Biomarkers of Aging: From Function to Molecular Biology

Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is a considerable variation in the extent of disease and functional impairment risk, revealing a need for valid biomarkers to aid in characterizing the complex aging processes. The identification of biomarkers is further complicated by the diversity of biological living situations, lifestyle activities and medical treatments. Thus, there has been no identification of a single biomarker or gold standard tool that can monitor successful or healthy aging. Within this short review the current knowledge of putative biomarkers is presented, focusing on their application to the major physiological mechanisms affected by the aging process including physical capability, nutritional status, body composition, endocrine and immune function. This review emphasizes molecular and DNA-based biomarkers, as well as recent advances in other biomarkers such as microRNAs, bilirubin or advanced glycation end products.

[1]  R. Boon,et al.  MicroRNAs in cardiovascular ageing , 2016, The Journal of physiology.

[2]  C. Price,et al.  Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation. , 2012, Mutation research.

[3]  G. Howard,et al.  Adiposity, inflammation, and risk for death in black and white men and women in the United States: the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. , 2011, The Journal of clinical endocrinology and metabolism.

[4]  P. Mecocci,et al.  Body mass index, lifestyles, physical performance and cognitive decline: The “Treviso Longeva (Trelong)” study , 2013, The journal of nutrition, health & aging.

[5]  B. Goichot,et al.  Increased reverse triiodothyronine is associated with shorter survival in independently-living elderly: the Alsanut study. , 2008, European journal of endocrinology.

[6]  R. Testa,et al.  Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases: A proof of principle on type 2 diabetes , 2013, Aging.

[7]  M. Hotopf,et al.  Mini-Mental State Examination as a Predictor of Mortality among Older People Referred to Secondary Mental Healthcare , 2014, PloS one.

[8]  M. Suematsu,et al.  Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians , 2015, EBioMedicine.

[9]  R. Marioni,et al.  The epigenetic clock and telomere length are independently associated with chronological age and mortality , 2016, International journal of epidemiology.

[10]  G. Cunningham Andropause or male menopause? Rationale for testosterone replacement therapy in older men with low testosterone levels. , 2013, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[11]  M. Memo,et al.  Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53 , 2009, Cancer Immunology, Immunotherapy.

[12]  M. Ebadi,et al.  Clinical significance of metallothioneins in cell therapy and nanomedicine , 2013, International journal of nanomedicine.

[13]  A. Bratić,et al.  The role of mitochondria in aging. , 2013, The Journal of clinical investigation.

[14]  T. Salthouse Selective review of cognitive aging , 2010, Journal of the International Neuropsychological Society.

[15]  C. Franceschi,et al.  Inflamm‐aging: An Evolutionary Perspective on Immunosenescence , 2000 .

[16]  S. Horvath,et al.  Epigenetic clock analyses of cellular senescence and ageing , 2016, Oncotarget.

[17]  J. Bond,et al.  Assessment of a large panel of candidate biomarkers of ageing in the Newcastle 85+ study , 2011, Mechanisms of Ageing and Development.

[18]  B. Weinert,et al.  Invited review: Theories of aging. , 2003, Journal of applied physiology.

[19]  Eckart Meese,et al.  Can circulating miRNAs live up to the promise of being minimal invasive biomarkers in clinical settings? , 2016, Wiley interdisciplinary reviews. RNA.

[20]  M. Wolzt,et al.  Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome. , 2013, Clinical science.

[21]  J. Danesh,et al.  Triglycerides and the Risk of Coronary Heart Disease: 10 158 Incident Cases Among 262 525 Participants in 29 Western Prospective Studies , 2007, Circulation.

[22]  C. Franceschi,et al.  Oxidative DNA damage repair and parp 1 and parp 2 expression in Epstein-Barr virus-immortalized B lymphocyte cells from young subjects, old subjects, and centenarians. , 2007, Rejuvenation research.

[23]  J. Kopchick,et al.  The GH/IGF-1 axis in ageing and longevity , 2013, Nature Reviews Endocrinology.

[24]  J. Baeyens,et al.  European working group on sarcopenia in older people. Sarcopenia: European consensus on definition and diagnosis: report of the European working group on sarcopenia in older people , 2010 .

[25]  Gordon H Guyatt,et al.  Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis , 2009, BMJ : British Medical Journal.

[26]  S. Studenski,et al.  Performance Measures Predict Onset of Activity of Daily Living Difficulty in Community‐Dwelling Older Adults , 2010, Journal of the American Geriatrics Society.

[27]  K. Walsh,et al.  Adipokines in inflammation and metabolic disease , 2011, Nature Reviews Immunology.

[28]  A. Newman,et al.  Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? , 2013, Epidemiologic reviews.

[29]  Bertrand Friguet,et al.  Mechanisms of Ageing and Development Mark-age Biomarkers of Ageing , 2022 .

[30]  A. Favier,et al.  Age-dependent DNA repair and cell cycle distribution of human skin fibroblasts in response to UVA irradiation. , 2006, Journal of photochemistry and photobiology. B, Biology.

[31]  M. Emdin,et al.  Distribution of plasma cardiac troponin I values in healthy subjects: pathophysiological considerations , 2008, Clinical chemistry and laboratory medicine.

[32]  R M Ruff,et al.  Gender- and Age-Specific Changes in Motor Speed and Eye-Hand Coordination in Adults: Normative Values for the Finger Tapping and Grooved Pegboard Tests , 1993, Perceptual and motor skills.

[33]  Thomas B. L. Kirkwood,et al.  Stress, DNA damage and ageing — an integrative approach , 2001, Experimental Gerontology.

[34]  M. Speth,et al.  Cardiac markers (BNP, NT-pro-BNP, Troponin I, Troponin T, in female amateur runners before and up until three days after a marathon. , 2008, Clinical laboratory.

[35]  D. Kuh,et al.  Objectively measured physical capability levels and mortality: systematic review and meta-analysis , 2010, BMJ : British Medical Journal.

[36]  W. Markesbery,et al.  Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer's disease , 2007, Nucleic acids research.

[37]  A. Newman,et al.  Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[38]  C. Burd,et al.  The Molecular Balancing Act of p16INK4a in Cancer and Aging , 2013, Molecular Cancer Research.

[39]  Luc P de Witte,et al.  Predicting ADL disability in community-dwelling elderly people using physical frailty indicators: a systematic review , 2011, BMC geriatrics.

[40]  M. Cesari,et al.  RECOMMENDATIONS FROM THE INTERNATIONAL WORKING GROUP ON SARCOPENIA , 2013 .

[41]  L. Ferrucci,et al.  Detection of a Novel, Integrative Aging Process Suggests Complex Physiological Integration , 2015, PloS one.

[42]  Monica Driscoll,et al.  MicroRNAs in C. elegans Aging: Molecular Insurance for Robustness? , 2009, Current genomics.

[43]  Oliver Neubauer,et al.  Super DNAging-New insights into DNA integrity, genome stability and telomeres in the oldest old. , 2015, Mutation research. Reviews in mutation research.

[44]  D. Mari,et al.  Leukocyte telomere length and prevalence of age-related diseases in semisupercentenarians, centenarians and centenarians' offspring , 2014, Experimental Gerontology.

[45]  H. Dickinson,et al.  Telomere length predicts poststroke mortality, dementia, and cognitive decline , 2006, Annals of neurology.

[46]  S. Cummings,et al.  Association of adiponectin with mortality in older adults: the Health, Aging, and Body Composition Study , 2009, Diabetologia.

[47]  V. Howard,et al.  Inflammation biomarkers and risk of all-cause mortality in the Reasons for Geographic And Racial Differences in Stroke cohort. , 2011, American journal of epidemiology.

[48]  R. Collins,et al.  Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies , 2009, The Lancet.

[49]  S. Lewington Prospective studies collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies (vol 360, pg 1903, 2002) , 2003 .

[50]  M. Fenech,et al.  Important variables that influence base-line micronucleus frequency in cytokinesis-blocked lymphocytes-a biomarker for DNA damage in human populations. , 1998, Mutation research.

[51]  P. Slijepcevic DNA damage response, telomere maintenance and ageing in light of the integrative model , 2008, Mechanisms of Ageing and Development.

[52]  G. Pawelec,et al.  Metallothionein downregulation in very old age: a phenomenon associated with cellular senescence? , 2008, Rejuvenation research.

[53]  R. Collins,et al.  Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths , 2007, The Lancet.

[54]  Robert Ross,et al.  Low Relative Skeletal Muscle Mass (Sarcopenia) in Older Persons Is Associated with Functional Impairment and Physical Disability , 2002, Journal of the American Geriatrics Society.

[55]  S. Studenski,et al.  Gait speed and survival in older adults. , 2011, JAMA.

[56]  R. Testa,et al.  Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells , 2014, Aging.

[57]  A. Trusina,et al.  Aging mechanism as the "down side" of adaptation: a network approach. , 2008, Journal of theoretical biology.

[58]  K. Wagner,et al.  Genome damage in peripheral blood lymphocytes of diabetic and non-diabetic individuals after intervention with vegetables and plant oil. , 2013, Mutagenesis.

[59]  Thomas E. Johnson,et al.  Recent results: Biomarkers of aging , 2006, Experimental Gerontology.

[60]  J. Shaw,et al.  International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes , 2009, Diabetes Care.

[61]  S. Horvath,et al.  Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring , 2015, Aging.

[62]  G. Giles,et al.  The association between waist circumference and risk of mortality considering body mass index in 65- to 74-year-olds: a meta-analysis of 29 cohorts involving more than 58 000 elderly persons. , 2012, International journal of epidemiology.

[63]  Robert Clarke,et al.  Age-specific relevance of usual blood pressure to vascular mortality , 2003, The Lancet.

[64]  R. Collins,et al.  Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies , 2002, The Lancet.

[65]  P. Yaswen,et al.  Cancer and aging: the importance of telomeres in genome maintenance. , 2005, The international journal of biochemistry & cell biology.

[66]  H. Wildiers,et al.  Circulating MicroRNAs as Easy-to-Measure Aging Biomarkers in Older Breast Cancer Patients: Correlation with Chronological Age but Not with Fitness/Frailty Status , 2014, PloS one.

[67]  H. Tschan,et al.  Is there a role for microRNAs in exercise immunology? A synopsis of current literature and future developments. , 2010, Exercise immunology review.

[68]  D. Melzer,et al.  Vitamin D and risk of cognitive decline in elderly persons. , 2010, Archives of internal medicine.

[69]  T. Kirkwood,et al.  Understanding the Odd Science of Aging , 2005, Cell.

[70]  S. Kritchevsky,et al.  One- and two-year change in body composition as measured by DXA in a population-based cohort of older men and women. , 2003, Journal of applied physiology.

[71]  V. Aboyans,et al.  The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society. , 2015, Atherosclerosis.

[72]  P. Zimmet,et al.  International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes , 2009, Diabetes Care.

[73]  F. Slack,et al.  MicroRNAs and the genetic network in aging. , 2013, Journal of molecular biology.

[74]  T. Kirkwood,et al.  Network theory of aging , 1997, Experimental Gerontology.

[75]  D. Cameron-Smith,et al.  Role of microRNAs in the age-related changes in skeletal muscle and diet or exercise interventions to promote healthy aging in humans , 2014, Ageing Research Reviews.

[76]  S. Kritchevsky,et al.  The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[77]  D. Houston,et al.  Does the amount of fat mass predict age-related loss of lean mass, muscle strength, and muscle quality in older adults? , 2011, The journals of gerontology. Series A, Biological sciences and medical sciences.

[78]  A. Giannoni,et al.  Measurement of circulating concentrations of cardiac troponin I and T in healthy subjects: a tool for monitoring myocardial tissue renewal? , 2009, Clinical chemistry and laboratory medicine.

[79]  J. Danesh,et al.  C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis , 2010, The Lancet.

[80]  A. Bulmer,et al.  Effects of unconjugated bilirubin on chromosomal damage in individuals with Gilbert's syndrome measured with the micronucleus cytome assay. , 2012, Mutagenesis.

[81]  D. Grobbee,et al.  Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. , 2005, The Journal of clinical endocrinology and metabolism.

[82]  H. Tschan,et al.  Influence of age and physical fitness on miRNA-21, TGF-β and its receptors in leukocytes of healthy women. , 2015, Exercise immunology review.

[83]  P. Hildebrandt,et al.  N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. , 2005, JAMA.

[84]  N. Greig,et al.  miRNAs as Circulating Biomarkers for Alzheimer's Disease and Parkinson's Disease. , 2016, Medicinal chemistry (Shariqah (United Arab Emirates)).

[85]  R. Gobbens,et al.  The prediction of disability by self-reported physical frailty components of the Tilburg Frailty Indicator (TFI). , 2014, Archives of gerontology and geriatrics.

[86]  R. Lobo Where are we 10 years after the Women's Health Initiative? , 2013, The Journal of clinical endocrinology and metabolism.

[87]  A. Baierl,et al.  The influence of age and aerobic fitness on chromosomal damage in Austrian institutionalised elderly. , 2014, Mutagenesis.

[88]  Stefano Bonassi,et al.  The effect of age, gender, diet and lifestyle on DNA damage measured using micronucleus frequency in human peripheral blood lymphocytes. , 2011, Mutagenesis.

[89]  R. Silber,et al.  Protein glycation — Between tissue aging and protection , 2015, Experimental Gerontology.

[90]  A. Bulmer,et al.  Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. , 2015, Clinical science.