, and 30. We estimated the association of APDQS with annual pulmonary function changes in a repeated measures regression model, adjusting for clinically relevant covariates.

Results
The study included 3,787 Black and White men and women aged 18-30 in 1985-86 and followed for 30 years. In multivariable repeated measures regression models, individuals in the lowest APDQS quintile (poorest diet) had declines in FEV 1 that were 1.6 ml/year greater than individuals in the highest quintile (35.0 vs. 33.4 ml/year, ß±SE per 1 SD change APDQS 0.94 ± 0.36, p = 0.009). Additionally, declines in FVC were 2.4 ml/year greater in the lowest APDQS quintile than those in the highest quintile (37.0 vs 34.6 ml/year, ß±SE per 1 SD change APDQS 1.71 ± 0.46, p < 0.001). The association was not different between never and ever smokers (p int = 0.07 for FVC and 0.32 for FEV 1 ). In sensitivity analyses where current asthma diagnosis and cardiorespiratory tness were further adjusted, results remained similar.

Conclusions
In this 30-year longitudinal cohort study, long-term adherence to a nutritionally-rich plant-centered diet was associated with slower decline in lung function, highlighting diet quality as a potential treatable trait supporting long-term lung health.

Background
Lung function is an important predictor of morbidity and mortality even among adults without chronic respiratory disease (1,2). Across the general population, lifetime lung function trajectories have been categorized as persistently poor, worsening, preserved impaired, preserved good, or preserved ideal lung health (3). As lung function trajectory over the lifespan is a major determinant of the development of future chronic lung disease(3), the early identi cation of modi able risk factors is critical.
Emerging evidence suggests that high quality plant-centered diets are associated with improved respiratory health. For example, a diet high in fruits and vegetables has been demonstrated to be associated with improved lung function among individuals without respiratory disease (4). In another study of smokers without respiratory disease, greater adherence to a Western diet pattern, with higher consumption of red and cured meats and sweets, and lower consumption of fruits, vegetables, legumes, and sh, was associated with increased risk of impaired lung function (5). Diets high in fruits and vegetables were associated cross-sectionally with a lower prevalence of current wheeze in children(6) and higher FEV 1 (4) in adults. In a meta-analysis of mostly cross-sectional studies of fruit and vegetable intake on prevalent wheeze and asthma severity, fruit intake was negatively associated with prevalent wheeze and asthma severity, and vegetable intake was negatively associated with prevalent asthma (7). While there is an established relationship between long-term consumption of a nutritionally-rich plantcentered diet and cardiovascular mortality throughout adulthood(8), its longitudinal association with lung health has not been explored. To address this gap, we tested the hypothesis that the consumption of a nutritionally-rich plant-centered dietary pattern is associated with improved lung function trajectory across early and middle adulthood among participants from The Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Methods
Study design, setting and participants CARDIA is a prospective multi-center cohort study of 5,115 young adults from four United States cities: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota, and Oakland, California. Participants were 18-30 years old at baseline and were followed for 30 years with 71% retention at year 30. There were no exclusion criteria. Participants were randomly selected and recruited by telephone from census tracts in Minneapolis and Chicago, by telephone exchanges within the Birmingham city limit, and from lists of the Kaiser-Permanente Health Plan membership in Oakland and Berkeley (9). The study protocol has been published elsewhere (10).

Assessment Of Plant-centered Diet Quality
Diet was assessed at years 0, 7, and 20 using the validated interviewer-administered CARDIA diet history. Adherence to a nutritionally-rich plant-centered diet was captured using the validated A Priori Diet Quality Score (APDQS), which weights 46 food groups rated a priori as bene cial, neutral, or adverse on the basis of current understanding of their known associations with cardiovascular risk. Higher scores, indicating better diet quality, are driven mainly by intake of nutritionally-rich plant foods. Plant-based foods such as fruits, avocado, green and yellow vegetables, and whole grains contribute to a higher score and are scored positively, whereas negatively scored foods include re ned carbohydrates, red meats, processed meats, soft drinks, and high-fat dairy products. While the main contributors to a higher score are plant foods, certain animal products, including nonfried sh and poultry, also contribute, in recognition of the nutritious value of some non-plant-based foods. Details of the APDQS have been previously described (11).

Assessment Of Outcome Variables
The primary outcome was lung function, including forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC ratio. Lung function was measured at years 0, 2, 5, 10, 20, and 30 using standard procedures per European Respiratory Society and American Thoracic Society guidelines (12). Extensive quality control of the measurement devices was carried out during each exam as well as between examinations, using waveform analysis to check comparability when a different device was used in one exam than in another (13). Lung function decline was calculated by subtracting spirometry parameters at year 30 from those parameters at each participant's estimated peak lung function and dividing by the difference in years, as has been done previously in this cohort (14). If year 30 data were not available, year 20 data were used. Obstructive lung physiology, de ned as a ratio of FEV 1 to FVC < 0.7, was a secondary outcome assessed only in smokers.

Other Covariates
Demographics and clinical data included age (years), sex, maximal educational attainment (highest grade completed), race (Black, White), cigarette smoking and pack year history, height, weight, eld center, and total daily energy intake. Smoking status was assessed yearly. Previous studies of CARDIA participants have shown strong correlation between self-reported cigarette smoking and year 0 cotinine measurements (15). Cardiorespiratory tness (assessed as treadmill time in seconds at years 0, 7, and 20) and history of asthma were included in sensitivity analyses.

Statistical analysis
Baseline descriptive statistics were reported according to quintiles of APDQS. We used a mixed linear model (SAS PROC MIXED) to evaluate associations between APDQS averaged over follow-up and pulmonary function changes, including FEV 1 , FVC, and FEV 1 /FVC. This averaging approach, where dietary data is remeasured or carried forward and serially averaged up to and including each measurement of spirometry, allows for minimization of random within-person error, better re ects the cumulative, long-term effect of diet, and preserves sample size. Annual pulmonary function changes, including FEV 1 , FVC and FEV 1 /FVC, were estimated per one standard deviation change in APDQS (SD = 13 points) in repeated measures regression models, adjusting for sex, education, race, peak lung function, smoking status (measured at every annual follow-up), pack-year history (years 0, 2, 5, 7, 10, 15, and 20), height, BMI, total energy intake (averaged over the time period prior to spirometry), and site. We adjusted models for age squared as prior work has shown lung function to have a quadratic decline(16). As a sensitivity analysis, we additionally adjusted for current asthma and cardiorespiratory tness, which we conceptualized as confounders with in uence on both diet and lung function. Cardiorespiratory tness has been previously shown to be associated with lung function trajectory (17). If data on exposures and outcomes of interest were missing, participants were excluded. For continuous covariates (height and cardiorespiratory tness), mean values were assigned if data were missing. To account for patients who had missing spirometry because of death before year 30, we evaluated the slope of FEV 1 % predicted among participants who died before year 30 by adding the interaction of death status with time to the main model.
Given that smokers may have important differences in both dietary pattern and susceptibility to environmental in uences on lung function, we also tested for an interaction between smoking status and diet.
For the outcome of air ow obstruction, Cox proportional-hazards regression models were created for incident obstructive lung physiology according to quintiles of the APDQS. Hazard ratios were adjusted for the same covariates.
Lifetime trajectories of percent predicted lung function were generated using a group-based trajectory modeling approach (SAS PROC TRAJ), previously described by Washko et al. (3), which ts a mixture model via maximum likelihood. Participants were assigned a priori to one of the ve trajectories derived from the model as persistently poor, worsening, preserved impaired, preserved good, or preserved ideal lung health(3), then strati ed by APDQS quintiles.
We further investigated the relationships of APDQS with lung function measurements at each exam cross-sectionally using a linear mixed effect approach with repeated APDQS assessments and repeated covariate measurements. The models were tted to the repeated measures of lung function, with random intercepts and xed slopes of APDQS×time interaction using the same covariates as the primary model. All covariates were time-varying except for race, sex, and height.
For the outcome of air ow obstruction, Cox proportional-hazards regression models were created for incident obstructive lung physiology according to quintiles of the APDQS. Hazard ratios were adjusted for the same covariates. All analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC).

Study Population
A total of 3,787 participants were included in this study, as shown in Table 1. We excluded participants who withdrew consent (n = 1), lacked outcome measures (n = 1,243), or lacked exposure measures at Y0 (n = 132), leaving 3787 participants as a nal sample. Ten participants (0.3%) and 24 (0.6%) were Page 7/22 missing data on height and cardiorespiratory tness, respectively. At enrollment, compared with the participants in the lowest APDQS quintile, those in the highest quintile were older, were more likely to be female and White, had higher maximal educational attainment, lower BMI, and lower energy intake, were less likely to be a current smoker, and had higher baseline FEV 1

Lung Function Trajectory Groups
The groups of participants with preserved good and preserved ideal lung health had a greater proportion of highest quintile APDQS (21% and 22%, respectively) than the group with persistently poor lung health (12%), whereas the group with persistently poor lung health had the highest proportion (34%) of lowest quintile APDQS (Fig. 1).

APDQS and Lung Function Decline
In multivariable repeated measures regression models, there were signi cant associations between APDQS and annual changes in both FVC and FEV 1 ( Table 2). Individuals in the lowest (poorest diet quality) APDQS quintile had declines in FEV 1 that were 1.6 ml/year greater than individuals in the highest (best diet quality) quintile (35.0 vs. 33.4 ml/year; ß±SE per 1 SD change APDQS, 0.94 ± 0.36, p = 0.009) and declines in FVC that were 2.4 ml/year greater than those in the highest quintile (37.0 vs 34.6 ml/year; ß±SE per 1 SD change APDQS, 1.71 ± 0.46, p < 0.001). APDQS was not signi cantly associated with FEV 1 /FVC. The association was not different between never and ever smokers (p int = 0.07 for FVC and 0.32 for FEV 1 ). In sensitivity analyses where current asthma diagnosis and cardiorespiratory tness were further adjusted, results remained similar. At cross-sectional analyses at each time point across young and middle adulthood, higher APDQS was associated with higher FEV 1 and FVC ( Fig. 2 and Table 3).   As expected, those with fewer FEV 1 measures had a higher death rate. In addition, those who died during follow-up had a faster decline in lung function than those who survived. Nevertheless, in a sensitivity analysis, accounting for those who died before year 30 and their trend in FEV 1 or FVC predicted did not substantially alter the associations between APDQS and change in FEV 1 or FVC (ß±SE 0.91 ± 0.36 (p = 0.01) and 1.67 ± 0.46 (p < 0.001), respectively).
Lastly, there was no signi cant difference in the development of incident obstructive lung physiology across quintiles of APDQS in any of the models (Table 4).

Discussion
In this 30-year follow-up longitudinal study, we found that a nutritionally-rich plant-centered diet was associated with signi cantly less decline in lung function, even after adjustment for demographic and lifestyle factors in uencing lung health. We found a difference of 1.6 ml/year decline in FEV 1 when comparing participants in the 1st and 5th quintiles of APDQS. Putting this into context, one cohort study estimated the excess FEV 1 decline from every 10 pack years of smoking at 2.5 ml/yr(18), while current asthma has been associated with excess FEV 1 decline of 3.7-9 ml/year(18-20). Importantly, smoking status did not signi cantly modify the bene ts of consuming a nutritionally-rich plant-centered diet.
Consistent with these ndings, a higher proportion of high quality APDQS was observed in participants with preserved good and preserved ideal lung health trajectories than in patients with worsening or persistently poor lung health. Consequently, consumption of a typical American diet that is nutrient poor and rich in processed, calorie-dense animal products may substantially contribute to the population burden of excess lung function decline and associated morbidity and mortality throughout adulthood. It is worth noting the possibility that higher lifetime lung function observed among those in the top quintiles of plant-centered diet intake may in part be a function of reaching and/or sustaining optimal peak lung health after adolescence, and hence may re ect nutritional exposures occurring in the prenatal or childhood life stages and altering respiratory programming (21). Research on critical windows is necessary to develop dietary recommendations for children and young adults to prevent adverse longterm respiratory outcomes.
Mechanistically, plant-centered diets rich in fruits and vegetables contain antioxidants (vitamin C, avonoids, and carotenoids), which attenuate oxidative stress and may play a role in the pathogenesis of COPD (22). In addition, dietary ber, a key component of plant-based foods, has been shown to attenuate in ammatory responses (23), possibly through alterations in the gut microbiome and increased production of anti-in ammatory metabolites such as short-chain fatty acids (24). In a study of mice exposed to cigarette smoke, a high ber diet decreased interleukin-6 and interferon-gamma in bronchoalveolar lavage and serum samples, attenuated development of emphysema, and was protective against alveolar destruction (25). An analysis of plant-based avonoids and age-related decline in lung function from the Veteran's Administration Normative Aging Study found that anthocyanins, a subclass of avonoids found primarily in berries, were strongly associated with less age-related decline in FEV 1 and FVC for the highest quartile of intake compared with the lowest(26).. On a micronutrient level, a nineyear longitudinal study of participants in Nottingham, England found that higher intake of vitamin Cabundant in fruits and vegetables -was associated with a lower rate of FEV 1 decline by 50.8 mL per 100 mg of vitamin C (27). Thus, individual components of a nutritionally-rich plant-centered diet, including vitamins, minerals, bers, and phytochemicals may work synergistically to provide bene cial effects on lung function (28).

Strengths and limitations
Our study has several important strengths. Follow-up was over an extended period, with excellent retention and repeated spirometry over 30 years, as well as repeated diet information collected through an interviewer-administered diet history. By capturing adults in early to middle adulthood, we gained insight into early in uences on lung function decline. The APDQS provides pragmatic, achievable pathways to healthy eating, reinforcing fruit and vegetable intake without excluding animal products. Smoking status was assessed annually with previous evaluations demonstrating a high degree of correlation between self-report of smoking status and cotinine concentrations (15).
There are a few limitations of the study worth noting. Residual confounding is impossible to eliminate, though we carefully adjusted for relevant covariates, including accounting for both the time-varying presence and extent of smoking behaviors. Diet questionnaires, while administered by trained interviewers, were ultimately self-reported and subject to recall bias. The CARDIA cohort comprised only White and Black participants, limiting generalizability to other races/ethnicities. The small number of years with complete diet data limits assessment of change in diet over time, which might in uence outcomes. The study had 71% retention at year 30, and participants with missing data may have been prognostically different. Participants for whom year 20 lung function data were used may not have had time to develop signi cant lung function decline, since lung function is usually maintained to around age 40; however, this would be expected to bias toward the null. Finally, the trajectory analysis is limited by its descriptive nature and smaller numbers of participants in the highest and lowest quintiles of APDQS.
Further analyses could elucidate which speci c foods contributed most to the primary outcome, the impact of dietary changes over the life course, and whether results differed by sex. Replication in an independent cohort would strengthen causal inferences. Since our study was not powered to determine the effect of plant-centered diet quality in smokers, future work should pay close attention to this vulnerable subgroup.

Conclusions
Although the absolute effect size of unhealthy diet on lung function (1.6 ml/year excess FEV 1 decline) appears modest, it is important to consider diet as a lifelong, modi able exposure. Together with efforts targeted at conventional risk factors for lung function decline such as smoking and poorly controlled chronic lung disease, public health initiatives emphasizing the importance of a nutritionally-rich, plantcentered diet early in adulthood may add to our arsenal of strategies to preserve lung health across the life course. Larger population-level analyses to con rm and expand upon these ndings are warranted. All participants provided written informed consent at all examinations, and research protocols were approved by institutional review boards at the CARDIA coordinating center and each eld center.
University of Alabama at Birmingham Institutional Review Board reviewed and approved the CARDIA study prior to data collection.

Consent for publication:
Not applicable Availability of data and materials: The data that support the ndings of this study are available from the CARDIA study, but restrictions apply to the availability of these data, which are not publicly available. Data are however available from the authors upon reasonable request with permission of the CARDIA investigators. More information is available at https://www.cardia.dopm.uab.edu/.
Jacobs have no interests to disclose. Jing Gennie Wang has received funding from the American Lung Association Early Career Investigator Award. George R. Washko reports serving on an advisory committee for Boehringer Ingelheim, CSL Behring, GlaxoSmithKline and Vertex; personal fees from Boehringer Ingelheim, CSL Behring, Janssen, Novartis, PulmonX and Vertex; serving on a data safety and monitoring board for PulmonX; received research support from Boehringer Ingelheim, BTG and Janssen, all outside the submitted work; has ownership and investment interest in Quantitative Image Solutions; and his spouse is an employee of Biogen. Ravi Kalhan reports receiving grant support, consulting fees, and lecture fees from Boehringer Ingelheim and GlaxoSmithKline, grant support from PneumRx/BTG and Spiration, grant support and consulting fees from Astra-Zeneca, and consulting fees from CVS Caremark, Aptus Health, Boston Scienti c, and Boston Consulting Group. Sonali Bose has received funding from the National Institutes of Health. She also receives research support from 4D Medical and the American Lung Association.

Authors' contributions:
RW was involved in conceptualization, methodology, visualization, writing of the original draft, and review & editing of the nal manuscript. EE was involved in writing of the original draft and review and editing of the manuscript. MKJ was involved in conceptualization, writing of the original draft and review and editing of the manuscript. YC performed data curation, formal analysis, methodology, and validation of the data. BL was involved in review and editing of the manuscript. CH contributed to conceptualization, project administration, supervision, validation, writing of the draft and review and editing of the manuscript. JGW was involved in writing of the original draft and review and editing of the manuscript. GRW was involved formal analysis of the data, methodology, writing of the original draft and review and editing of the manuscript. RK was involved in conceptualization, methodology, validation, and review and editing of the manuscript. DRJ contributed to conceptualization, methodology, validation, and review and editing of the manuscript. SB contributed to conceptualization, project administration, supervision, validation, writing of the original draft, and review and editing of the manuscript. Relative distribution of APDQS quintiles among different lung function trajectories (FEV 1 % predicted).
Only participants with year 30 data and at least one other timepoint (n=3097) were included to ensure that trajectories re ected lung function changes into middle age. Quintile 5 APDQS was more represented in participants with preserved ideal and preserved good lung health, whereas participants with persistently poor lung health were more likely to have scores in quintile 1. The median APDQS scores were 52, 59.7, 66, 72.5, and 82 for quintiles 1, 2, 3, 4, and 5 respectively.