Aging; Algorithms; Demography; Epidemiology; Life Expectancy; Longevity; Genetic Variation; Proportional Hazards Models; DNA Methylation; Computational Biology; Gene Expression Profiling; Gene Regulatory Networks; Biostatistics
Extensive Research Description
My research focuses on the development of high-dimensional biomarkers of human aging, and applying these and other aging outcome measures to study how genetic and social factors coalesce to produce between-person differences in the rate of aging, lifespans, and healthspan.
One of the major goals of geroscience research is to define 'biomarkers of aging'. At the population-level, aging can be measured as the mortality rate doubling time (MRDT), derived from the Gompertz equation. However, there remains a need for individual-level measures of aging that can account for differences in the timing of disease onset, functional decline, and risk of death over the life course. While chronological age is arguably the strongest risk factor for aging-related death and disease, it is important to distinguish chronological time from biological aging. Individuals of the same chronological age may exhibit greatly different susceptibilities to age-related diseases and death, which is likely reflective of differences in their underlying biological aging process. Reliable biomarkers of aging will be crucial for enabling instantaneous evaluation of interventions aimed at slowing the aging process, by providing a measurable outcome other than incidence of death and/or disease, which require extremely long follow-up observation. I have published a number of papers presenting various methods for calculating composite biological age estimates from clinical and/or molecular biomarkers. My most recent work has focused on the use of genome-wide DNA methylation to estimate "epigenetic aging", given that chronological time has been shown to elicit predictable hypo- and hyper-methylation changes at many regions across the genome. Many of the measures I have developed have been shown to predict remaining life expectancy and disease risk significantly better than chronological age. Further, my work has demonstrated that between-person differences in these measures relate to genetic, sociodemographic, and behavioral factors.
Cognitive Aging and Alzheimer’s Disease
My recent work has used multidisciplinary approaches and collaborations to examine the genomics, epigenomic, and transcriptomic networks associated with cognitive aging and Alzheimer’s disease. For instance, I have explored the associations between Alzheimer’s related neuropathology and epigenetic measures of aging in prefrontal cortex. I have also led work on modeling trajectories of cognitive decline for longitudinal studies. Based on this, I developed an easily interpretable composite measure of cognitive age, for which level and change can be contrasted against chronological age to characterize individuals with accelerated decline. Finally, as PI on an R01, I am integrating genetic, transcriptomic, epigenomic, and proteomic data (from three brain regions) to identify multi-scale networks that underlie AD resilience among high risk individuals, such as ApoE e4+.
Biological Resilience Susceptibility to aging and age-related disease may vary across individuals, as a result of complex interactions at the genetic, epigenetic, transcriptomic, proteomic, and environmental levels. Previously I’ve investigated underlying mechanisms of resilience by studying long-lived smokers. This work built upon the phenomena of hidden heterogeneity and mortality selection, showing that current smokers who had survived to age 80 and beyond did not exhibit higher mortality rates compared to never-smokers of the same age (mortality had 'selected for' a resilient group). In a subsequent study, I used network methods to compare the genetic signatures of long-lived smokers and normal-lived smokers, in order to identify mechanisms which allow certain individuals to survive despite repeated exposure to environmental stressors. My work has also examined whether epigenetic measures of aging capture resilience/vulnerability in relation to lung cancer risk among smokers.
Genetics of Complex Traits I have worked on a number of projects examining the genetics of complex traits, with the goal of developing polygenic scores. I have also worked on developing novel network-based methods for identifying pleiotropic gene networks that relate across aging and longevity phenotypes.
The Role of Behaviors and Environment in Aging, Health, and Mortality
I have examined how exogenous factors such as social disadvantage, education, trauma, race/ethnicity, smoking, diet, and air pollution influence health and aging, both in humans and in model organisms. For instance, my work has examined the role of protein consumption in lifespan and cancer, using data from humans, mice, and yeast. This paper was published as the cover article in Cell Metabolism, and to date, the article has the highest impact score in history for the journal. Additionally, my work has investigated alterations in late-life inflammatory gene expression in response to early-life and contemporaneous social environment, and has explored the effects of air pollution exposure on alterations in gene expression networks.
- Levine ME, Langfelder P, Horvath S. A Weighted SNP Correlation Network Method for Estimating Polygenic Risk Scores. Methods Mol Biol. 2017;1613:277-290. doi: 10.1007/978-1-4939-7027-8_10. PubMed PMID: 28849564.
- Levine ME, Crimmins EM, Weir DR, Cole SW. Contemporaneous Social Environment and the Architecture of Late-Life Gene Expression Profiles. Am J Epidemiol. 2017 Sep 1;186(5):503-509. doi: 10.1093/aje/kwx147. PubMed PMID: 28911009.
- Lu AT, Hannon E, Levine ME, Crimmins EM, Lunnon K, Mill J, Geschwind DH, Horvath S. Genetic architecture of epigenetic and neuronal ageing rates in human brain regions. Nat Commun. 2017 May 18;8:15353. doi: 10.1038/ncomms15353. PubMed PMID: 28516910; PubMed Central PMCID: PMC5454371.
- Woodward NC, Levine MC, Haghani A, Shirmohammadi F, Saffari A, Sioutas C, Morgan TE, Finch CE. Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo. J Neuroinflammation. 2017 Apr 14;14(1):84. doi: 10.1186/s12974-017-0858-x. PubMed PMID: 28410596; PubMed Central PMCID: PMC5391610.
- Quach A, Levine ME, Tanaka T, Lu AT, Chen BH, Ferrucci L, Ritz B, Bandinelli S, Neuhouser ML, Beasley JM, Snetselaar L, Wallace RB, Tsao PS, Absher D, Assimes TL, Stewart JD, Li Y, Hou L, Baccarelli AA, Whitsel EA, Horvath S. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging (Albany NY). 2017 Feb 14;9(2):419-446. doi: 10.18632/aging.101168. PubMed PMID: 28198702; PubMed Central PMCID: PMC5361673.
- Carroll JE, Irwin MR, Levine M, Seeman TE, Absher D, Assimes T, Horvath S. Epigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women's Health Initiative Study. Biol Psychiatry. 2017 Jan 15;81(2):136-144. doi: 10.1016/j.biopsych.2016.07.008. Epub 2016 Jul 26. PubMed PMID: 27702440; PubMed Central PMCID: PMC5536960.
- Schaefer JD, Caspi A, Belsky DW, Harrington H, Houts R, Israel S, Levine ME, Sugden K, Williams B, Poulton R, Moffitt TE. Early-Life Intelligence Predicts Midlife Biological Age. J Gerontol B Psychol Sci Soc Sci. 2016 Nov;71(6):968-977. Epub 2015 May 26. PubMed PMID: 26014827; PubMed Central PMCID: PMC5067943.
- Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai PC, Roetker NS, Just AC, Demerath EW, Guan W, Bressler J, Fornage M, Studenski S, Vandiver AR, Moore AZ, Tanaka T, Kiel DP, Liang L, Vokonas P, Schwartz J, Lunetta KL, Murabito JM, Bandinelli S, Hernandez DG, Melzer D, Nalls M, Pilling LC, Price TR, Singleton AB, Gieger C, Holle R, Kretschmer A, Kronenberg F, Kunze S, Linseisen J, Meisinger C, Rathmann W, Waldenberger M, Visscher PM, Shah S, Wray NR, McRae AF, Franco OH, Hofman A, Uitterlinden AG, Absher D, Assimes T, Levine ME, Lu AT, Tsao PS, Hou L, Manson JE, Carty CL, LaCroix AZ, Reiner AP, Spector TD, Feinberg AP, Levy D, Baccarelli A, van Meurs J, Bell JT, Peters A, Deary IJ, Pankow JS, Ferrucci L, Horvath S. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging (Albany NY). 2016 Sep 28;8(9):1844-1865. doi: 10.18632/aging.101020. PubMed PMID: 27690265; PubMed Central PMCID: PMC5076441.
- Levine ME, Lu AT, Chen BH, Hernandez DG, Singleton AB, Ferrucci L, Bandinelli S, Salfati E, Manson JE, Quach A, Kusters CD, Kuh D, Wong A, Teschendorff AE, Widschwendter M, Ritz BR, Absher D, Assimes TL, Horvath S. Menopause accelerates biological aging. Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9327-32. doi: 10.1073/pnas.1604558113. Epub 2016 Jul 25. PubMed PMID: 27457926; PubMed Central PMCID: PMC4995944.
- Horvath S, Gurven M, Levine ME, Trumble BC, Kaplan H, Allayee H, Ritz BR, Chen B, Lu AT, Rickabaugh TM, Jamieson BD, Sun D, Li S, Chen W, Quintana-Murci L, Fagny M, Kobor MS, Tsao PS, Reiner AP, Edlefsen KL, Absher D, Assimes TL. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 2016 Aug 11;17(1):171. doi: 10.1186/s13059-016-1030-0. PubMed PMID: 27511193; PubMed Central PMCID: PMC4980791.
- Levine ME, Crimmins EM. A Genetic Network Associated With Stress Resistance, Longevity, and Cancer in Humans. J Gerontol A Biol Sci Med Sci. 2016 Jun;71(6):703-12. doi: 10.1093/gerona/glv141. Epub 2015 Sep 9. PubMed PMID: 26355015; PubMed Central PMCID: PMC4888382.
- Mitchell UA, Ailshire JA, Brown LL, Levine ME, Crimmins EM. Education and Psychosocial Functioning Among Older Adults: 4-Year Change in Sense of Control and Hopelessness. J Gerontol B Psychol Sci Soc Sci. 2016 Mar 24. pii: gbw031. [Epub ahead of print] PubMed PMID: 27013537.
- Lu AT, Hannon E, Levine ME, Hao K, Crimmins EM, Lunnon K, Kozlenkov A, Mill J, Dracheva S, Horvath S. Genetic variants near MLST8 and DHX57 affect the epigenetic age of the cerebellum. Nat Commun. 2016 Feb 2;7:10561. doi: 10.1038/ncomms10561. PubMed PMID: 26830004; PubMed Central PMCID: PMC4740877.
- Woodward N, Levine M. Minimizing Air Pollution Exposure: A Practical Policy to Protect Vulnerable Older Adults from Death and Disability. Environ Sci Policy. 2016 Feb 1;56:49-55. PubMed PMID: 26640413; PubMed Central PMCID: PMC4667368.
- Arpawong TE, Lee J, Phillips DF, Crimmins EM, Levine ME, Prescott CA. Effects of Recent Stress and Variation in the Serotonin Transporter Polymorphism (5-HTTLPR) on Depressive Symptoms: A Repeated-Measures Study of Adults Age 50 and Older. Behav Genet. 2016 Jan;46(1):72-88. doi: 10.1007/s10519-015-9740-8. Epub 2015 Sep 2. PubMed PMID: 26330209; PubMed Central PMCID: PMC4720538.
- Levine ME, Lu AT, Bennett DA, Horvath S. Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer's disease related cognitive functioning. Aging (Albany NY). 2015 Dec;7(12):1198-211. PubMed PMID: 26684672; PubMed Central PMCID: PMC4712342.
- Cole SW, Levine ME, Arevalo JM, Ma J, Weir DR, Crimmins EM. Loneliness, eudaimonia, and the human conserved transcriptional response to adversity. Psychoneuroendocrinology. 2015 Dec;62:11-7. doi: 10.1016/j.psyneuen.2015.07.001. Epub 2015 Jul 8. PubMed PMID: 26246388; PubMed Central PMCID: PMC4637182.
- Levine ME, Hosgood HD, Chen B, Absher D, Assimes T, Horvath S. DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative. Aging (Albany NY). 2015 Sep;7(9):690-700. PubMed PMID: 26411804; PubMed Central PMCID: PMC4600626.
- Belsky DW, Caspi A, Houts R, Cohen HJ, Corcoran DL, Danese A, Harrington H, Israel S, Levine ME, Schaefer JD, Sugden K, Williams B, Yashin AI, Poulton R, Moffitt TE. Quantification of biological aging in young adults. Proc Natl Acad Sci U S A. 2015 Jul 28;112(30):E4104-10. doi: 10.1073/pnas.1506264112. Epub 2015 Jul 6. PubMed PMID: 26150497; PubMed Central PMCID: PMC4522793.
- Levine ME, Cole SW, Weir DR, Crimmins EM. Childhood and later life stressors and increased inflammatory gene expression at older ages. Soc Sci Med. 2015 Apr;130:16-22. doi: 10.1016/j.socscimed.2015.01.030. Epub 2015 Jan 21. PubMed PMID: 25658624; PubMed Central PMCID: PMC4394113.
- Levine ME, Crimmins EM. A comparison of methods for assessing mortality risk. Am J Hum Biol. 2014 Nov-Dec;26(6):768-76. doi: 10.1002/ajhb.22595. Epub 2014 Aug 4. PubMed PMID: 25088793; PubMed Central PMCID: PMC4286244.
- Levine ME, Crimmins EM. Evidence of accelerated aging among African Americans and its implications for mortality. Soc Sci Med. 2014 Oct;118:27-32. doi: 10.1016/j.socscimed.2014.07.022. Epub 2014 Jul 15. PubMed PMID: 25086423; PubMed Central PMCID: PMC4197001.
- Levine ME, Suarez JA, Brandhorst S, Balasubramanian P, Cheng CW, Madia F, Fontana L, Mirisola MG, Guevara-Aguirre J, Wan J, Passarino G, Kennedy BK, Wei M, Cohen P, Crimmins EM, Longo VD. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 2014 Mar 4;19(3):407-17. doi: 10.1016/j.cmet.2014.02.006. PubMed PMID: 24606898; PubMed Central PMCID: PMC3988204.
- Levine ME. Response to Dr. Mitnitski's and Dr. Rockwood's letter to the editor: Biological age revisited. J Gerontol A Biol Sci Med Sci. 2014 Mar;69(3):297-8. doi: 10.1093/gerona/glt138. Epub 2013 Oct 10. PubMed PMID: 24115775; PubMed Central PMCID: PMC3976142.
- Levine M, Crimmins E. Not all smokers die young: a model for hidden heterogeneity within the human population. PLoS One. 2014 Feb 10;9(2):e87403. doi: 10.1371/journal.pone.0087403. eCollection 2014. PubMed PMID: 24520332; PubMed Central PMCID: PMC3919713.
- Levine ME, Crimmins EM, Prescott CA, Phillips D, Arpawong TE, Lee J. A polygenic risk score associated with measures of depressive symptoms among older adults. Biodemography Soc Biol. 2014;60(2):199-211. doi: 10.1080/19485565.2014.952705. PubMed PMID: 25343367; PubMed Central PMCID: PMC4298361.
- Kogan AC, Gonzalez J, Hart B, Halloran S, Thomason B, Levine M, Enguidanos S. Be Well: results of a nutrition, exercise, and weight management intervention among at-risk older adults. J Appl Gerontol. 2013 Oct;32(7):889-901. doi: 10.1177/0733464812440043. Epub 2012 Apr 18. PubMed PMID: 25474803.
- Levine ME, Kim JK, Crimmins EM. The role of physiological markers of health in the association between demographic factors and periodontal disease. J Periodontal Res. 2013 Jun;48(3):367-72. doi: 10.1111/jre.12016. Epub 2012 Dec 11. PubMed PMID: 23231345; PubMed Central PMCID: PMC3609891.
- Levine ME. Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age? J Gerontol A Biol Sci Med Sci. 2013 Jun;68(6):667-74. doi: 10.1093/gerona/gls233. Epub 2012 Dec 3. PubMed PMID: 23213031; PubMed Central PMCID: PMC3660119.
- Levine ME, Crimmins EM. The impact of insulin resistance and inflammation on the association between sarcopenic obesity and physical functioning. Obesity (Silver Spring). 2012 Oct;20(10):2101-6. doi: 10.1038/oby.2012.20. Epub 2012 Feb 7. PubMed PMID: 22310233; PubMed Central PMCID: PMC3527629.
- Levine ME, Crimmins EM. Sarcopenic obesity and cognitive functioning: the mediating roles of insulin resistance and inflammation? Curr Gerontol Geriatr Res. 2012;2012:826398. doi: 10.1155/2012/826398. Epub 2012 May 7. PubMed PMID: 22611388; PubMed Central PMCID: PMC3352243.
- Canon ME, Crimmins EM. Sex differences in the association between muscle quality, inflammatory markers, and cognitive decline. J Nutr Health Aging. 2011 Aug;15(8):695-8. PubMed PMID: 21968867; PubMed Central PMCID: PMC4315164.
- Crimmins EM, Levine ME. Handbook of the Biology of Aging. 8 ed. Kaeberlein M, Martin G, editors. 225 Wyman Street, Waltham, MA 02451, USA: Elsevier Inc.; 2016. Chapter 18, Current Status of Research on Trends in Morbidity, Healthy Life Expectancy, and the Compression of Morbidity.
- Levine ME, Crimmins EM. Vienna Yearbook of Population Research. 11 ed. Vienna, Austria: Verlag der Österreichischen Akademie der Wissenschaften ; 2013. Evidence of resiliency among long-lived smokers; p.205-218.