Phenotypic age mediates effects of Life's Essential 8 on reduced mortality risk in US adults

Abstract

Objective: This study aimed to find out whether phenotypic age could mediate the protective effects of a healthy lifestyle on mortality.

Methods: We included adult participants with available data for individual phenotypic age (PhenoAge) and Life's Essential 8 (LE8) scores from the National Health and Nutrition Examination Survey 2005-2010 (three cycles) and linked mortality records until 31 December 2019. Adjusted hazard ratios (HR) were estimated to evaluate the associations of PhenoAge and LE8 scores with all-cause and cardiovascular mortality risk. Mediation analyses were performed to estimate the proportional contribution of PhenoAge to the effect of LE8 on mortality risks.

Results: A 1-year increment in PhenoAge was associated with a higher risk of all-cause (HR = 1.04 [95% confidence interval, 1.04-1.05]) and cardiovascular (HR = 1.04 [95% confidence interval, 1.04-1.05]) mortality, independent of chronological age, demographic characteristics, and disease history. High level of LE8 (score: 80-100) was associated with a 3.30-year younger PhenoAge. PhenoAge was estimated to mediate 36 and 22% of the effect of LE8 on all-cause and cardiovascular mortality, respectively (all P < 0.001). As for single-metric scores of LE8, PhenoAge mediated 30%, 11%, 9%, and 7% of the effects of the healthy diet, smoking status, blood pressure, and physical activity on all-cause mortality risk, respectively (all P < 0.05).

Conclusion: Adherence to LE8 recommendations slows phenotypic aging. PhenoAge could mediate the effect of LE8 on mortality risk.

Keywords

phenotypic age / Life's Essential 8 / all-cause mortality / cardiovascular mortality

Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Grants No. 82103920 and 81941018) and the National Key Research and Development Program (Grant No. 2023YFC2509400). The funding organizations were not involved in the design or conduct of the study; the collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Author contributions

Study conceptualization and design: D.S. Statistical analysis and interpretation of data: Y.Z. and H.Y. Writing-original drafting of manuscript: Y.Z. and H.Y. Critical review and editing of the manuscript for important intellectual content: Y.Z., Y.W., M.X., M.S., H.Y., C.L., Y.P., W.G., T.H., C.Y., J.L., S.L., L.Q., L.L. and D.S. Study supervision: D.S.

Supplementary materials

Supplementary data is available at PCMEDI Journal online.

Conflicts of interest

The authors declare that they have no conflicts of interests.

Ethics approval and consent to participate

All participants provided written informed consent, and the protocols were approved by research ethics boards of the National Center for Health Statistics webpage: https://www.cdc.gov/nchs/nhanes/irba98.htm.

Availability of data and materials

The datasets that support the findings of this study are publicly available on the National Health and Nutrition Examination Survey (NHANES) website: https://www.cdc.gov/nchs/nhanes/index.htm.

References

[1] Ferrucci L, Hesdorffer C, Bandinelli S et al. Frailty as a nexus between the biology of aging, environmental conditions and clinical geriatrics. Public Health Rev 2010;32:475-88. https://doi.org/10.1007/BF03391612.

[2] Ferrucci L, Levine ME, Kuo PL et al. Time and the metrics of aging. Circ Res 2018;123:740-4. https://doi.org/10.1161/circresaha.118.312816.

[3] Liu Z, Kuo PL, Horvath S et al. A new aging measure captures morbidity and mortality risk across diverse subpopulations from NHANES IV: A cohort study. PLoS Med 2018;15:e1002718. https://doi.org/10.1371/journal.pmed.1002718.

[4] Paul L. Diet, nutrition and telomere length. J Nutr Biochem 2011;22:895-901. https://doi.org/10.1016/j.jnutbio.2010.12.001.

[5] Tucker LA. Dietary Fiber and telomere length in 5674 U.S. Adults: an NHANES study of biological aging. Nutrients 2018;10:400. https://doi.org/10.3390/nu10040400.

[6] Fitzgerald KN, Hodges R, Hanes D et al. Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial. Aging (Albany NY) 2021;13:9419-32. https://doi.org/10.18632/aging.202913.

[7] Kresovich JK, Garval EL, Martinez Lopez AM et al. Associations of body composition and physical activity level with multiple measures of epigenetic age acceleration. Am J Epidemiol 2021;190:984-93. https://doi.org/10.1093/aje/kwaa251.

[8] Arsenis NC, You T, Ogawa EF et al. Physical activity and telomere length: impact of aging and potential mechanisms of action. Oncotarget 2017;8:45008-19. https://doi.org/10.18632/oncotarget.16726.

[9] Yang Y, Gao X, Just AC et al. Smoking-related DNA methylation is associated with DNA methylation phenotypic age acceleration: the Veterans Affairs Normative Aging Study. IntJ Environ Res Public Health 2019;16:2356. https://doi.org/10.3390/ijerph16132356.

[10] Robinson O, Chadeau Hyam M, Karaman I et al. Determinants of accelerated metabolomic and epigenetic aging in a UK cohort. Aging Cell 2020;19:e13149. https://doi.org/10.1111/acel.13149.

[11] Kresovich JK, Martinez Lopez AM, Garval EL et al. Alcohol consumption and methylation-based measures of biological age. J Gerontol A Biol Sci Med Sci 2021;76:2107-11. https://doi.org/10.1093/gerona/glab149.

[12] de Toro-Martín J, Guénard F, Tchernof A et al. Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity. Clin Epigenetics 2019;11:172. https://doi.org/10.1186/s13148-019-0754-6.

[13] Lin WY. Lifestyle factors and genetic variants on 2 biological age measures: evidence from 94443 Taiwan Biobank participants. J Gerontol A Biol Sci Med Sci 2022;77:1189-98. https://doi.org/10.1093/gerona/glab251.

[14] Gottesman RF, Lutsey PL, Benveniste H et al. Impact of sleep disorders and disturbed sleep on brain health: A scientific statement from the American Heart Association. Stroke 2024;55:e6176. https://doi.org/10.1161/str.0000000000000453.

[15] Ujma PP, Bódizs R. Sleep alterations as a function of 88 health indicators. BMC Med 2024;22:134. https://doi.org/10.1186/s12916-024-03358-3.

[16] Lloyd-Jones DM, Hong Y, Labarthe D et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic Impact goal through 2020 and beyond. Circulation 2010;121:586613. https://doi.org/10.1161/circulationaha.109.192703.

[17] Lloyd-Jones DM, Allen NB, Anderson CAM et al. Life's Essential 8: updating and enhancing the American Heart Association's Construct of Cardiovascular Health: A presidential advisory from the American Heart Association. Circulation 2022;146:e18-43. https://doi.org/10.1161/cir.0000000000001078.

[18] Yang Q, Cogswell ME, Flanders WD et al. Trends in cardiovascular health metrics and associations with all-cause and CVD mortality among US adults. JAMA 2012;307:1273-83. https://doi.org/10.1001/jama.2012.339.

[19] Fretts AM, Howard BV, McKnight B et al. Life's Simple 7 and incidence of diabetes among American Indians: the Strong Heart Family Study. Diabetes Care 2014;37:2240-5. https://doi.org/10.2337/dc13-2267.

[20] Kulshreshtha A, Vaccarino V, Judd SE et al. Life's Simple 7 and risk of incident stroke: the reasons for geographic and racial differences in stroke study. Stroke 2013;44:1909-14. https://doi.org/10.1161/strokeaha.111.000352.

[21] Perak AM, Ning H, Khan SS et al. Associations of late adolescent or young adult cardiovascular health with premature cardiovascular disease and mortality. J Am Coll Cardiol 2020;76:2695-707. https://doi.org/10.1016/j.jacc.2020.10.002.

[22] McEvoy JW. Lifetime risks of cardiovascular disease. N Engl J Med. 2012;366:1642. https://doi.org/10.1056/NEJMc1202276.

[23] Angell SY, McConnell MV, Anderson CAM et al. The American Heart Association 2030 impact goal: A Presidential advisory from the American Heart Association. Circulation 2020;141:e120e38. https://doi.org/10.1161/cir.0000000000000758.

[24] Mirel LB, Mohadjer LK, Dohrmann SM et al. National Health and Nutrition Examination Survey: estimation procedures, 20072010. Vital Health Stat 2 2013;159:1-17.

[25] Levine ME, Lu AT, Quach A et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 2018;10:573-91. https://doi.org/10.18632/aging.101414.

[26] Guenther PM, Kirkpatrick SI, Reedy J et al. The Healthy Eating Index-2010 is a valid and reliable measure of diet quality according to the 2010 Dietary Guidelines for Americans. J Nutr 2014;144:399-407. https://doi.org/10.3945/jn.113.183079.

[27] Lenth RV. Least-squares means: The R Package lsmeans. J Stat Softw 2016;69:1-33. https://doi.org/10.18637/jss.v069.i01.

[28] Schröder MS, Culhane AC, Quackenbush J et al. survcomp: an R/bioconductor package for performance assessment and comparison of survival models. Bioinformatics 2011;27:3206-8. https://doi.org/10.1093/bioinformatics/btr511.

[29] Uno H, Tian L, Cai T et al. A unified inference procedure for a class of measures to assess improvement in risk prediction systems with survival data. Stat Med 2013;32:2430-42. https://doi.org/10.1002/sim. 5647.

[30] Lee H, Herbert RD, McAuley JH. Mediation analysis. JAMA 2019;321:697-8. https://doi.org/10.1001/jama.2018.21973.

[31] Byeon S, Lee W. An introduction to causal mediation analysis with a comparison of 2 R packages. J Prev Med Public Health 2023;56:303-11. https://doi.org/10.3961/jpmph.23.189.

[32] Zhang R, Wu M, Zhang W et al. Association between life's essential 8 and biological ageing among US adults. J Transl Med 2023;21:622. https://doi.org/10.1186/s12967-023-04495-8.

[33] Liu Z, Chen X, Gill TM et al. Associations of genetics, behaviors, and life course circumstances with a novel aging and healthspan measure: evidence from the Health and Retirement Study. PLoS Med 2019;16:e1002827. https://doi.org/10.1371/journal.pmed. 1002827.

[34] Losito A, Nunzi E, Pittavini L et al. Cardiovascular morbidity and long term mortality associated with in hospital small increases of serum creatinine. J Nephrol 2018;31:71-7. https://doi.org/10.1007/s40620-017-0413-y.

[35] Krishnamurthy VR, Baird BC, Wei G et al. Associations of serum alkaline phosphatase with metabolic syndrome and mortality. Am J Med 2011;124:566. https://doi.org/10.1016/j.amjmed.2010.11.030.

[36] Maluf CB, Barreto SM, Giatti L et al. Association between C reactive protein and all-cause mortality in the ELSA-Brasil cohort. J Epidemiol Community Health 2020;74:421-7. https://doi.org/10.1136/jech-2019-213289.

[37] Limanjaya A, Song KM, Choi MJ et al. Calorie restriction reverses age-related alteration of cavernous neurovascular structure in the rat. Andrology 2017;5:1023-31. https://doi.org/10.1111/andr.12401.

[38] Guo L, Zhang S. Association between ideal cardiovascular health metrics and risk of cardiovascular events or mortality: A meta-analysis of prospective studies. Clin Cardiol 2017;40:133946. https://doi.org/10.1002/clc.22836.

[39] Kraus WE, Powell KE, Haskell WL et al. Physical activity, all-cause and cardiovascular mortality, and cardiovascular disease. Med Sci Sports Exerc 2019;51:1270-81. https://doi.org/10.1249/mss.0000000000001939.

[40] McTiernan A, Friedenreich CM, Katzmarzyk PT et al. Physical activity in cancer prevention and survival: A systematic review. Med Sci Sports Exerc 2019;51:1252-61. https://doi.org/10.1249/mss.0000000000001937.

[41] Jeong SW, Kim SH, Kang SH et al. Mortality reduction with physical activity in patients with and without cardiovascular disease. Eur HeartJ 2019;40:3547-55. https://doi.org/10.1093/eurheartj/ehz564.

[42] Doll R, Peto R, Boreham J et al. Mortality in relation to smoking: 50 years' observations on male British doctors. BMJ 2004;328:1519. https://doi.org/10.1136/bmj.38142.554479.AE.

[43] Godtfredsen NS, Prescott E. Benefits of smoking cessation with focus on cardiovascular and respiratory comorbidities. Clin Respir J 2011;5:187-94. https://doi.org/10.1111/j.1752-699X.2011.00262.x.

[44] Sun J, Li Y, Zhao M et al. Association of the American Heart Association's new "Life's Essential 8" with all-cause and cardiovascular disease-specific mortality: prospective cohort study. BMC Med 2023;21:116. https://doi.org/10.1186/s12916-023-02824-8.

[45] Ford ES, Greenlund KJ, Hong Y. Ideal cardiovascular health and mortality from all causes and diseases of the circulatory system among adults in the United States. Circulation 2012;125:987-95. https://doi.org/10.1161/circulationaha.111.049122.

[46] Yi J, Wang L, Guo X et al. Association of Life's Essential 8 with all-cause and cardiovascular mortality among US adults: A prospective cohort study from the NHANES 2005-2014. Nutr Metab Cardiovasc Dis 2023;33:1134-43. https://doi.org/10.1016/j.numecd.2023.01.021.

[47] Flegal KM, Graubard BI, Williamson DF et al. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005;293:1861-7. https://doi.org/10.1001/jama.293.15.1861.

[48] Shaper AG, Wannamethee SG, Whincup PH. Serum albumin and risk of stroke, coronary heart disease, and mortality: the role of cigarette smoking. J Clin Epidemiol 2004;57:195-202. https://doi.org/10.1016/j.jclinepi.2003.07.001.

[49] Naber TH, de Bree A, Schermer TR et al. Specificity of indexes of malnutrition when applied to apparently healthy people: the effect of age. AmJ Clin Nutr 1997;65:1721-5. https://doi.org/10.1093/ajcn/65.6.1721.

[50] Gom I, Fukushima H, Shiraki M et al. Relationship between serum albumin level and aging in community-dwelling selfsupported elderly population. J Nutr Sci Vitaminol (Tokyo) 2007;53:37-42. https://doi.org/10.3177/jnsv.53.37.

[51] Pawelec G. Immunity and ageing in man. Exp Gerontol 2006;41:1239-42. https://doi.org/10.1016/j.exger.2006.09.005.

[52] Goldberg RB, Temprosa MG, Mather KJ et al. Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention program except in those who develop diabetes. Diabetes Care 2014;37:2253-60. https://doi.org/10.2337/dc13-2471.

[53] Mahlknecht U, Kaiser S. Age-related changes in peripheral blood counts in humans. Exp Ther Med 2010;1:1019-25. https://doi.org/10.3892/etm.2010.150.

[54] Araki K, Rifkind JM. Age dependent changes in osmotic hemolysis of human erythrocytes. J Gerontol 1980;35:499-505. https://doi.org/10.1093/geronj/35.4.499.

[55] Sacks FM, Bray GA, Carey VJ et al. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med 2009;360:859-73. https://doi.org/10.1056/NEJMoa0804748.

[56] Appel LJ, Champagne CM, Harsha DW et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA 2003;289:2083-93. https://doi.org/10.1001/jama.289.16.2083.