Adherence to Healthy Dietary Patterns and Risk of Premature Aging in Adult Survivors of Childhood Cancer in the St. Jude Lifetime Cohort Study

Abstract

Background:

Adult survivors of childhood cancer are at higher risk of premature aging compared to their cancer-free peers due to the cancer and its treatments. However, little is known about the effect of adherence to healthy dietary patterns on aging in childhood cancer survivors.

Methods:

We conducted a cross-sectional analysis of 3,322 participants (mean age 30.5, SD 8.4) from the St. Jude Lifetime Cohort Study. Diet was measured by a food frequency questionnaire and used to assess the Healthy Eating Index (HEI)-2015 and alternate Mediterranean diet (aMED) scores. Premature aging was assessed by the deficit accumulation index (DAI) and categorized into low, medium, and high risk. Multinomial logistic regressions adjusting for confounders were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs).

Results:

The mean (SD) HEI-2015 score was 60.0 (10.9) out of 100, and the aMED score was 4.2 (2.0) out of 9. Twenty (20%) and eight (8%) percent of survivors were in the medium and high DAI categories, respectively. Higher adherence to HEI-2015 (OR_{high vs. low}=0.80, 95% CI: 0.69–0.93, per 10-point increment) and aMED (OR_{high vs. low}=0.91, 95% CI: 0.84–0.98, per 1-point increment) were associated with a lower risk of premature aging. The associations remained consistent among survivors who received radiation or chemotherapy.

Conclusion:

Adherence to a healthy diet may contribute to reducing the premature aging risk in adult survivors of childhood cancer. Interventions that support healthy eating in this population could potentially have benefits for long-term health outcomes.

Precis:

Adherence to a healthy diet may contribute to reducing the premature aging risk in adult survivors of childhood cancer. Promoting a healthy diet is important for supporting healthy aging and improving long-term health outcomes in this vulnerable population.

INTRODUCTION

The number of childhood cancer survivors continues to grow and is estimated to approach 580,000 by 2040 in the US.¹ Advances in cancer diagnosis and treatment over the past decades have improved the life expectancy of childhood cancer survivors.² However, they are at higher risk for premature aging compared with their peers without a history of cancer.^3–5 Among survivors participating in the St. Jude Lifetime Cohort Study (SJLIFE), the prevalence of frailty in adult survivors of childhood cancer (mean age 34 years) was comparable to that typically seen in adults aged 65 years or older.⁶ Survivors of childhood acute lymphoblastic leukemia and neuroblastoma have also demonstrated early onset of cellular aging processes, frailty, and impaired physical functioning.^{7, 8} The excess risk of premature aging in childhood cancer survivors is in part due to the long-term effects of early-life treatments, such as chemotherapy and radiation therapy.^9–12 Given such a high burden of premature aging in childhood cancer survivors, it is necessary to identify risk factors, especially those that can be modified in this growing, vulnerable population.

Diet is a well-established modifiable risk factor of the process of aging.¹³ Dietary patterns, which consider the overall composition and interaction of different food groups and nutrients, reflect an individual’s eating habits. Studies have shown that dietary habits, such as the Mediterranean diet, the Dietary Approaches to Stop Hypertension, and the prudent diet, were associated with a lower risk of aging-related chronic diseases in both the general population and adult cancers survivors.^14–17 However, little is known about the effect of a healthy diet on aging in childhood cancer survivors, who are particularly vulnerable to premature aging.

In our previous study of childhood cancer survivors, we found that certain individual foods and nutrients, such as sugar, and sugar-sweetened beverages, were associated with an increased risk of premature aging, whereas vegetables, nuts and seeds, and folate were associated with a lower risk.^{18, 19} We also found that a plant-based diet was associated with a lower risk of premature aging in adult survivors of childhood cancer.²⁰ However, it remains unclear whether adherence to broader, established dietary guidelines, such as the Dietary Guidelines for Americans and the Mediterranean diet, is beneficial in preventing premature aging. Therefore, we investigated the association of adherence to these healthy dietary patterns and risk of premature aging in adult survivors of childhood cancer.

METHODS

Participants

This analysis focused on childhood cancer survivors who were treated at St. Jude Children’s Research Hospital in Memphis, TN, survived at least 5 years after cancer diagnosis, and enrolled on SJLIFE. The details of the SJLIFE methods have been published elsewhere.²¹ Survivors completed at least one clinical assessment, which included surveys on health behaviors and psychosocial outcomes, a full medical history and physical examination, and comprehensive evaluations of organ function.^{10, 22} SJLIFE was approved by the St. Jude Institutional Review Board, and all participants provided informed consent.

For the present study, 4,079 adult survivors (aged ≥18 years) recruited from 2007–2017 met initial eligibility criteria for inclusion in the analysis. After excluding survivors who did not complete a food frequency questionnaire (FFQ, n=234), had inconsistent sex records (n=3), reported extreme energy intake (<600 or >5,000 kcal/day, n=232), were pregnant (n=42), and had insufficient data to calculate a Deficit Accumulation Index (DAI, n=246), a total of 3,322 cancer survivors were included in the analyses.

Dietary assessment

At study entry, diet over the past 1 year was assessed using a previously validated 110-item self-administered FFQ.²³ The FFQ assesses frequency of food intake from nine categories ranging from never to every day and the portion size of each food. Pictures of foods were provided to assist in portion size estimation. The FFQ also collected information on multivitamin and single supplement use. Nutrient intakes of reported foods were estimated based on the United States Department of Agriculture Food and Nutrient Database for Dietary studies. Food groups and their serving sizes (cup or ounce-equivalent) were defined by the MyPyramid Equivalents Database.

Healthy Eating Index–2015 (HEI-2015)

HEI-2015 assesses the adherence to the 2015–2020 Dietary Guidelines for Americans. It has nine dietary components that measure the adequacy of consumption (i.e., total fruit, whole fruit, total vegetables, greens and beans, whole grains, dairy, total protein foods, seafood and plant proteins, and fatty acid ratio) and four that measure foods that should be consumed in moderation (i.e., refined grains, sodium, added sugars, and saturated fats).²⁴ All components, except the fatty acid ratio, assess the intakes of food groups and nutrients on a density basis (i.e., per 1,000 kcal). Intakes between the minimum and maximum standards were scored proportionately. A total HEI score is the sum of each component score and ranges between 0 and 100. A higher score indicates better diet quality. A summary of the dietary components and standards for scoring is presented in Table S1.

Alternate Mediterranean Diet (aMED)

The aMED score is based on the Mediterranean diet score, modified for use in an American population. The score includes nine dietary components – vegetables (excluding potatoes), legumes, fruits, nuts, whole grains, fish, ratio of monounsaturated fatty acids to saturated fatty acids, red and processed meats, and alcohol. One point to each component, except for meat and alcohol, was assigned if an intake was above the median value of the energy-adjusted intake in the cohort. For meat, one point was assigned for intake less than the median. For alcohol, one point was assigned for consumption of 5–15 g/day for women and 10–25 g/day for men. A total aMED score is a sum of each component score, ranging from 0 to 9. A higher score reflects greater adherence to the Mediterranean diet (Table S1).

Deficit Accumulation Index

Deficit accumulation index (DAI) is a proxy measure of premature aging based on 45 aging-related health deficits including physical and psychosocial functions, activities of daily living, and health conditions in the questionnaires, comprehensive clinical and physical examinations, and medical records at baseline (Table S2).²⁵ In this study, the DAI was calculated from the same SJLIFE visit in which the diet was assessed. Each deficit was scored from 0 (absent) to 1 (present and/or most severe), summed across the items and divided by the total number of items available (Table S2). Thus, the DAI (range 0–1) was the proportion of deficits out of up to 44 items. DAI was categorized into low (DAI 0 to <0.2), medium (DAI 0.2 to <0.35), and high (DAI ≥0.35), which were associated with increased mortality and epigenetic age acceleration assessed by DNA methylation in the SJLIFE.^{25, 26} Survivors missing >10% of items were excluded from the DAI assessment.

Sociodemographic, health, and lifestyle factors

Survivors completed questionnaires that collected information on age, sex, race/ethnicity, education, other sociodemographics (e.g., income and marital status), and health behaviors (e.g., smoking, physical activity) at baseline. Body weight and height were measured by trained examiners. The neighborhood-level socioeconomic status was assessed using the area deprivation index (ADI), which incorporates factors such as education levels, employment rates, housing quality, and poverty indicators at the census block level.²⁷ The ADI ranges from 1 to 100, representing national percentiles, where a higher percentile indicates a greater disadvantage. Cancer diagnosis and detailed treatment information were obtained from survivors’ medical records.

Statistical analyses

Multinomial logistic regression using the PROC LOGISTIC procedure with generalized logit link function in SAS (version 9.4: SAS Institute Inc., Cary, NC) was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a dietary pattern score and DAI categories. Continuous HEI-2015 and aMED scores with and without alcohol score were used, and the low DAI group was used as a reference. The association between a diet pattern score and a continuous DAI was examined after confirming linearity between them by fitting cubic spline terms selected through a stepwise regression procedure and comparing the model fit with the linear term using the likelihood ratio test. When there was no evidence of deviation from linearity (p value for non-linearity >0.05), a linear regression with a continuous DAI was performed.

Both age-only and multivariable-adjusted analyses were performed. The multivariable models were adjusted for age, sex, race/ethnicity, education, ADI, smoking, multivitamin use, single supplement use, chest radiation, cranial radiation, other radiation, platinum-based chemotherapy, other chemotherapy, and total energy intake. Although there was no statistically significant interaction by sex, we performed analyses in men and women separately due to known sex differences in biological aging and risk of premature mortality.^{16, 28, 29}

The association between a dietary pattern score and DAI was also examined in subgroups stratified by age (<30 and ≥30 years), race (White and Others), age at cancer diagnosis (<10 and ≥10 years), and cancer treatments (chest, cranial, and abdominal radiation, and platinum-based agents, alkylating agents, and anthracycline chemotherapy). All tests were two-sided, and statistical significance was evaluated at the 0.05 level.

RESULTS

Among the 3,322 childhood cancer survivors (mean age: 30.5 years; SD: 8.4 years), 54% were men, and 83% were non-Hispanic Whites. The most common childhood cancer was leukemia (36%), followed by lymphoma (19%) and central nervous system tumors (13%). The mean age at diagnosis was 8.6 years (SD: 5.7 years). The mean (SD) HEI-2015 score (maximum 100) was 60.0 (10.9) in all, 62.3 (10.8) in women, and 57.9 (10.6) in men. The mean (SD) aMED score (maximum 9) was 4.2 (2.0) in all, 4.6 (1.9) in women, and 3.9 (2.0) in men. 20% and 8% of cancer survivors were in the medium or high DAI categories, respectively. A total of 31% of women and 24% of men were in the medium or high DAI categories.

Cancer survivors with a higher HEI-2015 score were more likely to be older, women, have higher educational attainment, live in less deprived areas (i.e., lower ADI), never smoke, not be obese, and use multivitamins or single dietary supplements (Table 1). Cancer treatment history was similar across HEI-2015 quintiles, except for platinum-based chemotherapy for which prevalence tended to be higher in lower HEI-2015 quintiles. Characteristics of survivors by aMED categories were similar to those by HEI-2015. Compared to survivors in the low DAI group, those in the high DAI group were more likely to be older, women, smokers, obese, have lower educational attainment, live in more deprived areas, and have lower HEI-2015 and aMED scores. They were also more likely to have a history of chest or cranial radiation therapy (Table S3).

Table 1.

Characteristics of adult survivors of childhood cancer by quintiles of Health Eating Index (HEI)-2015 and alternate Mediterranean Diet (aMED) scores in the St. Jude Lifetime Cohort Study

	HEI-2015			aMED
	Q1	Q3	Q5	Q1	Q2	Q3
Median score	46.1	59.4	74.8	2.0	4.0	7.0
N	664	664	664	1250	1166	906
Age, years (mean)	29.3	30.1	31.7	29.5	30.5	31.8
Sex (%)
Men	67.6	54.2	39.8	62.2	50.9	44.7
Women	32.4	45.8	60.2	37.8	49.1	55.3
Race (%)
White, non-Hispanic	82.2	81.0	87.3	82.2	82.0	84.4
Black, non-Hispanic	15.1	15.1	7.7	14.3	13.7	9.9
Others	2.7	3.9	5.0	3.4	4.3	5.6
Education1 (%)
Less than high school	13.9	8.1	3.2	12.0	7.9	4.1
High school graduate	26.7	15.1	10.2	24.3	19.0	9.3
Training after high school	34.3	39.2	27.4	36.2	32.9	30.9
College or post-graduate	17.5	29.5	51.2	19.2	33.3	48.5
Other	2.6	3.6	3.9	2.9	2.9	3.8
Smoking1 (%)
Never	61.3	73.6	77.0	64.3	72.1	76.3
Former	8.6	5.7	6.5	8.0	7.7	6.5
Current	22.0	14.6	8.3	19.9	13.7	9.3
Area Deprivation Index1 (%)
Quintile 1 (<43)	10.2	21.4	34.2	14.8	23.5	31.9
Quintile 2 (43 - <63)	23.8	21.8	25.2	22.1	23.1	24.4
Quintile 3 (63 - <82)	24.8	23.8	15.2	25.7	20.7	17.4
Quintile 4 (≥82)	31.3	23.2	13.6	28.5	21.2	15.1
Body mass index, kg/m2 (%)
<18.5	5.7	2.7	2.4	4.2	3.3	2.9
18.5 - <25	35.4	29.5	41.6	33.7	32.3	38.1
25 - <30	23.0	31.2	29.2	26.1	30.2	29.5
≥30	35.8	36.6	26.8	36.1	34.1	29.6
Multivitamin use (%)	13.9	24.2	39.6	18.0	26.0	35.8
Single supplement use (%)	23.3	38.1	56.6	27.4	40.7	51.8
Cancer diagnosis (%)
Central nervous system	15.1	14.3	8.9	13.4	13.8	11.3
Leukemia	33.4	37.8	37.0	36.2	36.6	33.2
Lymphoma	16.6	17.0	22.1	17.0	17.3	22.6
Other	34.9	30.9	31.9	33.4	32.2	32.9
Cancer treatment (%)
Chest radiation	23.8	22.4	23.3	23.4	23.1	25.3
Cranial radiation	30.7	34.6	31.9	32.5	33.0	31.0
Other radiation	6.3	5.9	5.1	6.8	6.6	5.6
Platinum–based chemotherapy	15.7	13.1	10.2	14.6	12.9	11.9
Other chemotherapy	84.5	84.2	85.1	85.2	84.2	84.7

^1.Numbers may not add up to 100% due to missing.

Greater adherence to both HEI-2015 and aMED was associated with a lower risk of being in the high DAI group (Table 2). In a multivariable model, comparing with the low DAI group, each 10-point increase in HEI-2015 was associated with a 13% (OR=0.87, 95% CI: 0.79–0.96) and a 20% (OR=0.80, 95% CI: 0.69–0.93) lower odds of being in the medium and high DAI group, respectively. Similarly, each 1-point increase in aMED was associated with a 4% (OR=0.96, 95% CI: 0.91–1.01) and 9% (OR=0.91, 95% CI: 0.84–0.98) lower odds of being in the medium and high DAI group, respectively. When the alcohol score was excluded from the total aMED score, the results remained largely unchanged (OR=0.96, 95% CI: 0.86–1.07 for the medium DAI group and OR=0.83, 95% CI: 0.70–0.99 for to high DAI group).

Table 2.

Odds ratios and 95% confidence intervals of deficit accumulation index (DAI)¹ categories by dietary pattern scores in the St. Jude Lifetime Cohort Study

	Increment	DAI category
		Low	Medium	High
All
HEI-20152	10 scores
Age-adjusted		1.00	0.81 (0.75–0.88)	0.69 (0.61–0.79)
Multivariable3		1.00	0.87 (0.79–0.96)	0.80 (0.69–0.93)
aMED4	1 score
Age-adjusted		1.00	0.91 (0.87–0.95)	0.83 (0.78–0.89)
Multivariable		1.00	0.96 (0.91–1.01)	0.91 (0.84–0.98)
aMED excluding alcohol	1 score
Age-adjusted		1.00	0.87 (0.79–0.96)	0.70 (0.61–0.82)
Multivariable		1.00	0.96 (0.86–1.07)	0.83 (0.70–0.99)
Women
HEI-2015	10 scores
Age-adjusted		1.00	0.76 (0.67–0.86)	0.62 (0.52–0.74)
Multivariable		1.00	0.83 (0.73–0.96)	0.74 (0.60–0.91)
aMED	1 score
Age-adjusted		1.00	0.89 (0.83–0.95)	0.78 (0.71–0.86)
Multivariable		1.00	0.95 (0.88–1.02)	0.87 (0.78–0.97)
aMED excluding alcohol	1 score
Age-adjusted		1.00	0.82 (0.71–0.94)	0.60 (0.49–0.74)
Multivariable		1.00	0.91 (0.77–1.06)	0.71 (0.56–0.89)
Men
HEI-2015	10 scores
Age-adjusted		1.00	0.78 (0.69–0.88)	0.67 (0.56–0.82)
Multivariable		1.00	0.92 (0.80–1.06)	0.89 (0.71–1.12)
aMED	1 score
Age-adjusted		1.00	0.90 (0.84–0.96)	0.83 (0.76–0.92)
Multivariable		1.00	0.98 (0.91–1.05)	0.95 (0.85–1.07)
aMED excluding alcohol	1 score
Age-adjusted		1.00	0.86 (0.74–0.99)	0.75 (0.60–0.94)
Multivariable		1.00	1.02 (0.87–1.20)	1.00 (0.78–1.29)

^1.Deficit Accumulation Index (DAI) was assessed based on 44 aging-related health conditions and grouped into low (<0.2), medium (0.2 - <0.35), and high (≥ 0.35) deficit accumulation categories.

^2.HEI-2015: Healthy Eating Index-2015.

^3.Adjusts for age; sex (in the men and women combined model), race (White, and others); education (less than high school, high school graduation, training after high school, and college or post-grad); smoking (never, former, and current); multivitamin use (yes and no); single supplement use (yes and no); and cancer treatment received: platinum based chemotherapy (yes and no); other chemotherapy (yes and no), chest radiation (yes and no), cranial radiation (yes and no), and other radiation (yes and no), intakes of total energy, and ADI (<43, 43 - <63, 63 - <82, and ≥82).

^4.aMED: Alternate Mediterranean diet.

In women, greater adherence to HEI-2015 and aMED was significantly associated with lower DAI in both age-adjusted and multivariable models. Multivariable OR_{high vs. low} was 0.74 (95% CI: 0.60–0.91) per 10-point increment of HEI-2015 and 0.87 (95% CI: 0.78–0.96) per 1-point increment of aMED score. However, in men, the associations observed in age-adjusted models were attenuated and no longer statistically significant in multivariable models (OR_{high vs. low} =0.89, 95% CI: 0.71–1.12, per 10-point increment in HEI-2015; OR_{high vs. low} =0.95, 95% CI: 0.85–1.07, per 1-point increment in aMED).

In analyses using DAI as a continuous variable (Figure 1), similar results were observed: HEI-2015 and aMED scores were both inversely associated with DAI in men and women combined (HEI-2015: coefficient = −0.0032, p value=0.001; aMED: coefficient = −0.0081, p value<0.001), in women (HEI-2015: coefficient = −0.0120, p value<0.001; aMED: coefficient = −0.0046, p value=0.002), but not significant in men (HEI-2015: coefficient = −0.0039, p value = 0.102; aMED: coefficient = −0.002, p value =0.167).

Figure 1.

Plot of multivariable-adjusted associations between dietary pattern scores and deficit accumulation index (DAI). A. Health Eating Index (HEI)-2015. B. Alternate Mediterranean Diet (aMED). Models were adjusted for age; sex (in the men and women combined model), race (White, and others); education (less than high school, high school graduation, training after high school, and college or post-grad); smoking (never, former, and current); multivitamin use (yes and no); single supplement use (yes and no); and cancer treatment received: platinum based chemotherapy (yes and no); other chemotherapy (yes and no), chest radiation (yes and no), cranial radiation (yes and no), and other radiation (yes and no), intakes of total energy, and ADI (<43, 43 - <63, 63 - <82, and ≥82). Deficit Accumulation Index (DAI) was assessed based on 44 aging-related health conditions and grouped into low (<0.2), medium (0.2 - <0.35), and high (≥ 0.35) deficit accumulation categories.

In subgroup analyses (Figure 2), greater adherence to the HEI-2015 and aMED was associated with a lower risk of high DAI in most subgroups. Notably, the inverse association between HEI-2015 and DIA was stronger in survivors who received radiation or chemotherapy than in those who did not.

Figure 2.

Multivariable-adjuted odds ratios and 95% confidence intervals of high vs low deficit accumulation index (DAI)² category for (A) HEI-2015³ and (B) aMED⁴ scores in subgroups in the St. Jude Lifetime Cohort Study. Models were adjusted for age; sex (in the men and women combined model), race (White, and others); education (less than high school, high school graduation, training after high school, and college or post-grad); smoking (never, former, and current); multivitamin use (yes and no); single supplement use (yes and no); and cancer treatment received: platinum based chemotherapy (yes and no); other chemotherapy (yes and no), chest radiation (yes and no), cranial radiation (yes and no), and other radiation (yes and no), intakes of total energy, and ADI (<43, 43 - <63, 63 - <82, and ≥82). Deficit Accumulation Index (DAI) was assessed based on 44 aging-related health conditions and grouped into low (<0.2), medium (0.2 - <0.35), and high (≥ 0.35) deficit accumulation categories.

DISCUSSION

In this study of adult survivors of childhood cancer, we found that greater adherence to the Dietary Guidelines for Americans (HEI-2015) or the Mediterranean diet was associated with a lower DAI, a proxy measure of premature aging. In addition, the protective association between healthy dietary patterns and aging was stronger in women and survivors who received chemotherapy or radiation treatment. As the first study to examine this relationship, our findings support the importance of diet as a modifiable factor for promoting healthy aging in childhood cancer survivors.

Despite differences in scoring, both HEI-2015 and aMED represent healthy dietary patterns that focus on high intake of vegetables, fruits, whole grains, and healthy fats, while aMED has greater emphasis on monounsaturated fats over saturated fats in its scoring criteria.^{30, 31} Both healthy dietary patterns have been shown to improve long-term health,^{14, 15} which likely explains their similar observed associations in our study. The inverse associations of HEI-2015 and aMED with premature aging in this study are consistent with our previous findings on individual food that higher intakes of dark green vegetables, nuts and seeds were associated with a lower risk of premature aging, while greater consumption of refined grains, sugar, and sugar-sweetened beverages was associated with increased risk of aging.^18–20 Moreover, in the general population, lower adherence to these healthy dietary patterns has been consistently found to be associated with a higher risk of frailty, cognitive decline, other aging-related outcomes, and mortality.^{17, 32–34}

Studies examining dietary behaviors in childhood cancer survivors consistently report low adherence to established dietary guidelines, with evidence of unhealthy diet from young adulthood to into later life.^35–37 In our study, the mean HEI-2015 score in adult survivors of childhood cancer was slightly lower than their age-, sex-, and race-matched community controls without a cancer history (60 in survivors vs. 62 in controls).^{38, 39} Moreover, more than 80% of survivors had unhealthy dietary patterns, characterized by high intakes of processed meat, high-fat dairy, added sugars, and sugar-sweetened beverages.³⁸ In contrast, 63% of the community controls had unhealthy patterns.³⁸ Overall, adult survivors of childhood cancer tended to have suboptimal diets and lower adherence to recommended dietary guidelines.

We observed that the association between a healthy diet and premature aging tended to be stronger among women than among men, although the difference was not statistically significant. This is likely due to a lower prevalence of premature aging (i.e., being in a medium or high DAI group 24% for men vs. 31% for women) and lower diet scores in men compared to women (HEI=57.9 in men vs 62.3 in women; aMED =3.9 in men vs 4.6 in women), which limited the power to detect an association in men. This observation is consistent with previous studies showing that women tend to be more frail, although they tolerate frailty better than men.⁴⁰ In addition, there are sex differences in several hallmarks of aging, such as cellular senescence and immune responses. Women are more prone to cellular senescence, and chronic low-grade inflammation, and autoimmune diseases than men. Women typically live longer but with greater health deterioration with advancing age, known as the men-women health-survival paradox.^41–44 Also, men may have reported their diet less accurately than women, which introduced greater measurement errors and attenuated the association.⁴⁵

Interestingly, we found that higher HEI-2015 and aMED scores were associated with a lower risk of premature aging among survivors who received chemotherapy or radiation therapy. These treatments may contribute to long-term damage to multiple organ systems, increase oxidative stress and inflammation, and elevate the risk of chronic conditions such as cardiovascular disease and cognitive decline.^{5, 46–48} However, these adverse effects may be mitigated through a healthy diet that provides nutrients such as vitamins, carotenoids, protein, and fiber, which help reduce oxidative stress, inflammation and support a healthy gut microbiome that influences DNA methylation and promotes healthy aging.^49–51 Survivors with such treatment histories may therefore have increased vulnerability to aging-related conditions and a correspondingly greater benefit from a healthy diet.

Our study has strengths. First, we were able to assess the association between different dietary patterns and the risk of premature aging more comprehensively by examining both HEI-2015 and aMED. Second, we assessed survivors’ usual diet using a validated FFQ. Lastly, our study included over 3,300 adult survivors of childhood cancer, the largest study of its kind, allowing for robust statistical analyses, including subgroup analyses. The subgroup analyses provided a thorough examination of the associations within homogeneous groups, reducing confounding by the stratified variable. However, our study also has limitations. The cross-sectional design limits our ability to establish temporal relationships and causality. Some survivors experiencing premature aging may have adopted healthier diets to manage existing health issues, which could attenuate the observed associations. A future study examining longitudinal associations between diet and premature aging is warranted. In addition, residual confounding and measurement errors in self-reported diet assessed by an FFQ are also likely. Measurement errors in the diet tended to attenuate the associations between diet and health outcomes. Finally, although DAI assessed 44 aging-related health conditions, using additional aging biomarkers could further strengthen analyses.

In conclusion, adhering to a healthy dietary pattern, such as the Dietary Guidelines for Americans and the Mediterranean diet, was associated with a lower the risk of premature aging in adult survivors of childhood cancer. Although maintaining a healthy diet can be challenging due to various personal and social factors, accessible dietary interventions may offer a potentially modifiable approach for promoting healthier aging among this vulnerable population.

Availability of data and materials:

Data can be obtained on request. Requests should be directed to the St. Jude LIFE (https://sjlife.stjude.org/) which has a protocol for approving data requests.