Abstract
The conceptual change of frailty, from a physical to a biopsychosocial phenotype, expanded the field of frailty, including social and behavioral domains with critical interaction between different frailty models. Environmental exposures – including physical exercise, psychosocial factors and diet – may play a role in the frailty pathophysiology. Complex underlying mechanisms involve the progressive interactions of genetics with epigenetics and of multimorbidity with environmental factors. Here we review the literature on possible mechanisms explaining the association between epigenetic hallmarks (i.e., global DNA methylation, DNA methylation age acceleration and microRNAs) and frailty, considered as biomarkers of aging. Frailty could be considered the result of environmental epigenetic factors on biological aging, caused by conflicting DNA methylation age and chronological age.
Plain language summary
The present narrative review describes the available evidence about epigenetic biological markers of frailty considered aging biomarkers, among others. Aging biomarkers can help in identifying frail and older individuals affected by multiple diseases to further increase the power of composite biomarker panels in the diagnostic and prognostic process. Among combined biomarkers, epigenetic regulators with different methylation patterns and small molecules such as microRNAs are included. Given that frailty involves multiple biological systems, it is possible to define it according to a novel model, including emotional and social domains and the influence of environmental factors, named the biopsychosocial phenotype. Different epigenetic biomarkers of frailty, from the first generation to the more specific and recent second-generation epigenetic aging biomarkers, may account for factors linked to different cellular types, such as heterogeneity, and a reverse causation process that requires integration with gene expression. A better understanding of the relationships among frailty, multimorbidity and overall mortality will help us to identify the best therapeutic targets.
Tweetable abstract
Frailty is considered the outcome of environmental epigenetic factors on biological aging caused by a mismatch between chronological age and DNA methylation age. Research on the epigenetic biomarkers of this process is underway.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. MAPT/DSA Group. Biomarkers of age-related frailty and frailty related to diseases: an exploratory, cross-sectional analysis from the MAPT study. J. Nutr. Health Aging 26, 545–551 (2022).
- 2. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014).
- 3. Different cognitive frailty models and health-and cognitive-related outcomes in older age: from epidemiology to prevention. J. Alz. Dis. 62(3), 993–1012 (2018).
- 4. Depressive and biopsychosocial frailty phenotypes: impact on late-life cognitive disorders. J. Alz. Dis. 94(3), 879–898 (2023). • Current evidence on the existing links between depressive and biopsychosocial frailty phenotypes and late-life cognitive disorders, with discussion of the common pathways and mechanisms underlying these links.
- 5. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 56(3), 146–156 (2001). •• Seminal study that provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition.
- 6. Physical frailty, multimorbidity, and all-cause mortality in an older population from southern Italy: results from the Salus in Apulia study. J. Am. Med. Dir. Assoc. 22(3), 598–605 (2021).
- 7. . Accumulation of deficits as a proxy measure of aging. Sci. World J. 1, 323–336 (2001).
- 8. Nutritional domains in frailty tools: working towards an operational definition of nutritional frailty. Ageing Res. Rev. 64, 101148 (2020).
- 9. Oral frailty and its determinants in older age: a systematic review. Lancet Healthy Longev. 2(8), e507–e520 (2021).
- 10. Prevalence of cognitive frailty phenotypes and associated factors in a community-dwelling elderly population. J. Nutr. Health Aging 24(2), 172–180 (2020).
- 11. Liver frailty and all-cause mortality in the older participants of the Salus in Apulia study. Geroscience 44(2), 835–845 (2022).
- 12. Association of social frailty with both cognitive and physical deficits among older people. J. Am. Med. Dir. Assoc. 18(7), 603–607 (2017).
- 13. Biopsychosocial frailty and the risk of incident dementia: the Italian longitudinal study on aging. Alzheimers Dement. 15(8), 1019–1028 (2019).
- 14. An old challenge with new promises: a systematic review on comprehensive geriatric assessment in long-term care facilities. Rejuvenation Res. 21(1), 3–14 (2018).
- 15. . Time and the metrics of aging. Circ. Res. 123(7), 740–744 (2018).
- 16. . The hallmarks of aging. Cell 153, 1194–1217 (2013). •• Review article that enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging.
- 17. . Genetic factors associated with longevity: a review of recent findings. Ageing Res. Rev. 19, 1–7 (2015).
- 18. Human longevity: 25 genetic loci associated in 389,166 UK Biobank participants. Aging 9, 2504 (2017).
- 19. A genome-wide association study of the frailty index highlights brain pathways in ageing. Aging Cell 20(9), e13459 (2021).
- 20. . Genetics of frailty: a longevity perspective. Transl. Res. 221, 83–96 (2020).
- 21. . Epigenetics and aging. Sci. Adv. 4(2), e1600584 (2016).
- 22. The role of biomarkers in psychiatry. Adv. Exp. Med. Biol. 1118, 135–162 (2019).
- 23. . Epigenetics of aging and aging-related disease. J. Gerontol. A Biol. Sci. Med. Sci. 69(Suppl. 1), S17–S20 (2014).
- 24. . Epigenetic control of aging. Antioxid. Redox Signal. 14(2), 241–259 (2011).
- 25. . DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19(6), 371–384 (2018). • Discusses how accelerated epigenetic age predicts several age-related phenotypes. The existing DNAm age and DNAm PhenoAge estimators have demonstrated that these epigenetic biomarkers of aging satisfy the properties of molecular biomarkers of aging.
- 26. . Function and information content of DNA methylation. Nature 517(7534), 321–326 (2015).
- 27. . Statistical and integrative system-level analysis of DNA methylation data. Nat. Rev. Genet. 19(3), 129–147 (2018).
- 28. Acquisition of aberrant DNA methylation is associated with frailty in the very old: findings from the Newcastle 85+ study. Biogerontology 15(4), 317–328 (2014).
- 29. . Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults. Epigenetics 12(2), 149–156 (2017).
- 30. . Frailty is associated with the epigenetic clock but not with telomere length in a German cohort. Clin. Epigenet. 8, 21 (2016).
- 31. . DNA methylation and the epigenetic clock in relation to physical frailty in older people: the Lothian Birth Cohort 1936. Clin. Epigenet. 10(1), 101 (2018).
- 32. . Identifying exosome-derived microRNAs as candidate biomarkers of frailty. J. Frailty Aging 7(2), 100–103 (2018).
- 33. Analysis of plasma microRNAs as predictors and biomarkers of aging and frailty in humans. Oxid. Med. Cell. Longev. 2018, 7671850 (2018).
- 34. . Epigenetic clock and leukocyte telomere length are associated with vitamin D status but not with functional assessments and frailty in the Berlin aging study II. J. Gerontol. A Biol. Sci. Med. Sci. 75(11), 2056–2063 (2020).
- 35. No association between frailty index and epigenetic clocks in Italian semi-supercentenarians. Mech. Ageing Dev. 197, 111514 (2021).
- 36. miRNome profiling detects miR-101-3p and miR-142-5p as putative blood biomarkers of frailty syndrome. Genes 13(2), 231 (2022). •• Study that identified two miRNAs (miR-101-3p and miR-142-5p) able to significantly differentiate frail patients (downregulated) from robust subjects.
- 37. Global DNA methylation in old subjects is correlated with frailty. Age 34(1), 169–179 (2012). • Study showing how modifications of DNA methylation, a drawbridge between the genetic and the environmental factors affecting the age-related decay of the organism, may play an important role in determining physiological changes of old age.
- 38. DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy. Aging 8(2), 394–401 (2016).
- 39. . The frailty index outperforms DNA methylation age and its derivatives as an indicator of biological age. Geroscience 39(1), 83–92 (2017).
- 40. . Methylomic survival predictors, frailty, and mortality. Aging 10(3), 339–357 (2018).
- 41. Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. Elife 9, e51507 (2020).
- 42. GrimAge outperforms other epigenetic clocks in the prediction of age-related clinical phenotypes and all-cause mortality. J. Gerontol. A Biol. Sci. Med. Sci. 76(5), 741–749 (2021). • Study indicating that the GrimAge clock may represent a step-improvement in the predictive utility of epigenetic clocks for identifying age-related decline in an array of clinical phenotypes, promising to advance precision medicine.
- 43. . Epigenetic age acceleration and change in frailty in MOBILIZE Boston. J. Gerontol. A Biol. Sci. Med. Sci. 77(9), 1760–1765 (2022). • Study showing that baseline frailty index was correlated with extrinsic, GrimAge and PhenoAge epigenetic age acceleration, but no epigenetic age acceleration measure was associated with change in frailty.
- 44. Epigenetic and metabolomic biomarkers for biological age: a comparative analysis of mortality and frailty risk. J. Gerontol. A Biol. Sci. Med. Sci. 78(10), 1753–1762 (2023).
- 45. . Genetic and epigenetic regulation of aging. Curr. Opin. Immunol. 21(4), 446–453 (2009).
- 46. . Age-related difference of site-specific histone modifications in rat liver. Biogerontology 10(4), 415–421 (2009).
- 47. . Epigenetic factors in aging and longevity. Pflugers Arch. 459(2), 247–258 (2010).
- 48. . Epigenetics and aging. Exp. Gerontol. 45(4), 253–254 (2010).
- 49. . Genomic 5-methyldeoxycytidine decreases with age. J. Biol. Chem. 262(21), 9948–9951 (1987).
- 50. . Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc. Natl Acad. Sci. USA 100(4), 1775–1780 (2003).
- 51. . Impact of aging on DNA methylation. Ageing Res. Rev. 2(3), 245–261 (2003).
- 52. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51(4), 615–622 (2008).
- 53. . Epigenetics and aging: the targets and the marks. Trends Genet. 23(8), 413–418 (2007).
- 54. The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma. Mol. Cancer 9, 109 (2010).
- 55. . Role of methylation of the hMLH1 gene promoter in the development of gastric and colorectal carcinoma in the elderly. Geriatr. Gerontol. Int. 10(Suppl. 1), S207–S212 (2010).
- 56. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 20(1), 249 (2019).
- 57. . DNA methylation age of human tissues and cell types. Genome Biol. 14(10), R115 (2013).
- 58. . A systematic review of biological, social and environmental factors associated with epigenetic clock acceleration. Ageing Res. Rev. 69, 101348 (2021).
- 59. . Clock work: deconstructing the epigenetic clock signals in aging, disease, and reprogramming. bioRxiv
doi: 10.1101/2022.02.13.480245 (2022) (Preprint). - 60. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49(2), 359–367 (2013).
- 61. . Morbidity profiles of centenarians: survivors, delayers, and escapers. J. Gerontol. A Biol. Sci. Med. Sci. 58(3), 232–237 (2003).
- 62. Shorter telomeres in peripheral blood mononuclear cells from older persons with sarcopenia: results from an exploratory study. Front. Aging Neurosci. 6, 233 (2014).
- 63. . Biological age predictors. EBioMedicine 21, 29–36 (2017).
- 64. Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts. Nat. Commun. 6, 10192 (2015).
- 65. Smoking-associated DNA methylation biomarkers and their predictive value for all-cause and cardiovascular mortality. Environ. Health Perspect. 124(1), 67–74 (2016).
- 66. . Circulating microRNA-19a as a potential novel biomarker for diagnosis of acute myocardial infarction. Int. J. Mol. Sci. 15(11), 20355–20364 (2014).
- 67. Refining epigenetic prediction of chronological and biological age. Genome Med. 15(1), 12 (2023).
- 68. DunedinPACE, a DNA methylation biomarker of the pace of aging. Elife 11, e73420 (2022).
- 69. DNA methylation GrimAge version 2. Aging 14(23), 9484–9549 (2022).
- 70. DNA methylation age and physical and cognitive aging. J. Gerontol. A Biol. Sci. Med. Sci. 75(3), 504–511 (2020).
- 71. Epigenetic age is associated with baseline and 3-year change in frailty in the Canadian Longitudinal Study on Aging. Clin. Epigenetics 13(1), 163 (2021).
- 72. An epigenetic biomarker of aging for lifespan and healthspan. Aging 10(4), 573–591 (2018).
- 73. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11(2), 303–327 (2019).
- 74. . The Tilburg frailty indicator (TFI): new evidence for its validity. Clin. Interv. Aging 15, 265–274 (2020).
- 75. . Development, construct validity, and predictive validity of a continuous frailty scale: results from 2 large US cohorts. Am. J. Epidemiol. 187(8), 1752–1762 (2018).
- 76. Development and validation of a multidimensional prognostic index for one-year mortality from comprehensive geriatric assessment in hospitalized older patients. Rejuvenation Res. 11(1), 151–161 (2008).
- 77. Italian Longitudinal Study on Aging Working Group. Additive role of a potentially reversible cognitive frailty model and inflammatory state on the risk of disability: the Italian Longitudinal Study on Aging. Am. J. Geriatr. Psychiatry 25(11), 1236–1248 (2017).
- 78. . The functions of animal microRNAs. Nature 431(7006), 350–355 (2004).
- 79. . MicroRNA. J. Allergy Clin. Immunol. 141(4), 1202–1207 (2018).
- 80. Involvement of plasma miRNAs, muscle miRNAs and mitochondrial miRNAs in the pathophysiology of frailty. Exp. Gerontol. 124, 110637 (2019).
- 81. . Omics biomarkers for frailty in older adults. Clin. Chim. Acta 510, 363–372 (2020).
- 82. . The frailty syndrome: definition and natural history. Clin. Geriatr. Med. 27(1), 1–15 (2011).
- 83. Sarcopenia: revised European consensus on definition and diagnosis. Age. Ageing 48(4), 601 (2019).
- 84. . Circulating inflamma-miRs in aging and age-related diseases. Front. Genet. 4, 121 (2013).
- 85. . MicroRNA controls of cellular senescence. BMB Rep. 51(10), 493–499 (2018).
- 86. . MicroRNA regulatory networks in the pathogenesis of sarcopenia. J. Cell. Mol. Med. 24(9), 4900–4912 (2020).
- 87. . MicroRNAs and the genetic nexus of brain aging, neuroinflammation, neurodegeneration, and brain trauma. Aging Dis. 10(2), 329–352 (2019).
- 88. Functional role of miR-34a in diabetes and frailty. Front. Aging 3, 949924 (2022).
- 89. . Role of miRNAs in skeletal muscle aging. Clin. Interv. Aging 13, 2407–2419 (2018).
- 90. . A new role for microRNAs, as ligands of Toll-like receptors. RNA Biol. 10(2), 169–174 (2013).
- 91. Circulating miR-21, miR-378, and miR-940 increase in response to an acute exhaustive exercise in chronic heart failure patients. Oncotarget 7(11), 12414–12425 (2016).
- 92. . Epigenomics and the regulation of aging. Epigenomics 5(2), 205–227 (2013).
- 93. . Biomarkers of aging: from function to molecular biology. Nutrients 8(6), 338 (2016).
- 94. . Sarcopenia, frailty and their prevention by exercise. Free Radic. Biol. Med. 132, 42–49 (2019).
- 95. Biology of frailty: modulation of ageing genes and its importance to prevent age-associated loss of function. Mol. Asp. Med. 50, 88–108 (2016).
- 96. Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis. Physiol. Genomics 43(10), 595–603 (2011).
- 97. . Skeletal muscle myomiR are differentially expressed by endurance exercise mode and combined essential amino acid and carbohydrate supplementation. Front. Physiol. 8, 182 (2017).
- 98. Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short-term endurance training. J. Physiol. 591(18), 4637–4653 (2013).
- 99. The miRNA plasma signature in response to acute aerobic exercise and endurance training. PLOS ONE 9(2), e87308 (2014).
- 100. Sarcopenia associates with SNAP-25 SNPs and a miRNAs profile which is modulated by structured rehabilitation treatment. J. Transl. Med. 19(1), 315 (2021).
- 101. . Evaluation of serum miRNAs expression in frail and robust subjects undergoing multicomponent exercise protocol (VIVIFRAIL). J. Transl. Med. 21(1), 67 (2023). • The findings suggest that serum miRNA-451a should be investigated as a potential biomarker for frailty and that a multicomponent program of physical exercise modulates circulatory miRNA expression.
- 102. Present and future of anti-ageing epigenetic diets. Mech. Ageing Dev. 136–137, 101–115 (2014).
- 103. The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clin. Epigenetics 7, 121 (2015).
- 104. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging 9(2), 419–446 (2017).
- 105. One-year Mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the NU-AGE project. Geroscience 42(2), 687–701 (2020). •• The findings suggest that a Mediterranean diet can promote epigenetic rejuvenation but with country-, sex-, and individual-specific effects, thus highlighting the need for a personalized approach to nutritional interventions.
- 106. A bio-psycho-social approach for frailty amongst Singaporean Chinese community-dwelling older adults – evidence from the Singapore Longitudinal Aging Study. BMC Geriatr. 19(1), 50 (2019).
- 107. . Social determinants of late life depression epigenetics. Epigenomics 12(7), 559–562 (2020).
- 108. . Telomere length and frailty in older adults – a systematic review and meta-analysis. Ageing Res. Rev. 54, 100914 (2019).
- 109. . Attitudes to ageing and change in frailty status: the English longitudinal study of ageing. Gerontology 64(1), 58–66 (2017). • Older people who have a more positive attitude to ageing are at reduced risk of becoming physically frail or pre-frail.
- 110. Frailty consensus: a call to action. J. Am. Med. Dir. Assoc. 14(6), 392–397 (2013).
- 111. Tau-directed approaches for the treatment of Alzheimer’s disease: focus on leuco-methylthioninium. Expert Rev. Neurother. 16(3), 259–277 (2016).
- 112. Anti-amyloid-β protein agents for the treatment of Alzheimer’s disease: an update on emerging drugs. Expert Opin. Emerg. Drugs 25(3), 319–335 (2020).
- 113. Associations between nutritional frailty and 8-year all-cause mortality in older adults: the Salus in Apulia study. J. Intern. Med. 290(5), 1071–1082 (2021).
- 114. The relationship between epigenetics and microbiota in neuropsychiatric diseases. Epigenomics 12(17), 1559–1568 (2020).